Methods for the design of molecular scaffolds and ligands

FIELD OF THE INVENTION

[0002] The present application relates to methods for designing ligands that bind to target molecules. The methods are useful in the design of drug products with superior properties.

BACKGROUND OF THE INVENTION

[0003] The information provided below is intended to assist in understanding the invention and does not constitute an admission that any of that information provided or references cited is prior art.

[0004] The design of new drugs has traditionally focused on the random design of potential drug candidates and the mass screening of those candidates for a desired property. After generating compounds using combinatorial chemistry and performing high throughput screening on thousands of compounds, a particular compound can be identified that has a desired property, which then goes on to become a more serious candidate for drug development. Most existing drugs have been discovered by this random screening approach, but these methods are highly inefficient.

[0005] There have also been attempts to use various methods of rational drug design. In most cases, such methods utilize structural information about the target molecule and attempt to design candidate drug molecules that will fit the target structure, either using de novo design or starting with a screening hit.

[0006] Yayon, PCT/IL01/00871, WO 02/24722 describes a method for designing candidate agonists and antagonists of the FGFR3, by using computer modeling with a crystal structure of the target to construct candidate agonist or antagonist compounds. The compounds are synthesized and their biological activity is assayed. (See, e.g., p.7, lines 14-20.)

[0007] Smit, PCT/EP01/01457, WO 01/58951 provides a set of atomic coordinates for acetylcholine binding protein, and states that the crystal structure “can be used to generate 3D models of the extracellular ligand-binding domain of ligand-gated ion channels, and thus for screening of drugs that act on these ion channels.” (Abstract; Table 1, p,72 ff.)

[0008] Scanlan et al., PCT/Us98/25296, W) 99/26966 describes atomic coordinates for crystals of rat and human thyroid hormone receptor (TR) ligand binding domain, and indicates that the structural information can be used to design synthetic ligands. (p.9)

[0009] Nienaber, U.S. Pat. No. 6,297,021, issued Oct. 2, 2001, states that “crystallography can be used to screen and identify compounds that are not know ligands of a target biolomecule for their ability to bind the target.” The method involves “obtaining a crystal of a target biomolecle, exposing the target to one or more test samples that are potential ligands of the target; and determining whether a ligand/biomolecule complex is formed. Structural information from the ligand/receptor complexes found are used to design new ligands that bind tighter, bind more specifically, have better biological activity or have better safety profile than known ligands.” (Col. 1, line 57 to col. 8, lines 5.))

SUMMARY OF THE INVENTION

[0010] The present invention provides methods of designing ligands that bind to target molecules by identifying compounds that bind, even weakly, to a target molecule or multiple members of a molecular compound family. Identification of such binding compounds is used to identify common core physical and structural features of binding compounds, thereby providing parent compounds for further ligand development. Binding compounds that bind to target with low or very low affinity and/or bind to a plurality of targets in a molecular family can be designated as molecular scaffolds. Such molecular scaffolds thus represent a minimal or neat minimal binding compound. Typically a large number of derivative binding compounds can be identified that share a common structural core (i.e., scaffold core) with a molecular scaffold, thus constituting a scaffold group or set.

[0011] Using analysis of co-crystals of one or more binding compounds (e.g., exemplary molecular scaffolds), the orientations (positioning) of the binding compounds at the binding site is determined, generally in three dimensions. Such analysis typically involves X-ray crystallography and/or nuclear magnetic resonance (NMR). The orientation information is used to guide the synthesis and/or selection of ligands that are modified from the initial binding compounds or molecular scaffolds, preferably by modification at chemically tractable locations on the molecule. Such modification provides compounds with altered specificity and/or binding affinity as compared to the original binding compounds or scaffolds.

[0012] This method of using molecular scaffolds as the basis for chemical modification to provide further compounds with altered binding and other activity properties allows focus on low molecular weight binding compounds, preferably about 150 to 350 Daltons. Focusing on small binding compounds provides molecular scaffolds that can be used for the develop of ligands for a variety of different molecules.

[0013] It is often difficult to identify compounds of this size with required specificity and activity properties using conventional compound screening. Thus, contrasted with conventional screening practice, the present invention removes binding compound potency or binding affinity as a primary criterion. Instead, all compounds showing activity, even quite low activity, can be utilized to lead to the synthesis of new ligands.

[0014] In addition, selecting compounds that are active across multiple members of a protein family or other target family, allows the identification of a scaffold, or preferably multiple different scaffolds, that can be used for development of ligands specific for a particular target, or targeting a subset of particular targets in the family.

[0015] Therefore, in a first aspect, the present invention provides methods of designing a ligand that binds to at least one target molecule that is a member of a molecular family. The methods involve identifying compounds as molecular scaffolds that bind to the binding site of the target molecule (or a plurality of target molecules in the molecular family) and produce a detectable signal in a binding assay and/or activity assay that indicates statistically significant binding to target at a confidence level of at least 90%, preferably at least 95, 97, 98, 99% or greater confidence level; determining the orientation of the molecular scaffolds at the binding site of the target molecule to identify chemically tractable structures of the scaffolds that, when modified, alter the binding affinity or binding specificity between the scaffold and the target molecule; and synthesizing or otherwise obtaining a ligand wherein one or more chemically tractable structures of the molecular scaffold is modified to provide a ligand that binds to the target molecule with altered binding affinity or binding specificity. The background signal of the binding assay can be measured under standard conditions, and a library of distinct compounds can be assayed for binding to a binding site of the target molecule.

[0016] In various embodiments, the methods include isolating co-crystals of one or more molecular scaffolds bound to the target molecule, and determining the orientation of the molecular scaffold by performing X-ray crystallography on the co-crystals. Common chemical structures of the molecular scaffolds can be identified and the molecular scaffolds placed into groups based on having at least one common chemical structure. The orientation of the molecular scaffolds at the binding site of the target molecule can thus be determined for a representative compound from a selected group or from a plurality of groups, e.g., at least 2, 4, 6, 8, 10, 20, 50, 100, 200, 300, 400, 500, 600, 800, 1000, or even more groups. In preferred embodiments, when modified, the resulting ligand can bind to the target molecule with greater binding affinity or greater binding specificity or both than the molecular scaffold. However, in some cases, it may be desirable to select a ligand that binds with a lower affinity, e.g., to enhance turnover or to prevent full inhibition of a type of target molecule. It can also be advantageous to co-crystallize ligands and determine their orientation at the binding site for performing designing further modified compounds as further ligands.

[0017] In other embodiments, the orientation of the molecular scaffold can be determined by nuclear magnetic resonance or NMR combined with crystallography results to determine orientation.

[0018] In preferred embodiments, each of a plurality of distinct compounds is assayed for binding to a plurality of members of the molecular family. In preferred embodiments, the distinct compounds have a molecular weight of from about 100 to about 350 daltons, or more preferably from about 150 to about 350 daltons or from 150 to 300 daltons, or from 200 to 300 daltons.

[0019] In preferred embodiments, the target molecule is a protein and the molecular family a protein family. In preferred embodiments, the protein is an enzyme or receptor. The protein family can be, for example, a protein kinase family or sub-family (e.g., tyrosine protein kinases, serine/threonine protein kinases, MAP protein kinases, cyclin-dependent protein kinases), proteases, and phosphatases (e.g., protein tyrosine phosphatases and serine/threonine phosphoprotein phosphatases).

[0020] The distinct compounds of the invention can be of a variety of structures. In some embodiments, the distinct compounds can have a ring structure, either a carbocyclic or heterocyclic ring, such as for example, a benzyl ring, an pyrrole, imidazole, pyridine, purine, or any ring structure.

[0021] In various embodiments, a compound or compounds binds with extremely low affinity, very low affinity, low affinity, moderate affinity, or high affinity; at least about 5% of the binding compounds bind with low affinity (and/or has low activity), or at least about 10%, 15%, or 20% of the compounds bind with low affinity (or very low or extremely low). After the identification of common chemical structures of the distinct compounds that bind, the compounds can be grouped into classes based on common chemical structures and at least one representative compound from at least one, or preferably a plurality, of the classes selected for performing orientation determination, e.g., by X-ray crystallography and/or NMR analysis.

[0022] In selecting the distinct compounds for assay in the present invention, the selection can be based on various criteria appropriate for the particular application, such as molecular weight, clogP (or other method of assessing lipophilicity), Polar Surface Area (PSA) (or other indicator of charge and polarity or related properties), and the number of hydrogen bond donors and acceptors. Compounds can also be selected using the presence of specific chemical moieties which, based on information derived from the molecular family, might be indicated as having predisposing some affinity for members of the family. Compounds with highly similar structures and/or properties can be identified and grouped using computational techniques to facilitate the selection of a representative subset of the group. As indicated above, in preferred embodiments, the molecular weight is from about 150 to about 350 daltons, more preferably from 150 to 300 daltons. The clog P is preferably less than 2, the number of hydrogen bond donors and acceptors is preferably less than 5 and the PSA less than 100. Compounds can be selected that include chemical structures of drugs having acceptable pharmacalogical properties and/or lacking chemical strutures that are know to result in undesirable pharmacological properties, e.g., excessive toxicity and lack of solubility.

[0023] In some embodiments, the assay is an enzymatic assay, and the number of groups of molecular scaffolds formed can conveniently be about 500. The binding of the ligand to the target molecule can cause a specific biochemical effect due to the inhibition of an enzyme. In some embodiments, the assay is a competition assay, e.g., a binding competition assay. Cell-based assays can also be used. As indicated above, compounds can be used that have low, very low, or extremely low activity in a biochemical or cell-based assay.

[0024] The modification of a molecular scaffold can be the addition, subtraction, or substitution of a chemical group. The modification may desirably cause the scaffold to be actively transported to or into particular cells and/or a particular organ. In various embodiments, the modification of the compound includes the addition or subtraction of a chemical atom, substituent or group, such as, for example, a hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g., forming a ketone, ether or N-oxide), and a sulphur atom (e.g., forming a thiol, thione, sulfonamide or di-alkylsulfoxide (sulfone)).

[0025] In preferred embodiments, the information provided by performing X-ray crystallography on the co-crystals is provided to a computer program, wherein the computer program provides a measure of the interaction between the molecular scaffold and the protein and a prediction of changes in the interaction between the molecular scaffold and the protein that result from specific modifications to the molecular scaffold, and the molecular scaffold is chemically modified based on the prediction of the biochemical result. The computer program can provide the prediction based on a virtual assay such as, for example, virtual docking of the compound to the protein, shape-based matching, molecular dynamics simulations, free energy perturbation studies, and similarity to a three-dimensional pharmacophore. A variety of such programs are well-known in the art.

[0026] Chemical modification of a chemically tractable structure can result, or be selected to provide one or more physical changes, e.g., to result, in a ligand that fills a void volume in the protein-ligand complex, or in an attractive polar interaction being produced in the protein-ligand complex. The modification can also result in a sub-structure of the ligand being present in a binding pocket of the protein binding site when the protein-ligand complex is formed. After common chemical structures of the compounds that bind are identified, the compounds can be grouped based on having a common chemical sub-structure and a representative compound from each group (or a plurality of groups) can be selected for co-crystallization with the protein and performance of the X-ray crystallography. The X-ray crystallography is preferably performed on the co-crystals under at least 20, 30, 40, or 50 distinct environmental conditions, or more preferably under about 96 distinct environmental conditions. The X-ray crystallography and the modification of a chemically tractable structure of the compound can each be performed a plurality of times, e.g., 2, 3, 4, or more rounds of crystallization and modification.

[0027] Also in certain embodiments, one or molecular scaffolds are selected to have binding to a plurality of members of a molecular compound family, e.g., a protein family.

[0028] The method can also include the identification of conserved residues in a binding site(s) of a target protein that interact with a molecular scaffold, ligand or other binding compound. Conserved residues can, for example, be identified by sequence alignment of different members of a family, and identifying binding site residues that are the same or at least similar between multiple member of the family. Interacting residues can be characterized as those within a selected distance from the binding compound(s), e.g., 3, 3.5, 4, 4.5, or 5 angstroms.

[0029] In a related aspect, the present invention provides a method for designing a ligand that binds to at least one target molecule by assaying a plurality of distinct compounds for binding to a binding site of the target molecule, where at least one compound binds with low affinity. Generally the target molecule is a member of a molecular family. One or more compounds that bind to the binding site of the target molecule are identified as molecular scaffolds, and the orientation of the one or more molecular scaffolds at the binding site of the target molecule determined to identify chemically tractable structures of the scaffolds that, when modified, alter the binding affinity or binding specificity between the scaffold and the target molecule. A ligand or a plurality of ligands can be synthesized wherein one or more of the chemically tractable structures of the molecular scaffold is modified to provide a ligand or ligands that bind to the target molecule with altered binding affinity or binding specificity.

[0030] Particular embodiments include those described for the first aspect above.

[0031] The invention also provides a method to identify properties that a likely binding compound will possess, thereby allowing, for example, more efficient selection of compounds for structure activity relationship determinations and/or for selection for screening. Thus, another aspect concerns a method for identifying binding characteristics of a ligand of a target protein, by identifying at least one conserved interacting residue in the target protein that interacts with at least two binding molecules; and identifying at least one common interaction property of those binding molecules with the conserved residue(s). The interaction property and location with respect to the structure of the binding compound defines the binding characteristic.

[0032] In various embodiments, the identification of conserved interacting residues involves comparing (e.g., by sequence alignment) a plurality of amino acid sequences in a protein family to which the target protein belongs and identifying binding site residues conserved in that protein family; identification of binding site residues by determining a co-crystal structure; identifying interacting residues (preferably conserved residues) within a selected distance of the binding compounds, e.g., 3, 3.5, 4, 4.5, or 5 angstroms; the interaction property involves hydrophobic interaction, charge-charge interaction, hydrogen bonding, charge-polar interaction, polar-polar interaction, or combinations thereof.

[0033] Another related aspect concerns a method for developing ligands for a target using a set of scaffolds. The method involves selected a target, selecting a molecular scaffold, or a compound from a scaffold group, from a set of at least 3 scaffolds or scaffold groups where each of the scaffolds or compounds from each scaffold group are known to bind to the target. In particular embodiments, the target is a protein, for example a kinase, a phosphatase, a hormone receptor, a phophodiesterase, or other target as described herein. The set of scaffolds or scaffold groups is at least 4, 5, 6, 7, 8, or even more scaffolds or scaffold groups.

[0034] Another aspect concerns a method for identifying structurally and energetically allowed sites on a binding compound for attachment of an additional component(s) by analyzing the orientation of the binding compound(s) in a target binding site (e.g., by analyzing co-crystal structures), thereby identifying accessible sites on the compound for attachment of the separate component.

[0035] In various embodiments, the method involves calculating the change in binding energy on attachment of the separate component at one or more of the accessible sites; the orientation is determined by co-crystallography; the separate component includes a linker, a label such as a fluorophore, a solid phase material such as a gel, bead, plate, chip, or well.

[0036] In a related aspect, the invention provides a method for attaching a binding compound to an attachment component(s), by identifying energetically allowed sites for attachment of a said attachment component on a binding compound (e.g., as described for the preceding aspect), and attaching the compound or derivative thereof to the attachment component(s) at the energetically allowed site(s).

[0037] In various embodiments, the attachment component is a linker (which can be a traceless linker) for attachment to a solid phase medium, and the method also involves attaching the compound or derivative to a solid phase medium through the linker attached at the energetically allowed site; the binding compound or derivative thereof is synthesized on a linker attached to the solid phase medium; a plurality of compounds or derivatives are synthesized in combinatorial synthesis; the attachment of the compound(s) to the solid phase medium provides an affinity medium

[0038] A related aspect concerns a method for making an affinity matrix for a target molecule, where the method involves identifying energetically allowed sites on a target binding compound for attachment to a solid phase matrix; and attaching the target binding compound to the solid phase matrix through the energetically allowed site.

[0039] Various embodiments are as described for attachment of a separate component above; identifying energetically allowed sites for attachment to a solid phase matrix is performed for at least 5, 10, 20, 30, 50, 80, or 100 different compounds; identifying energetically allowed sites is performed for molecular scaffolds or other target binding compounds having different core ring structures.

[0040] In yet another aspect, the invention provides a modulator of a target molecule, e.g., an inhibitor, identified by the scaffold-based drug discovery methods (i.e., ligand development) described herein. In particular embodiments, the inhibitor is directed to an enzyme, e.g., a kinase, phosphatase, phosphodiesterase, methyltransferase, or other enzyme target described herein.

[0041] As used herein in connection with the design or development of ligands, the term “bind” and “binding” and like terms refer to a non-convalent energetically favorable association between the specified molecules (i.e., the bound state has a lower free energy than the separated state, which can be measured calorimetrically). For binding to a target, the binding is at least selective, that is, the compound binds preferentially to a particular target or to members of a target family at a binding site, as compared to non-specific binding to unrelated proteins not having a similar binding site. For example, BSA is often used for evaluating or controlling for non-specific binding. In addition, for an association to be regarded as binding, the decrease in free energy going from a separated state to the bound state must be sufficient so that the association is detectable in an biochemical assay suitable for the molecules involved.

[0042] By “assaying” is meant the creation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. Likewise, for example, a compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules and/or to modulate an activity of a target molecule.

[0043] By “background signal” in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule. Persons of ordinary skill in the art will realize that accepted methods exist and are widely available for determining background signal.

[0044] When a decision is described as “based on” particular criteria, it is meant that the criteria selected are parameters of the decision and guide its outcome. A substantial change in the parameters is likely to result in a change in the decision.

[0045] By “binding site” is meant an area of a target molecule to which a ligand can bind non-covalently. Binding sites embody particular shapes and often contain multiple binding pockets present within the binding site. The particular shapes are often conserved within a class of molecules, such as a molecular family. Binding sites within a class also can contain conserved structures such as, for example, chemical moieties, the presence of a binding pocket, and/or an electrostatic charge at the binding site or some portion of the binding site, all of which can influence the shape of the binding site.

[0046] By “binding pocket” is meant a specific volume within a binding site. A binding pocket is a particular space within a binding site at least partially bounded by target molecule atoms. Thus a binding pocket is a particular shape, indentation, or cavity in the binding site. Binding pockets can contain particular chemical groups or structures that are important in the non-covalent binding of another molecule such as, for example, groups that contribute to ionic, hydrogen bonding, van der Waals, or hydrophobic interactions between the molecules.

[0047] By “chemical structure” or “chemical substructure” is meant any definable atom or group of atoms that constitute a part of a molecule. Normally, chemical substructures of a scaffold or ligand can have a role in binding of the scaffold or ligand to a target molecule, or can influence the three-dimensional shape, electrostatic charge, and/or conformational properties of the scaffold or ligand.

[0048] By “orientation”, in reference to a binding compound bound to a target molecule is meant the spatial relationship of the binding compound and at least some of its consitituent atoms to the binding pocket and/or atoms of the target molecule at least partially defining the binding pocket.

[0049] In the context of target molecules in the present invention, the term “crystal” refers to an ordered complex of target molecule, such that the complex produces an X-ray diffraction pattern when placed in an X-ray beam. Thus, a “crystal” is distinguished from a disordered or partially ordered complex or aggregate of molecules that do not produce such a diffraction pattern. Preferably a crystal is of sufficient order and size to be useful for X-ray crystallography. A crystal may be formed only of target molecule (with solvent and ions) or may be a co-crystal of more than one molecule, for example, as a co-crystal of target molecule and binding compound, and/or of a complex of proteins (such as a holoenzyme).

[0050] In the context of this invention, unless otherwise specified, by “co-crystals” is meant an ordered complex of the compound, molecular scaffold, or ligand bound non-covalently to the target molecule that produces a diffraction pattern when placed in an X-ray beam. Preferably the co-crystal is in a form appropriate for analysis by X-ray or protein crystallography. In preferred embodiments the target molecule-ligand complex can be a protein-ligand complex.

[0051] By “clog P” is meant the calculated log P of a compound, “P” referring to the partition coefficient of the compound between a lipophilic and an aqueous phase, usually between octanol and water.

[0052] By “chemically tractable structures” is meant chemical structures, sub-structures, or sites on a molecule that can be covalently modified to produce a ligand with a more desirable property. The desirable property will depend on the needs of the particular situation. The property can be, for example, that the ligand binds with greater affinity to a target molecule, binds with more specificity, or binds to a larger or smaller number of target molecules in a molecular family, or other desirable properties as needs require.

[0053] By “designing a ligand,” “preparing a ligand,” “discovering a ligand,” and like phrases is meant the process of considering relevant data (especially, but not limited to, any individual or combination of binding data, X-ray co-crystallography data, molecular weight, clogP, and the number of hydrogen bond donors and acceptors) and making decisions about advantages that can be achieved with resort to specific structural modifications to a molecule, and implementing those decisions. This process of gathering data and making decisions about structural modifications that can be advantageous, implementing those decisions, and determining the result can be repeated as many times as necessary to obtain a ligand with desired properties.

[0054] By “docking” is meant the process of attempting to fit a three-dimensional configuration of a binding pair member into a three-dimensional configuration of the binding site or binding pocket of the partner binding pair member, which can be a protein, and determining the extent to which a fit is obtained. The extent to which a fit is obtained can depend on the amount of void volume in the resulting binding pair complex (or target molecule-ligand complex). The configuration can be physical or a representative configuration of the binding pair member, e.g., an in silico representation or other model.

[0055] By “ligand” is meant a molecular scaffold that has been chemically modified at one or more chemically tractable structures to bind to the target molecule with altered or changed binding affinity or binding specificity relative to the molecular scaffold. The ligand can bind with a greater specificity or affinity for a member of the molecular family relative to the molecular scaffold. A ligand binds non-covalently to a target molecule, which can preferably be a protein or enzyme.

[0056] By binding with “low affinity” is meant binding to the target molecule with a dissociation constant (kd) of greater than 1 μM under standard conditions. In particular cases, low affinity binding is in a range of 1 μM-10 mM, 1 μM-1 mM, 1 μM -500 μM, 1 μM-200 μM, 1 μM-100 μM. By binding with “very low affinity” is meant binding with a kd of above about 100 μM under standard conditions, e.g., in a range of 100 μM-1 mM, 100 μM-500 μM, 100 μM-200 μM. By binding with “extremely low affinity” is meant binding at a kd of above about 1 mM under standard conditions. By “moderate affinity” is meant binding with a kd of from about 200 nM to about 1 μM under standard conditions. By “moderately high affinity” is meant binding at a kd of from about 1 nM to about 200 nM. By binding at “high affinity” is meant binding at a kd of below about 1 nM under standard conditions. For example, low affinity binding can occur because of a poorer fit into the binding site of the target molecule or because of a smaller number of non-covalent bonds, or weaker covalent bonds present to cause binding of the scaffold or ligand to the binding site of the target molecule relative to instances where higher affinity binding occurs. The standard conditions for binding are at pH 7.2 at 37° C. for one hour. For example, 100 μl/well can be used in HEPES 50 mM buffer at pH 7.2, NaCl 15 mM, ATP 2 μM, and bovine serum albumin 1 μg/well, 37° C. for one hour.

[0057] Binding compounds can also be characterized by their effect on the activity of the target molecule. Thus, a “low activity”-compound has an inhibitory concentration (IC50) or excitation concentration (EC50) of greater than 1 μM under standard conditions. By “very low activity” is meant an IC50 or EC50 of above 100 μM under standard conditions. By “extremely low activity” is meant an IC50 or EC50 of above 1 mM under standard conditions. By “moderate activity” is meant an IC50 or EC50 of 200 nM to 1 μM under standard conditions. By “moderately high activity” is meant an IC50 or EC50 of 1 nM to 200 nM. By “high activity” is meant an IC50 or EC50 of below 1 nM under standard conditions. The IC50 (or EC50) is defined as the concentration of compound at which 50% of the activity of the target molecule (e.g., enzyme or other protein) activity being measured is lost (or gained) relative to activity when no compound is present. Activity can be measured using methods known to those of ordinary skill in the art, e.g., by measuring any detectable product or signal produced by occurrence of an enzymatic reaction, or other activity by a protein being measured.

[0058] By “molecular scaffold” or “scaffold” is meant a small target binding molecule to which one or more additional chemical moieties can be covalently attached, modified, or eliminated to form a plurality of molecules with common structural elements. The moieties can include, but are not limited to, a halogen atom, a hydroxyl group, a methyl group, a nitro group, a carboxyl group, or any other type of molecular group including, but not limited to, those recited in this application. Molecular scaffolds bind to at least one target molecule with low or very low affinity and/or bind to a plurality of molecules in a target family (e.g., protein family), and the target molecule is preferably an enzyme, receptor, or other protein. Preferred characteristics of a scaffold include molecular weight of less than about 350 daltons; binding at a target molecule binding site such that one or more substituents on the scaffold are situated in binding pockets in the target molecule binding site; having chemically tractable structures that can be chemically modified, particularly by synthetic reactions, so that a combinatorial library can be easily constructed; having chemical positions where moieties can be attached that do not interfere with binding of the scaffold to a protein binding site, such that the scaffold or library members can be modified to form ligands, to achieve additional desirable characteristics, e.g., enabling the ligand to be actively transported into cells and/or to specific organs, or enabling the ligand to be attached to a chromatography column for additional analysis. Thus, a molecular scaffold is a small, identified target binding molecule prior to modification to improve binding affinity and/or specificity, or other pharmacalogic properties.

[0059] The term “scaffold core” refers to the core structure of a molecular scaffold onto which various substituents can be attached. Thus, for a number of scaffold molecules of a particular chemical class, the scaffold core is common to all the scaffold molecules. In many cases, the scaffold core will consist of or include one or more ring structures.

[0060] The term “scaffold group” refers to a set of compounds that share a scaffold core and thus can all be regarded as derivatives of one scaffold molecule.

[0061] In particular embodiments, the a scaffold or scaffold group for use in this invention is not a quinazoline; not a purine; not an oxindole; not a pyrimidine.

[0062] By “molecular family” is meant groups of molecules classed together based on structural and/or functional similarities. Examples of molecular families include proteins, enzymes, polypeptides, receptor molecules, oligosaccharides, nucleic acids, DNA, RNA, etc. Thus, for example, a protein family is a molecular family. Molecules can also be classed together into a family based on, for example, homology. The person of ordinary skill in the art will realize many other molecules that can be classified as members of a molecular family based on similarities in chemical structure or biological function.

[0063] By “protein-ligand complex” or “co-complex” is meant a protein and ligand bound non-covalently.

[0064] By “protein” is meant a polymer of amino acids. The amino acids can be naturally or non-naturally occurring. Proteins can also contain adaptations, such as being glycosylated, phosphorylated, or other common modifications.

[0065] By “protein family” is meant a classification of proteins based on structural and/or functional similarities. For example, kinases, phosphatases, proteases, and similar groupings of proteins are protein families. Proteins can be grouped into a protein family based on having one or more protein folds in common, a substantial similarity in shape among folds of the proteins, homology, or based on having a common function. In many cases, smaller families will be specified, e.g., tyrosine kinases, serine/threonine kinases, and the like.

[0066] “Protein folds” are 3-dimensional shapes exhibited by the protein and defined by the existence, number, and location in the protein of alpha helices, beta-sheets, and loops, i.e., the basic secondary structures of protein molecules. Folds can be, for example, domains or partial domains of a particular protein.

[0067] By “ring structure” is meant a molecule having a chemical ring or sub-structure that is a chemical ring. In most cases, ring strutures will be carbocyclic or heterocyclic rings. The chemical ring may be, but is not limited to, a benzyl ring, aryl ring, pyrrole ring, imidazole, pyridine, purine, or any ring structure.

[0068] By “specific biochemical effect” is meant a therapeutically significant biochemical change in a biological system causing a detectable result. This specific biochemical effect can be, for example, the inhibition or activation of an enzyme, the inhibition or activation of a protein that binds to a desired target, or similar types of changes in the body's biochemistry. The specific biochemical effect can cause alleviation of symptoms of a disease or condition or another desirable effect. The detectable result can also be detected through an intermediate step.

[0069] By “standard conditions” is meant conditions under which an assay is performed to obtain scientifically meaningful data. Standard conditions are dependent on the particular assay, and can be generally subjective. Normally the standard conditions of an assay will be those conditions that are optimal for obtaining useful data from the particular assay. The standard conditions will generally minimize background signal and maximize the signal sought to be detected.

[0070] By “standard deviation” is meant the square root of the variance. The variance is a measure of how spread out a distribution is. It is computed as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is:

σ^{2} = \frac{{(1 - 2)}^{2} + {(2 - 2)}^{2} + {(3 - 2)}^{2}}{3} = 0.667

[0071] By a “set” of compounds is meant a collection of compounds. The compounds may or may not be structurally related.

[0072] In the context of this inveniton, by “target molecule” is meant a molecule that a compound, molecular scaffold, or ligand is being assayed for binding to. The target molecule has an activity that binding of the molecular scaffold or ligand to the target molecule will alter or change. The binding of the compound, scaffold, or ligand to the target molecule can preferably cause a specific biochemical effect when it occurs in a biological system. A “biological system” includes, but is not limited to, a living system such as a human, animal, plant, or insect. In most but not all cases, the target molecule will be a protein or nucleic acid molecule.

[0073] By “pharmacophore” is meant a representation of molecular features that are considered to be responsible for a desired activity, such as interacting or binding with a receptor. A pharmacophore can include 3-dimensional (hydrophobic groups, charged/ionizable groups, hydrogen bond donors/acceptors), 2D (substructures), and ID (physical or biological) properties.

[0074] As used herein in connection with numerical values, the terms “approximately” and “about” mean 110% of the indicated value.

[0075] Additional embodiments will be apparent from the Detailed Description of the Invention and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0076]
FIG. 1 is a schematic diagram illustrating some characteristics of a good scaffold.

[0077]
FIG. 2A illustrates binding of a scaffold in a kinase homology surface. FIG. 2B illustrates the interaction of a kinase inhibitor in a homology surface.

[0078]
FIG. 3 is a schematic showing initial steps in scaffold-based drug discovery approach, combining biochemical screening including identification of low affinity hits and crystallization and structure determination of target protein.

[0079]
FIG. 4 shows the application of co-crystallization, as well as filters for selection of advantageous scaffolds to use for ligand development.

[0080]
FIG. 5 provides a schematic view of an exemplary embodiment of the present invention. By assaying a large number of compounds for binding activity to members of a protein family, about 400 broadly acting “hits” or molecular scaffold embodiments are obtained. The orientations of at least some of these molecular scaffold compounds at the binding site of the target molecule are determined, and a plurality of the scaffold compounds are modified at chemically tractable structures, resulting in a smaller number of lead compounds with a greater specificity and/or greater affinity, directed to one or more respective targets that are members of a protein family.

[0081]
FIG. 6 illustrates a binding site surface with a molecular scaffold bound thereto, and illustrates that a modification of the scaffold can be performed to fill void volume at the target molecule-scaffold co-complex, or to eliminate a sub-molecular barrier to binding and provide greater access of the scaffold to the binding site, thereby resulting in a ligand that binds with greater affinity and/or greater specificity.

[0082]
FIG. 7 illustrates a scaffold (hydrogens not shown) bound in PIM-1 binding site (panel A), and a derivative compound bound at the same site with an added substituent making a hydrophobic interaction with a nearby hydrophobic target surface (panel B).

[0083]
FIG. 8 provides an illustration of a scaffold at the binding site of a target compound. 5a illustrates a scaffold with broad binding activity, binding to HCK; and 5b and 5c show how the scaffold can be modified to arrive at ligands that are specific for individual targets, CSK and Lyn, which are homologous to HCK. Thus, beginning with one molecular scaffold, a plurality of ligands can be designed specific for particular target molecules within a molecular family. The initial selection of ligands can also be utilized as molecular scaffolds providing bases for further modification and design of ligands.

DETAILED DESCRIPTION OF THE INVENTION

[0084] The Tables will first be briefly described.

[0085] Table 1 provides atomic coordinates for human PIM-1. In this table and in Table 4, the various columns have the following content, beginning with the left-most column:

[0086] ATOM: Refers to the relevant moiety for the table row.

[0087] Atom number: Refers to the arbitrary atom number designation within the coordinate table.

[0088] Atom Name: Identifier for the atom present at the particular coordinates.

[0089] Chain ID: Chain ID refers to one monomer of the protein in the crystal, e.g., chain “A”, or to other compound present in the crystal, e.g., HOH for water, and L for a ligand or binding compound. Multiple copies of the protein monomers will have different chain Ids.

[0090] Residue Number: The amino acid residue number in the chain.

[0091] X, Y, Z: Respectively are the X, Y, and Z coordinate values.

[0092] Occupancy: Describes the fraction of time the atom is observed in the crystal. For example, occupancy=1 means that the atom is present all the time; occupancy=0.5 indicates that the atom is present in the location 50% of the time.

[0093] B-factor: A measure of the thermal motion of the atom.

[0094] Element: Identifier for the element.

[0095] Table 2 provides atomic coordinates for PIM-1 with AMP-PNP in the binding site. Table entries are as for Table 1.

[0096] Table 3 provides an alignment of kinase domains of several PIM kinases, including human PIM-1, PIM-2, and PIM-3 as well as PIM kinases from other species.

[0097] Table 4 provides atomic coordinates for PYK2 with (5′-adenylylimidodiphosphate) AMPPNP in the binding site. Table entries are as for Table 1.

[0098] Table 5 provides an alignment of kinase domains for several kinases, including human PYK2, providing identification of residues conserved between various members of the set. The residue number is for PYK2.

[0099] Table 6 provides the nucleic acid and amino acid sequences for human PYK2 kinase domain.

[0100] Table 7 provides representative assay results for kinase activity of PYK2 kinase domain in the presence of ATP and in the presence of several ATP analogs.

[0101] The present invention provides methods for designing ligands active on particular biological targets, such as cellular enzymes and receptors. While such methods can be implemented in many ways, highly preferably the process utilizes molecular scaffolds. Such molecular scaffolds are low molecular weight molecules that bind with low or very low affinity to the target and typically have low or very low activity on that target and/or act broadly across families of target molecules.

[0102] The ability of a scaffold or other compound to act broadly across multiple members of a target family is advantageous in developing ligands. For example, a scaffold or set of scaffolds can serve as starting compounds for developing ligands with desired specificity or with desired cross-activity on a selected subset of members of a target family. Further, identification of a set of scaffolds that each bind with members of a target family provides an advantageous basis for selecting a starting point for ligand development for a particular target or subset of targets. In many cases, the ability of a scaffold to bind to and/or have activity on multiple members of a target family is related to active site or binding site homology that exists across the target family.

[0103] The relationship of the target homology and binding of a scaffold is illustrated in FIG. 2. As shown in the figure, a homology surface can be created, showing the presence of various levels of homology among kinase structures. A scaffold active across multiple members of the kinase family interacts with surfaces or residues of relatively high homology, i.e., binds to conserved regions of the binding pockets. Scaffolds that bind with multiple members can be modified to provide greater specificity or to have a particular cross-reactivity, e.g., by exploiting differences between target binding sites to provide specificity, and exploiting similarities to design in cross-reactivities. Adding substituents that provide attractive interactions with the particular target typically increases the binding affinity, often increasing the activity. The various parts of the ligand development process are described in more detail in following sections, but the following describes an advantageous approach for scaffold-based ligand development.

[0104] While understanding that scaffold-based ligand development (scaffold-based drug discovery) can be implemented in a variety of ways, the early steps of an illustrative approach is shown in FIG. 3. As shown, large scale expression of protein is useful to provide material for crystallization, co-crystallization, and biochemical screening (e.g., binding and activity assays). For crystallization, crystallization conditions can be established for apo protein and a structure determined from those crystals. For screening, preferably a biased library selected for the particular target family is screening for binding and/or activity on the target. Highly preferably a plurality of members from the target family are screened. Such screening, whether on a single target or on multiple members of a target family provides screening hits. Low affinity and/or low activity hits are selected. Such low affinity hits can either identify a scaffold molecule, or allow identification of a scaffold molecule by analyzing common features between binding molecules. Simpler molecules containing the common features can then be tested to determine if they retain binding and/or activity, thereby allowing identification of a scaffold molecule.

[0105] When multiple members of a particular target family are used for screening, the overlap in binding and/or activity of compounds can provide a useful selection for compounds that will be subjected to crystallization. For example, for 3 target molecules from a target family, if each target has about 500-200 hits in screening of a particular library, much smaller subsets of those hits will be common to any 2 of the 3 targets, and a still smaller subset will be common to all 3 targets, e.g., 100-300. In many cases, compounds in the subset common to all 3 targets will be selected for co-crystallography, as they provide the broadest potential for ligand development.

[0106] Once compounds for co-crystallography are selected, conditions for forming co-crystals are determined, allowing determination of co-crystal structure and the orientation of binding compound in the binding site of the target is determined by solving the structure (this can be highly assisted if an apo protein crystal structure has been determined or if the structure of a close homolog is available for use in a homology model. Preferably the co-crystals are formed by direct co-crystallization rather than by soaking the compound into crystals of apo protein.

[0107] From the co-crystals and knowledge of the structure of the binding compounds, additional selection of scaffold (or other binding compounds can be made as shown in FIG. 4, by applying selection filters, e.g., for (1) binding mode, (2) multiple sites for substitution, and/or (3) tractable chemistry. A binding mode filter can, for example, be based on the demonstration of a dominant binding mode. That is, a scaffold or compounds of a scaffold group bind with a consistent orientation, preferably a consistent orientation across multiple members of a target family. Filtering scaffolds for multiple sites for substitution provides greater potential for developing ligands for specific targets due to the greater capacity for appropriately modifying the structure of the scaffold. Filtering for tractable chemistry also facilitates preparation of ligands derived from a scaffold because the synthetic paths for making derivative compounds are available. Some of the characteristics for a good scaffold are illustrated schematically in FIG. 1, which shows a schematic of a scaffold bound with a target. As indicated in the figure, such scaffolds facilitate preparation of focused libraries of derivative compounds with varied substituents.

[0108] Carrying out such a process of development provides scaffolds, preferably of divergent structure. This is illustrated by the four different strutures in FIG. 4 (the illustration of these structures does not mean that the compounds represented by those structures are actual scaffolds for any target).

[0109] In some cases, it may be impractical or undesirable to work with a particular target for some or all of the development process. For example, a particular target may be difficult to express, by easily degraded, or be difficult to crystallize. In these cases, a surrogate target from the target family. It is desirable to have the surrogate be as similar as possible to the desired target, thus a family member that has high homolgy in the binding site should be used, or the binding site can be modified to be more similar to that of the desired target, or part of the sequence of the desired target can be inserted in the family member replacing the corresponding part of the sequence of the family member.

[0110] Once one or more scaffolds are identified for a target family, the scaffolds can be used to develop multiple products directed at specific members of the family, or at specific subsets of family members. Thus, starting from a scaffold that acts on multiple member of the target family, derivative compounds (ligands) can be designed and tested that have increasing selectivity. In addition, such ligands are typically developed to have greater activity, and will also typically have greater binding affinity. In this process, starting with the broadly acting scaffold, ligands are developed that have improved selectivity and activity profiles, leading to identification of lead compounds for drug development, leading to drug candidates, and final drug products.

[0111] Scaffolds

[0112] Typically it is advantageous to select scaffolds (and/or compound sets or libraries for scaffold or binding compound identification) with particular types of characteristics, e.g., to select compounds that are more likely to bind to a particular target and/or to select compounds that have physical and/or synthetic properties to simplify preparation of derivatives, to be drug-like, and/or to provide convenient sites and chemistry for modification or synthesis.

[0113] Useful chemical properties of molecular scaffolds can include one or more of the following characteristics, but are not limited thereto: an average molecular weight below about 350 daltons, or between from about 150 to about 350 daltons, or from about 150 to about 300 daltons; having a clogP below 3; a number of rotatable bonds of less than 4; a number of hydrogen bond donors and acceptors below 5 or below 4; a Polar Surface Area of less than 100 Å2; binding at protein binding sites in an orientation so that chemical substituents from a combinatorial library that are attached to the scaffold can be projected into pockets in the protein binding site; and possessing chemically tractable structures at its substituent attachment points that can be modified, thereby enabling rapid library construction.

[0114] The term “Molecular Polar Surface Area (PSA)” refers to the sum of surface contributions of polar atoms (usually oxygens, nitrogens and attached hydrogens) in a molecule. The polar surface area has been shown to correlate well with drug transport properties, such as intestinal absorption, or blood-brain barrier penetration.

[0115] Additional useful chemical properties of distinct compounds for inclusion in a combinatorial library include the ability to attach chemical moieties to the compound that will not interfere with binding of the compound to at least one protein of interest, and that will impart desirable properties to the library members, for example, causing the library members to be actively transported to cells and/or organs of interest, or the ability to attach to a device such as a chromatography column (e.g., a streptavidin column through a molecule such as biotin) for uses such as tissue and proteomics profiling purposes.

[0116] A person of ordinary skill in the art will realize other properties that can be desirable for the scaffold or library members to have depending on the particular requirements of the use, and that compounds with these properties can also be sought and identified in like manner. Methods of selecting compounds for assay are known to those of ordinary skill in the art, for example, methods and compounds described in U.S. Pat. Nos. 6,288,234, 6,090,912, 5,840,485, each of which is hereby incorporated by reference in its entirety, including all charts and drawings.

[0117] In various embodiments, the present invention provides methods of designing ligands that bind to a plurality of members of a molecular family, where the ligands contain a common molecular scaffold. Thus, a compound set can be assayed for binding to a plurality of members of a molecular family, e.g., a protein family. One or more compounds that bind to a plurality of family members can be identified as molecular scaffolds. When the orientation of the scaffold at the binding site of the target molecules has been determined and chemically tractable structures have been identified, a set of ligands can be synthesized starting with one or a few molecular scaffolds to arrive at a plurality of ligands, wherein each ligand binds to a separate target molecule of the molecular family with altered or changed binding affinity or binding specificity relative to the scaffold. Thus, a plurality of drug lead molecules can be designed to individually target members of a molecular family based on the same molecular scaffold, and act on them in a specific manner.

[0118] Protein Families

[0119] Many classes or families of proteins are contemplated for use as target molecules in the present invention. For example protein kinases (e.g., tyrosine kinases and serine/threonine kinases), proteases (including serine proteases, cysteine proteases, metalloproteases (including matrix metalloproteases), and thrubedel proteases), phosphatases, nuclear hormone receptors, TNF receptors, G-protein coupled receptors, G-proteins, phospodiesterases, ATP or GTP cyclases, adaptor molecules (such as SH2, SH3, PTB, and WW), ATPases, GTPases, methyl transferases, acetyl transferases, sulfonyl transferases, dehydrogenases, CDK/cyclin exosite inhibitors, integrins, ligases (including ubiquitin ligases), bcl-2 homologs, NAD(P) oxoreductases, monooxygenases, integrases, cyclases, DNA and RNA polymerases, heperanases, helicases, ABC transporters, ion channels, immunoglobulins, and similar groups are contemplated. The protein classes or families are made based on the structural, chemical, or functional similarities of their members. For example, a protein class or family can be based on the common arrangement of secondary structure elements in three-dimensions that provides the core of a protein structure, such as the kinase fold, aspartyl protease fold, or hormone receptor fold. A protein class or family can also be represented by functional similarities, for example the cytokines.

[0120] Proteins that belong to protein families of interest can be obtained by any suitable methods. For example, standard methods of PCR cloning of cDNA libraries, or standard purification can be used to prepare nucleotide sequences encoding members of protein families. Plasmids for expressing protein can then be generated for expression of the protein in a suitable expressions system, such as (for example) E. coli, insect cell expression, or a commercially available “in vitro” translation and expression system (e.g., Roche Bioscience, Palo Alto, Calif.). These expression systems can then be used for obtaining protein for screening and co-crystallization studies. Proteins are typically expressed with a poly-histidine tag at either the N or C terminus of the protein sequence, which can greatly aid purification of the protein. The activity of the protein can initially be tested; for example kinases can be tested for phosphorylation activity, or nuclear receptors for hormone binding activity. Proteins showing activity can be screened against the compound collection and crystallized. In some cases, vectors with sequences encoding a designed protein will be publically available, such as from a commercial source or from a depository.

[0121] Protein expression can be carried out in any suitable system, for example, by growing cells transformed with the expression plasmid in either E. coli or insect cells using baculovirus. In the case of an “in vitro” expression system, a standard commercially available protein expression systems can be used (e.g., RTS500®, Roche Biosciences, Palo Alto, Calif.). Cells can then be lysed in buffers. A preferred buffer contains 20 mM Tris HCl pH 8.0, 200 mM NaCl, protease inhibitors, and 1-3% glycerol or propane diol. Batch purification of the protein can be done with the lysate from the cells using cobalt chelated beads, with the protein being isolated from the beads followed by a combination of ion exchange chromatography (such as Q-sepharose) or gel filtration (such as Sephadex 200). The buffers described above can be used or combinations of different buffer systems can be used that optionally contain other chemical additives.

[0122] G Protein Receptors

[0123] An exemplary protein family, also having sub-families is the G protein-coupled receptors (GPCRs). G protein-coupled receptors constitute an important family of validated drug targets within biomedical research; over half of approved drugs elicit their therapeutic effects by selectively addressing members of that target family. Many pharmacological drug companies are interested in the study of G-coupled proteins. It is possible to co-express a G-coupled protein receptor and its associated G-protein to study their pharmacological characteristics (Strosberg and Marullo, Functional expression of receptors in microorganisms. TIPS, 1992. 13: 95-98).

[0124] G protein coupled receptors (GPCRs) are reviewed by Sautel and Milligan, Molecular manipulation of G-protein-coupled receptors: a new avenue into drug discovery. (Review), Curr Med Chem 2000 889-96; Hibert et al., This is not a G protein-coupled receptor. (Review), Trends Pharmacol Sci 1993, 14:7-12; Wilson et al., Orphan G-protein-coupled receptors: the next generation of drug targets? (Review), Br J Pharmacol 1998, 125:1387-92; Roth et al., G protein-coupled receptor (GPCR) trafficking in the central nervous system: relevance for drugs of abuse. (Review), Drug Alcohol Depend 1998, 51:73-85; Ferguson and Caron, G protein-coupled receptor adaptation mechanisms. (Review), Semin Cell Dev Biol 1998, 9:119-27; Wank, G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family, Am J Physiol 1998, 274:G607-13; Rohrer and Kobilka, G protein-coupled receptors: functional and mechanistic insights through altered gene expression. (Review), Physiol Rev 1998, 78:35-52; and Larhammar et al., The receptor revolution—multiplicity of G-protein-coupled receptors. (Review), Drug Des Discov 1993, 9:179-88.

[0125] GPCR localization and regulation has been studied using Green Fluorescent Protein comprising fusion proteins Kallal and Benovic, Using green fluorescent proteins to study G-protein-coupled receptor localization and trafficking. (Review), Trends Pharmacol Sci 2000 21:175-80; and Ferguson, Using green fluorescent protein to understand the mechanisms of G-protein-coupled receptor regulation. (Review), Braz J Med Biol Res 1998, 31:1471-7; chimeric GPCRs, Milligan and Rees, Chimaeric G alpha proteins: their potential use in drug discovery. (Review), Erratum in: Trends Pharmacol Sci 1999 June; 20(6):252.

[0126] Members of the membrane protein gene superfamily of G-protein coupled receptors have been characterized as having seven putative transmembrane domains. The transmembrane domains are believed to represent transmembrane alpha-helices connected by extracellular or cytoplasmic loops. A functional G-protein is a trimer which consists of variable alpha subunit coupled to much more tightly-associated and constant beta and gamma subunits. A variety of ligands have been identified which function through GPCRs.

[0127] In general, binding of an appropriate ligand to a GPCR leads to the activation of the receptor. G-protein coupled receptors include a wide range of biologically active receptors, such as hormone, viral, growth factor and neuroreceptors. Typically, activation of a GPCR initiates the regulatory cycle of a corresponding G-protein. This cycle consists of GTP exchange for GDP, dissociation of the alpha and beta/gamma subunits, activation of the second messenger pathway by a complex of GTP and the alpha subunit of the G-protein, and return to the resting state by GTP hydrolysis via the innate GTP-ase activity of the G-protein alpha subunit A.

[0128] G-protein coupled receptors have been characterized as including these seven conserved hydrophobic stretches of about 20 to 30 amino acids, connecting at least eight divergent hydrophilic loops. The G-protein family of coupled receptors includes dopamine receptors which bind to neuroleptic drugs used for treating psychotic and neurological disorders. Other examples of members of this family include calcitonin, adrenergic, endothelin, cAMP, adenosine, muscarinic, acetylcholine, serotonin, histamine, thrombin, kinin, follicle stimulating hormone, opsins and rhodopsins, odorant, cytomegalovirus receptors, and the like.

[0129] Most GPCRs havesingle conserved cysteine residues in each of the first two extracellular loops which form disulfide bonds that are believed to stabilize functional protein structure. The 7 transmembrane regions are designated as TM1, TM2, TM3, TM4, TM5, TM6, and TM7. TM3 is also implicated in signal transduction.

[0130] Binding Assays

[0131] The methods of the present invention involve assays that are able to detect the binding of compounds to a target molecule at a signal of at least about three times the standard deviation of the background signal, or at least about four times the standard deviation of the background signal. The assays of the present invention can also include assaying compounds for low affinity binding to the target molecule. A large variety of assays indicative of binding are known for different target types and can be used for this invention. Compounds that act broadly across protein families are not likely to have a high affinity against individual targets, due to the broad nature of their binding. Thus, assays (e.g., as described herein) highly preferably allow for the identification of compounds that bind with low affinity, very low affinity, and extremely low affinity. Therefore, potency (or binding affinity) is not the primary, nor even the most important, indicia of identification of a potentially useful binding compound. Rather, even those compounds that bind with low affinity, very low affinity, or extremely low affinity can be considered as molecular scaffolds that can continue to the next phase of the ligand design process.

[0132] As indicated above, to design or discover scaffolds that act broadly across protein families, proteins of interest can be assayed against a compound collection or set. The assays can preferably be enzymatic or binding assays. In some embodiments it may be desirable to enhance the solubility of the compounds being screened and then analyze all compounds that show activity in the assay, including those that bind with low affinity or produce a signal with greater than about three times the standard deviation of the background signal. The assays can be any suitable assay such as, for example, binding assays that measure the binding affinity between two binding partners. Various types of screening assays that can be useful in the practice of the present invention are known in the art, such as those described in U.S. Pat. Nos. 5,763,198, 5,747,276, 5,877,007, 6,243,980, 6,294,330, and 6,294,330, each of which is hereby incorporated by reference in its entirety, including all charts and drawings.

[0133] In various embodiments of the assays at least one compound, at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 25% of the compounds can bind with low affinity. In many cases, up to about 20% of the compounds can show activity in the screening assay and these compounds can then be analyzed directly with high-throughput co-crystallography, computational analysis to group the compounds into classes with common structural properties (e.g., structural core and/or shape and polarity characteristics), and the identification of common chemical structures between compounds that show activity.

[0134] The person of ordinary skill in the art will realize that decisions can be based on criteria that are appropriate for the needs of the particular situation, and that the decisions can be made by computer software programs. Classes can be created containing almost any number of scaffolds, and the criteria selected can be based on increasingly exacting criteria until an arbitrary number of scaffolds is arrived at for each class that is deemed to be advantageous.

[0135] Surface Plasmon Resonance

[0136] Binding parameters can be measured using surface plasmon resonance, for example, with a BIAcore® chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of reaction between an sFv or other ligand directed against target molecules. Such methods are generally described in the following references which are incorporated herein by reference. Vely F. et al., BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121:313-21, 2000; Liparoto et al., Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12:316-21, 1999; Lipschultz et al., Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. 20(3):310-8, 2000; Malmqvist., BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27:335-40, 1999; Alfthan, Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics. 13:653-63, 1998; Fivash et al., BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9:97-101, 1998; Price et al.; Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19 Suppl 1:1-20, 1998; Malmqvist et al, Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. 1:378-83, 1997; O'Shannessy et al., Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236:275-83, 1996; Malmborg et al., BIAcore as a tool in antibody engineering, Journal of Immunological Methods. 183:7-13, 1995; Van Regenmortel, Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83:143-51, 1994; and O'Shannessy, Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. 5:65-71, 1994.

[0137] BIAcore® uses the optical properties of surface plasmon resonance (SPR) to detect alterations in protein concentration bound to a dextran matrix lying on the surface of a gold/glass sensor chip interface, a dextran biosensor matrix. In brief, proteins are covalently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix. Near infrared light, directed onto the opposite side of the sensor chip surface is reflected and also induces an evanescent wave in the gold film, which in turn, causes an intensity dip in the reflected light at a particular angle known as the resonance angle. If the refractive index of the sensor chip surface is altered (e.g., by ligand binding to the bound protein) a shift occurs in the resonance angle. This angle shift can be measured and is expressed as resonance units (RUs) such that 1000 RUs is equivalent to a change in surface protein concentration of 1 ng/mm2. These changes are displayed with respect to time along the y-axis of a sensorgram, which depicts the association and dissociation of any biological reaction.

[0138] High Throughput Screening (HTS) Assays

[0139] HTS typically uses automated assays to search through large numbers of compounds for a desired activity. Typically HTS assays are used to find new drugs by screening for chemicals that act on a particular enzyme or molecule. For example, if a chemical inactivates an enzyme it might prove to be effective in preventing a process in a cell which causes a disease. High throughput methods enable researchers to assay thousands of different chemicals against each target molecule very quickly using robotic handling systems and automated analysis of results.

[0140] As used herein, “high throughput screening” or “HTS” refers to the rapid in vitro screening of large numbers of compounds (libraries); generally tens to hundreds of thousands of compounds, using robotic screening assays. Ultra high-throughput Screening (uHTS) generally refers to the high-throughput screening accelerated to greater than 100,000 tests per day.

[0141] To achieve high-throughput screening, it is advantageous to house samples on a multicontainer carrier or platform. A multicontainer carrier facilitates measuring reactions of a plurality of candidate compounds simultaneously. Multi-well microplates may be used as the carrier. Such multi-well microplates, and methods for their use in numerous assays, are both known in the art and commercially available.

[0142] Screening assays may include controls for purposes of calibration and confirmation of proper manipulation of the components of the assay. Blank wells that contain all of the reactants but no member of the chemical library are usually included. As another example, a known inhibitor (or activator) of an enzyme for which modulators are sought, can be incubated with one sample of the assay, and the resulting decrease (or increase) in the enzyme activity used as a comparator or control. It will be appreciated that modulators can also be combined with the enzyme activators or inhibitors to find modulators which inhibit the enzyme activation or repression that is otherwise caused by the presence of the known the enzyme modulator. Similarly, when ligands to a target are sought, known ligands of the target can be present in control/calibration assay wells.

[0143] Measuring Enzymatic and Binding Reactions During Screening Assays

[0144] Techniques for measuring the progression of enzymatic and binding reactions, e.g., in multicontainer carriers, are known in the art and include, but are not limited to, the following.

[0145] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of calorimetric assays for the detection of peroxides, as disclosed in Example 1(b) and Gordon, A. J. and Ford, R. A., The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, N.Y., 1972, Page 437.

[0146] Fluorescence spectrometry may be used to monitor the generation of reaction products. Fluorescence methodology is generally more sensitive than the absorption methodology. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al., Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd. (1987); and Bell, Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press (1981).

[0147] In spectrofluorometric methods, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is nonfluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, SMase activity can be detected using the Amplex® Red reagent (Molecular Probes, Eugene, Oreg.). In order to measure sphingomyelinase activity using Amplex® Red, the following reactions occur. First, SMase hydrolyzes sphingomyelin to yield ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to yield choline. Third, choline is oxidized by choline oxidase to betaine. Finally, H2O2, in the presence of horseradish peroxidase, reacts with Amplex Red to produce the fluorescent product, Resorufin, and the signal therefrom is detected using spectrofluorometry.

[0148] Fluorescence polarization (FP) is based on a decrease in the speed of molecular rotation of a fluorophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing for polarized fluorescent emission by the bound ligand. FP is empirically determined by measuring the vertical and horizontal components of fluorophore emission following excitation with plane polarized light. Polarized emission is increased when the molecular rotation of a fluorophore is reduced. A fluorophore produces a larger polarized signal when it is bound to a larger molecule (i.e. a receptor), slowing molecular rotation of the fluorophore. The magnitude of the polarized signal relates quantitatively to the extent of fluorescent ligand binding. Accordingly, polarization of the “bound” signal depends on maintenance of high affinity binding.

[0149] FP is a homogeneous technology and reactions are very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prepared, resulting in high reproducibility. Because of these properties, FP has proven to be highly automatable, often performed with a single incubation with a single, premixed, tracer-receptor reagent. For a review, see Owicki et al., Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27, 1997.

[0150] FP is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., Nature 375:254-256, 1995; Dandliker, W. B., et al., Methods in Enzymology 74:3-28, 1981) and is thus insensitive to the presence of colored compounds that quench fluorescence emission. FP and FRET (see below) are well-suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example, Parker et al., Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays, J Biomol Screen 5:77-88, 2000.

[0151] Fluorophores, derived from sphingolipids that may be used in FP assays are commercially available. For example, Molecular Probes (Eugene, Oreg.) currently sells sphingomyelin and one ceramide flurophores. These are, respectively, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosyl phosphocholine (BODIPY® FL C5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosyl phosphocholine (BODIPY®) FL C12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine (BODIPY® FL C5-ceramide). U.S. Pat. No. 4,150,949, (Immunoassay for gentamicin), discloses fluorescein-labelled gentamicins, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores may be prepared using methods well known to the skilled artisan.

[0152] Exemplary normal-and-polarized fluorescence readers include the POLARION® fluorescence polarization system (Tecan ΔG, Hombrechtikon, Switzerland). General multiwell plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multiwell plate spectrophotometer (both from Molecular Devices).

[0153] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Heim et al., Curr. Biol. 6:178-182, 1996; Mitra et al., Gene 173:13-17 1996; and Selvin et al., Meth. Enzymol. 246:300-345, 1995. FRET detects the transfer of energy between two fluorescent substances in close proximity, having known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when a protein specifically interacts with a target molecule, the resonance energy can be transferred from one excited molecule to the other. As a result, the emission spectrum of the sample shifts, which can be measured by a fluorometer, such as a fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

[0154] Scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target molecule. SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al., J. Lipid Res. 38:2365-2373 (1997); Kahl et al., Anal. Biochem. 243:282-283 (1996); Undenfriend et al., Anal. Biochem. 161:494-500 (1987)). See also U.S. Pat. Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734. One commercially available system uses FLASHPLATE® scintillant-coated plates (NEN Life Science Products, Boston, Mass.).

[0155] The target molecule can be bound to the scintillator plates by a variety of well known means. Scintillant plates are available that are derivatized to bind to fusion proteins such as GST, His6 or Flag fusion proteins. Where the target molecule is a protein complex or a multimer, one protein or subunit can be attached to the plate first, then the other components of the complex added later under binding conditions, resulting in a bound complex.

[0156] In a typical SPA assay, the gene products in the expression pool will have been radiolabeled and added to the wells, and allowed to interact with the solid phase, which is the immobilized target molecule and scintillant coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when a radiolabel becomes sufficiently close to the scintillant coating, it produces a signal detectable by a device such as a TOPCOUNT NXT® microplate scintillation counter (Packard BioScience Co., Meriden Conn.). If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scintillant long enough to produce a detectable signal.

[0157] In contrast, the labeled proteins that do not bind to the target molecule, or bind only briefly, will not remain near the scintillant long enough to produce a signal above background. Any time spent near the scintillant caused by random Brownian motion will also not result in a significant amount of signal. Likewise, residual unincorporated radiolabel used during the expression step may be present, but will not generate significant signal because it will be in solution rather than interacting with the target molecule. These non-binding interactions will therefore cause a certain level of background signal that can be mathematically removed. If too many signals are obtained, salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols et al., Anal. Biochem. 257:112-119, 1998).

[0158] Assay Compounds and Molecular Scaffolds

[0159] As described above, preferred characteristics of a scaffold include being of low molecular weight (e.g., less than 350 Da, or from about 100 to about 350 daltons, or from about 150 to about 300 daltons). Preferably clog P of a scaffold is from −1 to 8, more preferably less than 6, 5, or 4, most preferably less than 3. In particular embodiments the clogP is in a range −1 to an upper limit of 2, 3, 4, 5, 6, or 8; or is in a range of 0 to an upper limit of 2, 3, 4, 5, 6, or 8. Preferably the number of rotatable bonds is less than 5, more preferably less than 4. Preferably the number of hydrogen bond donors and acceptors is below 6, more preferably below 5. An additional criterion that can be useful is a Polar Surface Area of less than 100. Guidance that can be useful in identifying criteria for a particular application can be found in Lipinski et al., Advanced Drug Delivery Reviews 23 (1997) 3-25, which is hereby incorporated by reference in its entirety.

[0160] A scaffold will preferably bind to a given protein binding site in a configuration that causes substituent moieties of the scaffold to be situated in pockets of the protein binding site. Also, possessing chemically tractable groups that can be chemically modified, particularly through synthetic reactions, to easily create a combinatorial library can be a preferred characteristic of the scaffold. Also preferred can be having positions on the scaffold to which other moieties can be attached, which do not interfere with binding of the scaffold to the protein(s) of interest but do cause the scaffold to achieve a desirable property, for example, active transport of the scaffold to cells and/or organs, enabling the scaffold to be attached to a chromatographic column to facilitate analysis, or another desirable property. A molecular scaffold can bind to a target molecule with any affinity, such as binding with an affinity measurable as about three times the standard deviation of the background signal, or at high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity.

[0161] Thus, the above criteria can be utilized to select many compounds for testing that have the desired attributes. Many compounds having the criteria described are available in the commercial market, and may be selected for assaying depending on the specific needs to which the methods are to be applied. In some cases sufficiently large numbers of compounds may meet specific criteria that additional methods to group similar compounds may be helpful. A variety of methods to assess molecular similarity, such as the Tanimoto coefficient have been used, see Willett et al, Journal of Chemical Information and Computer Science 38 (1998), 983-996. These can be used to select a smaller subset of a group of highly structurally redundant compounds. In addition, cluster analysis based on relationships between the compounds, or structural components of the compound, can also be carried out to the same end; see Lance and Williams Computer Journal 9 (1967) 373-380, Jarvis and Patrick IEEE Transactions in Computers C-22 (1973) 1025-1034 for clustering algorithms, and Downs et al. Journal of Chemical Information and Computer Sciences-34 (1994) 1094-1102 for a review of these methods applied to chemical problems. One method of deriving the chemical components of a large group of potential scaffolds is to virtually break up the compound at rotatable bonds so as to yield components of no less than 10 atoms. The resulting components may be clustered based on some measure of similarity, e.g. the Tanimoto coefficient, to yield the common component groups in the original collection of compounds. For each component group, all compounds containing that component may be clustered, and the resulting clusters used to select a diverse set of compounds containing a common chemical core structure. In this fashion, a useful library of scaffolds may be derived even from millions of commercial compounds.

[0162] A “compound library” or “library” is a collection of different compounds having different chemical structures. A compound library is screenable, that is, the compound library members therein may be subject to screening assays. In preferred embodiments, the library members can have a molecular weight of from about 100 to about 350 daltons, or from about 150 to about 350 daltons.

[0163] Libraries of the present invention can contain at least one compound that binds to the target molecule at low affinity. Libraries of candidate compounds can be assayed by many different assays, such as those described above, e.g., a fluorescence polarization assay. Libraries may consist of chemically synthesized peptides, peptidomimetics, or arrays of combinatorial chemicals that are large or small, focused or nonfocused. By “focused” it is meant that the collection of compounds is prepared using the structure of previously characterized compounds and/or pharmacophores.

[0164] Compound libraries may contain molecules isolated from natural sources, artificially synthesized molecules, or molecules synthesized, isolated, or otherwise prepared in such a manner so as to have one or more moieties variable, e.g., moieties that are independently isolated or randomly synthesized. Types of molecules in compound libraries include but are not limited to organic compounds, polypeptides and nucleic acids as those terms are used herein, and derivatives, conjugates and mixtures thereof.

[0165] Compound libraries useful for the invention may be purchased on the commercial market or prepared or obtained by any means including, but not limited to, combinatorial chemistry techniques, fermentation methods, plant and cellular extraction procedures and the like (see, e.g., Cwirla et al., Biochemistry 1990, 87, 6378-6382; Houghten et al., Nature 1991, 354, 84-86; Lam et al., Nature 1991, 354, 82-84; Brenner et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5381-5383; R. A. Houghten, Trends Genet. 1993, 9, 235-239; E. R. Felder, Chimia 1994, 48, 512-541; Gallop et al., J. Med. Chem. 1994, 37, 1233-125I; Gordon et al., J. Med. Chem. 1994, 37, 1385-1401; Carell et al., Chem. Biol. 1995, 3, 171-183; Madden et al., Perspectives in Drug Discovery and Design 2, 269-282; Lebl et al., Biopolymers 1995, 37 177-198); small molecules assembled around a shared molecular structure; collections of chemicals that have been assembled by various commercial and noncommercial groups, natural products; extracts of marine organisms, fungi, bacteria, and plants.

[0166] Preferred libraries can be prepared in a homogenous reaction mixture, and separation of unreacted reagents from members of the library is not required prior to screening. Although many combinatorial chemistry approaches are based on solid state chemistry, liquid phase combinatorial chemistry is capable of generating libraries (Sun CM., Recent advances in liquid-phase combinatorial chemistry, Combinatorial Chemistry & High Throughput Screening. 2:299-318, 1999).

[0167] Libraries of a variety of types of molecules are prepared in order to obtain members therefrom having one or more preselected attributes that can be prepared by a variety of techniques, including but not limited to parallel array synthesis (Houghton, Annu Rev Pharmacol Toxicol 2000 40:273-82, Parallel array and mixture-based synthetic combinatorial chemistry; solution-phase combinatorial chemistry (Merritt, Comb Chem High Throughput Screen 1998 1(2):57-72, Solution phase combinatorial chemistry, Coe et al., Mol Divers 1998-99;4(1):31-8, Solution-phase combinatorial chemistry, Sun, Comb Chem High Throughput Screen 1999 2(6):299-318, Recent advances in liquid-phase combinatorial chemistry); synthesis on soluble polymer (Gravert et al., Curr Opin Chem Biol 1997 1(1):107-13, Synthesis on soluble polymers: new reactions and the construction of small molecules); and the like. See, e.g., Dolle et al., J Comb Chem 1999 1(4):235-82, Comprehensive survey of cominatorial library synthesis: 1998. Freidinger R M., Nonpeptidic ligands for peptide and protein receptors, Current Opinion in Chemical Biology; and Kundu et al., Prog Drug Res 1999;53:89-156, Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries). Compounds may be clinically tagged for ease of identification (Chabala, Curr Opin Biotechnol 1995 6(6):633-9, Solid-phase combinatorial chemistry and novel tagging methods for identifying leads).

[0168] The combinatorial synthesis of carbohydrates and libraries containing oligosaccharides have been described (Schweizer et al., Curr Opin Chem Biol 1999 3(3):291-8, Combinatorial synthesis of carbohydrates). The synthesis of natural-product based compound libraries has been described (Wessjohann, Curr Opin Chem Biol 2000 4(3):303-9, Synthesis of natural-product based compound libraries).

[0169] Libraries of nucleic acids are prepared by various techniques, including byway of non-limiting example the ones described herein, for the isolation of aptamers. Libraries that include oligonucleotides and polyaminooligonucleotides (Markiewicz et al., Synthetic oligonucleotide combinatorial libraries and their applications, Farmaco. 55:174-7, 2000) displayed on streptavidin magnetic beads are known. Nucleic acid libraries are known that can be coupled to parallel sampling and be deconvoluted without complex procedures such as automated mass spectrometry (Enjalbal C. Martinez J. Aubagnac J L, Mass spectrometry in combinatorial chemistry, Mass Spectrometry Reviews. 19:139-61, 2000) and parallel tagging. (Perrin D M., Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future, Combinatorial Chemistry & High Throughput Screening 3:243-69).

[0170] Peptidomimetics are identified using combinatorial chemistry and solid phase synthesis (Kim H O. Kahn M., A merger of rational drug design and combinatorial chemistry: development and application of peptide secondary structure mimetics, Combinatorial Chemistry & High Throughput Screening 3:167-83, 2000; al-Obeidi, Mol Biotechnol 1998 9(3):205-23, Peptide and peptidomimetric libraries. Molecular diversity and drug design). The synthesis may be entirely random or based in part on a known polypeptide.

[0171] Polypeptide libraries can be prepared according to various techniques. In brief, phage display techniques can be used to produce polypeptide ligands (Gram H., Phage display in proteolysis and signal transduction, Combinatorial Chemistry & High Throughput Screening. 2:19-28, 1999) that may be used as the basis for synthesis of peptidomimetics. Polypeptides, constrained peptides, proteins, protein domains, antibodies, single chain antibody fragments, antibody fragments, and antibody combining regions are displayed on filamentous phage for selection.

[0172] Large libraries of individual variants of human single chain Fv antibodies have been produced. See, e.g., Siegel R W. Allen B. Pavlik P. Marks J D. Bradbury A., Mass spectral analysis of a protein complex using single-chain antibodies selected on a peptide target: applications to functional genomics, Journal of Molecular Biology 302:285-93, 2000; Poul M A. Becerril B. Nielsen U B. Morisson P. Marks J D., Selection of tumor-specific internalizing human antibodies from phage libraries. Source Journal of Molecular Biology. 301:1149-61, 2000; Amersdorfer P. Marks J D., Phage libraries for generation of anti-botulinum scFv antibodies, Methods in Molecular Biology. 145:219-40, 2001; Hughes-Jones N C. Bye J M. Gorick B D. Marks J D. Ouwehand W H., Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, British Journal of Haematology. 105:811-6, 1999; McCall A M. Amoroso A R. Sautes C. Marks J D. Weiner L M., Characterization of anti-mouse Fe gamma RII single-chain Fv fragments derived from human phage display libraries, Immunotechnology. 4:71-87, 1998; Sheets M D. Amersdorfer P. Finnern R. Sargent P. Lindquist E. Schier R. Hemingsen G. Wong C. Gerhart J C. Marks J D. Lindquist E., Efficient construction of a large nonimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens (published erratum appears in Proc Natl Acad Sci USA 1999 96:795), Proc Natl AcadSci USA 95:6157-62, 1998).

[0173] Focused or smart chemical and pharmacophore libraries can be designed with the help of sophisticated strategies involving computational chemistry (e.g., Kundu B. Khare S K. Rastogi S K., Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries, Progress in Drug Research 53:89-156, 1999) and the use of structure-based ligands using database searching and docking, de novo drug design and estimation of ligand binding affinities (Joseph-McCarthy D., Computational approaches to structure-based ligand design, Pharmacology & Therapeutics 84:179-91, 1999; Kirkpatrick D L. Watson S. Ulhaq S., Structure-based drug design: combinatorial chemistry and molecular modeling, Combinatorial Chemistry & High Throughput Screening. 2:211-21, 1999; Eliseev A V. Lehn J M., Dynamic combinatorial chemistry: evolutionary formation and screening of molecular libraries, Current Topics in Microbiology & Immunology 243:159-72, 1999; Bolger et al., Methods Enz. 203:21-45, 1991; Martin, Methods Enz. 203:587-613, 1991; Neidle et al., Methods Enz. 203:433-458, 1991; U.S. Pat. No. 6,178,384).

[0174] Selecting a library of potential scaffolds and a set of assays measuring binding to representative target molecules which are in a particular protein family thus allows the creation of a data set profiling binding of the library to the target protein family. Groups of scaffolds with different sets of binding properties can be identified using the information within this dataset. Thus, groups of scaffolds binding to one, two or three members of the family may be selected for particular applications.

[0175] In many cases, a group of scaffolds exhibiting binding to two or more members of a target protein family will contain scaffolds with a greater likelihood that such binding results from specific interactions with the individual target proteins. This would be expected to substantially reduce the effect of so-called “promiscuous inhibitors” which severely complicate the interpretation of screening assays (see McGovern et al Journal of Medicinal Chemistry 45:1712-22, 2002). Thus, in many preferred applications the property of displaying binding to multiple target molecules in a protein family may be used as a selection criteria to identify molecules with desirable properties. In addition, groups of scaffolds binding to specific subsets of a set of potential target molecules may be selected. Such a case would include the subset of scaffolds that bind to any two of three or three of five members of a target protein family.

[0176] Such subsets may also be used in combination or opposition to further define a group of scaffolds that have additional desirable properties. This would be of significant utility in cases where inhibiting some members of a protein family had known desirable effects, such as inhibiting tumor growth, whereas inhibiting other members of the protein family which were found to be essential for normal cell function would have undesirable effects. A criteria that would be useful in such a case includes selecting the subset of scaffolds binding to any two of three desirable target molecules and eliminating from this group any that bound to more than one of any three undesirable target molecules.

[0177] Crystallography

[0178] After binding compounds have been determined, the orientation of compound bound to target is determined. Preferably this determination involves crystallography on co-crystals of molecular scaffold compounds with target. Most protein crystallographic platforms can preferably be designed to analyze up to about 500 co-complexes of compounds, ligands, or molecular scaffolds bound to protein targets due to the physical parameters of the instruments and convenience of operation.

[0179] If the number of scaffolds that have binding activity exceeds a number convenient for the application of crystallography methods, the scaffolds can be placed into groups based on having at least one common chemical structure or other desirable characteristics, and representative compounds can be selected from one or more of the classes. Classes can be made with increasingly exacting criteria until a desired number of classes (e.g., 10, 20, 50, 100, 200, 300, 400, 500) is obtained. The classes can be based on chemical structure similarities between molecular scaffolds in the class, e.g., all possess a pyrrole ring, benzene ring, or other chemical feature. Likewise, classes can be based on shape characteristics, e.g., space-filling characteristics.

[0180] The co-crystallography analysis can be performed by co-complexing each scaffold with its target, e.g., at concentrations of the scaffold that showed activity in the screening assay. This co-complexing can, for example, be accomplished with the use of low percentage organic solvents with the target molecule and then concentrating the target with each of the scaffolds. In preferred embodiments these solvents are less than 5% organic solvent such as dimethyl sulfoxide (DMSO), ethanol, methanol, or ethylene glycol in water or another aqueous solvent.

[0181] Each scaffold complexed to the target molecule can then be screened with a suitable number of crystallization screening conditions at appropriate temperature, e.g., both 4 and 20 degrees. In preferred embodiments, about 96 crystallization screening conditions can be performed in order to obtain sufficient information about the co-complexation and crystallization conditions, and the orientation of the scaffold at the binding site of the target molecule. Crystal structures can then be analyzed to determine how the bound scaffold is oriented physically within the binding site or within one or more binding pockets of the molecular family member.

[0182] It is desirable to determine the atomic coordinates of the compounds bound to the target proteins in order to determine which is a most suitable scaffold for the protein family. X-ray crystallographic analysis is therefore most preferable for determining the atomic coordinates. Those compounds selected can be further tested with the application of medicinal chemistry. Compounds can be selected for medicinal chemistry testing based on their binding position in the target molecule. For example, when the compound binds at a binding site, the compound's binding position in the binding site of the target molecule can be considered with respect to the chemistry that can be performed on chemically tractable structures or sub-structures of the compound, and how such modifications on the compound are expected to interact with structures or sub-structures on the binding site of the target. Thus, one can explore the binding site of the target and the chemistry of the scaffold in order to make decisions on how to modify the scaffold to arrive at a ligand with higher potency and/or selectivity.

[0183] The structure of the target molecule bound to the compound may also be superimposed or aligned with other structures of members of the same protein family. In this way modifications of the scaffold can be made to enhance the binding to members of the target family in general, thus enhancing the utility of the scaffold library. Different useful alignments may be generated, using a variety of criteria such as minimal RMSD superposition of α-carbons or backbone atoms of homologous or structurally related regions of the proteins.

[0184] These processes allow for more direct design of ligands, by utilizing structural and chemical information obtained directly from the co-complex, thereby enabling one to more efficiently and quickly design lead compounds that are likely to lead to beneficial drug products. In various embodiments it may be desirable to perform co-crystallography on all scaffolds that bind, or only those that bind with a particular affinity, for example, only those that bind with high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity. It may also be advantageous to perform co-crystallography on a selection of scaffolds that bind with any combination of affinities.

[0185] Standard X-ray protein diffraction studies such as by using a Rigaku RU-200@ (Rigaku, Tokyo, Japan) with an X-ray imaging plate detector or a synchrotron beam-line can be performed on co-crystals and the diffraction data measured on a standard X-ray detector, such as a CCD detector or an X-ray imaging plate detector.

[0186] Performing X-ray crystallography on about 200 co-crystals should generally lead to about 50 co-crystal structures, which should provide about 10 scaffolds for validation in chemistry, which should finally result in about 5 selective leads for target molecules.

[0187] Additives that promote co-crystallization can of course be included in the target molecule formulation in order to enhance the formation of co-crystals. In the case of proteins or enzymes, the scaffold to be tested can be added to the protein formulation, which is preferably present at a concentration of approximately 1 mg/ml. The formulation can also contain between 0%-10% (v/v) organic solvent, e.g. DMSO, methanol, ethanol, propane diol, or 1,3 dimethyl propane diol (MPD) or some combination of those organic solvents. Compounds are preferably solubilized in the organic solvent at a concentration of about 10 mM and added to the protein sample at a concentration of about 100 mM. The protein-compound complex is then concentrated to a final concentration of protein of from about 5 to about 20 mg/ml. The complexation and concentration steps can conveniently be performed using a 96 well formatted concentration apparatus (e.g., Amicon Inc., Piscataway, N.J.). Buffers and other reagents present in the formulation being crystallized can contain other components that promote crystallization or are compatible with crystallization conditions, such as DTT, propane diol, glycerol.

[0188] The crystallization experiment can be set-up by placing small aliquots of the concentrated protein-compound complex (e.g., 1 μl) in a 96 well format and sampling under 96 crystallization conditions. (Other formats can also be used, for example, plates with fewer or more wells.) Crystals can typically be obtained using standard crystallization protocols that can involve the 96 well crystallization plate being placed at different temperatures. Co-crystallization varying factors other than temperature can also be considered for each protein-compound complex if desirable. For example, atmospheric pressure, the presence or absence of light or oxygen, a change in gravity, and many other variables can all be tested. The person of ordinary skill in the art will realize other variables that can advantageously be varied and considered. Conveniently, commercially available crystal screening plates with specified conditions in individual wells can be utilized.

[0189] Virtual Assays

[0190] Commercially available software that generates three-dimensional graphical representations of the complexed target and compound from a set of coordinates provided can be used to illustrate and study how a compound is oriented when bound to a target. (e.g., InsightII®, Accelerys, San Diego, Calif.; or Sybyl®, Tripos Associates, St. Louis, Mo.). Thus, the existence of binding pockets at the binding site of the targets can be particularly useful in the present invention. These binding pockets are revealed by the crystallographic structure determination and show the precise chemical interactions involved in binding the compound to the binding site of the target. The person of ordinary skill will realize that the illustrations can also be used to decide where chemical groups might be added, substituted, modified, or deleted from the scaffold to enhance binding or another desirable effect, by considering where unoccupied space is located in the complex and which chemical substructures might have suitable size and/or charge characteristics to fill it. The person of ordinary skill will also realize that regions within the binding site can be flexible and its properties can change as a result of scaffold binding, and that chemical groups can be specifically targeted to those regions to achieve a desired effect. Specific locations on the molecular scaffold can be considered with reference to where a suitable chemical substructure can be attached and in which conformation, and which site has the most advantageous chemistry available.

[0191] An understanding of the forces that bind the compounds to the target proteins reveals which compounds can most advantageously be used as scaffolds, and which properties can most effectively be manipulated in the design of ligands. The person of ordinary skill will realize that steric, ionic, polar, hydrogen bond, and other forces can be considered for their contribution to the maintenance or enhancement of the target-compound complex. Additional data can be obtained with automated computational methods, such as docking and/or molecular dynamics simulations, which can afford a measure of the energy of binding. In addition, to account for other effects such as entropies of binding and desolvation penalties, methods which provide a measure of these effects can be integrated into the automated computational approach. The compounds selected can be used to generate information about the chemical interactions with the target or for elucidating chemical modifications that can enhance selectivity of binding of the compound.

[0192] An exemplary calculation of binding energies between protein-ligand complexes can be obtained using the FlexX score (an implementation of the Bohm scoring function) within the Tripos software suite (Tripos Associates, St. Louis, Mo.). The form for that equation is shown below:

ΔGbind=ΔGtr+ΔGhb+ΔGion+ΔGlipo+ΔGarom+ΔGrot

[0193] where: ΔGtr is a constant term that accounts for the overall loss of rotational and translational entropy of the lignand, ΔGhb accounts for hydrogen bonds formed between the ligand and protein, ΔGion accounts for the ionic interactions between the ligand and protein, ΔGlipo accounts for the lipophilic interaction that corresponds to the protein-ligand contact surface, ΔGarom accounts for interactions between aromatic rings in the protein and ligand, and ΔGrot accounts for the entropic penalty of restricting rotatable bonds in the ligand upon binding. The calculated binding energy for compounds that bind strongly to a given target will likely be lower than −25 kcal/mol, while the calculated binding affinity for a good scaffold or an unoptimized compound will generally be in the range of −15 to −20. The penalty for restricting a linker such as the ethylene glycol or hexatriene is estimated as typically being in the range of +5 to +15.

[0194] This method estimates the free energy of binding that a lead compound should have to a target protein for which there is a crystal structure, and it accounts for the entropic penalty of flexible linkers. It can therefore be used to estimate the penalty incurred by attaching linkers to molecules being screened and the binding energy that a lead compound must attain in order to overcome the penalty of the linker. The method does not account for solvation, and the entropic penalty is likely overestimated when the linkers are bound to the solid phase through an additional binding complex, e.g., a biotin:streptavidin complex.

[0195] Another exemplary method for calculating binding energies is the MM-PBSA technique (Massova and Kollman, Journal of the American Chemical Society 121:8133-43,1999; Chong et al, Proceedings of the National Academy of Sciences 96:14330-5,1999; Donini and Kollman, Journal of Medicinal Chemistry 43:4180-8,2000). This method uses a Molecular Dynamics approach to generate many sample configurations of the compound and complexed target molecule, then calculates an interaction energy using the well-known AMBER force field (Cornell, et al Journal of the American Chemical Society 117:5179-97 1995) with corrections for desolvation and entropy of binding from the ensemble.

[0196] Use of this method yields binding energies highly correlated with those found experimentally. The absolute binding energies calculated with this method are reasonably accurate, and the variation of binding energies is approximately linear with a slope of 1+/−0.5. Thus, the binding energies of compounds interacting strongly with a given target will be lower than about −8 kcal/mol, while a binding energy of a good scaffold or unoptimized compound will be in the range of −3 to −7 kcal/mol.

[0197] Computer models, such as homology models (i.e., based on a known, experimentally derived structure) can be constructed using data from the co-crystal structures. A computer program such as Modeller (Accelrys, San Diego Calif.) may be used to assign the three dimensional coordinates to a protein sequence using an alignment of sequences and a set or sets of template coordinates. When the target molecule is a protein or enzyme, preferred co-crystal structures for making homology models contain high sequence identity in the binding site of the protein sequence being modeled, and the proteins will preferentially also be within the same class and/or fold family. Knowledge of conserved residues in active sites of a protein class can be used to select homology models that accurately represent the binding site. Homology models can also be used to map structural information from a surrogate protein where an apo or co-crystal structure exists to the target protein.

[0198] Virtual screening methods, such as docking, can also be used to predict the binding configuration and affinity of scaffolds, compounds, and/or combinatorial library members to homology models. Using this data, and carrying out “virtual experiments” using computer software can save substantial resources and allow the person of ordinary skill to make decisions about which compounds can be suitable scaffolds or ligands, without having to actually synthesize the ligand and perform co-crystallization. Decisions thus can be made about which compounds merit actual synthesis and co-crystallization. An understanding of such chemical interactions aids in the discovery and design of drugs that interact more advantageously with target proteins and/or are more selective for one protein family member over others. Thus, applying these principles, compounds with superior properties can be discovered.

[0199] Ligand Design and Preparation

[0200] The design and preparation of ligands can be performed with or without structural and/or co-crystallization data by considering the chemical structures in common between the active scaffolds of a set. In this process structure-activity hypotheses can be formed and those chemical structures found to be present in a substantial number of the scaffolds, including those that bind with low affinity, can be presumed to have some effect on the binding of the scaffold. This binding can be presumed to induce a desired biochemical effect when it occurs in a biological system (e.g., a treated mammal). New or modified scaffolds or combinatorial libraries derived from scaffolds can be tested to disprove the maximum number of binding and/or structure-activity hypotheses. The remaining hypotheses can then be used to design ligands that achieve a desired binding and biochemical effect.

[0201] But in many cases it will be preferred to have co-crystallography data for consideration of how to modify the scaffold to achieve the desired binding effect (e.g., binding at higher affinity or with higher selectivity). Using the case of proteins and enzymes, co-crystallography data shows the binding pocket of the protein with the molecular scaffold bound to the binding site, and it will be apparent that a modification can be made to a chemically tractable group on the scaffold. For example, a small volume of space at a protein binding site or pocket might be filled by modifying the scaffold to include a small chemical group that fills the volume. Filling the void volume can be expected to result in a greater binding affinity, or the loss of undesirable binding to another member of the protein family. Similarly, the co-crystallography data may show that deletion of a chemical group on the scaffold may decrease a hindrance to binding and result in greater binding affinity or specificity.

[0202] Various software packages have implemented techniques which facilitate the identification and characterization of interactions of potential binding sites from complex structure, or from an apo structure of a target molecule, i.e. one without a compound bound (e.g. SiteID, Tripos Associates, St. Louis Mo. and SiteFinder, Chemical Computing Group, Montreal Canada, GRID, Molecular Discovery Ltd., London UK). Such techniques can be used with the coordinates of a complex between the scaffold of interest and a target molecule, or these data in conjunction with data for a suitably aligned or superimposed related target molecule, in order to evaluate changes to the scaffold that would enhance binding to the desired target molecule structure or structures. Molecular Interaction Field-computing techniques, such as those implemented in the program GRID, result in energy data for particular positive and negative binding interactions of different computational chemical probes being mapped to the vertices of a matrix in the coordinate space of the target molecule. These data can then be analyzed for areas of substitution around the scaffold binding site which are predicted to have a favorable interaction for a particular target molecule. Compatible chemical substitution on the scaffold e.g. a methyl, ethyl or phenyl group in a favorable interaction region computed from a hydrophobic probe, would be expected to result in an improvement in affinity of the scaffold. Conversely, a scaffold could be made more selective for a particular target molecule by making such a substitution in a region predicted to have an unfavorable hydrophobic interaction in a second, related undesirable target molecule.

[0203] It can be desirable to take advantage of the presence of a charged chemical group located at the binding site or pocket of the protein. For example, a positively charged group can be complemented with a negatively charged group introduced on the molecular scaffold. This can be expected to increase binding affinity or binding specificity, thereby resulting in a more desirable ligand. In many cases, regions of protein binding sites or pockets are known to vary from one family member to another based on the amino acid differences in those regions. Chemical additions in such regions can result in the creation or elimination of certain interactions (e.g., hydrophobic, electrostatic, or entropic) that allow a compound to be more specific for one protein target over another or to bind with greater affinity, thereby enabling one to synthesize a compound with greater selectivity or affinity for a particular family member. Additionally, certain regions can contain amino acids that are known to be more flexible than others. This often occurs in amino acids contained in loops connecting elements of the secondary structure of the protein, such as alpha helices or beta strands. Additions of chemical moieties can also be directed to these flexible regions in order to increase the likelihood of a specific interaction occurring between the protein target of interest and the compound. Virtual screening methods can also be conducted in silico to assess the effect of chemical additions, subtractions, modifications, and/or substitutions on compounds with respect to members of a protein family or class.

[0204] The addition, subtraction, or modification of a chemical structure or sub-structure to a scaffold can be performed with any suitable chemical moiety. For example the following moieties, which are provided by way of example and are not intended to be limiting, can be utilized: hydrogen, alkyl, alkoxy, phenoxy, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenylthio, phenyl, phenylalkyl, phenylalkylthio, hydroxyalkyl-thio, alkylthiocarbbamylthio, cyclohexyl, pyridyl, piperidinyl, alkylamino, amino, nitro, mercapto, cyano, hydroxyl, a halogen atom, halomethyl, an oxygen atom (e.g., forming a ketone or N-oxide) or a sulphur atom (e.g., forming a thiol, thione, di-alkylsulfoxide or sulfone) are all examples of moieties that can be utilized.

[0205] Additional examples of structures or sub-structures that may be utilized are an aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; an amine of formula —NX2X3, where X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties; halogen or trihalomethyl; a ketone of formula —COX4, where X4 is selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties; a carboxylic acid of formula —(X5)nCOOH or ester of formula (X6)nCOOX7, where X5, X6, and X7 and are independently selected from the group consisting of alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1; an alcohol of formula (X8)nOH or an alkoxy moiety of formula —(X8)nOX9, where X8 and X9 are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester and where n is 0 or 1; an amide of formula NHCOX10, where X10 is selected from the group consisting of alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester; SO2, NX11 X12, where X11 and X12 are selected from the group consisting of hydrogen, alkyl, and homocyclic or heterocyclic ring moieties; a homocyclic or heterocyclic ring moiety optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester moieties; an aldehyde of formula —COH; a sulfone of formula —SO2X13, where X13 is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties; and a nitro of formula —NO2.

[0206] With respect to the compounds and functional groups, the following definitions apply.

[0207] “Halo” or “Halogen”—alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).

[0208] “Hydroxyl” refers to the group —OH.

[0209] “Thiol” or “mercapto” refers to the group —SH.

[0210] “Alkyl”—alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined). It is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6, yet more preferably 1-4 and most preferably 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “lower alkyl” is used herein to describe the straight chain alkyl groups described immediately above. Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like. Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0211] The term “saturated alkyl” refers to an alkyl moiety that does not contain any alkene or alkyne moieties. The alkyl moiety can be branched or non-branched.

[0212] The term “unsaturated alkyl” refers to an alkyl moiety that contains at least one alkene or alkyne moiety. The alkyl moiety can be branched or non-branched.

[0213] “Alkenyl”—alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. In the case of a cycloalkyl group, conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring. Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.

[0214] “Alkynyl”—alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. A substituted alkynyl refers to the straight chain alkynyl or branched alkenyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound.

[0215] “Alkyl alkenyl” refers to a group —R—CR′═CR′″R″″, where R is lower alkyl, or substituted lower alkyl, R′, R′″, R″″ may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0216] “Alkyl alkynyl” refers to a groups —RCCR′ where R is lower alkyl or substituted lower alkyl, R′ is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0217] “Alkoxy” denotes the group —OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

[0218] “Alkylthio” or “thioalkoxy” denotes the group —SR, —S(O)n=1-2—R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

[0219] “Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl and the like as defined herein.

[0220] “Aryloxy” denotes groups —OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0221] “Amino” or substituted amine denotes the group NRR′, where R and R′ may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted heteroaryl as defined herein, acyl or sulfonyl.

[0222] “Amido” denotes the group —C(O)NRR′, where R and R′ may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

[0223] “Carboxyl” denotes the group —C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.

[0224] “Aryl”—alone or in combination means an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g. phenyl) and heterocyclic aryl groups (e.g. pyridine), for example, phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0225] The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures, and where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings in which the ring backbone contains at least one atom which is different from carbon.

[0226] “Substituted aryl” refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

[0227] “Heterocycle” refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0228] “Heteroaryl”—alone or in combination means an aryl group which contains at least one heterocyclic ring, preferably a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and the like. A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.

[0229] “Heterocyclyl”—alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. A substituted hetercyclyl contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.

[0230] “Substituted heteroaryl” refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0231] “Aralkyl” refers to the group —R—Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0232] “Heteroalkyl” refers to the group —R-Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0233] “Heteroarylalkyl” refers to the group -R-HetAr where HetAr is an heteroaryl group and R lower alkyl or substituted lower alkyl. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0234] “Cycloalkyl” refers to a divalent cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.

[0235] “Substituted cycloalkyl” refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0236] “Cycloheteroalkyl” refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).

[0237] “Substituted cycloheteroalkyl” refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0238] “Alkyl cycloalkyl” denotes the group —R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0239] “Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkyl where R is a lower alkyl or substituted lower alkyl. Cycloheteroalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0240] The term “amine” refers to a chemical moiety of formula NR1R2 where R1 and R2 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties, where the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, and ester moieties.

[0241] The term “ketone” refers to a chemical moiety with formula —(R)nCOR′, where R and R′ are selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.

[0242] The term “carboxylic acid” refers to a chemical moiety with formula —(R)nCOOH, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties, and where n is 0 or 1.

[0243] The term “alcohol” refers to a chemical substituent of formula —ROH, where R is selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring moieties, where the ring moiety is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, and ester moieties.

[0244] The term “ester” refers to a chemical moiety with formula —(R)nCOOR′, where R and R′ are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.

[0245] The term “alkoxy” refers to a chemical substituent of formula —OR, where R is hydrogen or a saturated or unsaturated alkyl moiety.

[0246] The term “amide” refers to a chemical substituent of formula —NHCOR, where R is selected from the group consisting of hydrogen, alkyl, hydroxyl, and homocyclic or heterocyclic ring moieties, where the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro, or ester.

[0247] The term “aldehyde” refers to a chemical moiety with formula —(R)nCHO, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties and where n is 0 or 1.

[0248] The term “sulfone” refers to a chemical moiety with formula —SO2R, where R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties.

[0249] The term “phenylalkyl” means the aforementioned alkyl groups substituted by a phenyl group such as benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl and 2-benzylpropyl.

[0250] The term “hydroxy-alkyl” means the aforementioned alkyl groups substituted by a single hydroxyl group such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxybutyl and 6-hydroxyhexyl.

[0251] The terms “alkylthio, alkenylthio, alkynylthio, alkylthio, hydroxy-alkylthio and phenyl-alkylthio” as used herein mean the aforementioned alkyl, alkenyl, alkynyl, hydroxy-alkyl and phenyl-alkyl groups linked through a sulfur atom to group R.

[0252] The term “substituted” as used herein means that the group in question, e.g., alkyl group, aryl group, etc., can bear one or more substituents including but not limited to halogen, hydroxy, cyano, amino, nitro, mercapto, carboxy and other substituents known to those skilled in the art.

[0253] The terms “saturated” as used herein means an organic compound with neither double or triple bonds. The term “unsaturated” as used herein means an organic compound containing either double or triple bonds.

[0254] In various embodiments it may be desirable to modify all scaffolds that bind, or only those that bind with a particular affinity, for example, only those that bind with high affinity, moderate affinity, low affinity, very low affinity, or extremely low affinity. It may also be advantageous to perform modification on a selection of scaffolds that bind with any combination of affinities.

[0255] The person of ordinary skill in the art will realize that the principles described herein can be applied to any interactions between molecules that participate in any binding reaction. Preferably, a small molecule will be one of the binding partners. But protein-ligand, protein-protein, protein-nucleic acid interactions, protein-carbohydrate interaction, or binding between any two molecules can be enhanced or improvements designed into the reaction using the principles described herein.

[0256] Identification of Binding Characteristics of Binding Compounds

[0257] It can also be beneficial in selecting compounds for testing to first identify binding characteristics that a ligand should advantageously possess. This can be accomplished by analyzing the interactions that a plurality of different binding compounds have with a particular target, e.g., interactions with one or more conserved residues in the binding site. These interactions are identified by considering the nature of the interacting moieties. In this way, atoms or groups that can participate in hydrogen bonding, polar interactions, charge-charge interactions, and the like are identified based on known structural and electronic factors.

[0258] Identification of Energetically Allowed Sites for Attachment

[0259] In addition to the identification and development of ligands, determination of the orientation of a molecular scaffold or other binding compound in a binding site allows identification of energetically allowed sites for attachment of the binding molecule to another component. For such sites, any free energy change associated with the presence of the attached component should not destablize the binding of the compound to the target to an extent that will disrupt the binding. Preferably, the binding energy with the attachment should be at least 4 kcal/mol., more preferably at least 6, 8, 10, 12, 15, or 20 kcal/mol. Preferably, the presence of the attachment at the particular site reduces binding energy by no more than 3, 4, 5, 8, 10, 12, or 15 kcal/mol.

[0260] In many cases, suitable attachment sites will be those that are exposed to solvent when the binding compound is bound in the binding site. In some cases, attachment sites can be used that will result in small displacements of a portion of the enzyme without an excessive energetic cost. Exposed sites can be identified in various ways. For example, exposed sites can be identified using a graphic display or 3-dimensional model. In a graphic display, such as a computer display, an image of a compound bound in a binding site can be visually inspected to reveal atoms or groups on the compound that are exposed to solvent and oriented such that attachment at such atom or group would not preclude binding of the enzyme and binding compound. Energetic costs of attachment can be calculated based on changes or distortions that would be caused by the attachment as well as entropic changes.

[0261] Many different types of components can be attached. Persons with skill are familiar with the chemistries used for various attachments. Examples of components that can be attached include, without limitation: solid phase components such as beads, plates, chips, and wells; a direct or indirect label; a linker, which may be a traceless linker; among others. Such linkers can themselves be attached to other components, e.g., to solid phase media, labels, and/or binding moieties.

[0262] The binding energy of a compound and the effects on binding energy for attaching the molecule to another component can be calculated approximately by manual calculation, or by using any of a variety of available computational virtual assay techniques, such as docking or molecular dynamics simulations. A virtual library of compounds derived from the attachment of components to a particular scaffold can be assembled using a variety of software programs (such as Afferent, MDL Information Systems, San Leandro, Calif. or CombiLibMaker, Tripos Associates, St. Louis, Mo.). This virtual library can be assigned appropriate three dimensional coordinates using software programs (such as Concord, Tripos Associates, St. Louis, Mo. or Omega, Openeye Scientific Software, Santa Fe, N. Mex.). These structures may then be submitted to the appropriate computational technique for evaluation of binding energy to a particular target molecule. This information can be used for purposes of prioritizing compounds for synthesis, for selecting a subset of chemically tractable compounds for synthesis, and for providing data to correlate with the experimentally determined binding energies for the synthesized compounds.

[0263] The crystallographic determination of the orientation of the scaffold in the binding site specifically enables more productive methods of assessing the likelihood of the attachment of a particular component resulting in an improvement in binding energy. Such an example is shown for a docking-based strategy in Haque et al Journal of Medicinal Chemistry 42:1428-40, 1999, wherein an “Anchor and Grow” technique which relied on a crystallographically determined fragment of a larger molecule, potent and selective inhibitors were rapidly created. The use of a crystallographically characterized small molecule fragment in guiding the selection of productive compounds for synthesis has also been demonstrated in Boehm et al, Journal of Medicinal Chemistry 43:2664-74, 2000. An illustration of the use of crystallographic data and molecular dynamics simulations in the prospective assessment of inhibitor binding energies can be found in Pearlman and Charifson, Journal of Medicinal Chemistry 44, 3417-23, 2001. Another important class of techniques which rely on a well defined structural starting point for computational design is the combinatorial growth algorithm based systems, such as the Grow Mol program (Bohacek and McMartin, Journal of the American Chemical Society 116:5560-71, 1994. These techniques have been used to enable the rapid computational evolution of virtual inhibitor computed binding energies, and directly led to more potent synthesized compounds whose binding mode was validated crystallographically (see Organic Letters (2001) 3(15):2309-2312).

[0264] Linkers

[0265] Linkers suitable for use in the invention can be of many different types. Linkers can be selected for particular applications based on factors such as linker chemistry compatible for attachment to a binding compound and to another component utilized in the particular application. Additional factors can include, without limitation, linker length, linker stability, and ability to remove the linker at an appropriate time. Exemplary linkers include, but are not limited to, hexyl, hexatrienyl, ethylene glycol, and peptide linkers. Traceless linkers can also be used, e.g., as described in Plunkett, M. J., and Ellman, J. A., 1995, J. Org. Chem., 60:6006.

[0266] Typical functional groups, that are utilized to link binding compound(s), include, but not limited to, carboxylic acid, amine, hydroxyl, and thiol. (Examples can be found in Solid-supported combinatorial and parallel synthesis of small molecular weight compound libraries; Tetrahedron organic chemistry series Vol.17; Pergamon, 1998; p85).

[0267] Labels

[0268] As indicated above, labels can also be attached to a binding compound or to a linker attached to a binding compound. Such attachment may be direct (attached directly to the binding compound) or indirect (attached to a component that is directly or indirectly attached to the binding compound). Such labels allow detection of the compound either directly or indirectly. Attachment of labels can be performed using conventional chemistries. Labels can include, for example, fluorescent labels, radiolabels, light scattering particles, light absorbent particles, magnetic particles, enzymes, and specific binding agents (e.g., biotin or an antibody target moiety).

[0269] Solid Phase Media

[0270] Additional examples of components that can be attached directly or indirectly to a binding compound include various solid phase media. Similar to attachment of linkers and labels, attachment to solid phase media can be performed using conventional chemistries. Such solid phase media can include, for example, small components such as beads, nanoparticles, and fibers (e.g., in suspension or in a gel or chromatographic matrix). Likewise, solid phase media can include larger objects such as plates, chips, slides, and tubes. In many cases, the binding compound will be attached in only a portion of such an objects, e.g., in a spot or other local element on a generally flat surface or in a well or portion of a well.

EXAMPLES

[0271] The examples below are illustrative of the present invention, including the identification and description of scaffold groups for particular targets. However, it should be recognized that the various aspects of the invention can be carried out in a number of different ways. An example involving a particular target, the kinase PIM-1, is described in U.S. Application 60/411,398, and is incorporated herein in its entirety, including drawings. Selected information from that application is included in the examples below. Likewise, exemplary information is provided concerning another kinase target, PYK2.

Example 1

Scaffold Discovery

[0272] In an initial selection of a screening library, 6,347 compounds were obtained on the commercial market (Maybridge, Cornwall, England; Chembridge, San Diego, Calif.) and were selected for bias toward scaffold-like properties (having the properties of MW<350, clogP=3, and number of rotatable bonds less than 4) and were screened at 100 μM concentrations of each compound with a radioisotope Ser/Thr kinase enzymatic assay, using the lyn kinase assay. The assay was based on the extent of phosphorylation of the enzyme substrate with detection performed using an antibody to the phosphorylated substrate.

[0273] Of the 6,347 scaffold-like compounds screened, 10% or more resulted in a signal about twice that of sigma of the background signal. The number of compounds obtained was less than 500, so the compounds did not need to be clustered based on chemical similarity. In cases where large numbers of active compounds are found, e.g., more than 500 compounds are active, active compounds may be clustered into chemical families based on the similarity of substructures contained within those compounds. 500 compounds (or other convenient number) can be conveniently chosen as representative members for high-throughput co-crystallization and co-crystallography structure determinations. One manner of selecting the representative compounds can be using a suitable software program such as, e.g., ISIS® software (Molecular Design Labs, San Leandro, Calif.).

[0274] The 500 compounds were added at 100 μM concentrations to 5 mg of the purified protein in a 96 well format and were concentrated to a protein concentration of 5 mg/ml-15 mg/ml. Each sample was subjected to a crystallization trial under 96 different protein crystallization conditions. The compounds that crystallized with the protein were harvested as co-crystals and exposed to X-rays in an X-ray diffraction experiment in order to collect a unique set of data. Using these data one can determine the crystal structures of the compounds bound to the proteins, and create a model of the interaction between the compound and the protein target. These structures provide the basis for 1) determining which of these compounds have the most advantageous structures for exploring the unoccupied regions of the molecular space in the protein binding pocket in order to enhance binding, selectivity, or other desirable physical properties of the compounds themselves; and 2) these structures can also be utilized for making decisions and guiding the chemistry in a rational or focused method. Thus, one efficiently uses the chemical resource to synthesize compounds that are drug “lead” compounds that interact specifically with individual members of the protein family.

[0275] Software is available for performing the compound clustering based on chemical structure similarity, using a measure such as the Tanimoto coefficient. Thus, this step may be conveniently performed using, for example, ISIS® software (Molecular Design Labs, (San Leandro, Calif.). Alternatively, other commonly used types of molecular clustering can be easily used in other software packages (Unity, Tripos Associates St. Louis Mo. and MOE, Chemical Computing Group, Montreal, Quebec, Canada).

Example 2

Scaffold Discovery

[0276] 975 compounds biased toward scaffold-like properties (as described in Example 1) were screened at 100 μM concentrations of each compound with an enzymatic assay. The assay was based on the amount of ATP left in the sample as determined by a luciferase fluorescence signal. Of the 975 compounds screened, 101 compounds gave a signal of twice the background signal shown by controls and the non-biased compounds.

[0277] The 101 compounds were then added at 100 μM concentrations to 5 mg of the purified protein in a 96 well format and concentrated to a protein concentration of between mg/ml-15 mg/ml. Each sample was then subjected to a co-crystallization trial under 96 different co-crystallization conditions. The compounds that co-crystallize with the protein was harvested as co-crystals. The co-crystals were then exposed to X-rays through X-ray diffraction to collect data that enables the definitive determination of the crystal structures of the compounds bound to the proteins. These structures therefore provide the basis for 1) determining which compounds have the most advantageous chemical structures for exploring the unoccupied regions of molecular space in the binding pocket for enhancing binding, selectivity, and desirable physical properties of the compounds themselves; and 2) these structures can also be used to make decisions guiding the scaffold design in a rational or focused manner that efficiently uses the physical and chemical data to synthesize drug “lead” compounds for specifically interacting with individual members of the protein family.

Example 3

Assaying Compounds for Binding Activity With Protein(s) of Interest

[0278] The person of ordinary skill will realize assays suitable for identifying compounds that bind to the protein(s) of interest. One assay that can be used is a lyn kinase assay. His-Lyn (M16038, kinase domain) can be produced in HEK293T cells by transient expression. His-Lyn can be captured on a metal-chelate plate (96 well). The kinase reaction can be carried out in 100 μl wells with HEPES 50 mM, pH 7.2, 15 mM NaCl, 2 μM ATP, 1 ug/well bovine serum albumin, at 37 C for one hour. The compounds can be diluted with DMSO by a ratio of 1:2, with a final concentration of DMSO of 1% in all wells. A positive control (PC) can be 4 wells with ATP and DMSO, and a negative control (NC) can be 4 wells without ATP. Phospho-tyrosine is detected by PT20-HRP (Santa Cruz Biotech, Santa Cruz, Calif.) at 1:2000. Bounded PY20—HRP is measured by TMB (3,3′, 5,5′-tetramethyl benzidine) conversion. The data can be processed as % control=[(treatments−NC)/(PC−NC)]×100. IC50 of an inhibitor is estimated at the concentration where the percent of inhibition reaches 50%.

Example 4

Csk and Pyk2 Low Affinity Binding Assays

[0279] In other embodiments, compounds were assayed for activity with Csk and Pyk2. Human Csk is a non-receptor protein tyrosine kinase. One of its major functions in vivo is to specifically phosphorylate a conserved C-terminal tyrosine on the proto-oncogene Src and Src family members (including Lck, Fyn, Yes etc.) and down-regulate them by shutting off their kinase activity. In this way, Csk plays a role in cell growth and differentiation in a variety of tissues including the immune system, bone, and the nervous system.

[0280] Proline-rich tyrosine kinase 2 (Pyk2) is a non-receptor tyrosine kinase which is a homologue of focal adhesion kinase (FAK). Pyk 2 is expressed in the central nervous system and blood cells. Elevation of intracellular calcium and protein kinase C activation leads to the autophosphorylation of Pyk2 and the formation of a complex with protein tyrosine kinase Src.

[0281] Csk (and Pyk2 in a separate assay) were mixed with poly(Glu:Tyr) and coated on an ELISA plate in kinase buffer. Test compounds were added to each well at a concentration of about 200 uM. ATP was added to a final concentration of 2 uM. After 1 hour of incubation at 37 C, phospho-Tyr was detected with ELISA solution. Color development of TMB was measured at 650 nm. The Csk was the (His)6-kinase domain fusion, and the Pyk2 was the kinase domain-(His)6 fusion, both produced in BL21 E. coli. The kinase buffer was 50 mM HEPES, pH 7.2 with 100 uM of manganese. The ELISA solution was 1:1000 at 5% milk.

[0282] The person of ordinary skill in the art will realize that a variety of assays are available and suitable for use in the present invention, or that the assays described herein can be modified when desirable and in ways known to the person of ordinary skill.

Example 5

HisP Low Affinity Binding Assay

[0283] One class of ABC transporter inhibitor acts by competing for the binding of the substrate, ATP, to the nucleotide binding domain, his P. The following methods enable screens of such inhibitors at low affinity.

[0284] Cloning of the hisP Gene from Salmonella typhimurium and Expression of the Encoded Protein in Bacteria.

[0285] Common genetic engineering methods were applied to make a plasmid vector designed for over-expression of hisP in bacteria. Two oligonucleotides were synthesized suitable for priming PCR reactions to amplify the his P gene from Salmonella typhimurium, using the genomic DNA of this organism available from the American Type Culture Collection. The oligonucleotides designed for synthesizing the coding strand of the gene was designed to add a flanking NdeI site that encodes the codon for the initiating Met residue. The oligonucleotide designed for synthesizing the non-coding strand was designed to replace the termination codon with a SalI hexamer restriction site encoding the residues Glu-Val. The resulting PCR product was cleaved with NdeI and SalI restriction enzymes, and the cleaved product ligated to complementary sites of C-terminal His-tagged glutathione S-transferase (GST) expression vector under a lac-regulated promoter. The final vector encodes the full-length his P protein fused with an N-terminal GST and with a C-terminal tail of Glu-Val-His-His-His-His-His-His.

[0286] Preparation of hisP from E. coli and Metal Affinity Purification in the Presence of Phosphate Buffer for Stabilization.

[0287] In order to effectively assay compounds that inhibit the ATPase activity of his P by competing for the binding of the substrate ATP, it is required to reduce the ATP concentration to sub-saturating levels. However the stability and solubility of the his P protein requires saturating doses of ATP. We discovered that his P can also be stably prepared in the presence of phosphate-containing buffer at zero ATP concentrations, as it is the phosphate moieties that appear to be the stabilizing feature of the ATP molecule.

[0288] One liter of bacterial strain BL21 (Novagen Inc.) harboring the GST-hisP-hexa His expression plasmid is grown at 22° C. in 2YT broth with 100 μg/ml Ampicillin antibiotic. At an OD600 of 0.6, the inducer isopropyl-thiogalactopyranoside is added to a concentration of 0.1 mM, and the culture is continued for another 3-6 hours. The cells are harvested by centrifugation and the pellets flash-frozen in liquid N2 and stored at −80 C.

[0289] The frozen pellets from 1 liter culture are thawed and suspended in 20 ml extraction buffer 1 (100 mM NaPO4, pH8, 150 mM NaCl, 0.05% Tween 20, 10% glycerol, 0.5% monothioglycerol (MTG), and 0.1 mM phenylmethysulfonyl fluoride (PMSF)). To this is added 1 ml 10 mg/ml lysozyme, with incubation on ice for 15 min. The suspension is sonicated until the chromosomal DNA is sufficiently fragmented to create a non-viscous solution, approximately 1 minute. The solution is transferred to a polycarbonate centrifuge tube and centrifuged for 60 min at 20,000 rpm in a Sorvall SA20 rotor. The supematent is recovered into a separate tube.

[0290] 2 ml buffer 1-washed slurry of Talon metal affinity resin (Clontech, Palo Alto, Calif.) is mixed with the E. coli supernatent with 2 mM imidazole added, and incubated at 4 C for 1 hour with constant mixing on a nutator. The resin is batch-washed by serially centrifuging the resin and resuspending, first in 10 ml extraction buffer 1+2 mM imidazole, secondly with 10 ml buffer 2 (100 mM NaPO4, 100 mM NaCl, 20% glycerol, 0.5% MTG, 0.1 mM PMSF, and 2 mM imidazole), and thirdly with 5 ml buffer 3 (100 mM KPO4, 20% glycerol, 0.5% MTG, 0.1 mM PMSF, and 2 mM imidazole). The centrifuged beads are then batch-eluted with 4 ml of buffer 4 (100 mM KPO4, 20% glycerol, 0.5% MTG, 0.1 mM PMSF, and 100 mM imidazole). To the 4 ml of eluate is added EDTA to a final concentration of 0.1 mM, and DTT to a final concentration of 0.1 mM. The solution is concentrated in a centriprep filter concentrator (Centricon) to a concentration of 15 mg/ml, and this is flash-frozen in liquid N2 and stored at −80 C. The Talon™ metal affinity resin is a durable immobilized metal affinity chromatography (IMAC) resin that uses cobalt ions for purifying recombinant polyhistidine-tagged proteins. The matrix is made of Sepharoseg 6B-CL with 6% cross-linked agarose, with a bead size of 45-165 μm and a maximum linear flow rate of 75-150 cm/h.

[0291] Assay of the ATPase Activity of hisP In Vitro Using Firefly Luciferase to Monitor the Amount of ATP Degraded, and Showing the Effects of Compounds That Inhibit the ATPase

[0292] The most commonly used system to assay ATPase activity monitors the production of inorganic phosphate. However, this is not possible when phosphate buffers are used to stabilize the enzyme. Instead one may employ the highly-sensitive enzyme, firefly luciferase, to assay the amount of ATP remaining after the incubation of the his P ATPase. This method is quite suitable for the screening of potential inhibitor compounds because of three properties: 1) the luciferase has an extremely wide dynamic range with low background, yielding a signal over background in this step of up to 1,000,000-fold), 2) the luciferase assay is very simply set up and read in a luminometer, thus making it suitable for high-throughput screening, and 3) inhibitory compounds give rise to an increased signal, thus decreasing the possibilities of false-positives from non-specific interference effects.

[0293] The compounds of interest are dissolved in DMSO at 100× strength, and 1 ul each transferred to a single well of a 96-well microtiter plate. As a control, DMSO lacking any compound is dispensed into separate wells of the plate. To these are added 50 μl of a mixture containing 60 mM MOPS buffer pH 7.0, 4% glycerol, 2 mM MgCl2, 200 μM ATP. Then 50 μl of a mixture containing 60 mM MOPS pH 7.0, 4% glycerol, 600 μg/ml GST-his P-hexaHis is added, and the mixture shaken for 1 min. and incubated 1.5 hours at 37 C. Following the incubation, 4 μl of the reaction mix is transferred to 100 μl in another 96-well plate of Luciferase ATP assay mix (Roche), diluted 1:10 from the manufacturers protocol in 40 mM Tris buffer pH 7.8. The plates are then read using a luminometer Wallac 1420 multilabel counter.

[0294] Quantification of the Relative Capacities of Compounds to Occupy the ATP Binding Site of hisP by Measurement of Their Abilities to Block the Binding of a Fluorescent Analog of ATP in a Fluorescence Polarization Assay

[0295] The fluorescent derivative of ATP (Fluorescein-N6-ATP, catalog NEL-502, NEN Life Sciences, Boston, Mass.) binds to his P to give a polarized fluorescence signal. This signal is diminished in a concentration-dependent manner by compounds that bind to hisP at the ATP-binding site. This observation can be utilized to quantify the relative binding affinities of compounds of potential interest as competitive inhibitors of his P.

[0296] The compounds of interest are dissolved in DMSO and serially diluted in DMSO to obtain solutions that differ in each compounds concentration. 1 μl of each dilution is transferred to separate wells of a 96-well microtiter plate. To each is added 100 μl of a reaction mixture containing 60 mM MOPS buffer pH 7.0, 4% glycerol, 0.1 mM EDTA, 1 mM MgCl2, 2.5 nM Fluorescein-N6-ATP, and 15 ug/ml GST-his P-hexaHis, and the signal read in a multilabel counter.

Example 7

Cloning of PIM-1

[0297] An exemplary application of the present invention involved the kinase PIM-1 as target. The PIM-1 DNA encoding amino acids 1-313 and 29-313 was amplified from human brain cDNA (Clonetech) by PCR protocols and cloned into a modified pET 29 vector (Novagen) between NdeI and SalI restriction enzyme sites. The amino acid sequences of the cloned DNA were confirmed by DNA sequencing and the expressed proteins contain a hexa-histidine sequence at the C terminus. The protein was expressed in E. coli BL21(DE3)pLysS (Novagen). The bacteria were grown at 22° C. in Terrific broth to 1-1.2 OD600 and protein was induced by 1 mM IPTG for 16-18 h. The bacterial pellet was collected by centrifugation and stored at −70° C. until used for protein purification. PIM-2 and PIM-3 are cloned similarly.

Example 8

Purification of PIM-1

[0298] The bacterial pellet of approximately 250-300 g (usually from 16 L) expressing PIM-1 kinase domain (29-313) was suspended in 0.6 L of Lysis buffer (0.1 M potassium phosphate buffer, pH 8.0, 10% glycerol, 1 mM PMSF) and the cells were lysed in a French Pressure cell at 20,000 psi. The cell extract was clarified at 17,000 rpm in a Sorval SA 600 rotor for 1 h. The supernatant was re-centrifuged at 17000 rpm for another extra hour. The clear supernatant was added with imidazole (pH 8.0) to 5 mM and 2 ml of cobalt beads (50% slurry) to each 40 ml cell extract. The beads were mixed at 4° C. for 3-4 h on a nutator. The cobalt beads were recovered by centrifugation at 4000 rpm for 5 min. The pelleted beads were washed several times with lysis buffer and the beads were packed on a Biorad disposable column. The bound protein was eluted with 3-4 column volumes of 0.1 M imidazole followed by 0.25 M imidazole prepared in lysis buffer. The eluted protein was analyzed by SDS gel electrophoresis for purity and yield.

[0299] The eluted protein from cobalt beads was concentrated by Centriprep-10 (Amicon) and separated on Pharmacia Superdex 200 column (16/60) in low salt buffer (25 mM Tris-HCl, pH 8.0, 150 mM NaCl, 14 mM beta mercaptoethanol). The peak fractions containing PIM-1 kinase was further purified on a Pharmacia Source Q column (10/10) in 20 mM Tris-HCl pH 7.5 and 14 mM beta mercaptoethanol using a NaCl gradient in an AKTA-FPLC (Pharmacia). The PIM-1 kinase eluted approximately at 0.2 M NaCl gradient. The peak fractions were analyzed by SDS gel electrophoresis and were pooled and concentrated by Centriprep 10. The concentrated PIM-1 protein (usually 50-60 A280/ml) was aliquoted into many tubes (60 ul), flash frozen in liquid nitrogen and stored at −70° C. until used for crystallization. The frozen PIM-1 kinase still retained kinase activity as concluded from activity assays. PIM-2 and PIM-3 can be purified in the same way with small adjustments to conditions, e.g., elution conditions.

Example 9

Crystallization of PIM-1

[0300] PIM-1 Protein Crystal Growth:

[0301] All materials were purchased through Hampton Research, Inc. (Laguna Niguel, Calif.) unless otherwise noted. PIM-1 protein @ 7 and 14 mg/ml was screened against Hampton Crystal Screen 1 and 2 kits (HS 1 and HS2) and yielded successful crystals growing in at least 10 conditions from HS 1 alone. Crystals were grown initially using sitting drops against the Hampton screening conditions set in Greiner 96 well CrystalQuick crystallization plates with 100 ul reservoir and 1 ul protein+1 ul reservoir added per platform (1 of 3 available). Conditions from Hampton Screen 1 yielded obvious protein crystals in conditions: #2,7,14,17,23,25,29,36,44, and 49. These crystals were grown at 4° C., and grew in size to varying dimensions, all hexagonal rod shaped and hardy.

[0302] Crystals of larger dimensions, 100 uM wide×400 uM long, were then grown in larger drop volumes and in larger dimension plates. Refined grids were performed with both hanging and sitting drop methods in VDX plates (cat. # HR3-140) or CrysChem plates (cat. # HR3-160). There appeared to be no obvious difference of crystal size or quality between the two methods, but there was a preference to use hanging drops to facilitate mounting procedures.

[0303] We proceeded with refining conditions by gridding 4 independent reservoir conditions initially obtained from the screening kits.

[0304] 1) HS1 ft 17 was optimized to 0.2 M LiCl, 0.1 M Tris pH 8.5 and 5%-15% Polyethylene glycol 4000;

[0305] 2) HS1 # 25 was optimized to 0.4 M-0.9 M Sodium Acetate trihydrate pH 6.5 and 0.1 M Imidazole;

[0306] 3) HS1 # 29 was optimized to 0.2M-0.7 M Sodium Potassium tartrate and 0.1 M MES buffer pH 6.5;

[0307] 4) HS1 # 44 was optimized to 0.25 M Magnesium formate.

[0308] These optimized conditions produced crystals with the most consistent size and quality of appearance. Conditions were further evaluated by x-ray diffraction analysis of the resulting protein crystals, and keeping in mind the utility for forming compound co-crystals in these conditions as well (ie. salt composition and concentration effects are important to develop suitable compound solubility in the crystallization experiments). Native crystals grew as rods in many drops to large dimensions of approximately 100 um wide and 500 um long.

[0309] Seleno Methionine labeled PIM-] protein crystal growth.

[0310] Se-Met labeled PIM-1 protein was expressed and purified as described by Hendrickson, W. A., and Ogata, C. M. (1997) “Phase determination from multiwavelength anomalous diffraction measurements, Methods Enzymol., 276, 494-523, and Hendrickson, W. A., Horton, J. R., and LeMaster, D. M. (1990) “Selenomethionyl proteins produced for analysis by multiwavelength anomalous diffraction (MAD): a vehicle for direct determination of three-dimentional structure, EMBO J., 9, 1665-1672. This preparation appeared to be less soluble as evidenced by more pronounced nucleation within the screen drops and due to the hydrophobic nature of Se labeled proteins. Crystals grew small and in showers compared to the previously evaluated similar drop conditions that the native protein grew well in. Upon finer gridding, 20 μm wide×100 μm long crystals were obtained in condition HS1 # 17 optimized at 0.2 M LiCl, 0.1 M Tris pH 8.5 and 5%-15% PEG 4000. These crystals and all others were carefully mounted in 50-100 uM nylon loops on copper stem magnetic bases that were flash frozen in liquid nitrogen in appropriate cryogenic buffer and taken to the Lawerence Berkeley Lab synchrotron, the Advanced Light Source (ALS) beamline 8.3.1.

[0311] PIM-1 Protein/Molecular Scaffolds Co-Crystal Growth:

[0312] In order to add compounds to PIM-1 protein, compounds were added directly from their DMSO stocks (20-200 mM) into the protein solution at high concentration. The procedure involved adding the DMSO stocks containing compound as a thin layer to the wall of the 1.5 ml eppendorf tube that contains the protein. The solution was then gently rolled over the wall of the tube until the compound was in the protein solution. The final concentration of compounds in the PIM-1 solution usually achieved was between 0.5 and 1 mM with DMSO concentrations less than 2% being added. The solutions were then set-up in trays immediately as previously described.

[0313] PIM-1/Compound Co-Crystal Screening in HS1:

[0314] Two conditions for crystal growth have resulted in the best results with PIM-1 protein and added compounds. The optimized Na—K tartrate and Na-acetate tetrahydrate solutions listed above. Crystals varied greatly in size but data has been collected on various crystals that are between 20 uM and 100 uM in width. These crystals were typically several hundred microns long and some required manipulation as well as being broken to facilitate mounting procedures into loops.

Example 10

Diffraction Analysis of PIM-1

[0315] Crystals were first determined to diffract on a Rigaku RU-200 rotating copper anode x-ray source equipped with Yale focusing optics and an R-AXIS 2C imaging plate system. A crystal grown in the optimized condition HS1 # 17 (DY plate Dec. 14, 2001) was used to conduct initial diffraction experiments.

[0316] After x-ray diffraction was initially determined as described above, large native protein crystals grown in Mg-Formate (DY plate) and were frozen in cryoprotectant by submersion in liquid nitrogen and then tested for diffraction at ALS beamline 8.3.1. Data was originally collected, indexed and reduced using Mosflm. The spacegroup was determined to be P65.

[0317] We have collected 3 native data sets, the highest resolution obtained with good statistics after merging is to 2.0 angstroms.

[0318] We have collected a MAD data set on the Se-Met labeled PIM-1 crystal using the experimentally determined 12668 eV peak and 11000 eV remote for selenium to 3.2 angstroms. Subsequently a 2.6 angstrom Se peak data set was collected at the experimentally determined peak of 12668 eV radiation.

[0319] We have collected more than 50 PIM-1/binding compound co-crystal data sets. All data was indexed and reduced as indicated in the computational crystallographic work that follows.

[0320] PIM-1 Structure Determination and Refinement

[0321] Data Set: Native, Resolution: 2.13

[0322] The primary structure determination was carried out using Molecular Replacement method with programs

[0323] EPMR (Public domain)

[0324] AmoRe (from CCP4))

[0325] And a homology model of PIM-1 based on the protein Phosphorylase Kinase (PDB ID: 1PHK—Owen et al., 1995, Structure 3:467)

[0326] The molecular replacement was carried out in all of the P6 space groups (P61, P62, . . . P65). The best solution was obtained in P65.

[0327] The molecular replacement solution was improved by several rounds of the cycles of

[0328] Model Building in O (from DatOno AB)

[0329] Annealing in CNX (from Accelerys)

[0330] SigmaA weighting and Solvent Flattening the resultant map with DM (from CCP4)

[0331] The statistics at the end of these cycles were R ˜36%.

[0332] Data set: SeMet (2 wavelengths), Resolution: 3.3

[0333] The MAD phased data (with SOLVE (from Los Alamos National Laboratory)) helped improve the model in the refinement with REFMAC (from CCP4).

[0334] Data set: SeMet (1 wavelength), Resolution: 2.6

[0335] Further improvement of the model was obtained using SAD Phasing with SOLVE and subsequent improvement with RESOLVE produced an excellent map into which the PIM1 model could be rebuilt completely.

[0336] The newly built model refined with CNX/Anneal and then with CCP4/Refmac=to give R=27.7% and Rfree=31.9%

[0337] Data set: Native, Resolution: 2.1

[0338] The above model has been further refined against the native data with CCP4/Refmac, giving R=22.1%, Rfree=24.2%.

[0339] Atomic coordinates for the native PIM-1 apo protein crystal are provided in Table 1.

Example 11

PIM-1 Co-Crystal Structures

[0340] Exemplary co-crystal structures have been determined for numerous compounds with PIM-1, using methods as generally described above. Those co-crystals include the following (the number indicates the compound id and the compound source is provided in parentheses):

[0341] PIM1—5104579 (Chembridge)

[0342] PIM1—5317991 (Chembridge)

[0343] PIM1—5348396 (Chembridge)

[0344] PIM1—5377348 (Chembridge)

[0345] PIM1_NRB02258 (Maybridge)

[0346] PIM1_NRB05093 (Maybridge)

[0347] PIM1_RJF00907 (Maybridge)

[0348] Also, PIM-2 was co-crystallized with AMPPNP. Atomic coordinates for the co-crystal are provided in Table 2.

Example 12

PIM Binding Assays

[0349] Such binding assays can be performed in a variety of ways, including a variety of ways known in the art. For example, competitive binding to PIM-1 can be measured on Nickel-FlashPlates, using His-tagged PIM-1 (˜100 ng) and ATPy[35S] (˜10 nCi). As compound is added, the signal decreases, since less ATPy[35S] is bound to PIM1 which is proximal to the scintillant in the FlashPlate. The binding assay can be performed by the addition of compound (10 μl; 20 mM) to PIM-1 protein (90 10 μl) followed by the addition of ATPγ[35S] and incubating for 1 hr at 37° C. The radioactivity is measured through scintillation counting in Trilus (Perkin-Elmer).

[0350] Alternatively, any method which can measure binding of a ligand to the ATP-binding site can be used. For example, a fluorescent ligand can be used. When bound to PIM1, the emitted fluorescence is polarized. Once displaced by inhibitor binding, the polarization decreases.

[0351] Determination of IC50 for compounds by competitive binding assays. (Note that K1 is the dissociation constant for inhibitor binding; KD is the dissociation constant for substrate binding.) For this system, the IC50, inhibitor binding constant and substrate binding constant can be interrelated according to the following formula:

[0352] When using radiolabeled substrate

K_{I} = \frac{IC50}{1 + [L^{*}] / K_{D}},

[0353] the IC50˜K1 when there is a small amount of labeled substrate.

Example 13

PIM Activity Assays and Ligand Development

[0354] Inhibitory or exhitory activity of compounds binding to PIM-1 was determined using a kinase assay. A number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group or kinases. In addition to the assays mentioned below, one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application.

[0355] An assay for kinase activity that can be used for PIM kinases, e.g., PIM-1, can be performed according to the following procedure using purified kinase using myelin basic protein (MBP) as substrate. An exemplary assay can use the following materials: MBP (M-1891, Sigma); Kinase buffer (KB=HEPES 50 mM, pH7.2, MgCl2:MnCl2 (200 μM); ATP (γ-33P):NEG602H (10 mCi/mL)(Perkin-Elmer); ATP as 100 mM stock in kinase buffer; EDTA as 100 mM stock solution.

[0356] Coat scintillation plate suitable for radioactivity counting (e.g., FlashPlate from Perkin-Elmer, such as the SMP200(basic)) with kinase+MBP mix (final 100 ng+300 ng/well) at 90-μL/well in kinase buffer. Add compounds at 1 μL/well from 10 mM stock in DMSO. Positive control wells are added with 1 μL of DMSO. Negative control wells are added with 2 μL of EDTA stock solution. ATP solution (10 μL) is added to each well to provide a final concentration of cold ATP is 2 μM, and 50 nCi ATPγ[33P]. The plate is shaken briefly, and a count is taken to initiate count (IC) using an apparatus adapted for counting with the plate selected, e.g., Perkin-Elmer Trilux. Store the plate at 37° C. for 4 hrs, then count again to provide final count (FC).

[0357] Net 33P incorporation (NI) is calculated as: NI=FC−IC.

[0358] The effect of the present of a test compound can then be calculated as the percent of the positive control as: % PC=[(NI−NC)/(PC−NC)]×100, where NC is the net incorporation for the negative control, and PC is the net incorporation for the positive control.

[0359] As indicated above, other assays can also be readily used. For example, kinase activity can be measured on standard polystyrene plates, using biotinylated MBP and ATPγ[33P] and with Streptavidin-coated SPA (scintillation proximity) beads providing the signal.

[0360] Additional alternative assays can employ phospho-specific antibodies as detection reagents with biotinylated peptides as substrates for the kinase. This sort of assay can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified luminescentproximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.

[0361] Exemplary compounds within Formula I, Formula II, and Formula III as described below were assayed for inhibitory activity with PIM-1. The ability to develop ligands is illustrated by 2 compounds from the quinolinone molecular scaffold group (Formula III). A compound with R1, R2, R3, R4, R5, and R6=H, had 100% inhibition of PIM-1 at 200 μM concentration, while a compound with R1 =phenyl group, R2, R3, R5, and R7=H, and R4=OCF3, had only 3% inhibition of PIM-1 at 200 μM.

[0362] Another example of the ability to discover ligands is illustrated by two compounds from the 7-azaindole group (Formula II) and the co-crystal structures of these compounds with PIM-1. One compound (Formula III, R1=R2=R3=R4=R5=H) was found to be weakly active when assayed for inhibitory activity against PIM-1 (IC50>200 μM, 8% inhibition at 200 μM). Co-crystallography of this compound with PIM-1, results shown below left, revealed a binding mode for the scaffold placing it next to a hydrophobic contact surface, a feature which is present in this region in many kinases. The identification of an energetically allowed site of substitution for this scaffold could be determined using the DRY probe from the GRID program (Molecular Discovery Ltd. London UK) which indicated that two positions in Formula II (R2 and R3) allowed for substitution in energetically favorable regions consistent with interaction at this site. Addition of an analino subsitutent (R2=NH-Phenyl) resulted in a compound which was determined by co-crystallography to bind to PIM-1 in the expected fashion. This also resulted in an improvement in inhibitory activity against PIM-1 to 169 μM. This activity trend was also observed for the compounds in Pyk-2, where the inhibitory activity of the two compounds improved from an IC50>200 μM in the former to an IC50=21 μM in the latter.

Example 14

PIM-1 Scaffolds and Binding Compounds

[0363] A number of different molecular scaffolds that bind to PIM-1 have been identified based on demonstrated activity of simple compounds, validated with co-crystallography. Derivative PIM-1 binding compounds have been prepared, providing corresponding scaffold groups. Three such scaffolds and derivative compounds are described below.

[0364] One scaffold group is represented by compounds of Formula I. Compounds of this group have been validated by co-crystallography with PIM-1. The simplest scaffold has H at each of the R positions.

[0365] where:

[0366] R1 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R20, —C(X)NR16R17, or —S(O2)R

[0367] R2 is hydrogen, trifluormethyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R20, C(X)NR16R17, or —S(O2)R21;

[0368] R3 and R4 are independently hydrogen, hydroxy, fluorine, chlorine, trifluoromethyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R20, or —S(O2)R21;

[0369] R5 is hydrogen, hydroxyl, fluorine, chlorine, trifluoromethyl, optionally substituted lower alkoxy, optionally substituted lower thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, —NR16C(X)NR16R17, —C(X)R20, or —S(O2)R21;

[0370] R6 is hydrogen, hydroxyl, fluorine, chlorine, optionally substituted lower alkoxy, optionally substituted lower thioalkoxy, or optionally substituted amine;

[0371] R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;

[0372] R20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0373] R21 is optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0374] X=O, or S.

[0375] A second scaffold group with members validated in co-crystals with PIM-1 is provided by compounds of Formula II:

[0376] where:

[0377] R1 is hydrogen, hydroxy, fluorine, chlorine, trifluoromethyl, optionally substituted alkoxyl, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —NR16C(X)NR R17, —C(X)R20, or —S(O2)R21;

[0378] R2 is hydrogen, fluorine, chlorine, trifluoromethyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —NR16C(X)NR16R17, —C(X)R20, or —S(O2)R21;

[0379] R3 and R4 are independently hydrogen, hydroxy, fluorine, chlorine, trifluoromethyl, optionally substituted alkoxyl, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —NR16C(X)NR16R17, —C(X)R20, or —S(O2)R721;

[0380] R5 is hydrogen, fluorine, chlorine, trifluoromethyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, or —NR16C(X)NR16R17;

[0381] R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;

[0382] R20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0383] R21 is optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0384] X=O or S.

[0385] A third scaffold group with members validated with PIM-1 is provided by compounds of formula III.

[0386] where:

[0387] Z=O, S, NR18, or CR18R9;

[0388] R1 is hydrogen, hydroxyl, halogen, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —NR16R17S(O2)R21 or —C(X)R20;

[0389] R2 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R20, or —S(O2)R21;

[0390] R3 is hydrogen, hydroxyl, fluorine, chlorine, optionally substituted alkoxyl, optionally substituted amine, NR16C(X)NR16R17, —C(X)R20, or —S(O2)R21;

[0391] R4 is hydrogen, fluorine, chlorine, trifluoromethyl, optionally substituted lower alkoxy, optionally substituted amine, or optionally substituted lower alkyl;

[0392] R5 and R6 are independently hydrogen, hydroxyl, fluorine, chlorine, trifluoromethyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R20, or —S(O2)R21;

[0393] R7 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or —C(X)R8;

[0394] R8 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0395] R9 is optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0396] R16 and R17 are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;

[0397] R18 is hydrogen, optionally substituted alkyl, optionally substituted lower alkenyl, optionally substituted lower alkylnyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, C(X)R20, C(X)NR16R17, or —S(O2)R21;

[0398] R19 is hydrogen, optionally substituted alkyl, optionally substituted lower alkenyl, optionally substituted lower alkylnyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, C(X)R20, C(X)NR16R17, or —S(O2)R21;

[0399] R20 is hydroxyl, optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0400] R21 is optionally substituted lower alkoxy, optionally substituted amine, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;

[0401] X=O or S.

[0402] “Halo” or “Halogen”—alone or in combination means all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).

[0403] “Hydroxyl” refers to the group —OH.

[0404] “Thiol” or “mercapto” refers to the group —SH.

[0405] “Alkyl”—alone or in combination means an alkane-derived radical containing from 1 to 20, preferably 1 to 15, carbon atoms (unless specifically defined). It is a straight chain alkyl, branched alkyl or cycloalkyl. Preferably, straight or branched alkyl groups containing from 1-15, more preferably 1 to 8, even more preferably 1-6, yet more preferably 1-4 and most preferably 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “lower alkyl” is used herein to describe the straight chain alkyl groups described immediately above. Preferably, cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like. Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl, or cycloalkyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0406] “Alkenyl”—alone or in combination means a straight, branched, or cyclic hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. In the case of a cycloalkyl group, conjugation of more than one carbon to carbon double bond is not such as to confer aromaticity to the ring. Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is the straight chain alkenyl, branched alkenyl or cycloalkenyl group defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or the like attached at any available point to produce a stable compound.

[0407] “Alkynyl”—alone or in combination means a straight or branched hydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. A substituted alkynyl refers to the straight chain alkynyl or branched alkenyl defined previously, independently substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like attached at any available point to produce a stable compound.

[0408] “Alkyl alkenyl” refers to a group —R—CR′═CR′″R″″, where R is lower alkyl, or substituted lower alkyl, R′, R′″, R”” may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0409] “Alkyl alkynyl” refers to a groups —RCCR′ where R is lower alkyl or substituted lower alkyl, R′ is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0410] “Alkoxy” denotes the group —OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

[0411] “Alkylthio” or “thioalkoxy” denotes the group —SR, —S(O)n=1-2—R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

[0412] “Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl and the like as defined herein.

[0413] “Aryloxy” denotes groups —OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0414] “Amino” or substituted amine denotes the group NRR′, where R and R′ may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted heteroaryl as defined herein, acyl or sulfonyl.

[0415] “Amido” denotes the group —C(O)NRR′, where R and R′ may independently by hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

[0416] “Carboxyl” denotes the group —C(O)OR, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, and substituted hetaryl as defined herein.

[0417] “Aryl”—alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like.

[0418] “Substituted aryl” refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

[0419] “Heterocycle” refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0420] “Heteroaryl”—alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or di-substituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or the like. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and the like. A substituted heteroaryl contains a substituent attached at an available carbon or nitrogen to produce a stable compound.

[0421] “Heterocyclyl”—alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl. Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. A substituted hetercyclyl contains a substituent nitrogen attached at an available carbon or nitrogen to produce a stable compound.

[0422] “Substituted heteroaryl” refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0423] “Aralkyl” refers to the group —R—Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0424] “Heteroalkyl” refers to the group —R-Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0425] “Heteroarylalkyl” refers to the group —R-HetAr where HetAr is an heteroaryl group and R lower alkyl or substituted lower alkyl. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0426] “Cycloalkyl” refers to a divalent cyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.

[0427] “Substituted cycloalkyl” refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0428] “Cycloheteroalkyl” refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).

[0429] “Substituted cycloheteroalkyl” refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0430] “Alkyl cycloalkyl” denotes the group —R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0431] “Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkyl where R is a lower alkyl or substituted lower alkyl. Cycloheteroalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

Example 15

Synthesis of the Compounds of Formula I

[0432]

[0433] The 2-aminobenzimidazole derivatives, represented by formula I, can be prepared as shown in Scheme-1.

[0434] Step-1 Preparation of Formula (3)

[0435] The compound of formula (3) is prepared conventionally by reaction of a compound of formula (1), where X═F or Cl (e.g. 2-fluoronitrobenzene), with an amine of formula (2), in an inert solvent (e.g. DMF), in the presence of a base (e.g. K2CO3), typically heated near 80° C. for 12-36 hours.

[0436] Step-2 Preparation of Formula (4)

[0437] The compound of formula (4) is prepared conventionally by reaction of a compound of formula (3) with a reducing agent (e.g. ammonium formate, HCO2NH4), in the presence of a catalyst (e.g. Pd/C), in a suitable solvent (e.g. methanol) at room temperature for several hours. When the reaction is substantially complete, the product of formula (4) is isolated by conventional means; for example, filtration through Celite.

[0438] Step-3 Preparation of Formula I

[0439] The compound of formula (4) and an isothiocyanate of formula (5) are reacted in the presence of a carbodiimide (e.g. carbonyldiimidazole), in an inert solvent (e.g. DMF). When the reaction is substantially complete, the product of formula I is isolated by conventional means (e.g. reverse phase HPLC). Smith, et. al., (1999) J. Comb. Chem., 1, 368-370; and references therein.

Example 16

Synthesis of Compounds of Formula II

[0440]

[0441] The 7-azaindole derivatives, represented by formula II, can be prepared as shown in Scheme-2.

[0442] Step-1 Preparation of Formula (8)

[0443] A compound of formula (6) (e.g. 2-tert-butoxycarbonylamino-3-methylpyridine) is reacted with a strong organic base (e.g. n-butyllithium) in an inert solvent (e.g. THF) while cooling. A compound of formula (7) (where X═F, Cl, Br, I, e.g. benzyl bromide), is then added and allowed to react for 30 minutes, at which time the reaction is warmed and quenched with water. The product of formula (8) is isolated by conventional means; for example, aqueous workup, extraction of the product into organic solvent, removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel.

[0444] Step-2 Preparation of Formula (10)

[0445] A compound of formula (8) is reacted with a strong organic base (e.g. n-butyllithium) in an inert solvent (e.g. THF) while cooling. Addition of a compound of formula (9), where Y=CH3 (e.g. DMF) or Y=OCH3, (i.e. a Weinreb amide, e.g. N-methoxy-N-methylbenzamide), and reaction for approximately an hour at 0° C. results in intermediate of formula (10), which is isolated by conventional means (e.g. aqueous workup) or the reaction mixture is treated as described for Step-3 to directly provide a compound of formula II.

[0446] Step-3 Preparation of Formula II

[0447] A compound of formula (10) is treated with acid (e.g. 5.5 M HCl) and heated near 45° C. for approximately 1 hour, or the reaction mixture of Step 2 is directly quenched with acid (e.g. 5.5 M HCl) and heated near 40° C. for approximately 2 hours. The product of formula II is isolated by conventional means (e.g. reverse phase HPLC, Kugelrohr distillation, or formation of the tartaric acid salt, followed by filtration and neutralization.) Hands, et. al., (1996) Synthesis, 7, 877; Merour and Joseph, (2001) Curr. Org. Chem. 5, 471-506.

Example 17

Synthesis of the Compound of Formula III where Z=O

[0448]

[0449] The quinolinone derivatives, represented by Formula III, where Z=0, can be prepared as shown in Scheme-3.

[0450] Step-1 Preparation of Formula (13):

[0451] The compound of formula (13) can be prepared conventionally by the reaction of a compound (11), for example ethyl 2-aminobenzoate, with an acid chloride of formula (12) in an inert solvent, for example dichloromethane, in presence of a tertiary organic base, for example triethylamine, at room temperature for about 2-24 hours, preferably overnight. When the reaction is substantially complete, the product of formula (13) can be isolated by conventional means, for example aqueous workup, extraction of the product in an organic solvent, removal of the solvent under reduced pressure followed by chromatography of the residue on silica gel.

[0452] Step-2 Preparation of Formula (14):

[0453] The compound of formula (14) can be prepared from compound of formula (13), by Diekmann cyclization, by stirring with a tertiary organic base or an alkali metal alkoxide, for example potassium t-butoxide, in an inert solvent, for example tetrahydrofuran, at 0° C. to room temperature, preferably room temperature, for about 2-24 hours, preferably 2 hours. When the reaction is substantially complete, product of formula (14) can be isolated by conventional means, for example quenching of the reaction mixture, extraction of the product with organic solvent, for example ethyl acetate, and removal of the solvent under reduced pressure followed by crystallization.

[0454] An alternative synthesis of compound of formula (14) starting from 2-nitro-benzoic acid derivative is shown in Scheme-4.

[0455] The compound of formula (16) can be reacted with a solution or a suspension of compound of formula (17) and an alkali metal amide, for example lithium diisopropionamide, in an inert solvent, for example THF, −40° C. to room temperature, preferably −40° C., for 2-24 hours, preferably 2 hours. When the reaction is substantially complete, product of formula (14) can be isolated by conventional means, for example quenching of the reaction mixture, extraction of the product with organic solvent, for example ethyl acetate, and removal of the solvent under reduced pressure followed by crystallization.

[0456] The compound of formula (16) can be prepared from compound of formula (15) by reduction, for example with hydrazine and ferric chloride in aqueous sodium hydroxide under reflux, cyclization, for example stirring with oxalyl chloride at room temperature, followed by alkylation, for example stirring with R2-halide and sodium hydride in DMF at room temperature as described in Bioorganic and Medicinal Chemistry Letters 12 (2002) 85-88.

[0457] Step-3 Preparation of formula III, where Z=0:

[0458] The compound of formula I can be prepared by the reaction of compound of formula (14) with an alkylating agent, for example dimethyl sulfate, in a mixture of solvents, for example methanol and water, under reflux conditions for 2-24 hours, preferably 6 hours. When the reaction is substantially complete, the product of formula III, where Z=0, can be isolated by conventional means.

Example 18

Atomic Coordinates for PIM-1 apo protein crystal and co-crystal of PIM-1 with AMPPNP

[0459] Solving the structures for PIM-1 crystals and co-crystals provides sets of atomic coordinates for PIM-1 apo protein, and for co-crystals of PIM-1 with binding compounds. Coordinate tables for the apo protein and for PIM-1 co-crystallized with AMP-PNP are provided as Tables 1 and 2 respectively.

[0460] In Tables 1 and 2, the various columns have the following content, beginning with the left-most column:

[0461] ATOM: Refers to the relevant moeity for the table row.

[0462] Atom number: Refers to the arbitrary atom number designation within the coordinate table.

[0463] Atom Name: Identifier for the atom present at the particular coordinates.

[0464] Chain ID: Chain ID refers to one monomer of the protein in the crystal, e.g., chain “A”, or to other compound present in the crystal, e.g., HOH for water, and L for a ligand or binding compound. Multiple copies of the protein monomers will have different chain Ids.

[0465] Residue Number: The amino acid residue number in the chain.

[0466] X, Y, Z: Respectively are the X, Y, and Z coordinate values.

[0467] Occupancy: Describes the fraction of time the atom is observed in the crystal. For example, occupancy=1 means that the atom is present all the time; occupancy=0.5 indicates that the atom is present in the location 50% of the time.

[0468] B-factor: A measure of the thermal motion of the atom.

[0469] Element: Identifier for the element.

[0470] Atomic coordinates such as those provided allow construction of models and manipulation and analysis of those models.

[0471] A number of examples involved in the present invention are described below. In most cases, alternative techniques could also be used. For example, techniques, methods, and other information described in U.S. Pat. No. 5,837,815; U.S. Pat. No. 5,837,524; U.S. Patent Publication 2002/0048782; PCT/US98/02797, WO 98/35056; and McShan et al., Internat. J Oncology 21:197-205 (2002) can be used in the present invention. Such techniques and information include, without limitation, cloning, culturing, purification, assaying, screening, use of modulators, sequence information, and information concerning biological role of PYK2. Each of these references is incorporated by reference herein in its entirety, including drawings.

Example 19

Cloning of PYK2 Kinase Domain

[0472] Another exemplary identification of scaffolds and use of co-crystals utilized PYK2 kinase. Kinase domain of PYK2 (amino acids 420-691) was amplified by polymerase chain reaction (PCR) using the specific primers 5′-TCCACAGCATATGATTGCCCGTGAAGA TGTGGT-3′ (SEQ ID NO: 5) and 5′-CTCTCGTCGACCTACATGGCAATGTCCTTCTCCA-3′ (SEQ ID NO: 6). The resulting PCR fragment was digested with NdeI and SalI and was ligated into a modified pET15b vector (Novagen) with a cleavable N-terminal hexa-histidine tag (designated pET1S). PYK2 coding sequence has been deposited with GenBank under accession number U33284. A desired PYK2 sequence can be obtained using PCR with a brain (e.g., human brain) cDNA library, such as obtaining kinase domain using the above primers in PCR. The multi-cloning site of the pET15S vector is shown in the following sequence (SEQ ID NO: 7), including the sequence encoding the N-terminal hexa-histadine tag:

[0473] pET15S vector is derived from pET15b vector (Novagen) for bacterial expression to produce the proteins with N-terminal His6. This vector was modified by replacement of NdeI-BamHI fragment to others to create SalI site and stop codon (TAG). Vector size is 5814 bp. Insert can be put using NdeI-SalI site.

[0474] The amino acid and nucleic acid sequences for the PYK2 kinase domain utilized are provided in Table 6 (SEQ ID NO:1 and 3 respectively).

Example 2

Expression and Purification of PYK2 Kinase Domain

[0475] For protein expression Pyk2 kinase domain was transformed into E. coli strain BL21 (DE3) pLysS and transformants were selected on LB plates containing Kanamycin. Single colonies were grown overnight at 37° C. in 200 ml TB (terrific broth) media. 16×1L of fresh TB media in 2.8L flasks were inoculated with 10 ml of overnight culture and grown with constant shaking at 37° C. Once cultures reached an absorbance of 1.0 at 600 nm, 1 mM isopropyl-β-D-thiogalactopyranoside (IPTG) was added and cultures were allowed to grow for a further 12 hrs at 22° C. with constant shaking. Cells were harvested by centrifugation at 7000×g and pellets were frozen in liquid nitrogen and stored at −80° C. until ready for lysis.

[0476] The cell pellet was suspended in lysis buffer containing 0.1M Potassium phosphate buffer pH 8.0, 200 mM NaCl, 10% Glycerol, 2 mm PMSF and EDTA free protease inhibitor cocktail tablets (Roche). Cells were lysed using a microfuidizer processor (Microfuidics Corporation) and insoluble cellular debris was removed using centrifugation at 30,000×g. The cleared supernatant was added to Talon resin (Clonetech) and incubated for 4 hrs at 4° C. with constant rocking. The suspension was loaded onto a column and washed with 20 column volumes of lysis buffer plus 10 mM Imadazole. Protein was eluted step wise with addition of lysis buffer plus 200 mM Imadazole pH7.5 and 1 ml fractions collected. Fractions containing PYK2 were pooled, concentrated and loaded onto a Pharmacia HiLoad 26/60 Superdex 200 sizing column (Pharmacia) pre-equilibrated with 20 mM Tris pH7.5, 150 mM NaCl.

[0477] Peak fractions were collected and assayed by SDS-PAGE. Fractions containing PYK2 were pooled and diluted in Tris buffer pH 7.5, until 30 mM NaCl was reached. Diluted protein was further subjected to anion exchange chromatography using a Source 15Q (Pharmacia) sepharose column equilibrated with 20 mM Tris pH7.5. Elution was performed using a linear gradient of sodium chloride (0-500 mM). Eluted protein was treated with 2U thrombin per mg protein to remove N-terminal Histidine tag. Following cleavage Pyk2 was re-applied to Source 15Q (Pharmacia) sepharose column equilibrated with 20 mM Tris pH7.5, and eluted using a linear sodium chloride gradient. Purified protein was concentrated to 100 mg/ml and stored at −80° C. until ready for crystallization screening.

Example 3

Crystallization of PYK2 Kinase Domain

[0478] Crystallization conditions were initially identified in the Hampton Research (Riverside, Calif.) screening kit(1). Optimized crystals were grown by vapor diffusion in sitting drop plates with equal volumes of protein solution of 10 mg/ml containing 20 mM Tris-HCl pH 8.0, 150 mM NaCl, 14 mM BME, 1 mM DTT and reservoir solution containing 8% polyethylene glycol (PEG) 8000, 0.2M Sodium Acetate, 0.1M Cacodylate pH 6.5, 20% Glycerol). Blades of crystals grew overnight at 4° C. Microseeding was used to produce larger, single crystals, the largest crystal being around 0.3 mm X 0.05 mm×0.02 mm.

Example 4

Diffraction Analysis of PYK2

[0479] Synchrotron X-ray data for Pyk2 was collected at beamline 8.3.1 of the Advanced Light Source (ALS, Lawrence Berkeley National Laboratory, Berkeley) on a Quantum 210 charge-coupled device detector (λ=1.10 Å). The mother liquor from the reservoir was used as cryo-protectant for the crystal. Detector distance was 10 mm and exposure time was 10 s per frame. 200 frames were collected with 0.5° oscillation over a wedge of 100°. The quality and resolution limits of the diffraction pattern were considerably improved by annealing the crystal. The crystal was briefly allowed to warm up for 10 seconds by shutting off the Nitrogen cryo stream and refrozen by resuming cooling with the cryo stream. Crystals of PYK2 diffracted to a resolution limit of 1.45 Å with cell dimensions of a=37 Å, b=47 Å, c=81 Å, α=90°, β=92°, γ=90°. The data were processed using Mosflm( ) and scaled and reduced with Scala( ) in CCP4 ( ) in space group P2. The data processing process was driven by the ELVES automation scripts (J. M. Holton, unpublished data). An inspection of the OKO zone indicated that all odd (2n+1) reflections were very weak compared with the even reflections, suggesting the space group to be P21.

[0480] PYK2 Structure Determination and Refinement

[0481] The initial phases for the dataset were obtained by molecular replacement. A homology model of the protein Pyk2 was generated using the LCK kinase structure (PDBID: lqpc) as a template. This model was trimmed by excising all loops before being used in molecular replacement program EPMR ( ), which resulted in a solution with CC=0.372. The molecular replacement solution phases were improved by the program Arp-Warp ( ). The resultant model was further improved by manual model building and extension in O ( ) and refinement with CNX 0 and Refmac5 ( ) in CCP4. The cycle of model building and refinement continued till the model was complete and refinement converged to the R/Rfree of 20.83/26.94%. The geometric analysis of the model was performed by PROCHECK ( ) which indicated the structure to have excellent geometry.

[0482] Data collection and refinement statistics for PYK2 kinase domain crystal, and for PYK2 kinase domain/binding compound AMPPNP cocrystal are summarized in the following table:

1Data Collection and Refinement StatisticsPyk2 (APO)Pyk2 + PLX099323Crystal ParametersSpace GroupP21P21Unit Cell (Å)a = 37.17, b = 46.97,a = 37.32, b = 46.98,c = 80.36, =92.63c = 81.11, =92.83Number of molecules/11AUVM (Å3/Dalton)2.42.4Solvent content (%)4848Data Collection and ProcessingResolution (Å)1.451.80Wavelength (Å)1.11.1Unique reflections4784326149Redundancy (last shell*)2.0 (1.8)4.0 (2.9)Completeness (last shell)97.5 (88.9)99.8 (97.8)(%)I/(last shell)10.9 (1.3)12.0 (2.3)Rsym (last shell)0.043 (0.487)0.063 (0.459)*Last shell (Å)1.49-1.451.85-1.80RefinementRwork/Rfree (%)16.93/20.6818.62/22.81Number of Atoms25832507Rmsd from ideal0.012 (bond distance),0.010 (bond distance),geometry1.434 (bond angle)1.372 (bond angle)SigmaA coordinate error0.16 Å0.14 Å(for 5.0-1.45 Å)(for 5.0-1.80 Å)Average B-factors (Å2)19.320.5Protein atoms16.419.0Waters37.634.3Ligand—44.41

[0483] The model of Pyk2 contains 273 amino acids (spanning the PYK2 sequence 420-691 with one residue from the cloning vector) and 180 water molecules. The Pyk2 structure adopts the standard kinase fold consisting of an N-terminal β-sheet domain and a C-terminal α-helical domain linked by a 5 residue linker. The linker segment contains the canonical H-bond acceptor/donor residues E503 and Y505 that would normally interact with the adenosine ring of ATP. In the apo structure these residues make H-bonds with water molecules.

[0484] Atomic coordinates for PYK2 kinase domain co-crystallized with a binding compound (AMPPNP) are provided in Table 4.

[0485] Active Loop Conformation

[0486] In many protein kinases, the activation loop, or A-loop, plays an important role in regulating the kinase activity. In active kinases, the A-loops adopt a highly similar conformation characterized by the formation of three small β-sheet moieties: two with the main body of the protein (the beginning of the catalytic or C-loop and the αEF/αF loop, respectively), and one with the substrate peptide. In contrast, the inactive conformation of A-loop differs markedly from protein to protein, albeit having the similar effect of blocking ATP binding, substrate-binding, or both. In comparison with the active insulin receptor (INSR) and IGFR1 kinase domain strutures, the A-loop in the solved Pyk2 structure is clearly in an inactive conformation. The loop is stabilized by a unique set of intra- and inter-loop interactions that differentiate it from all known A-loop structures.

[0487] The A-loop in our Pyk2 structure starts to deviate from the standard active conformation at the DFG motif (for comparison, we modeled the active A-loop conformation of Pyk2 based on the IGFR1 structure). The first two residues of the DFG motif (D567 and F568) have similar orientations as their counterparts in the active A-loop form, with D567 interacting with K457 (β3) and F568 locked in a hydrophobic pocket sandwiched by two residues (I477 and M478) from aC. However, the third residue in the motif, G569, adopts a completely different conformation, resulting in the formation of a hydrogen bond beween G567:NH and H547:CO. This hydrogen bond forces the A-loop to a different path that precludes it from forming a β-sheet with C-loop. A similar hydrogen bond has also been observed in two other tyrosine kinases: HCK (1qcf) and SRC (1 fink).

[0488] There are multiple interactions that help to stabilize the A-loop in its observed conformation. Most of them involve a unique sequence moiety of Pyk2. Among the tyrosine kinases of known structure, Pyk2 contains a unique ED repeat (E575-D578) in the A-loop. In the Pyk2 structure, E575 is exposed to solvent, whereas D576 initiates a tight β-turn. Beside providing the canonical β-turn backbone hydrogen bond between D576:CO-Y579:NH, the side chain of D576 also interacts with D578:NH. The β-turn region of A-loop is held to the αEF/αF loop by two side-chain-backbone hydrogen bonds: one between E577:CO-R600:Ne and the other between K581:NZ-N598:CO. The side chain of E577 interacts with the end of the activation loop via two hydrogen bonds, one with T585 (OG) and the other with R586 (NH). The most interesting feature of the Pyk2 A-loop is the salt bridge formed between D588 and R547 from the C-loop (the distances between the two OD and two NH atoms are 2.9A). Neither of the two tyrosines Y579 and y580 is phosphorylated in our structure. Y579 is exposed to solvent, whereas y580 binds to the hydrophobic portions of the E575 and E577 side chains.

[0489] Because FAK does not have the second ED, the conformation of the A-loop in an inactive FAK is expected to be different.

[0490] Implications for Substrate Binding and Autophosphorylation

[0491] An important event in the enzymatic activation of FAK/Pyk2 is the autophosphorylation of a tyrosine residue before the catalytic domain (Y402). The phosphorylated Y402 provides the binding site for Src and other related kinases and facilitates Src-dependent phosphorylation of other tyrosine residues on Pyk2 including Y579 and Y580. It is not clear how autophosphorylation could occur before Y579 and Y580 are phosphorylated.

[0492] To test whether Y402 can reach the substrate binding site, we modeled the 7 residue peptide D400IYAEIPD407 containing Y402 into the substrate binding site based on the cocrystal structure of IGFR1 kinase domain with its substrate peptide. In our protein construct, the Pyk2 insert starts at 1420. There are four residues (GSHM) N-terminal to 1420 left by the His-tag used, of those only M419 is visible. We then modeled the 11 residues that link D419 to M407. The model shows that, in order to reach the substrate binding site, the N-terminal region has to transverse along the back of aC. The link would also fix the A-loop in the active conformation. This may provide the mechanism that the protein used to autophosphorylate Y402. Once Y402 is phosphorylated, the N-terminus is then released and subject to SH2 binding. The A-loop also becomes flexible and accessible to Src.

[0493] Because the residues surrounding the P+1 and P+3 binding pocket are mostly hydrophobic in tyrosine kinases, substrate P+1 and P+3 sites are mostly hydrophobic residues. The residue that might interact with P+2 varies. Acidic and other polar site chains might be preferred because of the nearby residue R586. The P−1 site is an acidic residue in INSR and IGFR1. The residue for interacting with P−1 is Arg; this residue is changed to Gly in Pyk2, leaving the space largely hydrophobic. The autophosphorylation site sequence in Pyk2, IYAEIPD, and the sequences of several other known Pyk2 phosphorylation sites fit well the substrate selectivity profile of Pyk2.

Example 5

PYK2 Binding Assays

[0494] As with PIM-1, binding assays can be performed in a variety of ways, including as described above for PIM-1.

[0495] The Pyk2 kinase domain residues 419 to 691 is an active kinase in AlphaScreen. At a concentration of 8 ng/well in 384-well plate, PYK2 shows a Kd of 7.34 uM, which is in general agreement with most protein kinases (Table 7). Inhibition by ATP analogs was tested with Pyk2 at 8 ng/well and ATP at 10 uM. The data is shown in Table 7. The affinity of ATP-g-S and ADP with Pyk2 is at 14 uM. Adenosine and AMP-PCP have little effect on PYK2 in the concentration tested.

Example 9

Synthesis of the Compounds of Formula IV

[0496]

[0497] The triazole derivatives, represented by Formula IV, can be prepared as shown in Scheme-5.

[0498] Step-1 Preparation of Formula (3)

[0499] The compound of formula (3) is prepared conventionally by reaction of a compound of formula (1), where R1=alkyl, aryl, heteroaryl (e.g. m-toluic hydrazide), with an isothiocyanate of formula (2), in a basic solvent (e.g. pyridine), typically heated near 65° C. for 2-6 hours.

[0500] Step-2 Preparation of Formula (5)

[0501] The compound of formula (5) is prepared conventionally by reaction of a compound of formula (3) with an alkylating agent of formula (4)(e.g. methyl iodide), in an inert solvent (e.g. THF) at room temperature for 24-48 hours.

[0502] Step-3 Preparation of Formula I

[0503] The compound of Formula IV is prepared by dissolving a compound of formula (5) in POCl3 and heated near 80° C. for 8-12 hours. When the reaction is substantially complete, the product of Formula I is isolated by conventional means (e.g. reverse phase HPLC). Smith, et. al., J. Comb. Chem., 1999, 1, 368-370; and references therein.

[0504] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

[0505] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

[0506] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, using other binding assays and other modifications to molecular scaffold compounds are all within the scope of the present invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

[0507] The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0508] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

[0509] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention.

[0510] Thus, additional embodiments are within the scope of the invention and within the following claims.

2TABLE 1HEADER----XX-XXX-XX xxxxCOMPND---REMARK3REMARK3REFINEMENT.REMARK3 PROGRAMREFMAC 5.1.19REMARK3 AUTHORSMURSHUDOV,VAGIN,DODSONREMARK3REMARK3 REFINEMENT TARGETMAXIMUM LIKELIHOODREMARK3REMARK3DATA USED IN REFINEMENT.REMARK3 RESOLUTION RANGE HIGH (ANGSTROMS)2.00REMARK3 RESOLUTION RANGE LOW (ANGSTROMS)84.52REMARK3 DATA CUTOFF (SIGMA(F))NONEREMARK3 COMPLETENESS FOR RANGE (%)99.27REMARK3 NUMBER OF REFLECTIONS28693REMARK3REMARK3FIT TO DATA USED IN REFINEMENT.REMARK3 CROSS-VALIDATION METHODTHROUGHOUTREMARK3 FREE R VALUE TEST SET SELECTIONRANDOMREMARK3 R VALUE (WORKING + TEST SET)0.22119REMARK3 R VALUE (WORKING SET)0.22012REMARK3 FREE R VALUE0.24194REMARK3 FREE R VALUE TEST SET SIZE (%)5.0REMARK3 FREE R VALUE TEST SET COUNT1498REMARK3REMARK3FIT IN THE HIGHEST RESOLUTION BIN.REMARK3 TOTAL NUMBER OF BINS USED20REMARK3 BIN RESOLUTION RANGE HIGH2.000REMARK3 BIN RESOLUTION RANGE LOW2.052REMARK3 REFLECTION IN BIN (WORKING SET)2096REMARK3 BIN R VALUE (WORKING SET)0.344REMARK3 BIN FREE R VALUE SET COUNT102REMARK3 BIN FREE R VALUE0.359REMARK3REMARK3NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.REMARK3 ALL ATOMS2382REMARK3REMARK3B VALUES.REMARK3 FROM WILSON PLOT (A**2)NULLREMARK3 MEAN B VALUE (OVERALL, A**2)49.236REMARK3 OVERALL ANISOTROPIC B VALUE.REMARK3B11 (A**2)1.32REMARK3B22 (A**2)1.32REMARK3B33 (A**2)−1.99REMARK3B12 (A**2)0.66REMARK3B13 (A**2)0.00REMARK3B23 (A**2)0.00REMARK3REMARK3ESTIMATED OVERALL COORDINATE ERROR.REMARK3 ESU BASED ON R VALUE (A)0.158REMARK3 ESU BASED ON FREE R VALUE (A)0.142REMARK3 ESU BASED ON MAXIMUM LIKELIHOOD (A)0.127REMARK3 ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2)4.758REMARK3REMARK3CORRELATION COEFFICIENTS.REMARK3 CORRELATION COEFFICIENT FO-FC0.954REMARK3 CORRELATION COEFFICIENT FO-FC FREE0.947REMARK3REMARK3RMS DEVIATIONS FROM IDEAL VALUESCOUNTRMSWEIGHTREMARK3 BOND LENGTHS REFINED ATOMS (A)22960.0110.021REMARK3 BOND ANGLES REFINED ATOMS (DEGREES)31141.0881.945REMARK3 TORSION ANGLES, PERIOD 1 (DEGREES)2733.8385.000REMARK3 CHIRAL-CENTER RESTRAINTS (A**3)3320.0810.200REMARK3 GENERAL PLANES REFINED ATOMS (A)17840.0040.020REMARK3 NON-BONDED CONTACTS REFINED ATOMS (A)10940.2150.200REMARK3 H-BOND (X...Y) REFINED ATOMS (A)1380.1210.200REMARK3 SYMMETRY VDW REFINED ATOMS (A)600.2820.200REMARK3 SYMMETRY H-BOND REFINED ATOMS (A)190.2470.200REMARK3REMARK3ISOTROPIC THERMAL FACTOR RESTRAINTS.COUNTRMSWEIGHTREMARK3 MAIN-CHAIN BOND REFINED ATOMS (A**2)13651.0581.500REMARK3 MAIN-CHAIN ANGLE REFINED ATOMS (A**2)22122.0102.000REMARK3 SIDE-CHAIN BOND REFINED ATOMS (A**2)9312.2403.000REMARK3 SIDE-CHAIN ANGLE REFINED ATOMS (A**2)9023.7664.500REMARK3REMARK3NCS RESTRAINTS STATISTICSREMARK3 NUMBER OF NCS GROUPSNULLREMARK3REMARK3REMARK3TLS DETAILSREMARK3 NUMBER OF TLS GROUPSNULLREMARK3REMARK3REMARK3BULK SOLVENT MODELLING.REMARK3 METHOD USEDBABINET MODEL WITH MASKREMARK3 PARAMETERS FOR MASK CALCULATIONREMARK3 VDW PROBE RADIUS1.40REMARK3 ION PROBE RADIUS0.80REMARK3 SHRINKAGE RADIUS0.80REMARK3REMARK3OTHER REFINEMENT REMARKSNULLREMARK3CISPEP1 GLU A 124 PRO A 125 0.00CRYST199.210 99.210 80.285 90.00 90.00 120.00 P 65SCALE10.010080 0.005819 0.000000 0.00000SCALE20.000000 0.011639 0.000000 0.00000SCALE30.000000 0.000000 0.012456 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1571.0068.55CATOM123OPHEA4916.78585.50912.9631.0069.15OATOM124NGLYA5016.66386.16415.1061.0066.20NATOM125CAGLYA5016.62587.58814.7951.0062.55CATOM126CGLYA5015.56288.35115.5781.0059.75CATOM127OGLYA5015.31688.05616.7541.0059.86OATOM128NSERA5114.94589.33214.9161.0056.20NATOM129CASERA5113.86690.14815.4801.0051.75CATOM130CBSERA5114.30091.61415.5871.0051.18CATOM131OGSERA5115.45491.75016.4011.0048.30OATOM132CSERA5112.69990.07614.5371.0049.79CATOM133OSERA5112.84890.34113.3441.0048.22OATOM134NVALA5211.53889.72415.0641.0047.77NATOM135CAVALA5210.34589.55114.2431.0046.96CATOM136CBVALA529.79588.09114.3121.0046.48CATOM137CG1VALA528.57087.92413.3971.0045.18CATOM138CG2VALA5210.87387.08213.9551.0045.83CATOM139CVALA529.26590.51514.7011.0047.44CATOM140OVALA528.87490.49315.8691.0048.09OATOM141NTYRA538.78491.34613.7791.0047.68NATOM142CATYRA537.72392.31514.0551.0048.21CATOM143CBTYRA538.10293.71113.5321.0047.13CATOM144CGTYRA539.29094.33514.2231.0046.28CATOM145CD1TYRA5310.59393.94913.8971.0043.98CATOM146CE1TYRA5311.68994.49514.5321.0042.59CATOM147CZTYRA5311.49895.47515.5211.0043.72CATOM148OHTYRA5312.59896.01216.1591.0043.55OATOM149CE2TYRA5310.22695.88415.8641.0044.06CATOM150CD2TYRA539.11795.30515.2211.0045.68CATOM151CTYRA536.43691.88613.3631.0049.25CATOM152OTYRA536.46691.33512.2581.0048.07OATOM153NSERA545.30692.16214.0081.0050.84NATOM154CASERA543.99691.95913.3981.0053.09CATOM155CBSERA542.88992.09214.4451.0053.24CATOM156OGSERA541.60991.93913.8541.0055.73OATOM157CSERA543.82693.01912.3421.0054.41CATOM158OSERA544.30394.12912.5101.0055.46OATOM159NGLYA553.15192.69111.2481.0056.17NATOM160CAGLYA553.04393.62510.1431.0058.09CATOM161CGLYA551.80093.3919.3271.0060.22CATOM162OGLYA551.16492.3439.4331.0060.35OATOM163NILEA561.45794.3818.5131.0062.12NATOM164CAILEA560.30794.3057.6351.0064.34CATOM165CBILEA56−0.84795.1888.1691.0064.42CATOM166CG1ILEA56−1.39194.6399.5001.0065.47CATOM167CD1ILEA56−2.24095.67010.2811.0066.61CATOM168CG2ILEA56−1.96995.2737.1491.0065.46CATOM169CILEA560.75994.7806.2671.0065.56CATOM170OILEA561.42295.8056.1551.0065.96OATOM171NARGA570.41994.0175.2331.0067.26NATOM172CAARGA570.73194.3863.8581.0068.96CATOM173CBARGA570.62893.1612.9461.0068.74CATOM174CGARGA571.13993.3611.5201.0068.49CATOM175CDARGA570.43392.4240.5321.0068.56CATOM176NEARGA571.26691.2720.1791.0068.20NATOM177CZARGA570.77790.086−0.2081.0068.80CATOM178NH1ARGA57−0.55189.870−0.2911.0069.12NATOM179NH2ARGA571.61689.106−0.5171.0069.04NATOM180CARGA57−0.25995.4483.4221.0070.41CATOM181OARGA57−1.43095.1463.1711.0070.64OATOM182NVALA580.21896.6913.3451.0072.30NATOM183CAVALA58−0.62697.8442.9981.0073.91CATOM184CBVALA580.19399.1772.9691.0073.84CATOM185CG1VALA58−0.704100.3732.6701.0073.85CATOM186CG2VALA580.92499.3944.2971.0073.45CATOM187CVALA58−1.34897.6021.6661.0074.98CATOM188OVALA58−2.46898.0811.4651.0075.68OATOM189NSERA59−0.71096.8220.7881.0075.93NATOM190CASERA59−1.26896.456−0.5211.0076.51CATOM191CBSERA59−0.25595.617−1.3201.0076.86CATOM192OGSERA591.10396.061−1.0491.0078.49OATOM193CSERA59−2.61795.721−0.4601.0076.40CATOM194OSERA59−3.38295.775−1.4221.0076.81OATOM195NASPA60−2.90295.0260.6451.0075.89NATOM196CAASPA60−4.17494.2990.7901.0075.35CATOM197CBASPA60−4.23093.077−0.1481.0075.67CATOM198CGASPA60−3.12492.0640.1261.0076.95CATOM199OD1ASPA60−2.83591.7881.3071.0078.19OATOM200OD2ASPA60−2.48891.483−0.7881.0077.92OATOM201CASPA60−4.54393.8722.2171.0074.33CATOM202OASPA60−5.33992.9472.3981.0074.34OATOM203NASNA61−3.96594.5413.2151.0072.99NATOM204CAASNA61−4.19494.2194.6331.0071.45CATOM205CBASNA61−5.59994.6515.0741.0072.10CATOM206CGASNA61−5.79096.1585.0261.0073.42CATOM207OD1ASNA61−5.33396.8855.9261.0074.58OATOM208ND2ASNA61−6.47196.6363.9751.0074.28NATOM209CASNA61−3.92892.7595.0351.0069.65CATOM210OASNA61−4.53592.2425.9751.0069.76OATOM211NLEUA62−3.02092.0984.3231.0067.18NATOM212CALEUA62−2.62390.7384.6801.0064.33CATOM213CBLEUA62−1.90190.0573.5181.0064.74CATOM214CGLEUA62−1.29188.6853.8211.0065.22CATOM215CD1LEUA62−2.38387.6354.0091.0065.88CATOM216CD2LEUA62−0.32588.2642.7251.0065.33CATOM217CLEUA62−1.69890.7665.8831.0061.89CATOM218OLEUA62−0.68291.4535.8631.0061.51OATOM219NPROA63−2.04490.0106.9201.0059.57NATOM220CAPROA63−1.16489.8408.0831.0057.75CATOM221CBPROA63−1.96388.8888.9831.0057.73CATOM222CGPROA63−3.37689.1068.5731.0058.58CATOM223CDPROA63−3.30389.2617.0801.0059.38CATOM224CPROA630.18089.2217.6941.0055.60CATOM225OPROA630.21188.1637.0751.0055.56OATOM226NVALA641.27489.9028.0251.0053.21NATOM227CAVALA642.60989.3757.7731.0050.67CATOM228CBVALA643.30690.0976.5901.0050.93CATOM229CG1VALA642.44190.0405.3261.0050.56CATOM230CG2VALA643.64191.5376.9431.0049.88CATOM231CVALA643.49289.4459.0251.0049.15CATOM232OVALA643.17590.1509.9811.0049.44OATOM233NALAA654.58788.6929.0151.0046.68NATOM234CAALAA655.60488.77410.0461.0044.84CATOM235CBALAA655.88187.38410.6541.0045.04CATOM236CALAA656.83489.3159.3561.0043.92CATOM237OALAA657.12388.9128.2181.0043.40OATOM238NILEA667.54790.23310.0121.0042.88NATOM239CAILEA668.71690.8839.4051.0042.53CATOM240CBILEA668.49492.4109.2521.0043.51CATOM241CG1ILEA667.26092.6798.3831.0044.11CATOM242CD1ILEA666.6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18.44183.152−5.5961.0082.78CATOM361CGLEUA8018.28983.870−4.2541.0083.30CATOM362CD1LEUA8017.54585.189−4.4321.0083.40CATOM363CD2LEUA8017.58882.965−3.2381.0083.57CATOM364CLEUA8019.34381.256−6.9981.0083.29CATOM365OLEUA8020.44081.256−7.5701.0083.54OATOM366NPROA8118.23580.753−7.5671.0083.78NATOM367CAPROA8118.22180.340−8.9861.0083.97CATOM368CBPROA8116.75879.937−9.2181.0083.94CATOM369CGPROA8116.26779.535−7.8711.0084.00CATOM370CDPROA8116.92780.513−6.9231.0083.86CATOM371CPROA8118.62381.488−9.9261.0084.09CATOM372OPROA8118.91081.267−11.1021.0084.07OATOM373NASNA8218.64482.700−9.3761.0084.20NATOM374CAASNA8219.07083.916−10.0641.0083.96CATOM375CBASNA8218.27685.106−9.4921.0084.25CATOM376CGASNA8218.73886.449−10.0261.0085.14CATOM377OD1ASNA8218.86986.643−11.2411.0085.89OATOM378ND2ASNA8218.97987.393−9.1151.0084.89NATOM379CASNA8220.58684.137−9.9351.0083.40CATOM380OASNA8221.19084.889−10.7091.0083.24OATOM381NGLYA8321.19183.461−8.9581.0082.90NATOM382CAGLYA8322.59783.634−8.6261.0082.10CATOM383CGLYA8322.84584.924−7.8631.0081.49CATOM384OGLYA8323.38285.883−8.4301.0081.74OATOM385NTHRA8422.43784.944−6.5901.0080.61NATOM386CATHRA8422.60986.097−5.6871.0079.41CATOM387CBTHRA8421.29086.893−5.5431.0079.60CATOM388OG1THRA8420.71887.127−6.8361.0080.05OATOM389CG2THRA8421.56188.322−5.0071.0079.91CATOM390CTHRA8423.08185.643−4.3021.0078.07CATOM391OTHRA8422.72884.557−3.8411.0078.47OATOM392NARGA8523.86686.489−3.6431.0075.99NATOM393CAARGA8524.44386.177−2.3381.0073.77CATOM394CBARGA8525.76886.943−2.1841.0074.21CATOM395CGARGA8526.45386.829−0.8331.0075.15CATOM396CDARGA8527.40485.638−0.7251.0075.91CATOM397NEARGA8528.21385.7310.4871.0076.30NATOM398CZARGA8528.95784.7390.9721.0077.02CATOM399NH1ARGA8529.00583.5600.3521.0076.24NATOM400NH2ARGA8529.65584.9292.0861.0077.19NATOM401CARGA8523.45786.502−1.1991.0071.72CATOM402OARGA8523.41587.632−0.6961.0071.91OATOM403NVALA8622.65385.514−0.8091.0068.61NATOM404CAVALA8621.66085.6930.2621.0065.46CATOM405CBVALA8620.19185.642−0.2651.0065.32CATOM406CG1VALA8619.97786.633−1.3941.0064.79CATOM407CG2VALA8619.82284.250−0.7091.0065.00CATOM408CVALA8621.86684.6561.3721.0063.06CATOM409OVALA8622.54383.6491.1441.0063.20OATOM410NPROA8721.30184.8872.5631.0060.50NATOM411CAPROA8721.39983.9073.6491.0058.23CATOM412CBPROA8720.57084.5444.7741.0058.22CATOM413CGPROA8720.59085.9994.4781.0059.47CATOM414CDPROA8720.53586.0822.9861.0060.10CATOM415CPROA8720.79782.5643.2371.0056.09CATOM416OPROA8719.80282.5242.5131.0055.24OATOM417NMETA8821.41681.4793.6811.0054.23NATOM418CAMETA8820.86680.1423.4581.0053.19CATOM419CBMETA8821.63879.1114.2951.0054.18CATOM420CGMETA8821.27377.6454.0251.0057.50CATOM421SDMETA8821.34177.2132.2471.0065.32SATOM422CEMETA8823.11377.1482.0021.0062.88CATOM423CMETA8819.36380.1033.7751.0050.99CATOM424OMETA8818.56579.5942.9791.0049.59OATOM425NGLUA8918.98280.6884.9181.0048.97NATOM426CAGLUA8917.57580.7545.3171.0046.86CATOM427CBGLUA8917.39281.6866.5221.0045.85CATOM428CGGLUA8915.94481.8036.9911.0045.51CATOM429CDGLUA8915.80382.5418.3031.0044.03CATOM430OE1GLUA8916.81983.0088.8561.0047.34OATOM431OE2GLUA8914.67182.6388.7901.0044.02OATOM432CGLUA8916.65381.1684.1711.0046.50CATOM433OGLUA8915.61280.5483.9621.0046.41OATOM434NVALA9017.03182.2153.4291.0046.05NATOM435CAVALA9016.24382.6692.2751.0045.86CATOM436CBVALA9016.75984.0181.7251.0046.25CATOM437CG1VALA9015.96684.4310.4911.0045.50CATOM438CG2VALA9016.66385.1022.8001.0046.57CATOM439CVALA9016.23481.6391.1371.0045.66CATOM440OVALA9015.21081.3990.5251.0045.75OATOM441NVALA9117.38981.0530.8511.0045.99NATOM442CAVALA9117.49080.034−0.1971.0046.17CATOM443CBVALA9118.91379.465−0.2791.0046.54CATOM444CG1VALA9118.97578.292−1.2841.0047.68CATOM445CG2VALA9119.89280.556−0.6741.0048.34CATOM446CVALA9116.49678.9090.0941.0044.94CATOM447OVALA9115.63178.603−0.7291.0045.36OATOM448NLEUA9216.59178.3521.3021.0043.94NATOM449CALEUA9215.70477.2601.7491.0042.33CATOM450CBLEUA9216.10676.7723.1371.0040.99CATOM451CGLEUA9217.57776.4173.3161.0040.75CATOM452CD1LEUA9217.79875.8674.7111.0037.63CATOM453CD2LEUA9218.06175.4102.2471.0040.38CATOM454CLEUA9214.24577.6411.7421.0042.09CATOM455OLEUA9213.40176.8881.2431.0041.96OATOM456NLEUA9313.93678.8122.2891.0042.17NATOM457CALEUA9312.55679.2802.3281.0043.42CATOM458CBLEUA9312.46180.6323.0511.0042.52CATOM459CGLEUA9312.41680.6454.5891.0042.30CATOM460CD1LEUA9312.57682.0745.0951.0039.64CATOM461CD2LEUA9311.11780.0695.1071.0039.20CATOM462CLEUA9311.94779.3820.9211.0044.51CATOM463OLEUA9310.82378.9400.6911.0044.42OATOM464NLYSA9412.69079.981−0.0121.0046.08NATOM465CALYSA9412.22280.098−1.3911.0047.69CATOM466CBLYSA9413.26680.807−2.2541.0048.80CATOM467CGLYSA9413.14682.329−2.1951.0052.89CATOM468CDLYSA9414.13383.009−3.1261.0057.20CATOM469CELYSA9413.76182.810−4.5981.0058.87CATOM470NZLYSA9412.41183.360−4.9191.0060.23NATOM471CLYSA9411.90378.730−1.9811.0047.52CATOM472OLYSA9410.87078.564−2.6331.0048.02OATOM473NLYSA9512.79277.766−1.7331.0047.55NATOM474CALYSA9512.61576.380−2.1851.0048.35CATOM475CBLYSA9513.83675.536−1.8291.0048.23CATOM476CGLYSA9515.02375.801−2.7471.0048.74CATOM477CDLYSA9516.29375.188−2.2121.0050.92CATOM478CELYSA9516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141.0030.59NATOM944CAVALA1514.57667.69111.0061.0031.25CATOM945CBVALA1515.22267.56212.4071.0031.59CATOM946CG1VALA1516.73667.70312.3281.0033.21CATOM947CG2VALA1514.66168.65213.3251.0031.32CATOM948CVALA1515.25966.7809.9811.0030.80CATOM949OVALA1516.14067.2159.2391.0030.84OATOM950NLEUA1524.84265.5219.9391.0031.70NATOM951CALEUA1525.42964.5649.0001.0032.14CATOM952CBLEUA1524.79263.1799.1941.0032.39CATOM953CGLEUA1525.51362.17610.1231.0033.85CATOM954CD1LEUA1526.72361.6119.4111.0035.80CATOM955CD2LEUA1525.95062.79911.4221.0036.98CATOM956CLEUA1525.21565.0527.5671.0031.63CATOM957OLEUA1526.13165.0246.7691.0032.44OATOM958NGLUA1533.99765.4717.2521.0031.63NATOM959CAGLUA1533.67165.9805.9071.0032.26CATOM960CBGLUA1532.17766.3305.7801.0032.59CATOM961CGGLUA1531.23365.1265.7361.0033.60CATOM962CDGLUA1531.42364.2154.5101.0035.47CATOM963OE1GLUA1531.61764.7173.3921.0038.01OATOM964OE2GLUA1531.38062.9914.6591.0034.71OATOM965CGLUA1534.53867.1915.5621.0031.87CATOM966OGLUA1535.07667.2814.4491.0030.83OATOM967NALAA1544.71668.1016.5311.0031.04NATOM968CAALAA1545.54869.2916.3181.0030.48CATOM969CBALAA1545.44070.2787.5371.0031.18CATOM970CALAA1547.00268.9336.0821.0031.22CATOM971OALAA1547.68369.5445.2381.0030.96OATOM972NVALA1557.50467.9676.8421.0031.29NATOM973CAVALA1558.89867.5806.7041.0032.75CATOM974CBVALA1559.33566.6517.8561.0032.61CATOM975CG1VALA15510.72966.1327.6311.0033.47CATOM976CG2VALA1559.29267.4399.1891.0035.41CATOM977CVALA1559.09466.9055.3361.0033.10CATOM978OVALA15510.09267.1554.6481.0033.39OATOM979NARGA1568.13066.0864.9311.0033.25NATOM980CAARGA1568.19065.4293.6061.0034.45CATOM981CBARGA1566.99264.4903.3961.0033.21CATOM982CGARGA1566.99963.2214.2191.0033.42CATOM983CDARGA1565.77862.3203.9371.0034.78CATOM984NEARGA1565.64462.0642.4941.0035.47NATOM985CZARGA1564.53361.6361.9031.0033.43CATOM986NH1ARGA1563.43561.4112.6091.0032.42NATOM987NH2ARGA1564.52561.4370.5941.0034.38NATOM988CARGA1568.21166.4912.5011.0034.92CATOM989OARGA1568.98666.4141.5421.0035.22OATOM990NHISA1577.36967.5012.6501.0036.13NATOM991CAHISA1577.35168.5881.6861.0036.56CATOM992CBHISA1576.29969.6292.0481.0037.38CATOM993CGHISA1576.36270.8631.1971.0039.12CATOM994ND1HISA1577.00572.0141.6081.0041.07NATOM995CE1HISA1576.92172.9260.6581.0039.75CATOM996NE2HISA1576.24972.407−0.3581.0040.88NATOM997CD2HISA1575.87371.124−0.0411.0038.81CATOM998CHISA1578.71069.2381.5551.0036.34CATOM999OHISA1579.17869.4750.4351.0036.86OATOM1000NCYSA1589.35469.5422.6831.0036.43NATOM1001CACYSA15810.66470.1842.6491.0036.33CATOM1002CBCYSA15811.17770.4924.0651.0036.27CATOM1003SGCYSA15810.20171.7544.9241.0037.34SATOM1004CCYSA15811.66369.2901.9371.0037.14CATOM1005OCYSA15812.43169.7511.0691.0036.89OATOM1006NHISA15911.67868.0192.3341.0036.70NATOM1007CAHISA15912.62467.0551.7841.0038.40CATOM1008CBHISA15912.52165.7322.5511.0038.71CATOM1009CGHISA15913.13665.8013.9161.0044.25CATOM1010ND1HISA15913.78864.7344.4991.0047.72NATOM1011CE1HISA15914.25865.1035.6811.0049.12CATOM1012NE2HISA15913.94866.3765.8801.0048.24NATOM1013CD2HISA15913.23866.8344.7981.0047.23CATOM1014CHISA15912.39266.8810.2771.0038.37CATOM1015OHISA15913.33766.781−0.4811.0036.82OATOM1016NASNA16011.12866.926−0.1271.0039.53NATOM1017CAASNA16010.74266.927−1.5291.0042.14CATOM1018CBASNA1609.23967.045−1.6291.0043.88CATOM1019CGASNA1608.60265.778−2.0131.0048.90CATOM1020OD1ASNA1608.72764.765−1.3121.0053.59OATOM1021ND2ASNA1607.91365.795−3.1601.0053.90NATOM1022CASNA16011.32268.100−2.2861.0042.07CATOM1023OASNA16011.66867.978−3.4611.0041.85OATOM1024NCYSA16111.39769.246−1.6161.0040.47NATOM1025CACYSA16111.88470.467−2.2251.0039.41CATOM1026CBCYSA16111.25471.669−1.5291.0039.11CATOM1027SGCYSA1619.49871.835−1.8451.0040.42SATOM1028CCYSA16113.39170.551−2.1291.0038.90CATOM1029OCYSA16113.97971.555−2.5181.0039.21OATOM1030NGLYA16214.02269.510−1.5961.0038.48NATOM1031CAGLYA16215.47469.511−1.4381.0037.84CATOM1032CGLYA16215.95770.269−0.2211.0037.83CATOM1033OGLYA16217.12270.693−0.1601.0036.57OATOM1034NVALA16315.08470.3880.7891.0037.66NATOM1035CAVALA16315.42071.1452.0071.0037.08CATOM1036CBVALA16314.48872.3532.1661.0037.80CATOM1037CG1VALA16314.74873.0823.5111.0038.56CATOM1038CG2VALA16314.66673.3061.0081.0036.79CATOM1039CVALA16315.33770.3053.2941.0037.35CATOM1040OVALA16314.36369.5893.5381.0035.09OATOM1041NLEUA16416.37370.4364.1101.0037.93NATOM1042CALEUA16416.46869.7905.4051.0038.78CATOM1043CBLEUA16417.81369.0895.4681.0039.15CATOM1044CGLEUA16418.08368.1536.6251.0041.81CATOM1045CD1LEUA16417.26066.8666.4661.0042.67CATOM1046CD2LEUA16419.55367.8436.7111.0043.27CATOM1047CLEUA16416.38270.9116.4721.0038.81CATOM1048OLEUA16417.20971.8346.4741.0038.57OATOM1049NHISA16515.38770.8307.3571.0038.45NATOM1050CAHISA16515.16471.8608.3881.0037.77CATOM1051CBHISA16513.75871.7318.9911.0037.59CATOM1052CGHISA16513.39872.8369.9371.0035.86CATOM1053ND1HISA16513.86772.89111.2291.0033.70NATOM1054CE1HISA16513.39173.96911.8231.0034.80CATOM1055NE2HISA16512.62874.61710.9591.0037.29NATOM1056CD2HISA16512.61273.9269.7741.0035.10CATOM1057CHISA16516.23671.8139.4641.0037.76CATOM1058OHISA16516.78472.8439.8241.0038.35OATOM1059NARGA16616.56370.6129.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5.69259.5235.2731.0042.45CATOM1510NE2HISA21925.98259.0106.4551.0043.76NATOM1511CD2HISA21924.93559.2467.3171.0041.90CATOM1512CHISA21921.40462.5217.8431.0039.33CATOM1513OHISA21920.77962.3708.8891.0038.64OATOM1514NGLYA22020.96563.2706.8361.0038.11NATOM1515CAGLYA22019.78464.1036.9501.0037.81CATOM1516CGLYA22018.52763.3947.4051.0038.27CATOM1517OGLYA22017.93163.7458.4291.0037.53OATOM1518NARGA22118.12262.3866.6471.0038.11NATOM1519CAARGA22116.85561.7176.8951.0038.50CATOM1520CBARGA22116.54260.7295.7671.0040.47CATOM1521CGARGA22116.58561.4014.3881.0045.37CATOM1522CDARGA22116.57560.4483.1851.0051.09CATOM1523NEARGA22116.58461.2001.9191.0053.82NATOM1524CZARGA22117.69061.4951.2221.0055.73CATOM1525NH1ARGA22118.89461.0991.6461.0056.00NATOM1526NH2ARGA22117.59462.1640.0751.0055.14NATOM1527CARGA22116.82461.0508.2561.0037.41CATOM1528OARGA22115.87361.2549.0131.0037.16OATOM1529NSERA22217.85860.2908.5971.0036.13NATOM1530CASERA22217.83659.5639.8631.0035.73CATOM1531CBSERA22218.90058.4489.8901.0034.73CATOM1532OGSERA22220.21558.9689.7721.0036.77OATOM1533CSERA22217.94160.51911.0691.0035.26CATOM1534OSERA22217.36560.25012.1371.0035.32OATOM1535NALAA22318.64761.63310.8991.0034.89NATOM1536CAALAA22318.74362.64311.9581.0034.34CATOM1537CBALAA22319.84763.66011.6661.0032.42CATOM1538CALAA22317.39963.35012.1011.0034.25CATOM1539OALAA22316.99263.72613.2141.0033.94OATOM1540NALAA22416.69963.52310.9831.0033.64NATOM1541CAALAA22415.38464.15211.0331.0032.93CATOM1542CBALAA22414.86264.4569.6511.0033.29CATOM1543CALAA22414.41063.26911.8121.0033.44CATOM1544OALAA22413.64563.77012.6511.0033.58OATOM1545NVALA22514.45561.96211.5621.0032.40NATOM1546CAVALA22513.56961.00312.2281.0031.69CATOM1547CBVALA22513.72459.57411.6221.0032.53CATOM1548CG1VALA22513.08358.50412.5071.0030.93CATOM1549CG2VALA22513.12359.54410.2191.0032.75CATOM1550CVALA22513.85660.98813.7401.0032.12CATOM1551OVALA22512.94360.87614.5521.0031.44OATOM1552NTRPA22615.12561.11714.1101.0031.95NATOM1553CATRPA22615.47661.17315.5301.0032.47CATOM1554CBTRPA22616.99061.27915.7211.0033.06CATOM1555CGTRPA22617.32261.49417.1831.0032.56CATOM1556CD1TRPA22617.33462.68217.8511.0032.49CATOM1557NE1TRPA22617.66062.47919.1731.0032.64NATOM1558CE2TRPA22617.83461.13419.3831.0031.73CATOM1559CD2TRPA22617.63160.48518.1481.0031.24CATOM1560CE3TRPA22617.75759.08918.0941.0032.89CATOM1561CZ3TRPA22618.09658.39119.2611.0032.32CATOM1562CH2TRPA22618.28659.08020.4781.0033.34CATOM1563CZ2TRPA22618.15760.44420.5521.0032.43CATOM1564CTRPA22614.75462.37216.1781.0032.00CATOM1565OTRPA22614.07162.22417.1921.0031.94OATOM1566NSERA22714.87263.54615.5581.0031.65NATOM1567CASERA22714.21764.75216.0731.0031.57CATOM1568CBSERA22714.61165.98215.2591.0031.61CATOM1569OGSERA22713.91666.04814.0161.0033.45OATOM1570CSERA22712.69564.59916.1611.0031.31CATOM1571OSERA22712.05265.15117.0721.0030.56OATOM1572NLEUA22812.12463.84115.2291.0030.36NATOM1573CALEUA22810.70163.54515.2171.0030.48CATOM1574CBLEUA22810.30062.86513.9011.0030.69CATOM1575CGLEUA22810.32563.76712.6611.0031.45CATOM1576CD1LEUA22810.06962.94711.3891.0030.81CATOM1577CD2LEUA2289.32164.91712.7841.0030.15CATOM1578CLEUA22810.31562.66116.3941.0029.84CATOM1579OLEUA2289.22762.81516.9581.0030.50OATOM1580NGLYA22911.20661.75116.7651.0029.67NATOM1581CAGLYA22911.00860.89517.9201.0029.67CATOM1582CGLYA22910.99461.72319.2081.0030.52CATOM1583OGLYA22910.16961.48620.1051.0028.98OATOM1584NILEA23011.92062.67019.3071.0030.54NATOM1585CAILEA23011.98663.58720.4591.0031.11CATOM1586CBILEA23013.19964.56420.3341.0031.68CATOM1587CG1ILEA23014.52663.79220.2811.0030.92CATOM1588CD1ILEA23014.82462.99221.5461.0030.66CATOM1589CG2ILEA23013.22965.55321.5331.0030.61CATOM1590CILEA23010.69364.39720.5321.0031.56CATOM1591OILEA23010.05064.48821.5961.0031.09OATOM1592NLEUA23110.28964.92819.3731.0030.97NATOM1593CALEUA2319.05065.71119.2571.0030.14CATOM1594CBLEUA2318.89466.23917.8281.0030.10CATOM1595CGLEUA2317.62767.04317.5561.0032.25CATOM1596CD1LEUA2317.73368.37218.3101.0030.47CATOM1597CD2LEUA2317.41967.24616.0651.0030.92CATOM1598CLEUA2317.79864.95019.6891.0030.59CATOM1599OLEUA2316.94965.48420.4391.0030.81OATOM1600NLEUA2327.65563.72119.2101.0029.58NATOM1601CALEUA2326.49962.91619.5521.0030.41CATOM1602CBLEUA2326.47061.60918.7451.0030.17CATOM1603CGLEUA2325.30160.64219.0331.0030.99CATOM1604CD1LEUA2323.94761.34618.9191.0033.55CATOM1605CD2LEUA2325.35959.46518.0731.0031.95CATOM1606CLEUA2326.43962.63021.0621.0030.78CATOM1607OLEUA2325.37162.72121.6671.0031.42OATOM1608NTYRA2337.57162.27221.6501.0030.02NATOM1609CATYRA2337.64662.04223.1031.0030.55CATOM1610CBTYRA2339.06861.66223.5261.0030.26CATOM1611CGTYRA2339.20961.37325.0081.0028.93CATOM1612CD1TYRA2339.25562.41625.9301.0029.15CATOM1613CE1TYRA2339.35362.17127.3111.0028.65CATOM1614CZTYRA2339.40760.88227.7691.0031.81CATOM1615OHTYRA2339.50560.68129.1321.0036.02OATOM1616CE2TYRA2339.36559.80126.8781.0030.59CATOM1617CD2TYRA2339.26760.05825.4861.0028.47CATOM1618CTYRA2337.21663.30623.8341.0031.37CATOM1619OTYRA2336.41663.25024.7691.0032.79OATOM1620NASPA2347.76264.43423.4071.0031.52NATOM1621CAASPA2347.41165.75023.9341.0033.52CATOM1622CBASPA2348.15666.83323.1621.0034.26CATOM1623CGASPA2347.95168.22423.7451.0037.82CATOM1624OD1ASPA2348.20668.45024.9561.0039.31OATOM1625OD2ASPA2347.53169.15623.0301.0039.97OATOM1626CASPA2345.92366.02323.9231.0034.29CATOM1627OASPA2345.36866.52424.9311.0035.28OATOM1628NMETA2355.25865.69522.8101.0033.03NATOM1629CAMETA2353.81965.90422.7131.0033.96CATOM1630CBMETA2353.29365.62521.3051.0033.12CATOM1631CGMETA2353.64166.70820.2861.0036.42CATOM1632SDMETA2352.96566.24618.6921.0039.55SATOM1633CEMETA2354.17465.26018.1471.0043.23CATOM1634CMETA2353.02065.07823.7031.0033.96CATOM1635OMETA2352.13365.60724.3371.0035.00OATOM1636NVALA2363.32263.78723.8161.0034.07NATOM1637CAVALA2362.51862.89324.6601.0035.02CATOM1638CBVALA2362.40561.47624.0551.0035.33CATOM1639CG1VALA2361.75761.56222.6731.0034.30CATOM1640CG2VALA2363.76360.80523.9371.0033.11CATOM1641CVALA2362.95562.84326.1291.0035.63CATOM1642OVALA2362.22562.32626.9701.0035.58OATOM1643NCYSA2374.13163.38926.4321.0036.11NATOM1644CACYSA2374.64263.38327.8141.0036.98CATOM1645CBCYSA2375.97262.63027.9091.0036.35CATOM1646SGCYSA2375.79660.84427.7571.0038.34SATOM1647CCYSA2374.79064.77828.4161.0037.40CATOM1648OCYSA2374.98364.90729.6281.0038.17OATOM1649NGLYA2384.72265.81227.5761.0036.49NATOM1650CAGLYA2384.79167.18328.0451.0036.34CATOM1651CGLYA2386.18667.71728.2591.0037.64CATOM1652OGLYA2386.35368.84228.7191.0037.75OATOM1653NASPA2397.19866.91627.9391.0038.11NATOM1654CAASPA2398.58067.36928.0091.0039.21CATOM1655CBASPA2399.05667.33929.4581.0040.74CATOM1656CGASPA23910.21468.30229.7351.0045.40CATOM1657OD1ASPA23910.58669.13528.8671.0049.01OATOM1658OD2ASPA23910.82268.27430.8281.0050.33OATOM1659CASPA2399.41866.43427.1421.0039.28CATOM1660OASPA2398.95765.35426.7691.0039.18OATOM1661NILEA24010.63066.85626.8091.0039.54NATOM1662CAILEA24011.52966.06625.9831.0039.95CATOM1663CBILEA24012.64166.96425.4401.0040.83CATOM1664CG1ILEA24013.30667.74026.5781.0041.83CATOM1665CD1ILEA24014.45568.62726.1251.0044.95CATOM1666CG2ILEA24012.09267.91124.3441.0039.77CATOM1667CILEA24012.10664.91626.8271.0040.26CATOM1668OILEA24012.18765.04628.0491.0040.89OATOM1669NPROA24112.47063.79126.2101.0040.14NATOM1670CAPROA24112.94162.62026.9711.0041.03CATOM1671CBPROA24112.87961.49425.9321.0040.79CATOM1672CGPROA24113.15062.18724.6221.0039.44CATOM1673CDPROA24112.44463.51824.7571.0039.54CATOM1674CPROA24114.36162.73727.5481.0042.89CATOM1675OPROA24114.63962.10928.5711.0042.98OATOM1676NPHEA24215.24363.50826.9121.0044.80NATOM1677CAPHEA24216.64463.55527.3401.0046.51CATOM1678CBPHEA24217.58962.94426.2851.0045.41CATOM1679CGPHEA24217.14561.61725.7351.0043.12CATOM1680CD1PHEA24216.88560.54526.5781.0042.42CATOM1681CE1PHEA24216.49659.31326.0681.0041.08CATOM1682CZPHEA24216.36759.14824.6761.0043.10CATOM1683CE2PHEA24216.61860.22223.8241.0040.87CATOM1684CD2PHEA24217.01261.43824.3501.0042.39CATOM1685CPHEA24217.10464.97327.6391.0048.94CATOM1686OPHEA24216.78365.91326.9031.0048.57OATOM1687NGLUA24317.88465.11228.7141.0052.57NATOM1688CAGLUA24318.51466.39129.0461.0055.94CATOM1689CBGLUA24318.20466.79330.4961.0057.25CATOM1690CGGLUA24316.93067.63430.6641.0062.51CATOM1691CDGLUA24316.91168.91229.8141.0068.14CATOM1692OE1GLUA24317.90169.69729.8541.0069.83OATOM1693OE2GLUA24315.89469.14029.1041.0069.55OATOM1694CGLUA24320.02266.36428.8131.0056.70CATOM1695OGLUA24320.59667.32928.2911.0057.61OATOM1696NHISA24420.65465.25029.1691.0057.00NATOM1697CAHISA24422.11165.14529.1281.0057.57CATOM1698CBHISA24422.63464.65330.4841.0057.93CATOM1699CGHISA24422.17765.49131.6411.0060.15CATOM1700ND1HISA24421.24365.04032.5631.0061.46NATOM1701CE1HISA24421.02165.98633.4591.0061.53CATOM1702NE2HISA24421.77267.04033.1451.0061.93NATOM1703CD2HISA24422.50166.76132.0081.0060.89CATOM1704CHISA24422.63264.25127.9991.0057.12CATOM1705OHISA24421.94663.32127.5641.0056.42OATOM1706NASPA24523.85064.55027.5421.0056.65NATOM1707CAASPA24524.53663.77826.5081.0056.51CATOM1708CBASPA24525.98264.25426.3641.0056.84CATOM1709CGASPA24526.09365.55125.6021.0058.28CATOM1710OD1ASPA24525.10966.32225.5551.0060.57OATOM1711OD2ASPA24527.13265.88925.0031.0061.68OATOM1712CASPA24524.52062.28926.7921.0055.85CATOM1713OASPA24524.24061.48725.9021.0055.84OATOM1714NGLUA24624.80761.92628.0381.0055.12NATOM1715CAGLUA24624.81460.52828.4731.0054.57CATOM1716CBGLUA24625.22760.41429.9481.0055.49CATOM1717CGGLUA24626.24761.43930.4191.0059.92CATOM1718CDGLUA24625.60162.74530.8531.0064.57CATOM1719OE1GLUA24624.86462.73231.8731.0066.43OATOM1720OE2GLUA24625.82463.77930.1651.0066.00OATOM1721CGLUA24623.46459.83828.2841.0052.76CATOM1722OGLUA24623.40558.63727.9981.0051.94OATOM1723NGLUA24722.38160.58328.4911.0051.08NATOM1724CAGLUA24721.03760.03128.2891.0050.00CATOM1725CBGLUA24719.98260.94928.8881.0050.91CATOM1726CGGLUA24720.04861.06930.3981.0054.76CATOM1727CDGLUA24719.07062.08930.9191.0059.14CATOM1728OE1GLUA24719.18963.28130.5681.0061.88OATOM1729OE2GLUA24718.17261.69331.6721.0063.68OATOM1730CGLUA24720.73459.78526.8101.0047.56CATOM1731OGLUA24720.17758.75726.4631.0046.72OATOM1732NILEA24821.10260.73825.9571.0046.28NATOM1733CAILEA24820.96460.59824.4981.0046.12CATOM1734CBILEA24821.44661.87623.7541.0045.90CATOM1735CG1ILEA24820.59963.09224.1411.0044.91CATOM1736CD1ILEA24821.11064.41923.5881.0044.29CATOM1737CG2ILEA24821.44461.65822.2331.0045.48CATOM1738CILEA24821.74159.39023.9881.0046.47CATOM1739OILEA24821.22158.61323.1991.0046.50OATOM1740NILEA24922.97759.22324.4621.0046.70NATOM1741CAILEA24923.84558.11924.0211.0047.73CATOM1742CBILEA24925.31558.34224.5161.0048.27CATOM1743CG1ILEA24925.88259.63423.9291.0050.01CATOM1744CD1ILEA24927.16260.11424.6381.0054.07CATOM1745CG2ILEA24926.20857.16724.1271.0049.80CATOM1746CILEA24923.34456.75224.4631.0047.21CATOM1747OILEA24923.47355.75423.7351.0047.14OATOM1748NARGA25022.79856.69725.6711.0046.59NATOM1749CAARGA25022.25955.45426.1971.0046.70CATOM1750CBARGA25022.05255.57327.7121.0046.73CATOM1751CGARGA25021.61254.29728.4151.0047.47CATOM1752CDARGA25021.70254.41529.9421.0049.11CATOM1753NEARGA25021.29053.19130.6311.0050.87NATOM1754CZARGA25020.21753.07631.4291.0050.66CATOM1755NH1ARGA25019.41254.11731.6561.0046.65NATOM1756NH2ARGA25019.95551.90932.0061.0050.26NATOM1757CARGA25020.94955.09725.4831.0046.42CATOM1758OARGA25020.61753.92225.3521.0047.00OATOM1759NGLYA25120.22456.11325.0181.0046.84NATOM1760CAGLYA25118.98255.93624.2691.0047.26CATOM1761CGLYA25117.85555.18024.9681.0047.36CATOM1762OGLYA25116.93654.70224.3181.0047.71OATOM1763NGLNA25217.92155.06726.2901.0046.77NATOM1764CAGLNA25216.87254.40027.0581.0046.61CATOM1765CBGLNA25217.43853.96528.4101.0047.77CATOM1766CGGLNA25216.74552.79729.0341.0053.27CATOM1767CDGLNA25217.36251.49528.5931.0058.82CATOM1768OE1GLNA25216.92250.90227.5871.0062.58OATOM1769NE2GLNA25218.38151.04029.3281.0059.71NATOM1770CGLNA25215.72055.38827.2641.0044.36CATOM1771OGLNA25215.91456.45827.8421.0043.90OATOM1772NVALA25314.53455.03626.7891.0042.26NATOM1773CAVALA25313.36655.91726.8871.0041.30CATOM1774CBVALA25312.51555.90025.5741.0040.85CATOM1775CG1VALA25311.39856.91725.6571.0041.13CATOM1776CG2VALA25313.38656.18424.3301.0041.05CATOM1777CVALA25312.45255.55828.0801.0040.21CATOM1778OVALA25311.87054.47528.1281.0039.18OATOM1779NPHEA25412.31256.49429.0041.0040.53NATOM1780CAPHEA25411.41556.34030.1471.0041.30CATOM1781CBPHEA25412.12556.74931.4461.0042.46CATOM1782CGPHEA25411.18156.97932.5971.0045.89CATOM1783CD1PHEA25410.69855.89033.3541.0048.15CATOM1784CE1PHEA2549.79456.08734.4531.0046.65CATOM1785CZPHEA2549.36857.39134.7621.0047.61CATOM1786CE2PHEA2549.84058.49933.9901.0048.28CATOM1787CD2PHEA25410.74258.28732.9221.0047.87CATOM1788CPHEA25410.19257.21629.9601.0040.77CATOM1789OPHEA25410.32458.38829.6301.0040.62OATOM1790NPHEA2559.01156.65630.2021.0039.76NATOM1791CAPHEA2557.77257.37730.0411.0040.05CATOM1792CBPHEA2556.74456.51229.2931.0038.87CATOM1793CGPHEA2557.04756.40827.8441.0038.12CATOM1794CD1PHEA2556.52057.33226.9451.0037.51CATOM1795CE1PHEA2556.83457.26725.5881.0037.08CATOM1796CZPHEA2557.71556.27725.1261.0038.31CATOM1797CE2PHEA2558.25155.35326.0341.0037.42CATOM1798CD2PHEA2557.91755.42927.3791.0036.49CATOM1799CPHEA2557.23357.90131.3551.0040.75CATOM1800OPHEA2556.97457.13932.2801.0041.63OATOM1801NARGA2567.07859.21431.4141.0042.10NATOM1802CAARGA2566.61359.91132.6141.0043.68CATOM1803CBARGA2567.28461.29132.7221.0044.33CATOM1804CGARGA2567.05062.23331.5491.0046.48CATOM1805CDARGA2567.91563.50831.6061.0049.15CATOM1806NEARGA2569.24863.27731.0341.0053.26NATOM1807CZARGA25610.33464.01831.2931.0054.62CATOM1808NH1ARGA25610.26065.06032.1331.0055.57NATOM1809NH2ARGA25611.50263.72030.7161.0052.61NATOM1810CARGA2565.09660.05132.6581.0043.59CATOM1811OARGA2564.52560.25133.7241.0044.72OATOM1812NGLNA2574.45459.93031.4981.0042.63NATOM1813CAGLNA2573.00159.94931.4031.0041.06CATOM1814CBGLNA2572.53861.06130.4451.0042.46CATOM1815CGGLNA2572.89062.45130.9011.0046.35CATOM1816CDGLNA2571.90862.98431.9161.0051.18CATOM1817OE1GLNA2570.69362.91731.7111.0052.75OATOM1818NE2GLNA2572.42863.50433.0201.0055.05NATOM1819CGLNA2572.51058.61830.8721.0038.68CATOM1820OGLNA2573.26757.84930.3001.0038.45OATOM1821NARGA2581.22658.35331.0471.0036.14NATOM1822CAARGA2580.61457.17730.4791.0036.06CATOM1823CBARGA258−0.82057.04830.9971.0034.77CATOM1824CGARGA258−1.40255.65930.8471.0039.04CATOM1825CDARGA258−1.62455.23029.4421.0040.99CATOM1826NEARGA258−1.79953.78929.3001.0040.39NATOM1827CZARGA258−2.32753.21928.2151.0043.89CATOM1828NH1ARGA258−2.73053.96627.1581.0045.06NATOM1829NH2ARGA258−2.44451.89928.1621.0040.81NATOM1830CARGA2580.59957.34528.9501.0035.62CATOM1831OARGA2580.07158.32528.4631.0035.32OATOM1832NVALA2591.15956.38528.2211.0034.94NATOM1833CAVALA2591.22356.44026.7551.0034.87CATOM1834CBVALA2592.62956.92626.2771.0035.54CATOM1835CG1VALA2592.78256.82424.7471.0034.21CATOM1836CG2VALA2592.90258.36526.7521.0033.65CATOM1837CVALA2590.96755.03326.2351.0035.77CATOM1838OVALA2591.57954.06226.7281.0035.74OATOM1839NSERA2600.05554.90125.2671.0035.24NATOM1840CASERA260−0.26953.60124.6981.0036.49CATOM1841CBSERA260−1.24753.74923.5251.0036.47CATOM1842OGSERA260−0.60854.28522.3771.0037.04OATOM1843CSERA2600.97352.85524.2261.0037.15CATOM1844OSERA2601.98153.46523.8741.0037.30OATOM1845NSERA2610.87651.53324.1781.0037.42NATOM1846CASERA2612.00050.70123.7671.0037.73CATOM1847CBSERA2611.65949.22523.9411.0038.27CATOM1848OGSERA2611.47548.93925.3161.0042.42OATOM1849CSERA2612.39950.96522.3251.0037.68CATOM1850OSERA2613.57850.91421.9971.0036.60OATOM1851NGLUA2621.41351.26021.4781.0037.69NATOM1852CAGLUA2621.66251.57820.0801.0038.33CATOM1853CBGLUA2620.34351.65519.3071.0040.07CATOM1854CGGLUA262−0.52250.40119.4441.0047.46CATOM1855CDGLUA262−1.13849.95418.1251.0055.14CATOM1856OE1GLUA262−1.71650.81117.4071.0058.98OATOM1857OE2GLUA262−1.05848.74017.7991.0059.70OATOM1858CGLUA2622.46952.87819.9451.0036.65CATOM1859OGLUA2623.44252.91119.2271.0036.27OATOM1860NCYSA2632.07353.93120.6511.0035.34NATOM1861CACYSA2632.82255.18820.6211.0034.46CATOM1862CBCYSA2632.05156.27221.3631.0034.30CATOM1863SGCYSA2632.72857.93121.2071.0034.38SATOM1864CCYSA2634.25055.02121.1811.0034.46CATOM1865OCYSA2635.22155.47720.5561.0032.45OATOM1866NGLNA2644.38554.32522.3211.0033.42NATOM1867CAGLNA2645.71554.00822.8591.0033.11CATOM1868CBGLNA2645.62953.11024.0971.0033.38CATOM1869CGGLNA2645.02253.78125.3641.0035.44CATOM1870CDGLNA2645.29652.96826.6471.0037.59CATOM1871OE1GLNA2646.16252.09826.6551.0039.41OATOM1872NE2GLNA2644.56653.26227.7171.0033.63NATOM1873CGLNA2646.57853.31421.7951.0033.15CATOM1874OGLNA2647.75353.68921.6061.0032.43OATOM1875NHISA2656.00152.32221.1101.0032.53NATOM1876CAHISA2656.71051.57520.0681.0034.99CATOM1877CBHISA2655.83650.45519.4691.0036.23CATOM1878CGHISA2656.51549.68718.3691.0039.71CATOM1879ND1HISA2656.48150.08617.0501.0040.80NATOM1880CE1HISA2657.18949.24416.3141.0042.05CATOM1881NE2HISA2657.68748.31217.1101.0042.46NATOM1882CD2HISA2657.28648.57018.4021.0042.81CATOM1883CHISA2657.22652.50818.9681.0034.14CATOM1884OHISA2658.41052.46318.6131.0034.55OATOM1885NLEUA2666.35553.37218.4451.0032.99NATOM1886CALEUA2666.77854.30617.3941.0032.41CATOM1887CBLEUA2665.58755.14716.8961.0032.45CATOM1888CGLEUA2665.86356.20915.8181.0033.18CATOM1889CD1LEUA2666.58455.61914.6051.0030.32CATOM1890CD2LEUA2664.51156.82015.3671.0030.03CATOM1891CLEUA2667.88555.21117.9041.0031.79CATOM1892OLEUA2668.90755.41717.2311.0031.14OATOM1893NILEA2677.70655.75019.1121.0031.36NATOM1894CAILEA2678.70256.66119.6661.0030.41CATOM1895CBILEA2678.27357.18421.0521.0029.95CATOM1896CG1ILEA2677.13458.21020.9241.0030.35CATOM1897CD1ILEA2676.41058.51322.2711.0030.22CATOM1898CG2ILEA2679.47257.84921.7511.0028.77CATOM1899CILEA26710.05255.95619.7821.0031.85CATOM1900OILEA26711.09356.48519.3401.0032.22OATOM1901NARGA26810.03454.77420.3881.0032.17NATOM1902CAARGA26811.24853.98820.5941.0034.65CATOM1903CBARGA26810.92752.71321.3691.0035.11CATOM1904CGARGA26810.70752.93122.8641.0039.57CATOM1905CDARGA26810.39851.63723.6001.0045.10CATOM1906NEARGA2689.72551.86624.8901.0048.08NATOM1907CZARGA26810.37052.33825.9351.0049.97CATOM1908NH1ARGA26811.66352.60925.8061.0053.48NATOM1909NH2ARGA2689.75352.55127.0931.0048.54NATOM1910CARGA26811.92153.62219.2781.0034.22CATOM1911OARGA26813.14053.49119.2231.0034.73OATOM1912NTRPA26911.12453.46418.2251.0034.43NATOM1913CATRPA26911.64953.13516.8891.0034.10CATOM1914CBTRPA26910.50352.65715.9921.0034.69CATOM1915CGTRPA26910.92152.00814.7161.0036.80CATOM1916CD1TRPA26912.19151.63214.3521.0039.30CATOM1917NE1TRPA26912.18251.08113.0901.0038.76NATOM1918CE2TRPA26910.89551.07112.6181.0037.50CATOM1919CD2TRPA26910.07451.66913.6091.0036.90CATOM1920CE3TRPA2698.70351.78713.3591.0035.95CATOM1921CZ3TRPA2698.19751.33212.1361.0037.55CATOM1922CH2TRPA2699.04750.76511.1721.0036.64CATOM1923CZ2TRPA26910.39250.61811.4011.0036.32CATOM1924CTRPA26912.34654.35116.2791.0034.12CATOM1925OTRPA26913.46154.24815.7661.0034.65OATOM1926NCYSA27011.70455.51416.3471.0033.89NATOM1927CACYSA27012.31556.76215.8811.0033.18CATOM1928CBCYSA27011.36457.95816.0301.0032.73CATOM1929SGCYSA2709.89457.93314.9801.0034.78SATOM1930CCYSA27013.59357.08516.6271.0033.31CATOM1931OCYSA27014.47157.75916.0851.0033.37OATOM1932NLEUA27113.68656.63517.8791.0032.81NATOM1933CALEUA27114.83556.93418.7111.0033.61CATOM1934CBLEUA27114.40557.34220.1431.0033.79CATOM1935CGLEUA27113.57358.64920.2231.0033.39CATOM1936CD1LEUA27113.17858.97121.6681.0032.58CATOM1937CD2LEUA27114.33059.82019.6021.0029.30CATOM1938CLEUA27115.80555.76618.7611.0034.83CATOM1939OLEUA27116.53655.61319.7271.0034.16OATOM1940NALAA27215.83654.95817.7051.0035.68NATOM1941CAALAA27216.79653.85317.6581.0037.00CATOM1942CBALAA27216.56352.99416.4291.0037.89CATOM1943CALAA27218.19154.46017.6581.0037.13CATOM1944OALAA27218.43655.46616.9961.0036.83OATOM1945NLEUA27319.08753.88618.4471.0038.00NATOM1946CALEUA27320.46454.37818.5371.0039.46CATOM1947CBLEUA27321.26653.53119.5321.0039.79CATOM1948CGLEUA27320.99053.79521.0111.0040.61CATOM1949CD1LEUA27321.92352.96621.9141.0040.75CATOM1950CD2LEUA27321.17455.27721.3041.0039.54CATOM1951CLEUA27321.14654.35017.1681.0040.47CATOM1952OLEUA27321.74255.33116.7471.0040.46OATOM1953NARGA27421.05153.22516.4701.0041.49NATOM1954CAARGA27421.67053.13815.1511.0043.63CATOM1955CBARGA27421.92951.68314.7531.0044.96CATOM1956CGARGA27422.91750.94315.6651.0051.46CATOM1957CDARGA27423.14549.47015.2751.0060.47CATOM1958NEARGA27423.42649.35413.8421.0066.38NATOM1959CZARGA27423.51148.21213.1721.0069.93CATOM1960NH1ARGA27423.34447.04813.7921.0071.16NATOM1961NH2ARGA27423.77548.23911.8681.0072.00NATOM1962CARGA27420.78453.82614.1171.0042.18CATOM1963OARGA27419.63253.46913.9591.0042.54OATOM1964NPROA27521.32554.80713.4091.0041.48NATOM1965CAPROA27520.56655.52912.3831.0041.53CATOM1966CBPROA27521.65556.30211.6481.0041.70CATOM1967CGPROA27522.61856.62912.7451.0041.06CATOM1968CDPROA27522.69355.34013.5461.0041.06CATOM1969CPROA27519.78454.62411.4291.0041.71CATOM1970OPROA27518.63354.93211.1321.0039.61OATOM1971NSERA27620.39353.51610.9931.0041.90NATOM1972CASERA27619.77452.58710.0401.0042.57CATOM1973CBSERA27620.83151.6249.4461.0043.08CATOM1974OGSERA27621.29050.68310.4191.0045.84OATOM1975CSERA27618.59751.79910.6131.0041.74CATOM1976OSERA27617.78651.2879.8451.0042.39OATOM1977NASPA27718.49751.69611.9421.0040.48NATOM1978CAASPA27717.34451.03812.5751.0039.45CATOM1979CBASPA27717.67650.52013.9811.0040.14CATOM1980CGASPA27718.67149.37413.9741.0041.45CATOM1981OD1ASPA27718.69748.57713.0101.0043.47OATOM1982OD2ASPA27719.47149.22114.9151.0043.49OATOM1983CASPA27716.10251.94612.6761.0038.59CATOM1984OASPA27715.01051.48613.0141.0037.61OATOM1985NARGA27816.26953.22712.3641.0037.09NATOM1986CAARGA27815.14554.15912.4481.0035.81CATOM1987CBARGA27815.65755.59812.5451.0034.54CATOM1988CGARGA27816.40755.83613.8361.0034.40CATOM1989CDARGA27817.01757.22513.9571.0035.33CATOM1990NEARGA27818.11957.18614.9131.0035.31NATOM1991CZARGA27819.16357.99614.9131.0036.13CATOM1992NH1ARGA27819.28658.97114.0101.0034.75NATOM1993NH2ARGA27820.10357.81515.8291.0036.28NATOM1994CARGA27814.22353.98311.2431.0036.08CATOM1995OARGA27814.68753.61010.1561.0036.69OATOM1996NPROA27912.93654.27511.4211.0035.45NATOM1997CAPROA27911.98454.19310.3141.0035.56CATOM1998CBPROA27910.62754.30311.0041.0035.57CATOM1999CGPROA27910.91555.14712.2241.0035.53CATOM2000CDPROA27912.28454.71012.6771.0035.37CATOM2001CPROA27912.17455.3229.3111.0035.53CATOM2002OPROA27912.78456.3549.6261.0035.63OATOM2003NTHRA28011.66155.1078.1011.0034.84NATOM2004CATHRA28011.61856.1457.0791.0034.43CATOM2005CBTHRA28011.50955.5135.6831.0034.63CATOM2006OG1THRA28010.34454.6905.6551.0034.43OATOM2007CG2THRA28012.71254.5555.3791.0035.88CATOM2008CTHRA28010.33456.9007.3371.0034.28CATOM2009OTHRA2809.50156.4588.1201.0033.22OATOM2010NPHEA28110.12958.0126.6371.0035.30NATOM2011CAPHEA2818.89358.7716.7971.0035.82CATOM2012CBPHEA2818.89260.0205.9071.0036.90CATOM2013CGPHEA2819.98461.0096.2231.0038.29CATOM2014CD1PHEA28110.33261.3007.5361.0039.19CATOM2015CE1PHEA28111.32062.2347.8231.0039.73CATOM2016CZPHEA28111.96862.8746.8101.0041.57CATOM2017CE2PHEA28111.62162.6085.4831.0043.04CATOM2018CD2PHEA28110.63361.6815.2001.0041.16CATOM2019CPHEA2817.69057.8946.4771.0036.17CATOM2020OPHEA2816.67157.9247.1791.0035.36OATOM2021NGLUA2827.81557.1015.4141.0035.33NATOM2022CAGLUA2826.74156.1944.9921.0035.04CATOM2023CBGLUA2827.15455.4613.7001.0035.95CATOM2024CGGLUA2826.09254.5303.1411.0038.88CATOM2025CDGLUA2826.50453.8721.8191.0042.76CATOM2026OE1GLUA2827.65454.0561.3621.0043.67OATOM2027OE2GLUA2825.65453.1821.2331.0043.19OATOM2028CGLUA2826.38555.1996.0841.0034.27CATOM2029OGLUA2825.20954.9866.3781.0034.51OATOM2030NGLUA2837.39754.5946.6931.0034.18NATOM2031CAGLUA2837.19453.6407.7951.0034.58CATOM2032CBGLUA2838.51253.0128.2081.0035.26CATOM2033CGGLUA2839.07752.0967.1311.0038.60CATOM2034CDGLUA28310.40651.5017.5021.0040.02CATOM2035OE1GLUA28311.34052.2577.8321.0041.52OATOM2036OE2GLUA28310.51750.2667.4351.0044.14OATOM2037CGLUA2836.52454.2599.0141.0033.96CATOM2038OGLUA2835.70053.6149.6741.0033.93OATOM2039NILEA2846.85955.5179.2981.0033.26NATOM2040CAILEA2846.20456.23310.4011.0031.63CATOM2041CBILEA2846.88957.59010.6501.0031.52CATOM2042CG1ILEA2848.28257.37311.2521.0029.17CATOM2043CD1ILEA2849.19558.58511.1901.0032.09CATOM2044CG2ILEA2846.00258.48911.6021.0029.23CATOM2045CILEA2844.73256.43010.0891.0031.80CATOM2046OILEA2843.85656.16510.9171.0031.97OATOM2047NGLNA2854.45156.9178.8861.0032.64NATOM2048CAGLNA2853.07057.2048.5151.0032.77CATOM2049CBGLNA2853.02258.0997.2801.0032.86CATOM2050CGGLNA2853.37359.5667.6131.0032.93CATOM2051CDGLNA2853.05660.5076.4851.0035.30CATOM2052OE1GLNA2853.63760.4015.3951.0034.32OATOM2053NE2GLNA2852.12261.4236.7251.0033.69NATOM2054CGLNA2852.23955.9488.3341.0033.74CATOM2055OGLNA2851.02155.9968.4541.0034.52OATOM2056NASNA2862.88954.8168.0841.0034.59NATOM2057CAASNA2862.16553.5338.0161.0036.22CATOM2058CBASNA2862.77052.6076.9661.0035.90CATOM2059CGASNA2862.45053.0425.5531.0037.57CATOM2060OD1ASNA2861.39753.6115.2831.0037.74OATOM2061ND2ASNA2863.37352.7854.6421.0039.91NATOM2062CASNA2862.07952.8059.3601.0036.58CATOM2063OASNA2861.43251.7679.4661.0037.11OATOM2064NHISA2872.72353.35610.3841.0036.48NATOM2065CAHISA2872.67752.77111.7171.0036.00CATOM2066CBHISA2873.52553.59612.6971.0035.69CATOM2067CGHISA2873.70352.93814.0291.0033.97CATOM2068ND1HISA2874.82652.21114.3591.0035.79NATOM2069CE1HISA2874.70651.74915.5921.0034.10CATOM2070NE2HISA2873.53752.13816.0661.0036.32NATOM2071CD2HISA2872.88852.87515.1031.0033.02CATOM2072CHISA2871.23852.72412.2231.0036.98CATOM2073OHISA2870.47553.66311.9851.0036.67OATOM2074NPROA2880.87051.63812.9091.0037.63NATOM2075CAPROA288−0.46551.48013.4681.0038.40CATOM2076CBPROA288−0.31850.20314.3151.0039.46CATOM2077CGPROA2880.68449.42013.5761.0040.31CATOM2078CDPROA2881.69950.44713.1741.0038.01CATOM2079CPROA288−0.93652.65214.3251.0037.78CATOM2080OPROA288−2.09653.02414.2271.0038.92OATOM2081NTRPA289−0.06253.23115.1431.0037.99NATOM2082CATRPA289−0.45954.38715.9511.0036.84CATOM2083CBTRPA2890.64254.77916.9321.0037.43CATOM2084CGTRPA2890.19755.89217.8621.0036.44CATOM2085CD1TRPA289−0.60155.77618.9691.0036.79CATOM2086NE1TRPA289−0.80057.01419.5421.0035.91NATOM2087CE2TRPA289−0.13657.95618.7951.0035.04CATOM2088CD2TRPA2890.50057.28117.7301.0035.44CATOM2089CE3TRPA2891.27558.03416.8221.0034.75CATOM2090CZ3TRPA2891.36559.41217.0001.0033.10CATOM2091CH2TRPA2890.71960.04618.0721.0032.65CATOM2092CZ2TRPA289−0.02459.33718.9801.0035.41CATOM2093CTRPA289−0.88655.59815.1021.0037.02CATOM2094OTRPA289−1.70356.40215.5511.0036.85OATOM2095NMETA290−0.37555.70413.8751.0037.67NATOM2096CAMETA290−0.68156.85713.0021.0039.50CATOM2097CBMETA2900.47557.11912.0381.0038.69CATOM2098CGMETA2901.77057.55212.7371.0039.97CATOM2099SDMETA2902.02659.34012.6601.0043.39SATOM2100CEMETA2900.82659.82613.6091.0036.57CATOM2101CMETA290−1.97356.78712.1861.0041.20CATOM2102OMETA290−2.26957.70311.3971.0040.58OATOM2103NGLNA291−2.73555.70912.3381.0043.28NATOM2104CAGLNA291−3.92855.51611.5041.0045.49CATOM2105CBGLNA291−4.29454.03111.4201.0046.70CATOM2106CGGLNA291−3.16953.16310.8631.0052.12CATOM2107CDGLNA291−2.98953.2579.3301.0058.53CATOM2108OE1GLNA291−3.10754.3398.7231.0059.20OATOM2109NE2GLNA291−2.67452.1138.7081.0062.36NATOM2110CGLNA291−5.11256.32912.0011.0045.68CATOM2111OGLNA291−5.16556.70813.1771.0045.87OATOM2112NASPA292−6.06456.59011.1001.0046.07NATOM2113CAASPA292−7.30557.33111.4101.0046.57CATOM2114CBASPA292−8.19556.55612.3911.0047.72CATOM2115CGASPA292−8.32455.09912.0181.0052.03CATOM2116OD1ASPA292−8.71454.83610.8581.0054.96OATOM2117OD2ASPA292−8.03154.16412.8051.0056.19OATOM2118CASPA292−7.07158.73911.9611.0045.48CATOM2119OASPA292−7.77959.18112.8801.0044.34OATOM2120NVALA293−6.06759.43311.4241.0044.87NATOM2121CAVALA293−5.75060.78711.8821.0044.61CATOM2122CBVALA293−4.49561.33811.1811.0044.85CATOM2123CG1VALA293−4.79161.6629.7351.0044.77CATOM2124CG2VALA293−3.98962.56811.8961.0043.11CATOM2125CVALA293−6.93561.70911.6401.0044.94CATOM2126OVALA293−7.65861.53210.6531.0045.74OATOM2127NLEUA294−7.14962.66812.5381.0044.60NATOM2128CALEUA294−8.20963.65012.3541.0044.83CATOM2129CBLEUA294−8.48964.41613.6411.0043.88CATOM2130CGLEUA294−9.00963.72114.8861.0044.35CATOM2131CD1LEUA294−9.11864.76015.9721.0042.61CATOM2132CD2LEUA294−10.33763.03614.6321.0045.06CATOM2133CLEUA294−7.76364.65511.3121.0045.35CATOM2134OLEUA294−6.57064.88811.1421.0045.48OATOM2135NLEUA295−8.72865.26610.6291.0046.10NATOM2136CALEUA295−8.44466.3589.7121.0046.34CATOM2137CBLEUA295−9.64566.5868.7901.0047.42CATOM2138CGLEUA295−9.55265.9687.3801.0050.24CATOM2139CD1LEUA295−9.35264.4607.4151.0051.66CATOM2140CD2LEUA295−10.81266.2886.5951.0054.37CATOM2141CLEUA295−8.12367.61210.5271.0046.02CATOM2142OLEUA295−8.53167.72311.6931.0044.80OATOM2143NPROA296−7.36668.5449.9551.0046.46NATOM2144CAPROA296−7.04869.79010.6581.0047.09CATOM2145CBPROA296−6.40570.6339.5611.0046.93CATOM2146CGPROA296−5.69869.6098.7411.0045.84CATOM2147CDPROA296−6.70868.4968.6381.0046.93CATOM2148CPROA296−8.28270.46511.2661.0048.28CATOM2149OPROA296−8.28070.73912.4741.0047.68OATOM2150NGLNA297−9.33570.68410.4801.0050.01NATOM2151CAGLNA297−10.53771.32811.0221.0051.78CATOM2152CGGLNA297−11.57271.6369.9331.0052.87CATOM2153CGGLNA297−12.55272.78110.2981.0055.96CATOM2154CDGLNA297−11.85874.12210.6321.0060.05CATOM2155OE1GLNA297−11.22174.7399.7651.0062.29OATOM2156NE2GLNA297−11.99274.57011.8841.0060.16NATOM2157CGLNA297−11.17570.55012.1811.0051.71CATOM2158OGLNA297−11.53671.14013.2011.0052.21OATOM2159NGLUA298−11.29269.23412.0341.0051.63NATOM2160CAGLUA298−11.81968.39113.1081.0051.67CATOM2161CBGLUA298−11.71466.92212.7361.0052.61CATOM2162CGGLUA298−12.71666.40611.7321.0056.45CATOM2163CDGLUA298−12.56864.90811.5521.0060.37CATOM2164OE1GLUA298−11.60664.48010.8741.0061.21OATOM2165OE2GLUA298−13.40364.16012.1121.0063.66OATOM2166CGLUA298−10.99168.58614.3721.0050.78CATOM2167OGLUA298−11.52368.66615.4901.0050.03OATOM2168NTHRA299−9.67668.62414.1861.0049.28NATOM2169CATHRA299−8.75668.81215.2911.0048.32CATOM2170CBTHRA299−7.31068.85514.7811.0048.02CATOM2171OG1THRA299−7.00767.63614.0961.0045.02OATOM2172CG2THRA299−6.32468.91015.9511.0047.18CATOM2173CTHRA299−9.07270.09516.0401.0048.76CATOM2174OTHRA299−9.13570.10117.2681.0047.62OATOM2175NALAA300−9.25271.18115.2931.0049.46NATOM2176CAALAA300−9.54072.46815.8871.0050.94CATOM2177CBALAA300−9.54173.55614.8201.0050.83CATOM2178CALAA300−10.87572.43816.6641.0051.99CATOM2179OALAA300−10.96172.94017.7931.0051.96OATOM2180NGLUA301−11.89671.83216.0641.0053.05NATOM2181CAGLUA301−13.21871.75716.6891.0054.49CATOM2182CBGLUA301−14.22071.09415.7541.0055.03CATOM2183CGGLUA301−14.92672.07314.8311.0058.47CATOM2184CDGLUA301−15.12971.51813.4291.0061.94CATOM2185OE1GLUA301−15.41870.30313.2871.0062.49OATOM2186OE2GLUA301−15.00672.30612.4591.0064.87OATOM2187CGLUA301−13.17771.01818.0261.0054.40CATOM2188OGLUA301−13.65271.53619.0481.0054.62OATOM2189NILEA302−12.58169.82618.0111.0054.14NATOM2190CAILEA302−12.48768.97019.1961.0053.52CATOM2191CBILEA302−12.12467.52918.7911.0053.66CATOM2192CG1ILEA302−13.15066.98117.7951.0053.26CATOM2193CD1ILEA302−12.81365.60917.2541.0052.59CATOM2194CG2ILEA302−12.04766.62420.0261.0053.65CATOM2195CILEA302−11.49669.46220.2461.0053.50CATOM2196OILEA302−11.80069.42221.4401.0053.33OATOM2197NHISA303−10.32269.93719.8221.0053.16NATOM2198CAHISA303−9.25870.22020.7931.0053.02CATOM2199CBHISA303−8.01869.39020.4591.0051.63CATOM2200CGHISA303−8.21267.92620.6801.0047.34CATOM2201ND1HISA303−8.39667.04319.6401.0045.24NATOM2202CE1HISA303−8.54065.82220.1191.0042.60CATOM2203NE2HISA303−8.45665.88321.4371.0042.67NATOM2204CD2HISA303−8.25167.18821.8151.0043.90CATOM2205CHISA303−8.86171.67120.9601.0054.55CATOM2206OHISA303−8.26572.03621.9791.0054.31OATOM2207NLEUA304−9.16872.50019.9661.0056.55NATOM2208CALEUA304−8.69673.87619.9991.0059.36CATOM2209CBLEUA304−7.96774.21118.7011.0058.46CATOM2210CGLEUA304−6.47973.87018.5491.0058.16CATOM2211CD1LEUA304−6.02672.66919.3901.0055.35CATOM2212CD2LEUA304−6.16073.65317.0611.0056.12CATOM2213CLEUA304−9.83274.87320.2731.0062.12CATOM2214OLEUA304−9.58676.06720.4311.0062.18OATOM2215NHISA305−11.06174.36120.3401.0065.89NATOM2216CAHISA305−12.27875.15020.5711.0069.84CATOM2217CBHISA305−12.20175.96321.8841.0070.73CATOM2218CGHISA305−11.78075.13823.0691.0074.80CATOM2219ND1HISA305−12.61174.20623.6641.0077.77NATOM2220CE1HISA305−11.97673.62924.6741.0078.93CATOM2221NE2HISA305−10.76074.14924.7531.0079.02NATOM2222CD2HISA305−10.61175.09323.7601.0077.72CATOM2223CHISA305−12.59176.04719.3821.0071.35CATOM2224OHISA305−12.45877.27219.4631.0072.07OATOM2225NSERA306−12.99875.42618.2751.0073.04NATOM2226CASERA306−13.37276.16117.0661.0074.54CATOM2227CBSERA306−12.56375.68515.8501.0074.28CATOM2228OGSERA306−11.27076.30915.8431.0074.68OATOM2229CSERA306−14.87876.06116.8041.0075.41CATOM2230OSERA306−15.58877.08016.8581.0076.03OATOM2231OXTSERA306−15.39774.96616.5421.0075.98OATOM2232N3IMDI18.12871.29826.4391.0062.13NATOM2233C4IMDI18.44171.42827.7551.0062.64CATOM2234C5IMDI17.73172.51328.2671.0061.10CATOM2235C2IMDI17.24572.27626.1251.0061.77CATOM2236N1IMDI17.00173.01627.2421.0061.00NATOM2237OHOHW1−0.73254.5289.7281.0045.36OATOM2238OHOHW219.63058.7166.5761.0043.01OATOM2239OHOHW30.31061.2642.8491.0032.73OATOM2240OHOHW418.44064.20621.5271.0032.96OATOM2241OHOHW512.98880.6688.4241.0039.01OATOM2242OHOHW6−1.36851.61730.4891.0040.35OATOM2243OHOHW716.48875.63310.8961.0039.22OATOM2244OHOHW822.71562.6954.2861.0041.65OATOM2245OHOHW915.54667.9759.9691.0034.80OATOM2246OHOHW109.87357.7333.2001.0034.66OATOM2247OHOHW1122.04177.1978.2231.0059.58OATOM2248OHOHW1213.92168.2957.8011.0043.48OATOM2249OHOHW13−2.00149.45429.3351.0040.96OATOM2250OHOHW1422.26159.91410.8821.0037.32OATOM2251OHOHW1519.41950.73416.9661.0040.82OATOM2252OHOHW1615.33857.1599.0221.0039.03OATOM2253OHOHW1717.96166.5499.8821.0039.50OATOM2254OHOHW184.81876.3410.5451.0044.94OATOM2255OHOHW198.85579.1967.5181.0039.17OATOM2256OHOHW2017.07254.13021.8441.0043.20OATOM2257OHOHW211.32569.5877.1101.0036.36OATOM2258OHOHW228.15061.6561.2201.0040.26OATOM2259OHOHW23−4.43566.66610.9791.0043.16OATOM2260OHOHW2410.51380.7139.1171.0042.28OATOM2261OHOHW2515.49765.16424.5571.0034.79OATOM2262OHOHW269.90052.8313.5891.0042.40OATOM2263OHOHW27−0.20071.7198.3871.0041.34OATOM2264OHOHW28−7.39859.98215.5511.0040.20OATOM2265OHOHW293.49281.32221.0131.0047.98OATOM2266OHOHW30−4.71467.42525.0261.0043.45OATOM2267OHOHW3115.25168.12212.6731.0036.68OATOM2268OHOHW32−5.70962.26015.1191.0039.90OATOM2269OHOHW334.55383.95511.4461.0045.99OATOM2270OHOHW3418.79157.16928.0571.0043.68OATOM2271OHOHW3518.23165.46414.8721.0037.87OATOM2272OHOHW368.97153.78930.8601.0043.70OATOM2273OHOHW375.18050.9839.9001.0039.96OATOM2274OHOHW38−4.08160.21125.4791.0043.04OATOM2275OHOHW39−1.65050.29824.9531.0050.05OATOM2276OHOHW40−0.32379.6862.1811.0064.08OATOM2277OHOHW41−4.01458.3329.2321.0045.77OATOM2278OHOHW4210.27350.30618.8991.0043.91OATOM2279OHOHW4316.89054.8838.9551.0043.73OATOM2280OHOHW443.73065.9932.0971.0044.04OATOM2281OHOHW4523.97270.5632.2751.0040.95OATOM2282OHOHW4624.63358.60210.0521.0042.68OATOM2283OHOHW4719.82861.6184.3581.0051.38OATOM2284OHOHW4822.51790.82315.9521.0070.96OATOM2285OHOHW4929.35460.9213.1671.0057.58OATOM2286OHOHW5011.46882.36912.2891.0050.02OATOM2287OHOHW5124.77262.519−4.1211.0045.22OATOM2288OHOHW523.21168.55431.5821.0069.57OATOM2289OHOHW537.93650.00223.1241.0047.40OATOM2290OHOHW5415.58771.21217.0461.0052.35OATOM2291OHOHW5515.88479.008−3.5801.0056.72OATOM2292OHOHW5625.27956.11010.2301.0044.21OATOM2293OHOHW5712.51458.7674.8371.0052.23OATOM2294OHOHW581.68878.2344.5431.0043.74OATOM2295OHOHW599.01882.80311.1681.0050.76OATOM2296OHOHW60−0.21785.7426.0961.0053.93OATOM2297OHOHW61−2.93082.30921.7721.0058.06OATOM2298OHOHW625.50451.2255.1301.0048.90OATOM2299OHOHW6320.07654.4697.3501.0061.18OATOM2300OHOHW645.72268.809−1.9341.0059.42OATOM2301OHOHW6527.88266.292−1.5121.0065.79OATOM2302OHOHW6619.67672.15323.2291.0061.17OATOM2303OHOHW67−5.50171.4145.3011.0061.16OATOM2304OHOHW6815.01658.0566.4731.0049.90OATOM2305OHOHW69−2.01255.7306.1301.0056.99OATOM2306OHOHW70−9.44770.1887.6821.0057.22OATOM2307OHOHW712.48455.120−0.0381.0049.25OATOM2308OHOHW72−7.90859.2378.4791.0065.73OATOM2309OHOHW7322.35373.25511.7641.0060.74OATOM2310OHOHW7419.47767.32411.8571.0050.67OATOM2311OHOHW7514.50647.97013.2801.0062.36OATOM2312OHOHW7616.86247.8078.7681.0052.55OATOM2313OHOHW7713.31353.08332.0981.0054.43OATOM2314OHOHW7817.50350.79819.0411.0055.72OATOM2315OHOHW79−12.73662.09418.1891.0053.56OATOM2316OHOHW8033.90862.97910.7121.0063.79OATOM2317OHOHW81−6.87060.60522.6281.0049.67OATOM2318OHOHW829.98747.58214.0461.0066.52OATOM2319OHOHW8323.18373.2872.5101.0052.15OATOM2320OHOHW8427.57855.7709.0601.0063.00OATOM2321OHOHW855.57682.970−1.7481.0062.58OATOM2322OHOHW86−0.50984.3303.8571.0059.32OATOM2323OHOHW8713.66591.473−3.5521.0061.08OATOM2324OHOHW88−2.86175.397−2.0381.0063.22OATOM2325OHOHW8910.20473.97929.7901.0066.32OATOM2326OHOHW9020.07078.9836.9711.0067.67OATOM2327OHOHW9117.16977.34721.9101.0065.17OATOM2328OHOHW92−2.87053.04518.1631.0059.47OATOM2329OHOHW9311.62771.62823.4401.0063.19OATOM2330OHOHW948.31074.960−2.6781.0055.47OATOM2331OHOHW95−12.00278.8514.3041.0058.94OATOM2332OHOHW965.56649.15722.7961.0051.78OATOM2333OHOHW9731.35861.4780.5971.0066.61OATOM2334OHOHW9824.03564.093−2.0911.0047.25OATOM2335OHOHW9911.29469.11134.2951.0070.13OATOM2336OHOHW10018.99964.123−2.1681.0062.14OATOM2337OHOHW101−9.73961.4937.6981.0082.68OATOM2338OHOHW10222.43552.02525.4391.0054.62OATOM2339OHOHW1035.04549.27612.1141.0055.83OATOM2340OHOHW104−3.96550.52412.2241.0062.13OATOM2341OHOHW10513.47275.94526.2501.0061.94OATOM2342OHOHW10615.56072.15626.2971.0058.39OATOM2343OHOHW107−0.19596.03419.6351.0069.60OATOM2344OHOHW1081.24388.090−4.0311.0062.22OATOM2345OHOHW10919.97383.75920.5851.0071.41OATOM2346OHOHW110−8.15273.4868.2881.0053.47OATOM2347OHOHW11123.42081.7229.2331.0071.36OATOM2348OHOHW1121.59682.691−0.0961.0071.76OATOM2349OHOHW1135.65756.059−1.3361.0064.94OATOM2350OHOHW11413.96751.5758.3741.0051.56OATOM2351OHOHW11512.41678.38925.2001.0066.19OATOM2352OHOHW11617.23583.39211.4471.0052.25OATOM2353OHOHW11714.76752.85221.3141.0047.79OATOM2354OHOHW11819.07560.231−4.0281.0064.68OATOM2355OHOHW11925.47666.80028.8231.0055.96OATOM2356OHOHW1204.47370.02130.0201.0056.80OATOM2357OHOHW1218.40080.05118.5801.0047.86OATOM2358OHOHW122−0.27481.3746.4671.0070.59OATOM2359OHOHW1238.01651.0833.8261.0050.11OATOM2360OHOHW124−5.76255.3238.6031.0059.77OATOM2361OHOHW12524.80194.210−1.1151.0067.33OATOM2362OHOHW1269.71048.66926.3281.0063.06OATOM2363OHOHW1278.68499.06314.1671.0063.47OATOM2364OHOHW12819.45183.6488.5111.0051.41OATOM2365OHOHW129−10.88961.95510.2151.0055.28OATOM2366OHOHW130−4.25361.86627.6521.0061.67OATOM2367OHOHW13127.03090.3403.8481.0080.85OATOM2368OHOHW13210.97787.13122.6231.0065.06OATOM2369OHOHW13314.63465.394−2.5211.0056.18OATOM2370OHOHW134−3.40552.80820.6921.0057.93OATOM2371OHOHW135−5.42055.45115.5251.0051.90OATOM2372OHOHW1368.05679.67122.6751.0059.54OATOM2373OHOHW13728.39257.7864.7551.0078.57OATOM2374OHOHW13818.31299.6899.7671.0061.28OATOM2375OHOHW13933.44663.25317.7231.0059.53OATOM2376OHOHW14024.28356.20617.4741.0054.00OATOM2377OHOHW14116.80850.39232.5001.0057.59OATOM2378OHOHW14215.74683.812−7.4611.0064.85OATOM2379OHOHW143−7.08294.424−2.1691.0067.76OATOM2380OHOHW14413.63149.31210.7491.0054.19OATOM2381OHOHW14530.24761.19323.4401.0071.27OATOM2382OHOHW14613.01080.075−6.5281.0068.99O

[0511]

3

TABLE 2

HEADER
----
XX-XXX-XX xxxx

COMPND
---

REMARK
3

REMARK
3
REFINEMENT.

REMARK
3
PROGRAM
REFMAC 5.1.21

REMARK
3
AUTHORS
MURSHUDOV, VAGIN, DODSON

REMARK
3

REMARK
3
REFINEMENT TARGET MAXIMUM LIKELIHOOD

REMARK
3

REMARK
3
DATA USED IN REFINEMENT.

REMARK
3
RESOLUTION RANGE HIGH
(ANGSTROMS)
2.03

REMARK
3
RESOLUTION RANGE LOW
(ANGSTROMS)
81.65

REMARK
3
DATA CUTOFF
(SIGMA(F))
NONE

REMARK
3
COMPLETENESS FOR RANGE
(%)
99.81

REMARK
3
NUMBER OF REFLECTIONS

25766

REMARK
3

REMARK
3
FIT TO DATA USED IN REFINEMENT.

REMARK
3
CROSS-VALIDATION METHOD
THROUGHOUT

REMARK
3
FREE R VALUE TEST SET SELECTION
RANDOM

REMARK
3
R VALUE (WORKING + TEST SET)
0.19077

REMARK
3
R VALUE (WORKING SET)
0.18920

REMARK
3
FREE R VALUE
0.22121

REMARK
3
FREE R VALUE TEST SET SIZE (%)
5.0

REMARK
3
FREE R VALUE TEST SET COUNT
1368

REMARK
3

REMARK
3
FIT IN THE HIGHEST RESOLUTION BIN.

REMARK
3
TOTAL NUMBER OF BINS USED
20

REMARK
3
BIN RESOLUTION RANGE HIGH
2.030

REMARK
3
BIN RESOLUTION RANGE LOW
2.083

REMARK
3
REFLECTION IN BIN (WORKING SET)
1894

REMARK
3
BIN R VALUE (WORKING SET)
0.289

REMARK
3
BIN FREE R VALUE SET COUNT
113

REMARK
3
BIN FREE R VALUE
0.297

REMARK
3

REMARK
3
NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.

REMARK
3
ALL ATOMS
2400

REMARK
3

REMARK
3
B VALUES.

REMARK
3
FROM WILSON PLOT
(A**2)
NULL

REMARK
3
MEAN B VALUE
(OVERALL, A**2)
27.297

REMARK
3
OVERALL ANISOTROPIC B VALUE.

REMARK
3
B11 (A**2)
0.50

REMARK
3
B22 (A**2)
0.50

REMARK
3
B33 (A**2)
−0.74

REMARK
3
B12 (A**2)
0.25

REMARK
3
B13 (A**2)
0.00

REMARK
3
B23 (A**2)
0.00

REMARK
3

REMARK
3
ESTIMATED OVERALL COORDINATE ERROR.

REMARK
3
ESU BASED ON R VALUE
(A)
0.151

REMARK
3
ESU BASED ON FREE R VALUE
(A)
0.140

REMARK
3
ESU BASED ON MAXIMUM LIKELIHOOD
(A)
0.105

REMARK
3
ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD
(A**2)
3.960

REMARK
3

REMARK
3
CORRELATION COEFFICIENTS.

REMARK
3
CORRELATION COEFFICIENT FO-FC
0.959

REMARK
3
CORRELATION COEFFICIENT FO-FC FREE
0.946

REMARK
3

REMARK
3
RMS DEVIATIONS FROM IDEAL VALUES
COUNT
RMS
WEIGHT

REMARK
3
BOND LENGTHS REFINED ATOMS
(A)
2334
0.011
0.021

REMARK
3
BOND ANGLES REFINED ATOMS
(DEGREES)
3174
1.105
1.959

REMARK
3
TORSION ANGLES, PERIOD 1
(DEGREES)
273
5.228
5.000

REMARK
3
CHIRAL-CENTER RESTRAINTS
(A**3)
336
0.080
0.200

REMARK
3
GENERAL PLANES REFINED ATOMS
(A)
1800
0.004
0.020

REMARK
3
NON-BONDED CONTACTS REFINED ATOMS
(A)
1070
0.202
0.200

REMARK
3
H-BOND (X...Y) REFINED ATOMS
(A)
150
0.145
0.200

REMARK
3
SYMMETRY VDW REFINED ATOMS
(A)
46
0.199
0.200

REMARK
3
SYMMETRY H-BOND REFINED ATOMS
(A)
10
0.267
0.200

REMARK
3

REMARK
3
ISOTROPIC THERMAL FACTOR RESTRAINTS.
COUNT
RMS
WEIGHT

REMARK
3
MAIN-CHAIN BOND REFINED ATOMS
(A**2)
1365
0.799
1.500

REMARK
3
MAIN-CHAIN ANGLE REFINED ATOMS
(A**2)
2214
1.519
2.000

REMARK
3
SIDE-CHAIN BOND REFINED ATOMS
(A**2)
969
2.024
3.000

REMARK
3
SIDE-CHAIN ANGLE REFINED ATOMS
(A**2)
960
3.247
4.500

REMARK
3

REMARK
3
NCS RESTRAINTS STATISTICS

REMARK
3
NUMBER OF NCS GROUPS NULL

REMARK
3

REMARK
3

REMARK
3
TLS DETAILS

REMARK
3
NUMBER OF TLS GROUPS 2

REMARK
3

REMARK
3
TLS GROUP 1

REMARK
3
NUMBER OF COMPONENTS GROUP 1

REMARK
3
COMPONENTS
C
SSSEQI
TO
C
SSSEQI

REMARK
3
RESIDUE RANGE
A
33

A
306

REMARK
3
ORIGIN FOR THE GROUP (A) 65.5800 27.1270 −0.6960

REMARK
3
T TENSOR

REMARK
3
T11
0.1410 T22
0.1266

REMARK
3
T33
0.0824 T12
−0.0364

REMARK
3
T13
−0.0112 T23
−0.0301

REMARK
3
L TENSOR

REMARK
3
L11
1.3945 L22
0.7253

REMARK
3
L33
0.8680 L12
0.1248

REMARK
3
L13
−0.3386 L23
0.0070

REMARK
3
S TENSOR

REMARK
3
S11
−0.0668 S12
0.0858 S13
0.0787

REMARK
3
S21
−0.0201 S22
0.1089 S23
0.0287

REMARK
3
S31
0.0298 S32
0.0689 S33
−0.0421

REMARK
3

REMARK
3
TLS GROUP 2

REMARK
3
NUMBER OF COMPONENTS GROUP 1

REMARK
3
COMPONENTS
C
SSSEQI
TO
C
SSSEQI

REMARK
3
RESIDUE RANGE
L
1

L
1

REMARK
3
ORIGIN FOR THE GROUP (A) 73.8810 32.6080 1.3720

REMARK
3
T TENSOR

REMARK
3
T11
0.1174 T22
0.1943

REMARK
3
T33
0.1391 T12
−0.1003

REMARK
3
T13
−0.0486 T23
−0.0722

REMARK
3
L TENSOR

REMARK
3
L11
14.6629 L22
15.7148

REMARK
3
L33
8.9109 L12
−11.1563

REMARK
3
L13
−1.8290 L23
−15.1157

REMARK
3
S TENSOR

REMARK
3
S11
0.2483 S12
0.1966 S13
0.0403

REMARK
3
S21
0.0302 S22
0.1725 S23
0.8712

REMARK
3
S31
−0.4688 S32
0.8689 S33
−0.4208

REMARK
3

REMARK
3

REMARK
3
BULK SOLVENT MODELLING.

REMARK
3
METHOD USED BABINET MODEL WITH MASK

REMARK
3
PARAMETERS FOR MASK CALCULATION

REMARK
3
VDW PROBE RADIUS
1.40

REMARK
3
ION PROBE RADIUS
0.80

REMARK
3
SHRINKAGE RADIUS
0.80

REMARK
3

REMARK
3
OTHER REFINEMENT REMARKS NULL

REMARK
3

CISPEP
1 GLU A 124 PRO A 125 0.00

CRYST1
95.566 95.566 80.862 90.00 90.00 120.00 P 65

SCALE1
0.010464 0.006041 0.000000 0.00000

SCALE2
0.000000 0.012083 0.000000 0.00000

SCALE3
0.000000 0.000000 0.012367 0.00000

ATOM
1
N
PRO
A
33
89.149
40.408
−18.445
1.00
67.30
N

ATOM
2
CA
PRO
A
33
88.476
41.476
−17.647
1.00
67.14
C

ATOM
3
CB
PRO
A
33
86.997
41.088
−17.742
1.00
67.23
C

ATOM
4
CG
PRO
A
33
86.877
40.393
−19.088
1.00
67.40
C

ATOM
5
CD
PRO
A
33
88.243
39.825
−19.451
1.00
67.35
C

ATOM
6
C
PRO
A
33
88.938
41.544
−16.180
1.00
66.89
C

ATOM
7
O
PRO
A
33
89.154
42.657
−15.690
1.00
67.00
O

ATOM
8
N
LEU
A
34
89.091
40.388
−15.519
1.00
66.32
N

ATOM
9
CA
LEU
A
34
89.499
40.274
−14.100
1.00
65.68
C

ATOM
10
CB
LEU
A
34
90.888
40.895
−13.835
1.00
65.85
C

ATOM
11
CG
LEU
A
34
91.302
41.230
−12.390
1.00
66.30
C

ATOM
12
CD1
LEU
A
34
91.714
39.982
−11.600
1.00
66.80
C

ATOM
13
CD2
LEU
A
34
92.418
42.268
−12.376
1.00
67.23
C

ATOM
14
C
LEU
A
34
88.454
40.795
−13.100
1.00
64.94
C

ATOM
15
O
LEU
A
34
87.873
41.869
−13.284
1.00
64.93
O

ATOM
16
N
GLU
A
35
88.242
40.036
−12.027
1.00
63.77
N

ATOM
17
CA
GLU
A
35
87.186
40.343
−11.061
1.00
62.65
C

ATOM
18
CB
GLU
A
35
86.798
39.087
−10.270
1.00
63.13
C

ATOM
19
CG
GLU
A
35
87.856
38.599
−9.297
1.00
65.02
C

ATOM
20
CD
GLU
A
35
87.245
37.871
−8.122
1.00
67.48
C

ATOM
21
OE1
GLU
A
35
87.017
38.518
−7.069
1.00
68.53
O

ATOM
22
OE2
GLU
A
35
86.987
36.654
−8.260
1.00
68.44
O

ATOM
23
C
GLU
A
35
87.444
41.549
−10.130
1.00
61.12
C

ATOM
24
O
GLU
A
35
86.859
41.645
−9.049
1.00
61.05
O

ATOM
25
N
SER
A
36
88.299
42.477
−10.561
1.00
59.16
N

ATOM
26
CA
SER
A
36
88.360
43.797
−9.923
1.00
56.76
C

ATOM
27
CB
SER
A
36
89.767
44.375
−9.977
1.00
57.09
C

ATOM
28
OG
SER
A
36
90.185
44.711
−8.665
1.00
57.93
O

ATOM
29
C
SER
A
36
87.321
44.757
−10.537
1.00
54.68
C

ATOM
30
O
SER
A
36
87.465
45.987
−10.482
1.00
54.42
O

ATOM
31
N
GLN
A
37
86.278
44.159
−11.121
1.00
51.69
N

ATOM
32
CA
GLN
A
37
85.055
44.844
−11.531
1.00
48.71
C

ATOM
33
CB
GLN
A
37
84.288
44.000
−12.556
1.00
48.70
C

ATOM
34
CG
GLN
A
37
85.032
43.705
−13.853
1.00
48.89
C

ATOM
35
CD
GLN
A
37
84.357
42.614
−14.681
1.00
48.93
C

ATOM
36
OE1
GLN
A
37
83.235
42.790
−15.159
1.00
48.57
O

ATOM
37
NE2
GLN
A
37
85.041
41.490
−14.849
1.00
49.23
N

ATOM
38
C
GLN
A
37
84.159
45.068
−10.309
1.00
46.45
C

ATOM
39
O
GLN
A
37
83.061
45.621
−10.425
1.00
45.80
O

ATOM
40
N
TYR
A
38
84.634
44.634
−9.142
1.00
43.79
N

ATOM
41
CA
TYR
A
38
83.815
44.599
−7.935
1.00
41.47
C

ATOM
42
CB
TYR
A
38
83.277
43.178
−7.683
1.00
40.80
C

ATOM
43
CG
TYR
A
38
82.415
42.680
−8.813
1.00
37.71
C

ATOM
44
CD1
TYR
A
38
81.078
43.060
−8.913
1.00
36.03
C

ATOM
45
CE1
TYR
A
38
80.283
42.622
−9.970
1.00
34.69
C

ATOM
46
CZ
TYR
A
38
80.834
41.799
−10.940
1.00
33.35
C

ATOM
47
OH
TYR
A
38
80.058
41.362
−11.982
1.00
33.33
O

ATOM
48
CE2
TYR
A
38
82.156
41.409
−10.861
1.00
33.59
C

ATOM
49
CD2
TYR
A
38
82.941
41.853
−9.801
1.00
35.25
C

ATOM
50
C
TYR
A
38
84.546
45.110
−6.711
1.00
40.70
C

ATOM
51
O
TYR
A
38
85.729
44.835
−6.522
1.00
40.55
O

ATOM
52
N
GLN
A
39
83.820
45.882
−5.907
1.00
39.47
N

ATOM
53
CA
GLN
A
39
84.267
46.331
−4.602
1.00
38.56
C

ATOM
54
CB
GLN
A
39
83.781
47.755
−4.350
1.00
39.00
C

ATOM
55
CG
GLN
A
39
84.391
48.448
−3.148
1.00
41.12
C

ATOM
56
CD
GLN
A
39
83.988
49.920
−3.066
1.00
44.96
C

ATOM
57
OE1
GLN
A
39
84.489
50.753
−3.833
1.00
45.76
O

ATOM
58
NE2
GLN
A
39
83.081
50.241
−2.139
1.00
46.18
N

ATOM
59
C
GLN
A
39
83.673
45.376
−3.567
1.00
37.29
C

ATOM
60
O
GLN
A
39
82.451
45.224
−3.473
1.00
36.66
O

ATOM
61
N
VAL
A
40
84.546
44.738
−2.797
1.00
35.79
N

ATOM
62
CA
VAL
A
40
84.124
43.757
−1.808
1.00
34.34
C

ATOM
63
CB
VAL
A
40
85.190
42.667
−1.580
1.00
34.42
C

ATOM
64
CG1
VAL
A
40
84.573
41.470
−0.871
1.00
34.56
C

ATOM
65
CG2
VAL
A
40
85.822
42.238
−2.908
1.00
34.84
C

ATOM
66
C
VAL
A
40
83.794
44.435
−0.487
1.00
33.17
C

ATOM
67
O
VAL
A
40
84.544
45.296
−0.021
1.00
32.88
O

ATOM
68
N
GLY
A
41
82.659
44.047
0.094
1.00
31.35
N

ATOM
69
CA
GLY
A
41
82.253
44.508
1.407
1.00
29.70
C

ATOM
70
C
GLY
A
41
82.304
43.395
2.438
1.00
28.50
C

ATOM
71
O
GLY
A
41
83.121
42.480
2.315
1.00
28.62
O

ATOM
72
N
PRO
A
42
81.435
43.470
3.446
1.00
27.60
N

ATOM
73
CA
PRO
A
42
81.406
42.494
4.543
1.00
27.00
C

ATOM
74
CB
PRO
A
42
80.355
43.073
5.501
1.00
27.10
C

ATOM
75
CG
PRO
A
42
80.182
44.506
5.089
1.00
27.33
C

ATOM
76
CD
PRO
A
42
80.416
44.521
3.618
1.00
27.63
C

ATOM
77
C
PRO
A
42
80.958
41.091
4.127
1.00
26.95
C

ATOM
78
O
PRO
A
42
80.212
40.921
3.149
1.00
26.22
O

ATOM
79
N
LEU
A
43
81.421
40.114
4.905
1.00
26.40
N

ATOM
80
CA
LEU
A
43
81.016
38.726
4.827
1.00
26.26
C

ATOM
81
CB
LEU
A
43
81.928
37.888
5.737
1.00
26.16
C

ATOM
82
CG
LEU
A
43
81.741
36.367
5.836
1.00
26.71
C

ATOM
83
CD1
LEU
A
43
81.971
35.666
4.486
1.00
25.17
C

ATOM
84
CD2
LEU
A
43
82.656
35.790
6.911
1.00
25.63
C

ATOM
85
C
LEU
A
43
79.573
38.592
5.292
1.00
26.23
C

ATOM
86
O
LEU
A
43
79.234
39.010
6.409
1.00
25.53
O

ATOM
87
N
LEU
A
44
78.737
37.998
4.439
1.00
25.89
N

ATOM
88
CA
LEU
A
44
77.321
37.786
4.746
1.00
26.23
C

ATOM
89
CB
LEU
A
44
76.460
37.994
3.500
1.00
25.73
C

ATOM
90
CG
LEU
A
44
76.500
39.383
2.881
1.00
25.94
C

ATOM
91
CD1
LEU
A
44
75.804
39.381
1.516
1.00
24.87
C

ATOM
92
CD2
LEU
A
44
75.881
40.399
3.846
1.00
26.24
C

ATOM
93
C
LEU
A
44
77.027
36.416
5.345
1.00
26.74
C

ATOM
94
O
LEU
A
44
76.107
36.274
6.148
1.00
26.63
O

ATOM
95
N
GLY
A
45
77.798
35.409
4.946
1.00
27.42
N

ATOM
96
CA
GLY
A
45
77.595
34.056
5.434
1.00
28.81
C

ATOM
97
C
GLY
A
45
78.642
33.077
4.932
1.00
29.90
C

ATOM
98
O
GLY
A
45
79.209
33.254
3.854
1.00
29.36
O

ATOM
99
N
SER
A
46
78.908
32.061
5.745
1.00
31.14
N

ATOM
100
CA
SER
A
46
79.794
30.964
5.385
1.00
33.14
C

ATOM
101
CB
SER
A
46
81.242
31.282
5.786
1.00
33.24
C

ATOM
102
OG
SER
A
46
81.336
31.607
7.161
1.00
31.40
O

ATOM
103
C
SER
A
46
79.263
29.723
6.104
1.00
34.64
C

ATOM
104
O
SER
A
46
78.131
29.727
6.594
1.00
35.16
O

ATOM
105
N
GLY
A
47
80.033
28.645
6.168
1.00
36.14
N

ATOM
106
CA
GLY
A
47
79.552
27.513
6.960
1.00
37.77
C

ATOM
107
C
GLY
A
47
78.827
26.410
6.202
1.00
38.06
C

ATOM
108
O
GLY
A
47
78.803
25.261
6.665
1.00
38.85
O

ATOM
109
N
GLY
A
48
78.228
26.756
5.058
1.00
38.13
N

ATOM
110
CA
GLY
A
48
77.816
25.765
4.072
1.00
37.47
C

ATOM
111
C
GLY
A
48
79.007
25.489
3.163
1.00
37.20
C

ATOM
112
O
GLY
A
48
80.154
25.459
3.631
1.00
37.27
O

ATOM
113
N
PHE
A
49
78.757
25.324
1.865
1.00
36.60
N

ATOM
114
CA
PHE
A
49
79.845
25.099
0.905
1.00
36.12
C

ATOM
115
CB
PHE
A
49
79.322
24.532
−0.421
1.00
36.73
C

ATOM
116
CG
PHE
A
49
78.733
23.153
−0.310
1.00
39.10
C

ATOM
117
CD1
PHE
A
49
77.363
22.960
−0.454
1.00
40.06
C

ATOM
118
CE1
PHE
A
49
76.806
21.681
−0.357
1.00
42.14
C

ATOM
119
CZ
PHE
A
49
77.624
20.575
−0.105
1.00
43.04
C

ATOM
120
CE2
PHE
A
49
79.003
20.755
0.045
1.00
43.48
C

ATOM
121
CD2
PHE
A
49
79.550
22.043
−0.061
1.00
42.11
C

ATOM
122
C
PHE
A
49
80.702
26.339
0.614
1.00
34.83
C

ATOM
123
O
PHE
A
49
81.884
26.195
0.286
1.00
35.14
O

ATOM
124
N
GLY
A
50
80.109
27.536
0.717
1.00
32.72
N

ATOM
125
CA
GLY
A
50
80.770
28.772
0.303
1.00
30.18
C

ATOM
126
C
GLY
A
50
80.831
29.895
1.335
1.00
28.53
C

ATOM
127
O
GLY
A
50
80.161
29.832
2.367
1.00
28.21
O

ATOM
128
N
SER
A
51
81.676
30.895
1.061
1.00
26.40
N

ATOM
129
CA
SER
A
51
81.722
32.156
1.803
1.00
23.83
C

ATOM
130
CB
SER
A
51
83.157
32.509
2.190
1.00
24.19
C

ATOM
131
OG
SER
A
51
83.773
31.474
2.937
1.00
23.82
O

ATOM
132
C
SER
A
51
81.167
33.245
0.888
1.00
22.65
C

ATOM
133
O
SER
A
51
81.640
33.423
−0.242
1.00
21.83
O

ATOM
134
N
VAL
A
52
80.150
33.948
1.369
1.00
20.93
N

ATOM
135
CA
VAL
A
52
79.427
34.917
0.568
1.00
20.09
C

ATOM
136
CB
VAL
A
52
77.917
34.574
0.518
1.00
19.63
C

ATOM
137
CG1
VAL
A
52
77.182
35.536
−0.391
1.00
19.68
C

ATOM
138
CG2
VAL
A
52
77.705
33.133
0.035
1.00
19.27
C

ATOM
139
C
VAL
A
52
79.629
36.330
1.119
1.00
20.59
C

ATOM
140
O
VAL
A
52
79.406
36.576
2.309
1.00
19.74
O

ATOM
141
N
TYR
A
53
80.053
37.241
0.250
1.00
20.61
N

ATOM
142
CA
TYR
A
53
80.316
38.624
0.640
1.00
21.62
C

ATOM
143
CB
TYR
A
53
81.737
39.034
0.247
1.00
21.19
C

ATOM
144
CG
TYR
A
53
82.842
38.256
0.922
1.00
22.16
C

ATOM
145
CD1
TYR
A
53
83.201
36.980
0.470
1.00
21.94
C

ATOM
146
CE1
TYR
A
53
84.225
36.265
1.078
1.00
22.80
C

ATOM
147
CZ
TYR
A
53
84.921
36.830
2.146
1.00
23.82
C

ATOM
148
OH
TYR
A
53
85.937
36.114
2.736
1.00
23.97
O

ATOM
149
CE2
TYR
A
53
84.597
38.099
2.614
1.00
23.07
C

ATOM
150
CD2
TYR
A
53
83.559
38.810
1.994
1.00
23.01
C

ATOM
151
C
TYR
A
53
79.354
39.597
−0.024
1.00
22.34
C

ATOM
152
O
TYR
A
53
78.888
39.373
−1.153
1.00
22.35
O

ATOM
153
N
SER
A
54
79.066
40.681
0.680
1.00
23.48
N

ATOM
154
CA
SER
A
54
78.404
41.822
0.074
1.00
24.82
C

ATOM
155
CB
SER
A
54
77.980
42.840
1.140
1.00
25.09
C

ATOM
156
OG
SER
A
54
77.307
43.939
0.545
1.00
25.39
O

ATOM
157
C
SER
A
54
79.384
42.461
−0.889
1.00
25.68
C

ATOM
158
O
SER
A
54
80.586
42.513
−0.616
1.00
25.83
O

ATOM
159
N
GLY
A
55
78.878
42.932
−2.023
1.00
26.75
N

ATOM
160
CA
GLY
A
55
79.720
43.609
−2.991
1.00
27.76
C

ATOM
161
C
GLY
A
55
78.986
44.633
−3.827
1.00
28.87
C

ATOM
162
O
GLY
A
55
77.762
44.772
−3.737
1.00
28.62
O

ATOM
163
N
ILE
A
56
79.750
45.358
−4.641
1.00
30.03
N

ATOM
164
CA
ILE
A
56
79.200
46.346
−5.557
1.00
31.52
C

ATOM
165
CB
ILE
A
56
79.291
47.773
−4.953
1.00
31.73
C

ATOM
166
CG1
ILE
A
56
78.306
47.955
−3.790
1.00
32.00
C

ATOM
167
CD1
ILE
A
56
78.762
48.992
−2.750
1.00
34.29
C

ATOM
168
CG2
ILE
A
56
79.038
48.830
−6.014
1.00
32.25
C

ATOM
169
C
ILE
A
56
79.927
46.274
−6.901
1.00
32.27
C

ATOM
170
O
ILE
A
56
81.153
46.245
−6.956
1.00
32.20
O

ATOM
171
N
ARG
A
57
79.147
46.225
−7.976
1.00
33.45
N

ATOM
172
CA
ARG
A
57
79.664
46.308
−9.332
1.00
34.77
C

ATOM
173
CB
ARG
A
57
78.574
45.902
−10.319
1.00
34.53
C

ATOM
174
CG
ARG
A
57
79.075
45.541
−11.692
1.00
35.85
C

ATOM
175
CD
ARG
A
57
78.037
45.746
−12.766
1.00
37.31
C

ATOM
176
NE
ARG
A
57
77.459
44.488
−13.210
1.00
38.72
N

ATOM
177
CZ
ARG
A
57
76.191
44.334
−13.580
1.00
39.18
C

ATOM
178
NH1
ARG
A
57
75.347
45.360
−13.561
1.00
38.58
N

ATOM
179
NH2
ARG
A
57
75.764
43.143
−13.967
1.00
40.00
N

ATOM
180
C
ARG
A
57
80.134
47.740
−9.604
1.00
35.42
C

ATOM
181
O
ARG
A
57
79.329
48.667
−9.609
1.00
35.07
O

ATOM
182
N
VAL
A
58
81.438
47.901
−9.822
1.00
36.96
N

ATOM
183
CA
VAL
A
58
82.069
49.221
−9.962
1.00
38.44
C

ATOM
184
CB
VAL
A
58
83.626
49.118
−10.083
1.00
38.53
C

ATOM
185
CG1
VAL
A
58
84.270
50.494
−10.251
1.00
38.65
C

ATOM
186
CG2
VAL
A
58
84.226
48.422
−8.863
1.00
38.97
C

ATOM
187
C
VAL
A
58
81.472
50.033
−11.125
1.00
39.26
C

ATOM
188
O
VAL
A
58
81.243
51.238
−10.989
1.00
39.41
O

ATOM
189
N
SER
A
59
81.194
49.357
−12.239
1.00
40.32
N

ATOM
190
CA
SER
A
59
80.704
50.007
−13.459
1.00
41.50
C

ATOM
191
CB
SER
A
59
80.627
49.012
−14.625
1.00
41.60
C

ATOM
192
OG
SER
A
59
80.059
47.777
−14.225
1.00
42.83
O

ATOM
193
C
SER
A
59
79.380
50.778
−13.310
1.00
41.87
C

ATOM
194
O
SER
A
59
79.205
51.830
−13.933
1.00
42.28
O

ATOM
195
N
ASP
A
60
78.463
50.269
−12.488
1.00
42.04
N

ATOM
196
CA
ASP
A
60
77.147
50.897
−12.330
1.00
41.97
C

ATOM
197
CB
ASP
A
60
76.118
50.187
−13.223
1.00
42.37
C

ATOM
198
CG
ASP
A
60
75.881
48.739
−12.810
1.00
43.55
C

ATOM
199
OD1
ASP
A
60
76.449
48.309
−11.781
1.00
44.32
O

ATOM
200
OD2
ASP
A
60
75.142
47.959
−13.451
1.00
43.86
O

ATOM
201
C
ASP
A
60
76.631
50.996
−10.878
1.00
41.41
C

ATOM
202
O
ASP
A
60
75.479
51.372
−10.657
1.00
41.59
O

ATOM
203
N
ASN
A
61
77.484
50.667
−9.905
1.00
40.49
N

ATOM
204
CA
ASN
A
61
77.122
50.639
−8.475
1.00
39.60
C

ATOM
205
CB
ASN
A
61
76.722
52.026
−7.961
1.00
39.96
C

ATOM
206
CG
ASN
A
61
77.888
52.981
−7.902
1.00
41.52
C

ATOM
207
OD1
ASN
A
61
78.785
52.837
−7.065
1.00
42.83
O

ATOM
208
ND2
ASN
A
61
77.883
53.971
−8.792
1.00
42.64
N

ATOM
209
C
ASN
A
61
76.058
49.615
−8.056
1.00
38.30
C

ATOM
210
O
ASN
A
61
75.557
49.667
−6.930
1.00
38.56
O

ATOM
211
N
LEU
A
62
75.724
48.685
−8.947
1.00
36.52
N

ATOM
212
CA
LEU
A
62
74.768
47.623
−8.623
1.00
34.93
C

ATOM
213
CB
LEU
A
62
74.519
46.720
−9.832
1.00
35.10
C

ATOM
214
CG
LEU
A
62
73.421
45.662
−9.712
1.00
35.38
C

ATOM
215
CD1
LEU
A
62
72.047
46.269
−9.961
1.00
36.89
C

ATOM
216
CD2
LEU
A
62
73.679
44.527
−10.677
1.00
35.30
C

ATOM
217
C
LEU
A
62
75.222
46.778
−7.425
1.00
33.33
C

ATOM
218
O
LEU
A
62
76.351
46.288
−7.404
1.00
32.86
O

ATOM
219
N
PRO
A
63
74.340
46.624
−6.436
1.00
32.03
N

ATOM
220
CA
PRO
A
63
74.576
45.708
−5.312
1.00
30.66
C

ATOM
221
CB
PRO
A
63
73.328
45.893
−4.440
1.00
30.79
C

ATOM
222
CG
PRO
A
63
72.770
47.219
−4.848
1.00
32.09
C

ATOM
223
CD
PRO
A
63
73.039
47.311
−6.319
1.00
32.13
C

ATOM
224
C
PRO
A
63
74.657
44.263
−5.804
1.00
28.94
C

ATOM
225
O
PRO
A
63
73.788
43.821
−6.570
1.00
28.84
O

ATOM
226
N
VAL
A
64
75.705
43.554
−5.393
1.00
26.63
N

ATOM
227
CA
VAL
A
64
75.862
42.135
−5.723
1.00
24.40
C

ATOM
228
CB
VAL
A
64
76.903
41.905
−6.870
1.00
24.56
C

ATOM
229
CG1
VAL
A
64
76.430
42.528
−8.195
1.00
23.44
C

ATOM
230
CG2
VAL
A
64
78.292
42.436
−6.471
1.00
23.53
C

ATOM
231
C
VAL
A
64
76.295
41.339
−4.488
1.00
23.30
C

ATOM
232
O
VAL
A
64
76.650
41.922
−3.451
1.00
22.79
O

ATOM
233
N
ALA
A
65
76.259
40.014
−4.609
1.00
21.63
N

ATOM
234
CA
ALA
A
65
76.828
39.124
−3.608
1.00
20.83
C

ATOM
235
CB
ALA
A
65
75.761
38.231
−2.984
1.00
20.55
C

ATOM
236
C
ALA
A
65
77.892
38.290
−4.281
1.00
20.04
C

ATOM
237
O
ALA
A
65
77.704
37.828
−5.408
1.00
21.14
O

ATOM
238
N
ILE
A
66
79.015
38.111
−3.600
1.00
18.86
N

ATOM
239
CA
ILE
A
66
80.165
37.439
−4.186
1.00
17.57
C

ATOM
240
CB
ILE
A
66
81.422
38.346
−4.117
1.00
17.68
C

ATOM
241
CG1
ILE
A
66
81.148
39.723
−4.747
1.00
18.56
C

ATOM
242
CD1
ILE
A
66
82.220
40.772
−4.424
1.00
19.55
C

ATOM
243
CG2
ILE
A
66
82.602
37.668
−4.775
1.00
16.32
C

ATOM
244
C
ILE
A
66
80.402
36.161
−3.408
1.00
16.96
C

ATOM
245
O
ILE
A
66
80.775
36.206
−2.227
1.00
16.17
O

ATOM
246
N
LYS
A
67
80.179
35.031
−4.077
1.00
16.24
N

ATOM
247
CA
LYS
A
67
80.255
33.718
−3.444
1.00
15.79
C

ATOM
248
CB
LYS
A
67
78.975
32.905
−3.707
1.00
15.38
C

ATOM
249
CG
LYS
A
67
79.010
31.493
−3.119
1.00
14.88
C

ATOM
250
CD
LYS
A
67
77.664
30.772
−3.303
1.00
17.48
C

ATOM
251
CE
LYS
A
67
77.585
29.486
−2.479
1.00
18.05
C

ATOM
252
NZ
LYS
A
67
76.184
28.951
−2.470
1.00
18.14
N

ATOM
253
C
LYS
A
67
81.478
32.943
−3.915
1.00
16.15
C

ATOM
254
O
LYS
A
67
81.667
32.705
−5.122
1.00
15.33
O

ATOM
255
N
HIS
A
68
82.293
32.534
−2.951
1.00
16.82
N

ATOM
256
CA
HIS
A
68
83.519
31.792
−3.235
1.00
17.55
C

ATOM
257
CB
HIS
A
68
84.683
32.368
−2.435
1.00
17.11
C

ATOM
258
CG
HIS
A
68
85.043
33.764
−2.818
1.00
17.46
C

ATOM
259
ND1
HIS
A
68
84.358
34.860
−2.348
1.00
18.28
N

ATOM
260
CE1
HIS
A
68
84.897
35.958
−2.844
1.00
17.55
C

ATOM
261
NE2
HIS
A
68
85.909
35.614
−3.617
1.00
17.90
N

ATOM
262
CD2
HIS
A
68
86.019
34.245
−3.622
1.00
17.05
C

ATOM
263
C
HIS
A
68
83.319
30.353
−2.829
1.00
18.47
C

ATOM
264
O
HIS
A
68
82.899
30.085
−1.707
1.00
17.74
O

ATOM
265
N
VAL
A
69
83.628
29.434
−3.735
1.00
19.87
N

ATOM
266
CA
VAL
A
69
83.538
28.016
−3.441
1.00
21.97
C

ATOM
267
CB
VAL
A
69
82.386
27.316
−4.229
1.00
22.09
C

ATOM
268
CG1
VAL
A
69
82.270
25.863
−3.809
1.00
22.01
C

ATOM
269
CG2
VAL
A
69
81.049
28.011
−3.992
1.00
22.34
C

ATOM
270
C
VAL
A
69
84.870
27.345
−3.768
1.00
23.59
C

ATOM
271
O
VAL
A
69
85.331
27.388
−4.903
1.00
23.28
O

ATOM
272
N
GLU
A
70
85.474
26.719
−2.766
1.00
26.14
N

ATOM
273
CA
GLU
A
70
86.719
25.981
−2.948
1.00
29.32
C

ATOM
274
CB
GLU
A
70
87.280
25.543
−1.599
1.00
29.52
C

ATOM
275
CG
GLU
A
70
88.286
26.512
−1.001
1.00
32.13
C

ATOM
276
CD
GLU
A
70
88.827
26.043
0.342
1.00
34.86
C

ATOM
277
OE1
GLU
A
70
89.185
24.847
0.448
1.00
34.79
O

ATOM
278
OE2
GLU
A
70
88.899
26.871
1.288
1.00
35.33
O

ATOM
279
C
GLU
A
70
86.486
24.760
−3.834
1.00
31.18
C

ATOM
280
O
GLU
A
70
85.485
24.044
−3.674
1.00
30.70
O

ATOM
281
N
LYS
A
71
87.402
24.540
−4.774
1.00
33.73
N

ATOM
282
CA
LYS
A
71
87.292
23.422
−5.718
1.00
36.85
C

ATOM
283
CB
LYS
A
71
88.426
23.459
−6.734
1.00
36.40
C

ATOM
284
CG
LYS
A
71
88.228
24.487
−7.822
1.00
35.73
C

ATOM
285
CD
LYS
A
71
89.373
24.457
−8.814
1.00
35.72
C

ATOM
286
CE
LYS
A
71
89.168
25.490
−9.898
1.00
35.77
C

ATOM
287
NZ
LYS
A
71
90.289
25.535
−10.874
1.00
35.56
N

ATOM
288
C
LYS
A
71
87.206
22.046
−5.047
1.00
39.35
C

ATOM
289
O
LYS
A
71
86.492
21.169
−5.536
1.00
39.62
O

ATOM
290
N
ASP
A
72
87.904
21.872
−3.922
1.00
42.63
N

ATOM
291
CA
ASP
A
72
87.873
20.615
−3.161
1.00
46.03
C

ATOM
292
CB
ASP
A
72
89.021
20.560
−2.145
1.00
46.33
C

ATOM
293
CG
ASP
A
72
90.396
20.511
−2.811
1.00
48.21
C

ATOM
294
OD1
ASP
A
72
90.519
19.935
−3.918
1.00
49.79
O

ATOM
295
OD2
ASP
A
72
91.418
21.025
−2.300
1.00
50.39
O

ATOM
296
C
ASP
A
72
86.539
20.371
−2.452
1.00
47.89
C

ATOM
297
O
ASP
A
72
86.138
19.221
−2.253
1.00
48.61
O

ATOM
298
N
ARG
A
73
85.861
21.457
−2.085
1.00
50.08
N

ATOM
299
CA
ARG
A
73
84.592
21.405
−1.352
1.00
52.11
C

ATOM
300
CB
ARG
A
73
84.430
22.662
−0.486
1.00
52.39
C

ATOM
301
CG
ARG
A
73
85.333
22.711
0.739
1.00
54.59
C

ATOM
302
CD
ARG
A
73
84.894
23.708
1.827
1.00
58.87
C

ATOM
303
NE
ARG
A
73
83.451
23.686
2.113
1.00
62.15
N

ATOM
304
CZ
ARG
A
73
82.792
22.682
2.708
1.00
63.76
C

ATOM
305
NH1
ARG
A
73
83.427
21.579
3.094
1.00
64.18
N

ATOM
306
NH2
ARG
A
73
81.484
22.779
2.917
1.00
63.67
N

ATOM
307
C
ARG
A
73
83.376
21.251
−2.272
1.00
52.88
C

ATOM
308
O
ARG
A
73
82.246
21.100
−1.793
1.00
52.85
O

ATOM
309
N
ILE
A
74
83.613
21.307
−3.585
1.00
54.14
N

ATOM
310
CA
ILE
A
74
82.553
21.153
−4.583
1.00
55.27
C

ATOM
311
CB
ILE
A
74
83.013
21.668
−5.983
1.00
55.13
C

ATOM
312
CG1
ILE
A
74
83.104
23.193
−5.985
1.00
54.96
C

ATOM
313
CD1
ILE
A
74
83.829
23.776
−7.180
1.00
55.18
C

ATOM
314
CG2
ILE
A
74
82.053
21.205
−7.084
1.00
55.44
C

ATOM
315
C
ILE
A
74
82.107
19.691
−4.638
1.00
56.17
C

ATOM
316
O
ILE
A
74
82.902
18.798
−4.973
1.00
56.10
O

ATOM
317
N
SER
A
75
80.836
19.459
−4.298
1.00
57.17
N

ATOM
318
CA
SER
A
75
80.287
18.101
−4.234
1.00
58.19
C

ATOM
319
CB
SER
A
75
78.943
18.064
−3.485
1.00
58.21
C

ATOM
320
OG
SER
A
75
78.112
19.161
−3.831
1.00
58.80
O

ATOM
321
C
SER
A
75
80.178
17.482
−5.629
1.00
58.59
C

ATOM
322
O
SER
A
75
80.890
16.520
−5.939
1.00
58.89
O

ATOM
323
N
ASP
A
76
79.313
18.055
−6.469
1.00
58.93
N

ATOM
324
CA
ASP
A
76
79.125
17.581
−7.840
1.00
59.19
C

ATOM
325
CB
ASP
A
76
77.646
17.265
−8.101
1.00
59.25
C

ATOM
326
CG
ASP
A
76
77.174
16.004
−7.377
1.00
60.21
C

ATOM
327
OD1
ASP
A
76
75.950
15.733
−7.378
1.00
60.76
O

ATOM
328
OD2
ASP
A
76
77.946
15.218
−6.783
1.00
61.47
O

ATOM
329
C
ASP
A
76
79.655
18.576
−8.875
1.00
59.17
C

ATOM
330
O
ASP
A
76
79.536
19.794
−8.702
1.00
59.08
O

ATOM
331
N
TRP
A
77
80.245
18.043
−9.943
1.00
59.21
N

ATOM
332
CA
TRP
A
77
80.737
18.850
−11.059
1.00
59.31
C

ATOM
333
CB
TRP
A
77
82.186
18.497
−11.399
1.00
58.89
C

ATOM
334
CG
TRP
A
77
83.207
18.816
−10.338
1.00
57.61
C

ATOM
335
CD1
TRP
A
77
83.449
18.112
−9.191
1.00
56.71
C

ATOM
336
NE1
TRP
A
77
84.469
18.695
−8.480
1.00
56.23
N

ATOM
337
CE2
TRP
A
77
84.921
19.793
−9.166
1.00
55.87
C

ATOM
338
CD2
TRP
A
77
84.149
19.899
−10.345
1.00
55.83
C

ATOM
339
CE3
TRP
A
77
84.416
20.957
−11.226
1.00
54.75
C

ATOM
340
CZ3
TRP
A
77
85.429
21.857
−10.909
1.00
54.49
C

ATOM
341
CH2
TRP
A
77
86.179
21.722
−9.728
1.00
54.62
C

ATOM
342
CZ2
TRP
A
77
85.942
20.700
−8.846
1.00
54.88
C

ATOM
343
C
TRP
A
77
79.880
18.620
−12.297
1.00
59.97
C

ATOM
344
O
TRP
A
77
79.309
17.539
−12.479
1.00
59.95
O

ATOM
345
N
GLY
A
78
79.814
19.636
−13.152
1.00
60.60
N

ATOM
346
CA
GLY
A
78
79.019
19.573
−14.362
1.00
61.69
C

ATOM
347
C
GLY
A
78
79.663
20.261
−15.546
1.00
62.62
C

ATOM
348
O
GLY
A
78
80.722
20.887
−15.425
1.00
62.53
O

ATOM
349
N
GLU
A
79
79.016
20.127
−16.700
1.00
63.55
N

ATOM
350
CA
GLU
A
79
79.470
20.764
−17.932
1.00
64.55
C

ATOM
351
CB
GLU
A
79
79.841
19.724
−19.007
1.00
64.74
C

ATOM
352
CG
GLU
A
79
78.740
18.730
−19.386
1.00
65.56
C

ATOM
353
CD
GLU
A
79
78.780
18.319
−20.857
1.00
67.08
C

ATOM
354
OE1
GLU
A
79
79.892
18.197
−21.428
1.00
67.41
O

ATOM
355
OE2
GLU
A
79
77.693
18.111
−21.446
1.00
66.84
O

ATOM
356
C
GLU
A
79
78.425
21.745
−18.456
1.00
64.93
C

ATOM
357
O
GLU
A
79
77.218
21.485
−18.388
1.00
64.82
O

ATOM
358
N
LEU
A
80
78.902
22.878
−18.963
1.00
65.56
N

ATOM
359
CA
LEU
A
80
78.039
23.875
−19.589
1.00
66.20
C

ATOM
360
CB
LEU
A
80
78.763
25.227
−19.663
1.00
66.19
C

ATOM
361
CG
LEU
A
80
79.128
25.944
−18.359
1.00
66.08
C

ATOM
362
CD1
LEU
A
80
79.914
27.225
−18.646
1.00
65.61
C

ATOM
363
CD2
LEU
A
80
77.881
26.238
−17.525
1.00
65.99
C

ATOM
364
C
LEU
A
80
77.662
23.402
−20.996
1.00
66.59
C

ATOM
365
O
LEU
A
80
78.387
22.585
−21.575
1.00
66.81
O

ATOM
366
N
PRO
A
81
76.539
23.885
−21.547
1.00
66.88
N

ATOM
367
CA
PRO
A
81
76.220
23.634
−22.963
1.00
66.94
C

ATOM
368
CB
PRO
A
81
75.035
24.573
−23.226
1.00
67.02
C

ATOM
369
CG
PRO
A
81
74.363
24.703
−21.892
1.00
67.04
C

ATOM
370
CD
PRO
A
81
75.477
24.665
−20.877
1.00
66.98
C

ATOM
371
C
PRO
A
81
77.408
23.972
−23.884
1.00
66.80
C

ATOM
372
O
PRO
A
81
77.505
23.438
−24.990
1.00
66.90
O

ATOM
373
N
ASN
A
82
78.296
24.842
−23.405
1.00
66.49
N

ATOM
374
CA
ASN
A
82
79.543
25.182
−24.087
1.00
66.14
C

ATOM
375
CB
ASN
A
82
80.114
26.482
−23.492
1.00
66.36
C

ATOM
376
CG
ASN
A
82
81.498
26.816
−24.015
1.00
67.00
C

ATOM
377
OD1
ASN
A
82
81.734
26.837
−25.225
1.00
67.52
O

ATOM
378
ND2
ASN
A
82
82.424
27.089
−23.100
1.00
67.69
N

ATOM
379
C
ASN
A
82
80.576
24.044
−24.035
1.00
65.50
C

ATOM
380
O
ASN
A
82
81.273
23.787
−25.019
1.00
65.53
O

ATOM
381
N
GLY
A
83
80.664
23.369
−22.888
1.00
64.74
N

ATOM
382
CA
GLY
A
83
81.614
22.284
−22.683
1.00
63.59
C

ATOM
383
C
GLY
A
83
82.826
22.690
−21.857
1.00
62.70
C

ATOM
384
O
GLY
A
83
83.967
22.600
−22.326
1.00
62.98
O

ATOM
385
N
THR
A
84
82.571
23.149
−20.632
1.00
61.37
N

ATOM
386
CA
THR
A
84
83.621
23.529
−19.682
1.00
59.87
C

ATOM
387
CB
THR
A
84
83.742
25.067
−19.576
1.00
60.05
C

ATOM
388
OG1
THR
A
84
83.799
25.643
−20.888
1.00
60.81
O

ATOM
389
CG2
THR
A
84
85.080
25.468
−18.954
1.00
60.25
C

ATOM
390
C
THR
A
84
83.309
22.938
−18.310
1.00
58.33
C

ATOM
391
O
THR
A
84
82.139
22.816
−17.930
1.00
58.41
O

ATOM
392
N
ARG
A
85
84.356
22.576
−17.572
1.00
56.14
N

ATOM
393
CA
ARG
A
85
84.198
22.026
−16.231
1.00
53.98
C

ATOM
394
CB
ARG
A
85
85.445
21.223
−15.844
1.00
54.58
C

ATOM
395
CG
ARG
A
85
85.227
20.243
−14.703
1.00
56.25
C

ATOM
396
CD
ARG
A
85
86.028
18.945
−14.819
1.00
58.89
C

ATOM
397
NE
ARG
A
85
85.870
18.099
−13.630
1.00
60.27
N

ATOM
398
CZ
ARG
A
85
84.879
17.226
−13.445
1.00
60.85
C

ATOM
399
NH1
ARG
A
85
83.933
17.065
−14.370
1.00
61.04
N

ATOM
400
NH2
ARG
A
85
84.834
16.506
−12.329
1.00
60.48
N

ATOM
401
C
ARG
A
85
83.906
23.130
−15.200
1.00
51.86
C

ATOM
402
O
ARG
A
85
84.789
23.931
−14.865
1.00
51.74
O

ATOM
403
N
VAL
A
86
82.659
23.172
−14.721
1.00
48.87
N

ATOM
404
CA
VAL
A
86
82.224
24.121
−13.680
1.00
45.97
C

ATOM
405
CB
VAL
A
86
81.335
25.276
−14.251
1.00
46.05
C

ATOM
406
CG1
VAL
A
86
82.074
26.064
−15.322
1.00
46.41
C

ATOM
407
CG2
VAL
A
86
80.008
24.755
−14.781
1.00
45.90
C

ATOM
408
C
VAL
A
86
81.462
23.409
−12.553
1.00
43.56
C

ATOM
409
O
VAL
A
86
80.984
22.292
−12.750
1.00
43.24
O

ATOM
410
N
PRO
A
87
81.345
24.040
−11.380
1.00
41.11
N

ATOM
411
CA
PRO
A
87
80.494
23.495
−10.314
1.00
39.00
C

ATOM
412
CB
PRO
A
87
80.654
24.499
−9.158
1.00
39.06
C

ATOM
413
CG
PRO
A
87
81.251
25.719
−9.759
1.00
40.31
C

ATOM
414
CD
PRO
A
87
82.015
25.287
−10.966
1.00
40.95
C

ATOM
415
C
PRO
A
87
79.037
23.413
−10.755
1.00
36.73
C

ATOM
416
O
PRO
A
87
78.567
24.258
−11.535
1.00
35.64
O

ATOM
417
N
MET
A
88
78.343
22.391
−10.255
1.00
34.56
N

ATOM
418
CA
MET
A
88
76.936
22.171
−10.564
1.00
32.47
C

ATOM
419
CB
MET
A
88
76.408
20.950
−9.799
1.00
33.23
C

ATOM
420
CG
MET
A
88
75.047
20.407
−10.263
1.00
36.09
C

ATOM
421
SD
MET
A
88
74.917
19.957
−12.033
1.00
43.02
S

ATOM
422
CE
MET
A
88
76.260
18.799
−12.218
1.00
41.30
C

ATOM
423
C
MET
A
88
76.110
23.423
−10.274
1.00
30.24
C

ATOM
424
O
MET
A
88
75.169
23.717
−11.006
1.00
29.10
O

ATOM
425
N
GLU
A
89
76.487
24.169
−9.231
1.00
28.21
N

ATOM
426
CA
GLU
A
89
75.773
25.392
−8.843
1.00
26.55
C

ATOM
427
CB
GLU
A
89
76.393
26.043
−7.576
1.00
26.83
C

ATOM
428
CG
GLU
A
89
75.711
27.347
−7.134
1.00
27.21
C

ATOM
429
CD
GLU
A
89
75.939
27.733
−5.670
1.00
29.78
C

ATOM
430
OE1
GLU
A
89
76.956
27.292
−5.073
1.00
29.01
O

ATOM
431
OE2
GLU
A
89
75.080
28.483
−5.118
1.00
29.29
O

ATOM
432
C
GLU
A
89
75.669
26.392
−10.000
1.00
25.41
C

ATOM
433
O
GLU
A
89
74.609
26.988
−10.223
1.00
25.07
O

ATOM
434
N
VAL
A
90
76.761
26.566
−10.744
1.00
24.25
N

ATOM
435
CA
VAL
A
90
76.747
27.435
−11.927
1.00
23.34
C

ATOM
436
CB
VAL
A
90
78.193
27.717
−12.452
1.00
23.97
C

ATOM
437
CG1
VAL
A
90
78.178
28.460
−13.796
1.00
23.00
C

ATOM
438
CG2
VAL
A
90
78.989
28.530
−11.411
1.00
23.11
C

ATOM
439
C
VAL
A
90
75.822
26.881
−13.020
1.00
22.89
C

ATOM
440
O
VAL
A
90
75.002
27.622
−13.570
1.00
22.78
O

ATOM
441
N
VAL
A
91
75.926
25.579
−13.305
1.00
22.51
N

ATOM
442
CA
VAL
A
91
75.048
24.917
−14.293
1.00
22.19
C

ATOM
443
CB
VAL
A
91
75.316
23.382
−14.399
1.00
22.50
C

ATOM
444
CG1
VAL
A
91
74.265
22.688
−15.314
1.00
22.61
C

ATOM
445
CG2
VAL
A
91
76.688
23.116
−14.934
1.00
22.68
C

ATOM
446
C
VAL
A
91
73.569
25.143
−13.965
1.00
21.66
C

ATOM
447
O
VAL
A
91
72.783
25.594
−14.807
1.00
20.36
O

ATOM
448
N
LEU
A
92
73.215
24.856
−12.715
1.00
21.61
N

ATOM
449
CA
LEU
A
92
71.833
24.963
−12.256
1.00
21.57
C

ATOM
450
CB
LEU
A
92
71.682
24.326
−10.873
1.00
21.14
C

ATOM
451
CG
LEU
A
92
72.112
22.854
−10.778
1.00
21.50
C

ATOM
452
CD1
LEU
A
92
71.945
22.365
−9.349
1.00
20.58
C

ATOM
453
CD2
LEU
A
92
71.378
21.928
−11.767
1.00
18.41
C

ATOM
454
C
LEU
A
92
71.331
26.408
−12.255
1.00
21.79
C

ATOM
455
O
LEU
A
92
70.212
26.671
−12.706
1.00
21.50
O

ATOM
456
N
LEU
A
93
72.159
27.332
−11.764
1.00
22.36
N

ATOM
457
CA
LEU
A
93
71.808
28.755
−11.756
1.00
23.34
C

ATOM
458
CB
LEU
A
93
72.861
29.584
−11.018
1.00
23.50
C

ATOM
459
CG
LEU
A
93
72.714
29.608
−9.482
1.00
24.22
C

ATOM
460
CD1
LEU
A
93
73.985
30.131
−8.852
1.00
23.74
C

ATOM
461
CD2
LEU
A
93
71.493
30.431
−9.048
1.00
22.10
C

ATOM
462
C
LEU
A
93
71.594
29.301
−13.162
1.00
23.97
C

ATOM
463
O
LEU
A
93
70.642
30.037
−13.409
1.00
23.67
O

ATOM
464
N
LYS
A
94
72.468
28.922
−14.088
1.00
24.87
N

ATOM
465
CA
LYS
A
94
72.265
29.290
−15.491
1.00
26.26
C

ATOM
466
CB
LYS
A
94
73.448
28.847
−16.356
1.00
26.36
C

ATOM
467
CG
LYS
A
94
74.664
29.745
−16.166
1.00
29.54
C

ATOM
468
CD
LYS
A
94
75.932
29.132
−16.750
1.00
34.13
C

ATOM
469
CE
LYS
A
94
76.210
29.633
−18.167
1.00
36.90
C

ATOM
470
NZ
LYS
A
94
76.658
31.059
−18.181
1.00
39.00
N

ATOM
471
C
LYS
A
94
70.946
28.761
−16.045
1.00
26.31
C

ATOM
472
O
LYS
A
94
70.240
29.481
−16.756
1.00
26.21
O

ATOM
473
N
LYS
A
95
70.610
27.515
−15.712
1.00
26.64
N

ATOM
474
CA
LYS
A
95
69.356
26.916
−16.172
1.00
28.04
C

ATOM
475
CB
LYS
A
95
69.295
25.427
−15.824
1.00
27.38
C

ATOM
476
CG
LYS
A
95
70.096
24.557
−16.777
1.00
28.63
C

ATOM
477
CD
LYS
A
95
70.218
23.114
−16.294
1.00
29.42
C

ATOM
478
CE
LYS
A
95
68.891
22.361
−16.392
1.00
30.74
C

ATOM
479
NZ
LYS
A
95
68.513
22.039
−17.803
1.00
31.02
N

ATOM
480
C
LYS
A
95
68.096
27.657
−15.674
1.00
28.66
C

ATOM
481
O
LYS
A
95
67.088
27.707
−16.379
1.00
28.72
O

ATOM
482
N
VAL
A
96
68.167
28.239
−14.480
1.00
30.05
N

ATOM
483
CA
VAL
A
96
67.017
28.940
−13.899
1.00
31.67
C

ATOM
484
CB
VAL
A
96
66.818
28.631
−12.383
1.00
31.32
C

ATOM
485
CG1
VAL
A
96
66.594
27.139
−12.159
1.00
30.44
C

ATOM
486
CG2
VAL
A
96
67.978
29.149
−11.546
1.00
29.93
C

ATOM
487
C
VAL
A
96
66.997
30.458
−14.119
1.00
33.63
C

ATOM
488
O
VAL
A
96
65.999
31.112
−13.783
1.00
33.80
O

ATOM
489
N
SER
A
97
68.074
31.018
−14.676
1.00
35.26
N

ATOM
490
CA
SER
A
97
68.109
32.455
−14.979
1.00
37.17
C

ATOM
491
CB
SER
A
97
69.490
32.907
−15.483
1.00
37.37
C

ATOM
492
OG
SER
A
97
69.844
32.265
−16.699
1.00
38.96
O

ATOM
493
C
SER
A
97
67.009
32.865
−15.962
1.00
38.05
C

ATOM
494
O
SER
A
97
66.797
32.223
−16.996
1.00
38.07
O

ATOM
495
N
SER
A
98
66.302
33.934
−15.603
1.00
39.50
N

ATOM
496
CA
SER
A
98
65.224
34.521
−16.409
1.00
40.49
C

ATOM
497
CB
SER
A
98
64.109
33.499
−16.685
1.00
40.48
C

ATOM
498
OG
SER
A
98
63.105
33.547
−15.681
1.00
41.42
O

ATOM
499
C
SER
A
98
64.671
35.738
−15.656
1.00
40.82
C

ATOM
500
O
SER
A
98
65.177
36.091
−14.582
1.00
41.27
O

ATOM
501
N
GLY
A
99
63.632
36.364
−16.210
1.00
40.95
N

ATOM
502
CA
GLY
A
99
63.015
37.535
−15.602
1.00
40.62
C

ATOM
503
C
GLY
A
99
62.281
37.294
−14.283
1.00
40.18
C

ATOM
504
O
GLY
A
99
61.912
38.263
−13.600
1.00
40.34
O

ATOM
505
N
PHE
A
100
62.056
36.019
−13.942
1.00
39.30
N

ATOM
506
CA
PHE
A
100
61.391
35.628
−12.694
1.00
38.13
C

ATOM
507
CB
PHE
A
100
61.038
34.135
−12.709
1.00
38.35
C

ATOM
508
CG
PHE
A
100
60.296
33.656
−11.471
1.00
37.90
C

ATOM
509
CD1
PHE
A
100
59.100
34.258
−11.069
1.00
36.99
C

ATOM
510
CE1
PHE
A
100
58.411
33.801
−9.924
1.00
37.18
C

ATOM
511
CZ
PHE
A
100
58.922
32.727
−9.177
1.00
35.96
C

ATOM
512
CE2
PHE
A
100
60.108
32.116
−9.573
1.00
35.95
C

ATOM
513
CD2
PHE
A
100
60.792
32.585
−10.718
1.00
37.98
C

ATOM
514
C
PHE
A
100
62.266
35.944
−11.491
1.00
37.35
C

ATOM
515
O
PHE
A
100
63.365
35.409
−11.354
1.00
37.45
O

ATOM
516
N
SER
A
101
61.768
36.814
−10.620
1.00
36.17
N

ATOM
517
CA
SER
A
101
62.534
37.263
−9.468
1.00
35.23
C

ATOM
518
CB
SER
A
101
62.048
38.647
−9.003
1.00
35.81
C

ATOM
519
OG
SER
A
101
60.697
38.612
−8.570
1.00
37.04
O

ATOM
520
C
SER
A
101
62.571
36.280
−8.291
1.00
33.45
C

ATOM
521
O
SER
A
101
63.260
36.544
−7.295
1.00
33.93
O

ATOM
522
N
GLY
A
102
61.856
35.157
−8.402
1.00
31.13
N

ATOM
523
CA
GLY
A
102
61.760
34.190
−7.310
1.00
28.02
C

ATOM
524
C
GLY
A
102
63.026
33.377
−7.066
1.00
26.06
C

ATOM
525
O
GLY
A
102
63.183
32.736
−6.040
1.00
24.79
O

ATOM
526
N
VAL
A
103
63.936
33.396
−8.030
1.00
25.16
N

ATOM
527
CA
VAL
A
103
65.213
32.726
−7.877
1.00
24.40
C

ATOM
528
CB
VAL
A
103
65.377
31.540
−8.863
1.00
24.34
C

ATOM
529
CG1
VAL
A
103
66.675
30.797
−8.585
1.00
25.25
C

ATOM
530
CG2
VAL
A
103
64.214
30.567
−8.737
1.00
23.66
C

ATOM
531
C
VAL
A
103
66.300
33.759
−8.104
1.00
24.50
C

ATOM
532
O
VAL
A
103
66.217
34.566
−9.040
1.00
24.27
O

ATOM
533
N
ILE
A
104
67.303
33.744
−7.232
1.00
23.78
N

ATOM
534
CA
ILE
A
104
68.477
34.576
−7.383
1.00
24.18
C

ATOM
535
CB
ILE
A
104
69.526
34.185
−6.324
1.00
24.30
C

ATOM
536
CG1
ILE
A
104
70.384
35.394
−5.954
1.00
23.11
C

ATOM
537
CD1
ILE
A
104
69.581
36.449
−5.162
1.00
22.00
C

ATOM
538
CG2
ILE
A
104
70.327
32.934
−6.766
1.00
23.91
C

ATOM
539
C
ILE
A
104
69.083
34.483
−8.789
1.00
24.77
C

ATOM
540
O
ILE
A
104
69.188
33.403
−9.366
1.00
25.02
O

ATOM
541
N
ARG
A
105
69.479
35.619
−9.337
1.00
25.08
N

ATOM
542
CA
ARG
A
105
70.070
35.622
−10.667
1.00
26.17
C

ATOM
543
CB
ARG
A
105
69.566
36.833
−11.454
1.00
27.31
C

ATOM
544
CG
ARG
A
105
70.349
37.173
−12.714
1.00
32.33
C

ATOM
545
CD
ARG
A
105
69.728
38.311
−13.536
1.00
39.80
C

ATOM
546
NE
ARG
A
105
68.331
38.040
−13.891
1.00
45.22
N

ATOM
547
CZ
ARG
A
105
67.573
38.838
−14.646
1.00
47.93
C

ATOM
548
NH1
ARG
A
105
68.062
39.976
−15.139
1.00
48.73
N

ATOM
549
NH2
ARG
A
105
66.319
38.498
−14.908
1.00
48.97
N

ATOM
550
C
ARG
A
105
71.593
35.590
−10.594
1.00
25.19
C

ATOM
551
O
ARG
A
105
72.211
36.402
−9.885
1.00
24.65
O

ATOM
552
N
LEU
A
106
72.188
34.634
−11.304
1.00
24.85
N

ATOM
553
CA
LEU
A
106
73.642
34.609
−11.499
1.00
24.90
C

ATOM
554
CB
LEU
A
106
74.136
33.223
−11.918
1.00
24.41
C

ATOM
555
CG
LEU
A
106
75.651
33.073
−12.127
1.00
24.89
C

ATOM
556
CD1
LEU
A
106
76.449
33.148
−10.796
1.00
24.67
C

ATOM
557
CD2
LEU
A
106
75.961
31.790
−12.871
1.00
23.97
C

ATOM
558
C
LEU
A
106
74.004
35.639
−12.554
1.00
25.16
C

ATOM
559
O
LEU
A
106
73.536
35.565
−13.695
1.00
25.41
O

ATOM
560
N
LEU
A
107
74.825
36.604
−12.163
1.00
25.22
N

ATOM
561
CA
LEU
A
107
75.217
37.703
−13.046
1.00
25.72
C

ATOM
562
CB
LEU
A
107
75.427
38.991
−12.240
1.00
25.54
C

ATOM
563
CG
LEU
A
107
74.167
39.501
−11.524
1.00
25.95
C

ATOM
564
CD1
LEU
A
107
74.478
40.685
−10.620
1.00
25.00
C

ATOM
565
CD2
LEU
A
107
73.067
39.868
−12.525
1.00
27.51
C

ATOM
566
C
LEU
A
107
76.465
37.363
−13.847
1.00
25.66
C

ATOM
567
O
LEU
A
107
76.553
37.678
−15.040
1.00
25.68
O

ATOM
568
N
ASP
A
108
77.420
36.717
−13.177
1.00
25.47
N

ATOM
569
CA
ASP
A
108
78.699
36.333
−13.762
1.00
25.47
C

ATOM
570
CB
ASP
A
108
79.624
37.557
−13.872
1.00
25.78
C

ATOM
571
CG
ASP
A
108
80.569
37.485
−15.071
1.00
27.00
C

ATOM
572
OD1
ASP
A
108
80.828
36.385
−15.610
1.00
27.45
O

ATOM
573
OD2
ASP
A
108
81.111
38.501
−15.537
1.00
29.70
O

ATOM
574
C
ASP
A
108
79.358
35.308
−12.856
1.00
25.21
C

ATOM
575
O
ASP
A
108
78.938
35.119
−11.711
1.00
23.96
O

ATOM
576
N
TRP
A
109
80.405
34.669
−13.369
1.00
25.09
N

ATOM
577
CA
TRP
A
109
81.235
33.785
−12.565
1.00
25.83
C

ATOM
578
CB
TRP
A
109
80.668
32.360
−12.565
1.00
26.03
C

ATOM
579
CG
TRP
A
109
80.690
31.729
−13.918
1.00
27.82
C

ATOM
580
CD1
TRP
A
109
79.727
31.818
−14.883
1.00
28.39
C

ATOM
581
NE1
TRP
A
109
80.102
31.102
−15.995
1.00
30.13
N

ATOM
582
CE2
TRP
A
109
81.332
30.539
−15.770
1.00
30.67
C

ATOM
583
CD2
TRP
A
109
81.732
30.914
−14.465
1.00
29.83
C

ATOM
584
CE3
TRP
A
109
82.970
30.460
−13.987
1.00
30.76
C

ATOM
585
CZ3
TRP
A
109
83.758
29.664
−14.809
1.00
32.48
C

ATOM
586
CH2
TRP
A
109
83.334
29.313
−16.107
1.00
33.06
C

ATOM
587
CZ2
TRP
A
109
82.126
29.739
−16.602
1.00
32.39
C

ATOM
588
C
TRP
A
109
82.689
33.808
−13.045
1.00
26.10
C

ATOM
589
O
TRP
A
109
82.973
34.170
−14.191
1.00
25.61
O

ATOM
590
N
PHE
A
110
83.599
33.425
−12.155
1.00
26.36
N

ATOM
591
CA
PHE
A
110
85.028
33.407
−12.449
1.00
26.90
C

ATOM
592
CB
PHE
A
110
85.734
34.607
−11.796
1.00
27.07
C

ATOM
593
CG
PHE
A
110
85.249
35.945
−12.285
1.00
28.66
C

ATOM
594
CD1
PHE
A
110
85.909
36.602
−13.330
1.00
30.61
C

ATOM
595
CE1
PHE
A
110
85.464
37.851
−13.785
1.00
31.43
C

ATOM
596
CZ
PHE
A
110
84.344
38.446
−13.195
1.00
31.46
C

ATOM
597
CE2
PHE
A
110
83.679
37.795
−12.153
1.00
30.52
C

ATOM
598
CD2
PHE
A
110
84.140
36.556
−11.701
1.00
28.63
C

ATOM
599
C
PHE
A
110
85.646
32.117
−11.924
1.00
27.02
C

ATOM
600
O
PHE
A
110
85.227
31.591
−10.879
1.00
26.50
O

ATOM
601
N
GLU
A
111
86.638
31.614
−12.655
1.00
26.99
N

ATOM
602
CA
GLU
A
111
87.454
30.500
−12.201
1.00
27.50
C

ATOM
603
CB
GLU
A
111
87.683
29.476
−13.323
1.00
27.99
C

ATOM
604
CG
GLU
A
111
88.309
28.179
−12.828
1.00
28.36
C

ATOM
605
CD
GLU
A
111
88.468
27.116
−13.894
1.00
29.75
C

ATOM
606
OE1
GLU
A
111
87.864
27.215
−14.989
1.00
31.47
O

ATOM
607
OE2
GLU
A
111
89.206
26.154
−13.622
1.00
30.33
O

ATOM
608
C
GLU
A
111
88.796
31.023
−11.696
1.00
27.98
C

ATOM
609
O
GLU
A
111
89.415
31.891
−12.310
1.00
28.26
O

ATOM
610
N
ARG
A
112
89.225
30.490
−10.560
1.00
28.31
N

ATOM
611
CA
ARG
A
112
90.541
30.760
−10.004
1.00
28.18
C

ATOM
612
CB
ARG
A
112
90.403
31.378
−8.614
1.00
28.37
C

ATOM
613
CG
ARG
A
112
90.263
32.883
−8.622
1.00
27.57
C

ATOM
614
CD
ARG
A
112
89.828
33.452
−7.293
1.00
27.27
C

ATOM
615
NE
ARG
A
112
89.976
34.899
−7.282
1.00
26.93
N

ATOM
616
CZ
ARG
A
112
89.758
35.671
−6.233
1.00
27.51
C

ATOM
617
NH1
ARG
A
112
89.360
35.146
−5.079
1.00
28.76
N

ATOM
618
NH2
ARG
A
112
89.932
36.979
−6.339
1.00
26.92
N

ATOM
619
C
ARG
A
112
91.255
29.413
−9.933
1.00
28.60
C

ATOM
620
O
ARG
A
112
90.627
28.379
−10.197
1.00
28.00
O

ATOM
621
N
PRO
A
113
92.556
29.402
−9.616
1.00
28.77
N

ATOM
622
CA
PRO
A
113
93.282
28.129
−9.517
1.00
28.93
C

ATOM
623
CB
PRO
A
113
94.697
28.557
−9.102
1.00
29.22
C

ATOM
624
CG
PRO
A
113
94.817
29.977
−9.608
1.00
29.25
C

ATOM
625
CD
PRO
A
113
93.444
30.560
−9.383
1.00
28.81
C

ATOM
626
C
PRO
A
113
92.642
27.163
−8.505
1.00
28.63
C

ATOM
627
O
PRO
A
113
92.473
25.982
−8.829
1.00
28.81
O

ATOM
628
N
ASP
A
114
92.239
27.664
−7.340
1.00
28.09
N

ATOM
629
CA
ASP
A
114
91.740
26.800
−6.269
1.00
27.57
C

ATOM
630
CB
ASP
A
114
92.605
26.991
−5.020
1.00
28.11
C

ATOM
631
CG
ASP
A
114
94.078
26.644
−5.272
1.00
30.45
C

ATOM
632
OD1
ASP
A
114
94.959
27.360
−4.740
1.00
31.83
O

ATOM
633
OD2
ASP
A
114
94.438
25.680
−5.998
1.00
30.94
O

ATOM
634
C
ASP
A
114
90.252
26.962
−5.921
1.00
26.62
C

ATOM
635
O
ASP
A
114
89.754
26.323
−4.980
1.00
26.49
O

ATOM
636
N
SER
A
115
89.549
27.806
−6.677
1.00
25.25
N

ATOM
637
CA
SER
A
115
88.150
28.130
−6.382
1.00
23.81
C

ATOM
638
CB
SER
A
115
88.100
29.182
−5.276
1.00
23.83
C

ATOM
639
OG
SER
A
115
88.650
30.403
−5.733
1.00
22.52
O

ATOM
640
C
SER
A
115
87.352
28.653
−7.586
1.00
23.20
C

ATOM
641
O
SER
A
115
87.917
28.964
−8.639
1.00
22.61
O

ATOM
642
N
PHE
A
116
86.039
28.761
−7.400
1.00
22.13
N

ATOM
643
CA
PHE
A
116
85.175
29.515
−8.306
1.00
21.81
C

ATOM
644
CB
PHE
A
116
84.074
28.627
−8.901
1.00
21.79
C

ATOM
645
CG
PHE
A
116
84.578
27.655
−9.921
1.00
22.56
C

ATOM
646
CD1
PHE
A
116
85.096
26.425
−9.532
1.00
23.50
C

ATOM
647
CE1
PHE
A
116
85.581
25.515
−10.487
1.00
25.19
C

ATOM
648
CZ
PHE
A
116
85.550
25.846
−11.835
1.00
24.86
C

ATOM
649
CE2
PHE
A
116
85.032
27.080
−12.230
1.00
25.05
C

ATOM
650
CD2
PHE
A
116
84.551
27.974
−11.271
1.00
24.09
C

ATOM
651
C
PHE
A
116
84.556
30.678
−7.553
1.00
21.29
C

ATOM
652
O
PHE
A
116
84.349
30.605
−6.341
1.00
21.62
O

ATOM
653
N
VAL
A
117
84.280
31.757
−8.275
1.00
20.75
N

ATOM
654
CA
VAL
A
117
83.674
32.944
−7.707
1.00
19.94
C

ATOM
655
CB
VAL
A
117
84.628
34.134
−7.791
1.00
20.10
C

ATOM
656
CG1
VAL
A
117
84.036
35.341
−7.089
1.00
19.06
C

ATOM
657
CG2
VAL
A
117
86.019
33.768
−7.189
1.00
20.50
C

ATOM
658
C
VAL
A
117
82.399
33.242
−8.489
1.00
19.85
C

ATOM
659
O
VAL
A
117
82.441
33.393
−9.713
1.00
20.09
O

ATOM
660
N
LEU
A
118
81.276
33.327
−7.785
1.00
19.32
N

ATOM
661
CA
LEU
A
118
79.981
33.584
−8.400
1.00
19.32
C

ATOM
662
CB
LEU
A
118
78.936
32.565
−7.912
1.00
19.30
C

ATOM
663
CG
LEU
A
118
78.914
31.157
−8.510
1.00
20.91
C

ATOM
664
CD1
LEU
A
118
80.203
30.381
−8.224
1.00
23.74
C

ATOM
665
CD2
LEU
A
118
77.741
30.382
−7.949
1.00
22.22
C

ATOM
666
C
LEU
A
118
79.514
34.981
−8.051
1.00
19.31
C

ATOM
667
O
LEU
A
118
79.574
35.387
−6.887
1.00
19.13
O

ATOM
668
N
ILE
A
119
79.048
35.715
−9.062
1.00
19.23
N

ATOM
669
CA
ILE
A
119
78.521
37.053
−8.860
1.00
19.06
C

ATOM
670
CB
ILE
A
119
79.093
38.062
−9.898
1.00
19.52
C

ATOM
671
CG1
ILE
A
119
80.627
37.931
−10.022
1.00
19.59
C

ATOM
672
CD1
ILE
A
119
81.434
38.222
−8.736
1.00
19.03
C

ATOM
673
CG2
ILE
A
119
78.652
39.509
−9.557
1.00
18.88
C

ATOM
674
C
ILE
A
119
77.008
36.958
−8.938
1.00
19.43
C

ATOM
675
O
ILE
A
119
76.446
36.592
−9.977
1.00
19.01
O

ATOM
676
N
LEU
A
120
76.358
37.266
−7.823
1.00
19.78
N

ATOM
677
CA
LEU
A
120
74.913
37.097
−7.683
1.00
20.66
C

ATOM
678
CB
LEU
A
120
74.609
36.193
−6.483
1.00
20.51
C

ATOM
679
CG
LEU
A
120
75.197
34.788
−6.594
1.00
21.71
C

ATOM
680
CD1
LEU
A
120
75.218
34.103
−5.236
1.00
23.12
C

ATOM
681
CD2
LEU
A
120
74.403
33.967
−7.591
1.00
22.78
C

ATOM
682
C
LEU
A
120
74.253
38.436
−7.455
1.00
20.91
C

ATOM
683
O
LEU
A
120
74.853
39.319
−6.848
1.00
20.71
O

ATOM
684
N
GLU
A
121
73.015
38.588
−7.919
1.00
21.58
N

ATOM
685
CA
GLU
A
121
72.238
39.775
−7.581
1.00
22.82
C

ATOM
686
CB
GLU
A
121
70.883
39.780
−8.308
1.00
23.93
C

ATOM
687
CG
GLU
A
121
69.759
39.096
−7.559
1.00
26.70
C

ATOM
688
CD
GLU
A
121
68.493
38.950
−8.387
1.00
30.59
C

ATOM
689
OE1
GLU
A
121
67.830
39.973
−8.654
1.00
33.17
O

ATOM
690
OE2
GLU
A
121
68.159
37.811
−8.759
1.00
31.26
O

ATOM
691
C
GLU
A
121
72.062
39.836
−6.065
1.00
22.52
C

ATOM
692
O
GLU
A
121
72.087
38.800
−5.391
1.00
22.12
O

ATOM
693
N
ARG
A
122
71.908
41.043
−5.533
1.00
22.16
N

ATOM
694
CA
ARG
A
122
71.677
41.212
−4.105
1.00
22.66
C

ATOM
695
CB
ARG
A
122
72.977
41.620
−3.390
1.00
21.96
C

ATOM
696
CG
ARG
A
122
72.814
41.952
−1.920
1.00
21.41
C

ATOM
697
CD
ARG
A
122
74.128
42.195
−1.161
1.00
21.79
C

ATOM
698
NE
ARG
A
122
74.932
43.293
−1.726
1.00
20.54
N

ATOM
699
CZ
ARG
A
122
74.781
44.581
−1.418
1.00
21.80
C

ATOM
700
NH1
ARG
A
122
73.860
44.973
−0.543
1.00
21.45
N

ATOM
701
NH2
ARG
A
122
75.568
45.489
−1.977
1.00
23.39
N

ATOM
702
C
ARG
A
122
70.575
42.249
−3.864
1.00
23.50
C

ATOM
703
O
ARG
A
122
70.764
43.419
−4.156
1.00
23.59
O

ATOM
704
N
PRO
A
123
69.429
41.818
−3.330
1.00
24.57
N

ATOM
705
CA
PRO
A
123
68.384
42.756
−2.888
1.00
25.12
C

ATOM
706
CB
PRO
A
123
67.233
41.832
−2.448
1.00
25.10
C

ATOM
707
CG
PRO
A
123
67.552
40.494
−3.044
1.00
25.14
C

ATOM
708
CD
PRO
A
123
69.047
40.411
−3.109
1.00
24.18
C

ATOM
709
C
PRO
A
123
68.860
43.599
−1.703
1.00
25.82
C

ATOM
710
O
PRO
A
123
69.678
43.129
−0.900
1.00
25.56
O

ATOM
711
N
GLU
A
124
68.358
44.830
−1.607
1.00
26.56
N

ATOM
712
CA
GLU
A
124
68.738
45.750
−0.533
1.00
27.26
C

ATOM
713
CB
GLU
A
124
69.952
46.591
−0.958
1.00
27.95
C

ATOM
714
CG
GLU
A
124
70.730
47.274
0.171
1.00
30.91
C

ATOM
715
CD
GLU
A
124
71.867
48.140
−0.367
1.00
35.36
C

ATOM
716
OE1
GLU
A
124
71.616
48.930
−1.311
1.00
37.56
O

ATOM
717
OE2
GLU
A
124
73.017
48.036
0.134
1.00
36.68
O

ATOM
718
C
GLU
A
124
67.544
46.649
−0.201
1.00
26.82
C

ATOM
719
O
GLU
A
124
67.053
47.358
−1.078
1.00
27.29
O

ATOM
720
N
PRO
A
125
67.061
46.617
1.045
1.00
25.92
N

ATOM
721
CA
PRO
A
125
67.599
45.755
2.101
1.00
24.79
C

ATOM
722
CB
PRO
A
125
67.062
46.403
3.373
1.00
24.95
C

ATOM
723
CG
PRO
A
125
65.759
46.993
2.960
1.00
24.96
C

ATOM
724
CD
PRO
A
125
65.936
47.437
1.530
1.00
25.81
C

ATOM
725
C
PRO
A
125
67.095
44.316
1.989
1.00
23.97
C

ATOM
726
O
PRO
A
125
66.109
44.040
1.287
1.00
23.35
O

ATOM
727
N
VAL
A
126
67.789
43.412
2.670
1.00
23.02
N

ATOM
728
CA
VAL
A
126
67.507
41.987
2.583
1.00
22.32
C

ATOM
729
CB
VAL
A
126
68.333
41.305
1.439
1.00
22.37
C

ATOM
730
CG1
VAL
A
126
69.815
41.129
1.837
1.00
21.96
C

ATOM
731
CG2
VAL
A
126
67.732
39.971
1.028
1.00
22.11
C

ATOM
732
C
VAL
A
126
67.809
41.342
3.925
1.00
22.20
C

ATOM
733
O
VAL
A
126
68.600
41.866
4.723
1.00
22.19
O

ATOM
734
N
GLN
A
127
67.159
40.209
4.166
1.00
21.35
N

ATOM
735
CA
GLN
A
127
67.429
39.378
5.323
1.00
20.84
C

ATOM
736
CB
GLN
A
127
66.653
39.883
6.540
1.00
20.45
C

ATOM
737
CG
GLN
A
127
66.866
39.053
7.796
1.00
20.49
C

ATOM
738
CD
GLN
A
127
66.156
39.632
8.999
1.00
22.00
C

ATOM
739
OE1
GLN
A
127
64.953
39.891
8.944
1.00
22.10
O

ATOM
740
NE2
GLN
A
127
66.892
39.842
10.082
1.00
20.41
N

ATOM
741
C
GLN
A
127
66.996
37.952
4.963
1.00
20.56
C

ATOM
742
O
GLN
A
127
65.917
37.760
4.392
1.00
20.00
O

ATOM
743
N
ASP
A
128
67.845
36.967
5.250
1.00
19.63
N

ATOM
744
CA
ASP
A
128
67.454
35.593
5.008
1.00
19.54
C

ATOM
745
CB
ASP
A
128
68.672
34.650
4.844
1.00
19.72
C

ATOM
746
CG
ASP
A
128
69.276
34.181
6.158
1.00
21.27
C

ATOM
747
OD1
ASP
A
128
68.578
34.093
7.189
1.00
22.90
O

ATOM
748
OD2
ASP
A
128
70.480
33.843
6.237
1.00
24.10
O

ATOM
749
C
ASP
A
128
66.381
35.126
6.016
1.00
19.14
C

ATOM
750
O
ASP
A
128
66.220
35.724
7.079
1.00
18.98
O

ATOM
751
N
LEU
A
129
65.642
34.077
5.658
1.00
18.65
N

ATOM
752
CA
LEU
A
129
64.485
33.651
6.429
1.00
18.28
C

ATOM
753
CB
LEU
A
129
63.611
32.662
5.619
1.00
17.80
C

ATOM
754
CG
LEU
A
129
62.291
32.181
6.245
1.00
17.80
C

ATOM
755
CD1
LEU
A
129
61.344
33.350
6.565
1.00
16.86
C

ATOM
756
CD2
LEU
A
129
61.591
31.180
5.327
1.00
15.45
C

ATOM
757
C
LEU
A
129
64.861
33.096
7.804
1.00
18.57
C

ATOM
758
O
LEU
A
129
64.095
33.220
8.760
1.00
18.46
O

ATOM
759
N
PHE
A
130
66.047
32.503
7.908
1.00
18.90
N

ATOM
760
CA
PHE
A
130
66.545
32.032
9.200
1.00
19.18
C

ATOM
761
CB
PHE
A
130
67.887
31.311
9.033
1.00
19.86
C

ATOM
762
CG
PHE
A
130
68.531
30.931
10.339
1.00
22.10
C

ATOM
763
CD1
PHE
A
130
69.471
31.764
10.933
1.00
23.65
C

ATOM
764
CE1
PHE
A
130
70.069
31.423
12.155
1.00
26.57
C

ATOM
765
CZ
PHE
A
130
69.712
30.232
12.792
1.00
25.84
C

ATOM
766
CE2
PHE
A
130
68.765
29.398
12.206
1.00
26.84
C

ATOM
767
CD2
PHE
A
130
68.179
29.748
10.982
1.00
24.38
C

ATOM
768
C
PHE
A
130
66.704
33.176
10.203
1.00
19.08
C

ATOM
769
O
PHE
A
130
66.287
33.060
11.374
1.00
17.75
O

ATOM
770
N
ASP
A
131
67.316
34.274
9.753
1.00
19.37
N

ATOM
771
CA
ASP
A
131
67.489
35.442
10.622
1.00
20.03
C

ATOM
772
CB
ASP
A
131
68.375
36.505
9.966
1.00
20.64
C

ATOM
773
CG
ASP
A
131
69.836
36.090
9.894
1.00
23.72
C

ATOM
774
OD1
ASP
A
131
70.258
35.197
10.671
1.00
28.11
O

ATOM
775
OD2
ASP
A
131
70.642
36.603
9.084
1.00
27.01
O

ATOM
776
C
ASP
A
131
66.136
36.030
10.947
1.00
19.62
C

ATOM
777
O
ASP
A
131
65.868
36.368
12.086
1.00
19.32
O

ATOM
778
N
PHE
A
132
65.275
36.133
9.936
1.00
19.50
N

ATOM
779
CA
PHE
A
132
63.969
36.758
10.094
1.00
19.48
C

ATOM
780
CB
PHE
A
132
63.233
36.740
8.754
1.00
19.50
C

ATOM
781
CG
PHE
A
132
61.939
37.481
8.749
1.00
20.08
C

ATOM
782
CD1
PHE
A
132
61.906
38.839
8.455
1.00
21.55
C

ATOM
783
CE1
PHE
A
132
60.704
39.535
8.433
1.00
22.42
C

ATOM
784
CZ
PHE
A
132
59.506
38.861
8.680
1.00
22.64
C

ATOM
785
CE2
PHE
A
132
59.522
37.505
8.962
1.00
21.42
C

ATOM
786
CD2
PHE
A
132
60.734
36.814
8.991
1.00
21.38
C

ATOM
787
C
PHE
A
132
63.186
36.015
11.167
1.00
20.30
C

ATOM
788
O
PHE
A
132
62.643
36.642
12.088
1.00
20.08
O

ATOM
789
N
ILE
A
133
63.131
34.682
11.064
1.00
20.79
N

ATOM
790
CA
ILE
A
133
62.411
33.875
12.064
1.00
21.52
C

ATOM
791
CB
ILE
A
133
62.195
32.429
11.583
1.00
21.38
C

ATOM
792
CG1
ILE
A
133
61.215
32.402
10.402
1.00
19.84
C

ATOM
793
CD1
ILE
A
133
61.200
31.104
9.665
1.00
16.74
C

ATOM
794
CG2
ILE
A
133
61.665
31.539
12.747
1.00
21.31
C

ATOM
795
C
ILE
A
133
63.097
33.868
13.438
1.00
22.84
C

ATOM
796
O
ILE
A
133
62.430
33.825
14.472
1.00
22.75
O

ATOM
797
N
THR
A
134
64.423
33.888
13.446
1.00
23.77
N

ATOM
798
CA
THR
A
134
65.167
34.000
14.696
1.00
25.24
C

ATOM
799
CB
THR
A
134
66.683
33.972
14.427
1.00
24.97
C

ATOM
800
OG1
THR
A
134
67.056
32.682
13.921
1.00
24.99
O

ATOM
801
CG2
THR
A
134
67.486
34.101
15.735
1.00
25.41
C

ATOM
802
C
THR
A
134
64.779
35.286
15.433
1.00
26.05
C

ATOM
803
O
THR
A
134
64.514
35.271
16.636
1.00
26.27
O

ATOM
804
N
GLU
A
135
64.728
36.386
14.693
1.00
27.17
N

ATOM
805
CA
GLU
A
135
64.424
37.693
15.268
1.00
28.48
C

ATOM
806
CB
GLU
A
135
64.830
38.807
14.302
1.00
28.91
C

ATOM
807
CG
GLU
A
135
66.282
39.221
14.449
1.00
32.87
C

ATOM
808
CD
GLU
A
135
66.702
40.288
13.450
1.00
37.37
C

ATOM
809
OE1
GLU
A
135
65.813
41.022
12.939
1.00
38.58
O

ATOM
810
OE2
GLU
A
135
67.927
40.383
13.177
1.00
38.32
O

ATOM
811
C
GLU
A
135
62.958
37.853
15.657
1.00
28.36
C

ATOM
812
O
GLU
A
135
62.656
38.416
16.710
1.00
27.93
O

ATOM
813
N
ARG
A
136
62.056
37.345
14.817
1.00
27.83
N

ATOM
814
CA
ARG
A
136
60.635
37.631
14.983
1.00
27.91
C

ATOM
815
CB
ARG
A
136
60.022
38.109
13.657
1.00
28.19
C

ATOM
816
CG
ARG
A
136
60.551
39.487
13.244
1.00
30.84
C

ATOM
817
CD
ARG
A
136
60.046
40.034
11.909
1.00
33.40
C

ATOM
818
NE
ARG
A
136
58.583
40.081
11.805
1.00
35.56
N

ATOM
819
CZ
ARG
A
136
57.907
40.978
11.081
1.00
35.76
C

ATOM
820
NH1
ARG
A
136
58.556
41.923
10.403
1.00
35.79
N

ATOM
821
NH2
ARG
A
136
56.580
40.938
11.041
1.00
34.21
N

ATOM
822
C
ARG
A
136
59.836
36.488
15.594
1.00
26.86
C

ATOM
823
O
ARG
A
136
58.683
36.677
15.980
1.00
27.36
O

ATOM
824
N
GLY
A
137
60.452
35.316
15.713
1.00
25.61
N

ATOM
825
CA
GLY
A
137
59.754
34.134
16.187
1.00
24.72
C

ATOM
826
C
GLY
A
137
58.763
33.584
15.156
1.00
24.39
C

ATOM
827
O
GLY
A
137
58.796
33.952
13.969
1.00
23.90
O

ATOM
828
N
ALA
A
138
57.880
32.699
15.615
1.00
23.04
N

ATOM
829
CA
ALA
A
138
56.864
32.089
14.760
1.00
22.25
C

ATOM
830
CB
ALA
A
138
55.895
31.269
15.612
1.00
22.29
C

ATOM
831
C
ALA
A
138
56.101
33.152
13.968
1.00
22.02
C

ATOM
832
O
ALA
A
138
55.694
34.174
14.523
1.00
21.11
O

ATOM
833
N
LEU
A
139
55.914
32.906
12.671
1.00
20.97
N

ATOM
834
CA
LEU
A
139
55.223
33.860
11.814
1.00
20.45
C

ATOM
835
CB
LEU
A
139
55.673
33.676
10.358
1.00
19.75
C

ATOM
836
CG
LEU
A
139
57.194
33.668
10.121
1.00
19.78
C

ATOM
837
CD1
LEU
A
139
57.509
33.578
8.624
1.00
17.80
C

ATOM
838
CD2
LEU
A
139
57.871
34.908
10.772
1.00
19.37
C

ATOM
839
C
LEU
A
139
53.706
33.707
11.938
1.00
20.32
C

ATOM
840
O
LEU
A
139
53.209
32.589
12.007
1.00
20.36
O

ATOM
841
N
GLN
A
140
52.979
34.828
11.950
1.00
19.81
N

ATOM
842
CA
GLN
A
140
51.530
34.796
11.751
1.00
19.77
C

ATOM
843
CB
GLN
A
140
50.958
36.210
11.624
1.00
20.35
C

ATOM
844
CG
GLN
A
140
50.938
37.006
12.913
1.00
24.46
C

ATOM
845
CD
GLN
A
140
50.666
38.484
12.674
1.00
30.48
C

ATOM
846
OE1
GLN
A
140
49.836
38.846
11.827
1.00
32.68
O

ATOM
847
NE2
GLN
A
140
51.357
39.343
13.421
1.00
32.67
N

ATOM
848
C
GLN
A
140
51.211
34.035
10.469
1.00
18.78
C

ATOM
849
O
GLU
A
140
51.957
34.118
9.494
1.00
17.03
O

ATOM
850
N
GLU
A
141
50.088
33.325
10.453
1.00
18.57
N

ATOM
851
CA
GLU
A
141
49.769
32.482
9.296
1.00
18.81
C

ATOM
852
CB
GLU
A
141
48.563
31.588
9.579
1.00
18.86
C

ATOM
853
CG
GLU
A
141
48.922
30.461
10.531
1.00
20.50
C

ATOM
854
CD
GLU
A
141
47.785
29.504
10.762
1.00
20.11
C

ATOM
855
OE1
GLU
A
141
47.107
29.151
9.779
1.00
20.79
O

ATOM
856
OE2
GLU
A
141
47.572
29.120
11.933
1.00
21.96
O

ATOM
857
C
GLU
A
141
49.605
33.235
7.970
1.00
18.75
C

ATOM
858
O
GLU
A
141
49.969
32.702
6.931
1.00
18.07
O

ATOM
859
N
GLU
A
142
49.048
34.454
8.002
1.00
18.37
N

ATOM
860
CA
GLU
A
142
48.939
35.263
6.787
1.00
18.46
C

ATOM
861
CB
GLU
A
142
48.216
36.589
7.078
1.00
18.72
C

ATOM
862
CG
GLU
A
142
48.076
37.515
5.889
1.00
20.48
C

ATOM
863
CD
GLU
A
142
47.411
38.836
6.241
1.00
24.11
C

ATOM
864
OE1
GLU
A
142
48.061
39.692
6.891
1.00
23.55
O

ATOM
865
OE2
GLU
A
142
46.232
39.017
5.851
1.00
25.93
O

ATOM
866
C
GLU
A
142
50.329
35.529
6.179
1.00
17.83
C

ATOM
867
O
GLU
A
142
50.506
35.530
4.959
1.00
17.80
O

ATOM
868
N
LEU
A
143
51.309
35.761
7.037
1.00
16.88
N

ATOM
869
CA
LEU
A
143
52.653
36.029
6.568
1.00
16.41
C

ATOM
870
CB
LEU
A
143
53.497
36.667
7.666
1.00
16.81
C

ATOM
871
CG
LEU
A
143
54.952
36.998
7.288
1.00
16.83
C

ATOM
872
CD1
LEU
A
143
54.999
37.909
6.049
1.00
15.94
C

ATOM
873
CD2
LEU
A
143
55.625
37.670
8.464
1.00
16.70
C

ATOM
874
C
LEU
A
143
53.307
34.749
6.057
1.00
15.72
C

ATOM
875
O
LEU
A
143
53.921
34.745
4.983
1.00
15.44
O

ATOM
876
N
ALA
A
144
53.173
33.670
6.824
1.00
14.81
N

ATOM
877
CA
ALA
A
144
53.692
32.364
6.404
1.00
14.61
C

ATOM
878
CB
ALA
A
144
53.444
31.327
7.470
1.00
14.33
C

ATOM
879
C
ALA
A
144
53.078
31.914
5.077
1.00
14.82
C

ATOM
880
O
ALA
A
144
53.754
31.270
4.253
1.00
14.19
O

ATOM
881
N
ARG
A
145
51.796
32.235
4.884
1.00
14.19
N

ATOM
882
CA
ARG
A
145
51.090
31.869
3.666
1.00
15.16
C

ATOM
883
CB
ARG
A
145
49.587
32.205
3.764
1.00
15.23
C

ATOM
884
CG
ARG
A
145
48.803
32.031
2.453
1.00
16.28
C

ATOM
885
CD
ARG
A
145
47.303
32.380
2.564
1.00
18.20
C

ATOM
886
NE
ARG
A
145
46.693
31.573
3.615
1.00
17.28
N

ATOM
887
CZ
ARG
A
145
46.238
32.049
4.761
1.00
17.72
C

ATOM
888
NH1
ARG
A
145
46.270
33.352
5.018
1.00
17.11
N

ATOM
889
NH2
ARG
A
145
45.747
31.212
5.657
1.00
18.63
N

ATOM
890
C
ARG
A
145
51.727
32.562
2.471
1.00
15.43
C

ATOM
891
O
ARG
A
145
52.034
31.917
1.470
1.00
16.61
O

ATOM
892
N
SER
A
146
51.941
33.868
2.578
1.00
15.08
N

ATOM
893
CA
SER
A
146
52.557
34.618
1.491
1.00
15.89
C

ATOM
894
CB
SER
A
146
52.558
36.114
1.823
1.00
15.77
C

ATOM
895
OG
SER
A
146
53.374
36.817
0.907
1.00
18.17
O

ATOM
896
C
SER
A
146
53.976
34.104
1.170
1.00
15.75
C

ATOM
897
O
SER
A
146
54.311
33.849
0.000
1.00
15.69
O

ATOM
898
N
PHE
A
147
54.777
33.926
2.220
1.00
15.20
N

ATOM
899
CA
PHE
A
147
56.145
33.423
2.104
1.00
15.40
C

ATOM
900
CB
PHE
A
147
56.801
33.392
3.487
1.00
15.25
C

ATOM
901
CG
PHE
A
147
57.345
34.724
3.939
1.00
16.31
C

ATOM
902
CD1
PHE
A
147
57.041
35.903
3.246
1.00
17.31
C

ATOM
903
CE1
PHE
A
147
57.552
37.121
3.663
1.00
18.81
C

ATOM
904
CZ
PHE
A
147
58.389
37.178
4.790
1.00
18.13
C

ATOM
905
CE2
PHE
A
147
58.696
36.017
5.480
1.00
17.81
C

ATOM
906
CD2
PHE
A
147
58.176
34.793
5.052
1.00
16.34
C

ATOM
907
C
PHE
A
147
56.195
32.024
1.483
1.00
14.94
C

ATOM
908
O
PHE
A
147
56.927
31.786
0.522
1.00
15.80
O

ATOM
909
N
PHE
A
148
55.407
31.114
2.033
1.00
14.80
N

ATOM
910
CA
PHE
A
148
55.354
29.733
1.549
1.00
15.37
C

ATOM
911
CB
PHE
A
148
54.409
28.887
2.418
1.00
14.71
C

ATOM
912
CG
PHE
A
148
54.574
27.399
2.224
1.00
14.42
C

ATOM
913
CD1
PHE
A
148
55.810
26.776
2.456
1.00
13.47
C

ATOM
914
CE1
PHE
A
148
55.962
25.379
2.277
1.00
10.13
C

ATOM
915
CZ
PHE
A
148
54.876
24.618
1.864
1.00
12.94
C

ATOM
916
CE2
PHE
A
148
53.635
25.237
1.625
1.00
14.02
C

ATOM
917
CD2
PHE
A
148
53.495
26.622
1.813
1.00
14.27
C

ATOM
918
C
PHE
A
148
54.898
29.648
0.089
1.00
15.20
C

ATOM
919
O
PHE
A
148
55.459
28.902
−0.703
1.00
14.97
O

ATOM
920
N
TRP
A
149
53.866
30.413
−0.253
1.00
15.54
N

ATOM
921
CA
TRP
A
149
53.393
30.477
−1.634
1.00
15.37
C

ATOM
922
CB
TRP
A
149
52.230
31.470
−1.739
1.00
15.34
C

ATOM
923
CG
TRP
A
149
51.671
31.606
−3.110
1.00
15.24
C

ATOM
924
CD1
TRP
A
149
52.070
32.494
−4.075
1.00
14.51
C

ATOM
925
NE1
TRP
A
149
51.301
32.333
−5.205
1.00
15.75
N

ATOM
926
CE2
TRP
A
149
50.394
31.326
−4.998
1.00
15.41
C

ATOM
927
CD2
TRP
A
149
50.595
30.845
−3.682
1.00
15.51
C

ATOM
928
CE3
TRP
A
149
49.766
29.804
−3.210
1.00
15.20
C

ATOM
929
CZ3
TRP
A
149
48.777
29.287
−4.064
1.00
14.40
C

ATOM
930
CH2
TRP
A
149
48.614
29.788
−5.376
1.00
15.19
C

ATOM
931
CZ2
TRP
A
149
49.405
30.804
−5.857
1.00
15.74
C

ATOM
932
C
TRP
A
149
54.516
30.881
−2.585
1.00
15.47
C

ATOM
933
O
TRP
A
149
54.709
30.266
−3.637
1.00
15.67
O

ATOM
934
N
GLN
A
150
55.267
31.913
−2.213
1.00
16.07
N

ATOM
935
CA
GLN
A
150
56.354
32.394
−3.063
1.00
16.16
C

ATOM
936
CB
GLN
A
150
56.926
33.704
−2.522
1.00
16.54
C

ATOM
937
CG
GLN
A
150
56.012
34.904
−2.760
1.00
17.72
C

ATOM
938
CD
GLN
A
150
56.654
36.188
−2.309
1.00
20.82
C

ATOM
939
OE1
GLN
A
150
57.668
36.594
−2.860
1.00
20.46
O

ATOM
940
NE2
GLN
A
150
56.078
36.825
−1.291
1.00
22.67
N

ATOM
941
C
GLN
A
150
57.470
31.366
−3.231
1.00
16.22
C

ATOM
942
O
GLN
A
150
58.068
31.271
−4.311
1.00
16.09
O

ATOM
943
N
VAL
A
151
57.747
30.613
−2.165
1.00
15.69
N

ATOM
944
CA
VAL
A
151
58.719
29.528
−2.219
1.00
15.67
C

ATOM
945
CB
VAL
A
151
58.973
28.914
−0.819
1.00
15.75
C

ATOM
946
CG1
VAL
A
151
59.838
27.661
−0.920
1.00
15.14
C

ATOM
947
CG2
VAL
A
151
59.648
29.950
0.087
1.00
14.26
C

ATOM
948
C
VAL
A
151
58.232
28.454
−3.186
1.00
15.73
C

ATOM
949
O
VAL
A
151
58.979
28.003
−4.048
1.00
15.25
O

ATOM
950
N
LEU
A
152
56.967
28.065
−3.046
1.00
16.29
N

ATOM
951
CA
LEU
A
152
56.348
27.138
−3.992
1.00
17.18
C

ATOM
952
CB
LEU
A
152
54.859
26.947
−3.658
1.00
17.37
C

ATOM
953
CG
LEU
A
152
54.467
25.690
−2.874
1.00
19.91
C

ATOM
954
CD1
LEU
A
152
54.643
24.445
−3.756
1.00
22.90
C

ATOM
955
CD2
LEU
A
152
55.236
25.494
−1.621
1.00
23.13
C

ATOM
956
C
LEU
A
152
56.512
27.572
−5.453
1.00
16.62
C

ATOM
957
O
LEU
A
152
56.889
26.765
−6.299
1.00
16.65
O

ATOM
958
N
GLU
A
153
56.217
28.841
−5.739
1.00
16.61
N

ATOM
959
CA
GLU
A
153
56.333
29.375
−7.096
1.00
16.62
C

ATOM
960
CB
GLU
A
153
55.832
30.827
−7.180
1.00
16.56
C

ATOM
961
CG
GLU
A
153
54.331
30.997
−6.968
1.00
17.23
C

ATOM
962
CD
GLU
A
153
53.514
30.514
−8.156
1.00
17.86
C

ATOM
963
OE1
GLU
A
153
53.901
30.807
−9.303
1.00
20.00
O

ATOM
964
OE2
GLU
A
153
52.487
29.843
−7.945
1.00
17.52
O

ATOM
965
C
GLU
A
153
57.777
29.297
−7.568
1.00
16.68
C

ATOM
966
O
GLU
A
153
58.038
28.986
−8.732
1.00
16.20
O

ATOM
967
N
ALA
A
154
58.712
29.559
−6.656
1.00
16.55
N

ATOM
968
CA
ALA
A
154
60.140
29.496
−6.992
1.00
16.97
C

ATOM
969
CB
ALA
A
154
61.004
30.188
−5.919
1.00
15.90
C

ATOM
970
C
ALA
A
154
60.621
28.063
−7.243
1.00
16.84
C

ATOM
971
O
ALA
A
154
61.345
27.818
−8.207
1.00
17.76
O

ATOM
972
N
VAL
A
155
60.218
27.126
−6.386
1.00
16.64
N

ATOM
973
CA
VAL
A
155
60.584
25.724
−6.564
1.00
16.78
C

ATOM
974
CB
VAL
A
155
60.201
24.871
−5.326
1.00
17.27
C

ATOM
975
CG1
VAL
A
155
60.395
23.386
−5.589
1.00
16.81
C

ATOM
976
CG2
VAL
A
155
61.032
25.313
−4.084
1.00
17.68
C

ATOM
977
C
VAL
A
155
59.958
25.163
−7.852
1.00
16.84
C

ATOM
978
O
VAL
A
155
60.621
24.445
−8.603
1.00
16.56
O

ATOM
979
N
ARG
A
156
58.690
25.491
−8.107
1.00
16.70
N

ATOM
980
CA
ARG
A
156
58.051
25.086
−9.374
1.00
17.03
C

ATOM
981
CB
ARG
A
156
56.603
25.570
−9.461
1.00
16.46
C

ATOM
982
CG
ARG
A
156
55.645
24.827
−8.564
1.00
17.08
C

ATOM
983
CD
ARG
A
156
54.201
25.302
−8.681
1.00
16.07
C

ATOM
984
NE
ARG
A
156
53.815
25.379
−10.087
1.00
15.86
N

ATOM
985
CZ
ARG
A
156
52.921
26.218
−10.591
1.00
16.05
C

ATOM
986
NH1
ARG
A
156
52.280
27.071
−9.805
1.00
14.03
N

ATOM
987
NH2
ARG
A
156
52.672
26.199
−11.895
1.00
15.89
N

ATOM
988
C
ARG
A
156
58.839
25.599
−10.573
1.00
17.05
C

ATOM
989
O
ARG
A
156
59.071
24.864
−11.529
1.00
17.34
O

ATOM
990
N
HIS
A
157
59.266
26.855
−10.522
1.00
17.35
N

ATOM
991
CA
HIS
A
157
60.090
27.397
−11.594
1.00
18.31
C

ATOM
992
CB
HIS
A
157
60.449
28.859
−11.330
1.00
18.48
C

ATOM
993
CG
HIS
A
157
61.374
29.443
−12.351
1.00
20.28
C

ATOM
994
ND1
HIS
A
157
62.696
29.733
−12.078
1.00
23.93
N

ATOM
995
CE1
HIS
A
157
63.262
30.241
−13.158
1.00
23.06
C

ATOM
996
NE2
HIS
A
157
62.356
30.288
−14.118
1.00
23.55
N

ATOM
997
CD2
HIS
A
157
61.168
29.796
−13.639
1.00
20.83
C

ATOM
998
C
HIS
A
157
61.361
26.559
−11.806
1.00
18.61
C

ATOM
999
O
HIS
A
157
61.691
26.199
−12.947
1.00
17.98
O

ATOM
1000
N
CYS
A
158
62.064
26.247
−10.715
1.00
18.74
N

ATOM
1001
CA
CYS
A
158
63.259
25.405
−10.800
1.00
19.66
C

ATOM
1002
CB
CYS
A
158
63.837
25.146
−9.413
1.00
19.79
C

ATOM
1003
SG
CYS
A
158
64.537
26.620
−8.683
1.00
22.60
S

ATOM
1004
C
CYS
A
158
62.979
24.077
−11.501
1.00
19.92
C

ATOM
1005
O
CYS
A
158
63.677
23.712
−12.447
1.00
20.10
O

ATOM
1006
N
HIS
A
159
61.955
23.365
−11.032
1.00
20.09
N

ATOM
1007
CA
HIS
A
159
61.580
22.085
−11.612
1.00
20.50
C

ATOM
1008
CB
HIS
A
159
60.484
21.410
−10.782
1.00
20.39
C

ATOM
1009
CG
HIS
A
159
60.934
20.995
−9.414
1.00
21.38
C

ATOM
1010
ND1
HIS
A
159
60.503
19.834
−8.814
1.00
22.95
N

ATOM
1011
CE1
HIS
A
159
61.055
19.727
−7.616
1.00
22.06
C

ATOM
1012
NE2
HIS
A
159
61.845
20.769
−7.426
1.00
21.41
N

ATOM
1013
CD2
HIS
A
159
61.790
21.577
−8.534
1.00
21.73
C

ATOM
1014
C
HIS
A
159
61.175
22.194
−13.092
1.00
20.62
C

ATOM
1015
O
HIS
A
159
61.558
21.340
−13.883
1.00
20.59
O

ATOM
1016
N
ASN
A
160
60.433
23.240
−13.463
1.00
20.97
N

ATOM
1017
CA
ASN
A
160
60.110
23.508
−14.882
1.00
21.47
C

ATOM
1018
CB
ASN
A
160
59.230
24.754
−15.042
1.00
21.81
C

ATOM
1019
CG
AASN
A
160
57.985
24.688
−14.251
0.50
22.71
C

ATOM
1020
CG
BASN
A
160
58.366
24.731
−16.318
0.50
21.42
C

ATOM
1021
OD1
AASN
A
160
57.565
25.688
−13.683
0.50
25.62
O

ATOM
1022
OD1
BASN
A
160
58.380
25.680
−17.103
0.50
21.10
O

ATOM
1023
ND2
AASN
A
160
57.364
23.518
−14.203
0.50
26.04
N

ATOM
1024
ND2
BASN
A
160
57.598
23.664
−16.506
0.50
19.99
N

ATOM
1025
C
ASN
A
160
61.353
23.728
−15.731
1.00
21.48
C

ATOM
1026
O
ASN
A
160
61.344
23.430
−16.925
1.00
21.00
O

ATOM
1027
N
CYS
A
161
62.404
24.278
−15.115
1.00
20.77
N

ATOM
1028
CA
CYS
A
161
63.691
24.462
−15.773
1.00
21.07
C

ATOM
1029
CB
CYS
A
161
64.395
25.716
−15.231
1.00
20.76
C

ATOM
1030
SG
CYS
A
161
63.499
27.235
−15.609
1.00
26.51
S

ATOM
1031
C
CYS
A
161
64.628
23.242
−15.665
1.00
20.01
C

ATOM
1032
O
CYS
A
161
65.791
23.329
−16.052
1.00
19.64
O

ATOM
1033
N
GLY
A
162
64.141
22.124
−15.130
1.00
18.99
N

ATOM
1034
CA
GLY
A
162
64.965
20.921
−15.005
1.00
18.24
C

ATOM
1035
C
GLY
A
162
65.968
20.898
−13.850
1.00
17.99
C

ATOM
1036
O
GLY
A
162
66.963
20.153
−13.878
1.00
16.70
O

ATOM
1037
N
VAL
A
163
65.696
21.678
−12.805
1.00
17.86
N

ATOM
1038
CA
VAL
A
163
66.634
21.799
−11.688
1.00
17.74
C

ATOM
1039
CB
VAL
A
163
67.173
23.251
−11.564
1.00
18.57
C

ATOM
1040
CG1
VAL
A
163
67.897
23.479
−10.215
1.00
17.79
C

ATOM
1041
CG2
VAL
A
163
68.078
23.608
−12.766
1.00
17.89
C

ATOM
1042
C
VAL
A
163
65.970
21.373
−10.374
1.00
17.54
C

ATOM
1043
O
VAL
A
163
64.851
21.780
−10.071
1.00
17.67
O

ATOM
1044
N
LEU
A
164
66.673
20.550
−9.612
1.00
17.14
N

ATOM
1045
CA
LEU
A
164
66.235
20.142
−8.288
1.00
17.15
C

ATOM
1046
CB
LEU
A
164
66.298
18.614
−8.170
1.00
17.23
C

ATOM
1047
CG
LEU
A
164
65.715
17.973
−6.909
1.00
18.35
C

ATOM
1048
CD1
LEU
A
164
64.183
18.038
−6.939
1.00
18.69
C

ATOM
1049
CD2
LEU
A
164
66.201
16.530
−6.783
1.00
15.82
C

ATOM
1050
C
LEU
A
164
67.151
20.802
−7.269
1.00
16.92
C

ATOM
1051
O
LEU
A
164
68.367
20.594
−7.305
1.00
17.02
O

ATOM
1052
N
HIS
A
165
66.574
21.583
−6.359
1.00
16.61
N

ATOM
1053
CA
HIS
A
165
67.356
22.378
−5.410
1.00
15.80
C

ATOM
1054
CB
HIS
A
165
66.462
23.440
−4.747
1.00
16.02
C

ATOM
1055
CG
HIS
A
165
67.212
24.444
−3.924
1.00
15.04
C

ATOM
1056
ND1
HIS
A
165
67.698
24.155
−2.668
1.00
13.63
N

ATOM
1057
CE1
HIS
A
165
68.311
25.218
−2.175
1.00
14.79
C

ATOM
1058
NE2
HIS
A
165
68.248
26.188
−3.071
1.00
16.20
N

ATOM
1059
CD2
HIS
A
165
67.571
25.726
−4.182
1.00
14.88
C

ATOM
1060
C
HIS
A
165
68.065
21.520
−4.352
1.00
16.12
C

ATOM
1061
O
HIS
A
165
69.281
21.692
−4.112
1.00
15.47
O

ATOM
1062
N
ARG
A
166
67.301
20.628
−3.708
1.00
15.81
N

ATOM
1063
CA
ARG
A
166
67.802
19.692
−2.685
1.00
16.34
C

ATOM
1064
CB
ARG
A
166
68.933
18.830
−3.231
1.00
16.34
C

ATOM
1065
CG
ARG
A
166
68.542
17.800
−4.282
1.00
17.58
C

ATOM
1066
CD
ARG
A
166
69.743
17.471
−5.131
1.00
23.63
C

ATOM
1067
NE
ARG
A
166
70.090
16.080
−5.010
1.00
27.91
N

ATOM
1068
CZ
ARG
A
166
71.277
15.551
−5.274
1.00
28.25
C

ATOM
1069
NH1
ARG
A
166
72.327
16.299
−5.636
1.00
26.61
N

ATOM
1070
NH2
ARG
A
166
71.404
14.246
−5.142
1.00
25.73
N

ATOM
1071
C
ARG
A
166
68.284
20.261
−1.348
1.00
17.04
C

ATOM
1072
O
ARG
A
166
68.778
19.491
−0.517
1.00
17.97
O

ATOM
1073
N
ASP
A
167
68.165
21.571
−1.127
1.00
16.44
N

ATOM
1074
CA
ASP
A
167
68.537
22.157
0.172
1.00
17.08
C

ATOM
1075
CB
ASP
A
167
70.018
22.615
0.164
1.00
16.76
C

ATOM
1076
CG
ASP
A
167
70.639
22.733
1.576
1.00
19.52
C

ATOM
1077
OD1
ASP
A
167
70.136
22.109
2.552
1.00
19.71
O

ATOM
1078
OD2
ASP
A
167
71.660
23.441
1.792
1.00
20.05
O

ATOM
1079
C
ASP
A
167
67.593
23.303
0.559
1.00
16.55
C

ATOM
1080
O
ASP
A
167
68.028
24.327
1.065
1.00
17.85
O

ATOM
1081
N
ILE
A
168
66.289
23.130
0.321
1.00
16.37
N

ATOM
1082
CA
ILE
A
168
65.304
24.165
0.643
1.00
15.43
C

ATOM
1083
CB
ILE
A
168
63.919
23.803
0.061
1.00
15.49
C

ATOM
1084
CG1
ILE
A
168
63.990
23.685
−1.467
1.00
15.11
C

ATOM
1085
CD1
ILE
A
168
62.816
22.891
−2.049
1.00
15.98
C

ATOM
1086
CG2
ILE
A
168
62.841
24.821
0.481
1.00
14.46
C

ATOM
1087
C
ILE
A
168
65.226
24.257
2.159
1.00
15.89
C

ATOM
1088
O
ILE
A
168
64.988
23.247
2.828
1.00
15.71
O

ATOM
1089
N
LYS
A
169
65.445
25.459
2.682
1.00
15.34
N

ATOM
1090
CA
LYS
A
169
65.458
25.724
4.116
1.00
15.97
C

ATOM
1091
CB
LYS
A
169
66.666
25.055
4.793
1.00
16.17
C

ATOM
1092
CG
LYS
A
169
68.018
25.601
4.321
1.00
18.35
C

ATOM
1093
CD
LYS
A
169
69.165
24.636
4.595
1.00
21.69
C

ATOM
1094
CE
LYS
A
169
69.449
24.497
6.073
1.00
23.35
C

ATOM
1095
NZ
LYS
A
169
70.883
24.061
6.239
1.00
24.28
N

ATOM
1096
C
LYS
A
169
65.542
27.234
4.314
1.00
15.57
C

ATOM
1097
O
LYS
A
169
65.954
27.971
3.392
1.00
15.50
O

ATOM
1098
N
ASP
A
170
65.213
27.676
5.526
1.00
15.04
N

ATOM
1099
CA
ASP
A
170
65.179
29.090
5.868
1.00
15.81
C

ATOM
1100
CB
ASP
A
170
64.849
29.284
7.358
1.00
15.73
C

ATOM
1101
CG
ASP
A
170
65.734
28.457
8.295
1.00
18.50
C

ATOM
1102
OD1
ASP
A
170
66.780
27.869
7.880
1.00
19.79
O

ATOM
1103
OD2
ASP
A
170
65.450
28.361
9.509
1.00
21.07
O

ATOM
1104
C
ASP
A
170
66.433
29.880
5.468
1.00
16.21
C

ATOM
1105
O
ASP
A
170
66.321
30.954
4.874
1.00
16.22
O

ATOM
1106
N
GLU
A
171
67.607
29.341
5.792
1.00
16.57
N

ATOM
1107
CA
GLU
A
171
68.918
29.951
5.480
1.00
17.89
C

ATOM
1108
CB
GLU
A
171
70.040
28.959
5.796
1.00
18.41
C

ATOM
1109
CG
GLU
A
171
70.770
29.167
7.082
1.00
24.87
C

ATOM
1110
CD
GLU
A
171
71.735
28.024
7.352
1.00
29.19
C

ATOM
1111
OE1
GLU
A
171
72.124
27.876
8.521
1.00
34.95
O

ATOM
1112
OE2
GLU
A
171
72.072
27.259
6.407
1.00
30.15
O

ATOM
1113
C
GLU
A
171
69.096
30.224
3.998
1.00
16.68
C

ATOM
1114
O
GLU
A
171
69.853
31.125
3.626
1.00
15.52
O

ATOM
1115
N
ASN
A
172
68.468
29.391
3.171
1.00
15.92
N

ATOM
1116
CA
ASN
A
172
68.601
29.487
1.707
1.00
15.37
C

ATOM
1117
CB
ASN
A
172
68.806
28.111
1.093
1.00
14.94
C

ATOM
1118
CG
ASN
A
172
70.122
27.517
1.493
1.00
15.14
C

ATOM
1119
OD1
ASN
A
172
71.047
28.264
1.760
1.00
15.76
O

ATOM
1120
ND2
ASN
A
172
70.218
26.188
1.567
1.00
13.68
N

ATOM
1121
C
ASN
A
172
67.454
30.228
1.026
1.00
15.23
C

ATOM
1122
O
ASN
A
172
67.198
30.038
−0.154
1.00
15.24
O

ATOM
1123
N
ILE
A
173
66.799
31.102
1.778
1.00
15.43
N

ATOM
1124
CA
ILE
A
173
65.714
31.920
1.252
1.00
15.78
C

ATOM
1125
CB
ILE
A
173
64.350
31.416
1.775
1.00
15.76
C

ATOM
1126
CG1
ILE
A
173
64.066
29.987
1.287
1.00
16.39
C

ATOM
1127
CD1
ILE
A
173
62.948
29.264
2.080
1.00
14.60
C

ATOM
1128
CG2
ILE
A
173
63.211
32.396
1.379
1.00
15.41
C

ATOM
1129
C
ILE
A
173
65.947
33.363
1.701
1.00
15.85
C

ATOM
1130
O
ILE
A
173
66.149
33.622
2.884
1.00
15.12
O

ATOM
1131
N
LEU
A
174
65.914
34.285
0.741
1.00
16.29
N

ATOM
1132
CA
LEU
A
174
66.139
35.707
0.992
1.00
16.81
C

ATOM
1133
CB
LEU
A
174
67.035
36.307
−0.105
1.00
16.84
C

ATOM
1134
CG
LEU
A
174
68.479
35.805
−0.189
1.00
17.08
C

ATOM
1135
CD1
LEU
A
174
69.217
36.628
−1.214
1.00
16.20
C

ATOM
1136
CD2
LEU
A
174
69.187
35.865
1.153
1.00
16.61
C

ATOM
1137
C
LEU
A
174
64.816
36.419
0.956
1.00
17.35
C

ATOM
1138
O
LEU
A
174
63.963
36.085
0.127
1.00
17.94
O

ATOM
1139
N
ILE
A
175
64.641
37.387
1.850
1.00
17.74
N

ATOM
1140
CA
ILE
A
175
63.470
38.255
1.833
1.00
18.68
C

ATOM
1141
CB
ILE
A
175
62.818
38.360
3.226
1.00
18.50
C

ATOM
1142
CG1
ILE
A
175
62.456
36.976
3.794
1.00
18.87
C

ATOM
1143
CD1
ILE
A
175
62.302
36.995
5.327
1.00
18.86
C

ATOM
1144
CG2
ILE
A
175
61.576
39.278
3.167
1.00
18.77
C

ATOM
1145
C
ILE
A
175
63.902
39.649
1.389
1.00
19.58
C

ATOM
1146
O
ILE
A
175
64.664
40.322
2.095
1.00
19.31
O

ATOM
1147
N
ASP
A
176
63.412
40.074
0.228
1.00
20.23
N

ATOM
1148
CA
ASP
A
176
63.581
41.449
−0.230
1.00
21.84
C

ATOM
1149
CB
ASP
A
176
63.315
41.541
−1.739
1.00
22.01
C

ATOM
1150
CG
ASP
A
176
63.414
42.967
−2.280
1.00
23.60
C

ATOM
1151
OD1
ASP
A
176
63.243
43.920
−1.502
1.00
23.50
O

ATOM
1152
OD2
ASP
A
176
63.625
43.217
−3.482
1.00
24.73
O

ATOM
1153
C
ASP
A
176
62.588
42.286
0.587
1.00
22.79
C

ATOM
1154
O
ASP
A
176
61.387
42.316
0.297
1.00
22.81
O

ATOM
1155
N
LEU
A
177
63.102
42.924
1.634
1.00
23.58
N

ATOM
1156
CA
LEU
A
177
62.271
43.537
2.660
1.00
24.93
C

ATOM
1157
CB
LEU
A
177
63.132
44.012
3.835
1.00
25.33
C

ATOM
1158
CG
LEU
A
177
63.764
42.908
4.700
1.00
25.91
C

ATOM
1159
CD1
LEU
A
177
64.830
43.473
5.621
1.00
26.41
C

ATOM
1160
CD2
LEU
A
177
62.715
42.118
5.504
1.00
27.00
C

ATOM
1161
C
LEU
A
177
61.345
44.658
2.164
1.00
25.53
C

ATOM
1162
O
LEU
A
177
60.231
44.789
2.661
1.00
26.29
O

ATOM
1163
N
ASN
A
178
61.789
45.433
1.177
1.00
25.87
N

ATOM
1164
CA
ASN
A
178
60.985
46.525
0.607
1.00
26.30
C

ATOM
1165
CB
ASN
A
178
61.875
47.492
−0.187
1.00
26.74
C

ATOM
1166
CG
ASN
A
178
62.544
48.534
0.690
1.00
28.73
C

ATOM
1167
OD1
ASN
A
178
62.308
48.600
1.904
1.00
31.92
O

ATOM
1168
ND2
ASN
A
178
63.382
49.361
0.078
1.00
30.86
N

ATOM
1169
C
ASN
A
178
59.857
46.042
−0.307
1.00
26.01
C

ATOM
1170
O
ASN
A
178
58.771
46.630
−0.338
1.00
25.84
O

ATOM
1171
N
ARG
A
179
60.134
44.986
−1.066
1.00
25.22
N

ATOM
1172
CA
ARG
A
179
59.202
44.497
−2.073
1.00
25.06
C

ATOM
1173
CB
ARG
A
179
59.951
44.089
−3.340
1.00
25.43
C

ATOM
1174
CG
ARG
A
179
60.482
45.270
−4.157
1.00
26.18
C

ATOM
1175
CD
ARG
A
179
61.170
44.845
−5.426
1.00
29.81
C

ATOM
1176
NE
ARG
A
179
61.712
45.951
−6.219
1.00
33.67
N

ATOM
1177
CZ
ARG
A
179
60.987
46.869
−6.859
1.00
35.31
C

ATOM
1178
NH1
ARG
A
179
59.658
46.854
−6.805
1.00
36.83
N

ATOM
1179
NH2
ARG
A
179
61.598
47.816
−7.559
1.00
36.82
N

ATOM
1180
C
ARG
A
179
58.330
43.355
−1.574
1.00
24.41
C

ATOM
1181
O
ARG
A
179
57.345
43.004
−2.221
1.00
24.91
O

ATOM
1182
N
GLY
A
180
58.675
42.786
−0.421
1.00
23.59
N

ATOM
1183
CA
GLY
A
180
57.977
41.611
0.083
1.00
22.56
C

ATOM
1184
C
GLY
A
180
58.160
40.359
−0.779
1.00
21.90
C

ATOM
1185
O
GLY
A
180
57.320
39.456
−0.754
1.00
21.19
O

ATOM
1186
N
GLU
A
181
59.263
40.310
−1.524
1.00
21.18
N

ATOM
1187
CA
GLU
A
181
59.542
39.216
−2.462
1.00
21.26
C

ATOM
1188
CB
GLU
A
181
60.001
39.767
−3.815
1.00
20.99
C

ATOM
1189
CG
GLU
A
181
58.883
40.426
−4.598
1.00
22.33
C

ATOM
1190
CD
GLU
A
181
59.360
41.165
−5.827
1.00
24.38
C

ATOM
1191
OE1
GLU
A
181
60.493
40.911
−6.310
1.00
25.63
O

ATOM
1192
OE2
GLU
A
181
58.578
42.011
−6.317
1.00
26.99
O

ATOM
1193
C
GLU
A
181
60.613
38.281
−1.928
1.00
20.80
C

ATOM
1194
O
GLU
A
181
61.659
38.735
−1.467
1.00
20.59
O

ATOM
1195
N
LEU
A
182
60.348
36.979
−2.002
1.00
20.60
N

ATOM
1196
CA
LEU
A
182
61.297
35.963
−1.555
1.00
20.56
C

ATOM
1197
CB
LEU
A
182
60.570
34.791
−0.891
1.00
20.37
C

ATOM
1198
CG
LEU
A
182
60.517
34.821
0.631
1.00
21.15
C

ATOM
1199
CD1
LEU
A
182
59.818
36.090
1.096
1.00
22.41
C

ATOM
1200
CD2
LEU
A
182
59.801
33.559
1.145
1.00
19.08
C

ATOM
1201
C
LEU
A
182
62.118
35.439
−2.725
1.00
20.73
C

ATOM
1202
O
LEU
A
182
61.612
35.341
−3.849
1.00
20.32
O

ATOM
1203
N
LYS
A
183
63.372
35.096
−2.442
1.00
20.55
N

ATOM
1204
CA
LYS
A
183
64.313
34.617
−3.448
1.00
20.89
C

ATOM
1205
CB
LYS
A
183
65.374
35.692
−3.759
1.00
21.35
C

ATOM
1206
CG
LYS
A
183
64.883
36.741
−4.750
1.00
24.94
C

ATOM
1207
CD
LYS
A
183
65.757
37.973
−4.773
1.00
26.84
C

ATOM
1208
CE
LYS
A
183
65.777
38.639
−6.149
1.00
30.89
C

ATOM
1209
NZ
LYS
A
183
64.436
38.886
−6.765
1.00
30.16
N

ATOM
1210
C
LYS
A
183
65.005
33.373
−2.927
1.00
19.72
C

ATOM
1211
O
LYS
A
183
65.572
33.384
−1.844
1.00
19.28
O

ATOM
1212
N
LEU
A
184
64.960
32.317
−3.725
1.00
18.78
N

ATOM
1213
CA
LEU
A
184
65.689
31.088
−3.462
1.00
18.80
C

ATOM
1214
CB
LEU
A
184
65.057
29.957
−4.278
1.00
18.65
C

ATOM
1215
CG
LEU
A
184
65.182
28.479
−3.925
1.00
22.15
C

ATOM
1216
CD1
LEU
A
184
64.840
28.132
−2.445
1.00
22.78
C

ATOM
1217
CD2
LEU
A
184
64.302
27.643
−4.894
1.00
19.46
C

ATOM
1218
C
LEU
A
184
67.166
31.270
−3.827
1.00
17.97
C

ATOM
1219
O
LEU
A
184
67.500
31.813
−4.895
1.00
17.51
O

ATOM
1220
N
ILE
A
185
68.048
30.840
−2.932
1.00
16.83
N

ATOM
1221
CA
ILE
A
185
69.482
30.849
−3.204
1.00
16.25
C

ATOM
1222
CB
ILE
A
185
70.215
31.922
−2.348
1.00
16.56
C

ATOM
1223
CG1
ILE
A
185
69.892
31.720
−0.859
1.00
15.91
C

ATOM
1224
CD1
ILE
A
185
70.811
32.451
0.107
1.00
16.54
C

ATOM
1225
CG2
ILE
A
185
69.924
33.333
−2.865
1.00
15.65
C

ATOM
1226
C
ILE
A
185
70.098
29.504
−2.880
1.00
16.22
C

ATOM
1227
O
ILE
A
185
69.411
28.607
−2.380
1.00
16.13
O

ATOM
1228
N
ASP
A
186
71.409
29.408
−3.127
1.00
15.92
N

ATOM
1229
CA
ASP
A
186
72.254
28.263
−2.788
1.00
15.84
C

ATOM
1230
CB
ASP
A
186
72.344
28.039
−1.269
1.00
16.13
C

ATOM
1231
CG
ASP
A
186
73.351
26.972
−0.898
1.00
15.73
C

ATOM
1232
OD1
ASP
A
186
73.977
26.372
−1.791
1.00
17.28
O

ATOM
1233
OD2
ASP
A
186
73.571
26.621
0.268
1.00
16.60
O

ATOM
1234
C
ASP
A
186
71.875
26.980
−3.505
1.00
17.14
C

ATOM
1235
O
ASP
A
186
71.185
26.128
−2.968
1.00
17.68
O

ATOM
1236
N
PHE
A
187
72.372
26.828
−4.721
1.00
17.98
N

ATOM
1237
CA
PHE
A
187
72.163
25.603
−5.459
1.00
19.11
C

ATOM
1238
CB
PHE
A
187
71.813
25.935
−6.905
1.00
19.00
C

ATOM
1239
CG
PHE
A
187
70.462
26.572
−7.042
1.00
18.98
C

ATOM
1240
CD1
PHE
A
187
70.277
27.914
−6.731
1.00
17.58
C

ATOM
1241
CE1
PHE
A
187
69.010
28.508
−6.832
1.00
19.96
C

ATOM
1242
CZ
PHE
A
187
67.917
27.743
−7.260
1.00
19.45
C

ATOM
1243
CE2
PHE
A
187
68.094
26.402
−7.575
1.00
18.98
C

ATOM
1244
CD2
PHE
A
187
69.366
25.817
−7.452
1.00
19.42
C

ATOM
1245
C
PHE
A
187
73.367
24.669
−5.342
1.00
19.81
C

ATOM
1246
O
PHE
A
187
73.540
23.776
−6.162
1.00
20.32
O

ATOM
1247
N
GLY
A
188
74.157
24.864
−4.285
1.00
20.15
N

ATOM
1248
CA
GLY
A
188
75.355
24.074
−4.027
1.00
20.64
C

ATOM
1249
C
GLY
A
188
75.130
22.581
−3.824
1.00
20.89
C

ATOM
1250
O
GLY
A
188
76.061
21.795
−4.008
1.00
20.70
O

ATOM
1251
N
SER
A
189
73.904
22.186
−3.460
1.00
20.61
N

ATOM
1252
CA
SER
A
189
73.585
20.774
−3.205
1.00
20.36
C

ATOM
1253
CB
SER
A
189
72.891
20.598
−1.843
1.00
20.68
C

ATOM
1254
OG
SER
A
189
73.701
21.035
−0.766
1.00
20.77
O

ATOM
1255
C
SER
A
189
72.668
20.218
−4.276
1.00
20.23
C

ATOM
1256
O
SER
A
189
72.229
19.079
−4.181
1.00
19.67
O

ATOM
1257
N
GLY
A
190
72.359
21.040
−5.273
1.00
19.66
N

ATOM
1258
CA
GLY
A
190
71.362
20.701
−6.256
1.00
20.11
C

ATOM
1259
C
GLY
A
190
71.779
19.655
−7.282
1.00
20.35
C

ATOM
1260
O
GLY
A
190
72.924
19.203
−7.309
1.00
20.22
O

ATOM
1261
N
ALA
A
191
70.830
19.271
−8.122
1.00
19.81
N

ATOM
1262
CA
ALA
A
191
71.085
18.339
−9.201
1.00
20.13
C

ATOM
1263
CB
ALA
A
191
70.902
16.875
−8.722
1.00
20.04
C

ATOM
1264
C
ALA
A
191
70.130
18.652
−10.323
1.00
20.23
C

ATOM
1265
O
ALA
A
191
69.126
19.344
−10.122
1.00
20.11
O

ATOM
1266
N
LEU
A
192
70.446
18.144
−11.512
1.00
20.33
N

ATOM
1267
CA
LEU
A
192
69.504
18.154
−12.617
1.00
20.48
C

ATOM
1268
CB
LEU
A
192
70.160
17.538
−13.870
1.00
20.65
C

ATOM
1269
CG
LEU
A
192
71.394
18.241
−14.460
1.00
21.30
C

ATOM
1270
CD1
LEU
A
192
72.025
17.441
−15.650
1.00
24.01
C

ATOM
1271
CD2
LEU
A
192
71.028
19.649
−14.922
1.00
20.92
C

ATOM
1272
C
LEU
A
192
68.301
17.329
−12.171
1.00
20.62
C

ATOM
1273
O
LEU
A
192
68.472
16.302
−11.520
1.00
20.87
O

ATOM
1274
N
LEU
A
193
67.092
17.787
−12.488
1.00
20.82
N

ATOM
1275
CA
LEU
A
193
65.883
17.033
−12.163
1.00
20.67
C

ATOM
1276
CB
LEU
A
193
64.626
17.901
−12.333
1.00
20.90
C

ATOM
1277
CG
LEU
A
193
63.271
17.308
−11.915
1.00
21.37
C

ATOM
1278
CD1
LEU
A
193
63.216
16.979
−10.428
1.00
19.30
C

ATOM
1279
CD2
LEU
A
193
62.103
18.226
−12.303
1.00
23.02
C

ATOM
1280
C
LEU
A
193
65.770
15.784
−13.042
1.00
20.94
C

ATOM
1281
O
LEU
A
193
66.005
15.837
−14.250
1.00
20.46
O

ATOM
1282
N
LYS
A
194
65.403
14.666
−12.423
1.00
20.70
N

ATOM
1283
CA
LYS
A
194
65.191
13.411
−13.140
1.00
20.09
C

ATOM
1284
CB
LYS
A
194
66.464
12.559
−13.094
1.00
20.03
C

ATOM
1285
CG
LYS
A
194
66.780
11.998
−11.717
1.00
18.07
C

ATOM
1286
CD
LYS
A
194
68.169
11.391
−11.691
1.00
19.71
C

ATOM
1287
CE
LYS
A
194
68.381
10.652
−10.385
1.00
20.42
C

ATOM
1288
NZ
LYS
A
194
69.586
9.789
−10.403
1.00
19.70
N

ATOM
1289
C
LYS
A
194
64.025
12.658
−12.505
1.00
19.94
C

ATOM
1290
O
LYS
A
194
63.669
12.913
−11.349
1.00
19.51
O

ATOM
1291
N
ASP
A
195
63.456
11.722
−13.260
1.00
19.71
N

ATOM
1292
CA
ASP
A
195
62.308
10.943
−12.808
1.00
19.96
C

ATOM
1293
CB
ASP
A
195
61.352
10.706
−13.972
1.00
20.12
C

ATOM
1294
CG
ASP
A
195
60.843
12.005
−14.573
1.00
21.01
C

ATOM
1295
OD1
ASP
A
195
60.213
12.792
−13.832
1.00
21.96
O

ATOM
1296
OD2
ASP
A
195
61.028
12.311
−15.770
1.00
22.33
O

ATOM
1297
C
ASP
A
195
62.684
9.613
−12.166
1.00
20.21
C

ATOM
1298
O
ASP
A
195
61.811
8.866
−11.740
1.00
20.16
O

ATOM
1299
N
THR
A
196
63.979
9.324
−12.111
1.00
20.34
N

ATOM
1300
CA
THR
A
196
64.459
8.086
−11.519
1.00
20.80
C

ATOM
1301
CB
THR
A
196
65.550
7.433
−12.402
1.00
20.79
C

ATOM
1302
OG1
THR
A
196
66.489
8.431
−12.832
1.00
19.71
O

ATOM
1303
CG2
THR
A
196
64.942
6.891
−13.701
1.00
20.94
C

ATOM
1304
C
THR
A
196
64.997
8.357
−10.132
1.00
21.32
C

ATOM
1305
O
THR
A
196
65.059
9.515
−9.686
1.00
21.17
O

ATOM
1306
N
VAL
A
197
65.387
7.290
−9.447
1.00
21.71
N

ATOM
1307
CA
VAL
A
197
65.741
7.385
−8.039
1.00
22.75
C

ATOM
1308
CB
VAL
A
197
65.661
5.983
−7.364
1.00
22.95
C

ATOM
1309
CG1
VAL
A
197
66.823
5.098
−7.798
1.00
24.30
C

ATOM
1310
CG2
VAL
A
197
65.592
6.094
−5.849
1.00
23.66
C

ATOM
1311
C
VAL
A
197
67.102
8.074
−7.834
1.00
22.86
C

ATOM
1312
O
VAL
A
197
68.044
7.862
−8.611
1.00
23.08
O

ATOM
1313
N
TYR
A
198
67.176
8.939
−6.823
1.00
22.60
N

ATOM
1314
CA
TYR
A
198
68.441
9.506
−6.375
1.00
22.42
C

ATOM
1315
CB
TYR
A
198
68.242
10.922
−5.829
1.00
21.98
C

ATOM
1316
CG
TYR
A
198
67.927
11.966
−6.869
1.00
19.83
C

ATOM
1317
CD1
TYR
A
198
66.610
12.197
−7.262
1.00
18.45
C

ATOM
1318
CE1
TYR
A
198
66.301
13.147
−8.205
1.00
16.56
C

ATOM
1319
CZ
TYR
A
198
67.307
13.909
−8.772
1.00
17.06
C

ATOM
1320
OH
TYR
A
198
66.949
14.848
−9.713
1.00
15.18
O

ATOM
1321
CE2
TYR
A
198
68.641
13.708
−8.410
1.00
16.87
C

ATOM
1322
CD2
TYR
A
198
68.942
12.732
−7.455
1.00
18.51
C

ATOM
1323
C
TYR
A
198
69.010
8.631
−5.266
1.00
22.99
C

ATOM
1324
O
TYR
A
198
68.273
8.209
−4.363
1.00
22.53
O

ATOM
1325
N
THR
A
199
70.314
8.370
−5.337
1.00
23.94
N

ATOM
1326
CA
THR
A
199
71.034
7.617
−4.302
1.00
25.22
C

ATOM
1327
CB
THR
A
199
71.694
6.331
−4.880
1.00
25.19
C

ATOM
1328
OG1
THR
A
199
72.604
6.688
−5.923
1.00
25.62
O

ATOM
1329
CG2
THR
A
199
70.681
5.427
−5.571
1.00
25.21
C

ATOM
1330
C
THR
A
199
72.111
8.475
−3.635
1.00
26.00
C

ATOM
1331
O
THR
A
199
72.881
7.982
−2.818
1.00
25.92
O

ATOM
1332
N
ASP
A
200
72.170
9.752
−4.007
1.00
27.25
N

ATOM
1333
CA
ASP
A
200
73.121
10.694
−3.424
1.00
28.69
C

ATOM
1334
CB
ASP
A
200
74.132
11.197
−4.477
1.00
29.29
C

ATOM
1335
CG
ASP
A
200
73.490
12.085
−5.559
1.00
32.11
C

ATOM
1336
OD1
ASP
A
200
73.879
13.277
−5.649
1.00
34.36
O

ATOM
1337
OD2
ASP
A
200
72.609
11.686
−6.370
1.00
34.31
O

ATOM
1338
C
ASP
A
200
72.374
11.855
−2.788
1.00
28.79
C

ATOM
1339
O
ASP
A
200
71.327
12.278
−3.283
1.00
28.34
O

ATOM
1340
N
PHE
A
201
72.904
12.350
−1.677
1.00
29.39
N

ATOM
1341
CA
PHE
A
201
72.328
13.501
−1.000
1.00
30.23
C

ATOM
1342
CB
PHE
A
201
71.140
13.077
−0.140
1.00
29.94
C

ATOM
1343
CG
PHE
A
201
70.534
14.196
0.660
1.00
28.00
C

ATOM
1344
CD1
PHE
A
201
69.676
15.109
0.062
1.00
27.14
C

ATOM
1345
CE1
PHE
A
201
69.104
16.143
0.791
1.00
27.27
C

ATOM
1346
CZ
PHE
A
201
69.381
16.266
2.148
1.00
27.00
C

ATOM
1347
CE2
PHE
A
201
70.244
15.357
2.763
1.00
28.69
C

ATOM
1348
CD2
PHE
A
201
70.811
14.322
2.012
1.00
28.58
C

ATOM
1349
C
PHE
A
201
73.381
14.192
−0.146
1.00
31.40
C

ATOM
1350
O
PHE
A
201
74.097
13.542
0.614
1.00
31.87
O

ATOM
1351
N
ASP
A
202
73.449
15.512
−0.274
1.00
32.09
N

ATOM
1352
CA
ASP
A
202
74.428
16.314
0.432
1.00
33.18
C

ATOM
1353
CB
ASP
A
202
75.581
16.677
−0.510
1.00
34.28
C

ATOM
1354
CG
ASP
A
202
76.918
16.282
0.054
1.00
37.84
C

ATOM
1355
OD1
ASP
A
202
77.292
15.090
−0.089
1.00
42.28
O

ATOM
1356
OD2
ASP
A
202
77.655
17.087
0.671
1.00
41.24
O

ATOM
1357
C
ASP
A
202
73.823
17.576
1.024
1.00
32.23
C

ATOM
1358
O
ASP
A
202
74.550
18.471
1.451
1.00
32.66
O

ATOM
1359
N
GLY
A
203
72.494
17.648
1.049
1.00
31.25
N

ATOM
1360
CA
GLY
A
203
71.801
18.764
1.677
1.00
29.41
C

ATOM
1361
C
GLY
A
203
71.721
18.616
3.189
1.00
28.69
C

ATOM
1362
O
GLY
A
203
72.489
17.863
3.792
1.00
28.32
O

ATOM
1363
N
THR
A
204
70.770
19.324
3.800
1.00
28.21
N

ATOM
1364
CA
THR
A
204
70.628
19.353
5.257
1.00
27.26
C

ATOM
1365
CB
THR
A
204
69.950
20.656
5.702
1.00
26.96
C

ATOM
1366
OG1
THR
A
204
70.654
21.769
5.142
1.00
26.09
O

ATOM
1367
CG2
THR
A
204
70.103
20.855
7.222
1.00
25.58
C

ATOM
1368
C
THR
A
204
69.847
18.152
5.776
1.00
27.62
C

ATOM
1369
O
THR
A
204
68.680
17.948
5.397
1.00
27.26
O

ATOM
1370
N
ARG
A
205
70.483
17.391
6.670
1.00
27.57
N

ATOM
1371
CA
ARG
A
205
69.928
16.139
7.173
1.00
27.70
C

ATOM
1372
CB
ARG
A
205
70.881
15.491
8.193
1.00
28.59
C

ATOM
1373
CG
ARG
A
205
70.306
14.238
8.883
1.00
31.06
C

ATOM
1374
CD
ARG
A
205
71.326
13.172
9.299
1.00
34.02
C

ATOM
1375
NE
ARG
A
205
71.717
12.397
8.132
1.00
37.36
N

ATOM
1376
CZ
ARG
A
205
71.619
11.073
7.997
1.00
37.19
C

ATOM
1377
NH1
ARG
A
205
71.156
10.302
8.970
1.00
36.97
N

ATOM
1378
NH2
ARG
A
205
71.995
10.523
6.856
1.00
36.80
N

ATOM
1379
C
ARG
A
205
68.508
16.270
7.748
1.00
27.42
C

ATOM
1380
O
ARG
A
205
67.600
15.482
7.393
1.00
27.39
O

ATOM
1381
N
VAL
A
206
68.323
17.271
8.611
1.00
26.15
N

ATOM
1382
CA
VAL
A
206
67.088
17.452
9.368
1.00
24.94
C

ATOM
1383
CB
VAL
A
206
67.268
18.408
10.593
1.00
25.07
C

ATOM
1384
CG1
VAL
A
206
68.149
17.763
11.651
1.00
24.65
C

ATOM
1385
CG2
VAL
A
206
67.842
19.792
10.167
1.00
23.92
C

ATOM
1386
C
VAL
A
206
65.986
17.956
8.455
1.00
25.16
C

ATOM
1387
O
VAL
A
206
64.835
18.077
8.883
1.00
25.56
O

ATOM
1388
N
TYR
A
207
66.343
18.226
7.195
1.00
24.00
N

ATOM
1389
CA
TYR
A
207
65.363
18.533
6.169
1.00
23.56
C

ATOM
1390
CB
TYR
A
207
65.792
19.777
5.388
1.00
23.98
C

ATOM
1391
CG
TYR
A
207
65.472
21.091
6.067
1.00
23.10
C

ATOM
1392
CD1
TYR
A
207
66.274
21.587
7.101
1.00
22.69
C

ATOM
1393
CE1
TYR
A
207
65.980
22.819
7.722
1.00
24.39
C

ATOM
1394
CZ
TYR
A
207
64.884
23.551
7.277
1.00
27.17
C

ATOM
1395
OH
TYR
A
207
64.556
24.776
7.844
1.00
30.13
O

ATOM
1396
CE2
TYR
A
207
64.080
23.064
6.243
1.00
25.83
C

ATOM
1397
CD2
TYR
A
207
64.382
21.851
5.647
1.00
24.73
C

ATOM
1398
C
TYR
A
207
65.141
17.371
5.198
1.00
22.93
C

ATOM
1399
O
TYR
A
207
64.299
17.469
4.285
1.00
22.62
O

ATOM
1400
N
SER
A
208
65.906
16.292
5.382
1.00
21.96
N

ATOM
1401
CA
SER
A
208
65.849
15.131
4.487
1.00
21.81
C

ATOM
1402
CB
SER
A
208
67.203
14.408
4.432
1.00
22.13
C

ATOM
1403
OG
SER
A
208
67.426
13.650
5.611
1.00
23.96
O

ATOM
1404
C
SER
A
208
64.738
14.139
4.876
1.00
20.92
C

ATOM
1405
O
SER
A
208
64.427
13.970
6.062
1.00
20.62
O

ATOM
1406
N
PRO
A
209
64.177
13.466
3.873
1.00
19.97
N

ATOM
1407
CA
PRO
A
209
62.999
12.620
4.067
1.00
19.59
C

ATOM
1408
CB
PRO
A
209
62.467
12.452
2.639
1.00
19.55
C

ATOM
1409
CG
PRO
A
209
63.689
12.524
1.774
1.00
19.80
C

ATOM
1410
CD
PRO
A
209
64.644
13.447
2.470
1.00
19.85
C

ATOM
1411
C
PRO
A
209
63.380
11.269
4.690
1.00
19.33
C

ATOM
1412
O
PRO
A
209
64.554
10.867
4.623
1.00
19.13
O

ATOM
1413
N
PRO
A
210
62.415
10.592
5.304
1.00
18.92
N

ATOM
1414
CA
PRO
A
210
62.668
9.300
5.961
1.00
19.08
C

ATOM
1415
CB
PRO
A
210
61.301
8.921
6.557
1.00
18.83
C

ATOM
1416
CG
PRO
A
210
60.302
9.737
5.821
1.00
19.11
C

ATOM
1417
CD
PRO
A
210
61.006
11.018
5.435
1.00
18.89
C

ATOM
1418
C
PRO
A
210
63.164
8.203
5.012
1.00
19.74
C

ATOM
1419
O
PRO
A
210
63.892
7.324
5.476
1.00
19.91
O

ATOM
1420
N
GLU
A
211
62.796
8.256
3.732
1.00
19.73
N

ATOM
1421
CA
GLU
A
211
63.273
7.278
2.766
1.00
20.85
C

ATOM
1422
CB
GLU
A
211
62.461
7.323
1.451
1.00
20.53
C

ATOM
1423
CG
GLU
A
211
62.554
8.649
0.684
1.00
20.57
C

ATOM
1424
CD
GLU
A
211
61.446
9.651
1.014
1.00
20.44
C

ATOM
1425
OE1
GLU
A
211
60.905
9.640
2.143
1.00
21.24
O

ATOM
1426
OE2
GLU
A
211
61.122
10.474
0.132
1.00
19.92
O

ATOM
1427
C
GLU
A
211
64.782
7.446
2.532
1.00
21.48
C

ATOM
1428
O
GLU
A
211
65.491
6.465
2.284
1.00
21.77
O

ATOM
1429
N
TRP
A
212
65.269
8.683
2.624
1.00
21.85
N

ATOM
1430
CA
TRP
A
212
66.702
8.917
2.576
1.00
22.59
C

ATOM
1431
CB
TRP
A
212
67.059
10.402
2.439
1.00
21.76
C

ATOM
1432
CG
TRP
A
212
68.537
10.610
2.665
1.00
23.30
C

ATOM
1433
CD1
TRP
A
212
69.128
11.209
3.745
1.00
23.54
C

ATOM
1434
NE1
TRP
A
212
70.497
11.187
3.610
1.00
24.29
N

ATOM
1435
CE2
TRP
A
212
70.828
10.556
2.441
1.00
23.65
C

ATOM
1436
CD2
TRP
A
212
69.618
10.169
1.817
1.00
22.66
C

ATOM
1437
CE3
TRP
A
212
69.684
9.497
0.589
1.00
22.34
C

ATOM
1438
CZ3
TRP
A
212
70.944
9.227
0.028
1.00
23.22
C

ATOM
1439
CH2
TRP
A
212
72.129
9.621
0.680
1.00
23.33
C

ATOM
1440
CZ2
TRP
A
212
72.093
10.288
1.882
1.00
24.31
C

ATOM
1441
C
TRP
A
212
67.375
8.324
3.814
1.00
22.99
C

ATOM
1442
O
TRP
A
212
68.368
7.609
3.695
1.00
23.46
O

ATOM
1443
N
ILE
A
213
66.812
8.611
4.986
1.00
23.54
N

ATOM
1444
CA
ILE
A
213
67.375
8.166
6.265
1.00
24.57
C

ATOM
1445
CB
ILE
A
213
66.566
8.729
7.468
1.00
24.25
C

ATOM
1446
CG1
ILE
A
213
66.550
10.265
7.469
1.00
24.58
C

ATOM
1447
CD1
ILE
A
213
67.945
10.927
7.479
1.00
24.84
C

ATOM
1448
CG2
ILE
A
213
67.143
8.217
8.788
1.00
24.24
C

ATOM
1449
C
ILE
A
213
67.480
6.646
6.350
1.00
25.27
C

ATOM
1450
O
ILE
A
213
68.523
6.113
6.741
1.00
25.42
O

ATOM
1451
N
ARG
A
214
66.409
5.963
5.955
1.00
26.19
N

ATOM
1452
CA
ARG
A
214
66.330
4.508
6.035
1.00
27.54
C

ATOM
1453
CB
ARG
A
214
64.873
4.052
6.126
1.00
27.97
C

ATOM
1454
CG
ARG
A
214
64.138
4.599
7.344
1.00
31.59
C

ATOM
1455
CD
ARG
A
214
62.621
4.436
7.296
1.00
37.14
C

ATOM
1456
NE
ARG
A
214
62.201
3.037
7.213
1.00
40.55
N

ATOM
1457
CZ
ARG
A
214
62.233
2.167
8.219
1.00
43.40
C

ATOM
1458
NH1
ARG
A
214
62.672
2.525
9.423
1.00
44.08
N

ATOM
1459
NH2
ARG
A
214
61.823
0.919
8.018
1.00
44.82
N

ATOM
1460
C
ARG
A
214
67.018
3.787
4.877
1.00
27.77
C

ATOM
1461
O
ARG
A
214
67.799
2.869
5.113
1.00
27.88
O

ATOM
1462
N
TYR
A
215
66.731
4.195
3.641
1.00
27.94
N

ATOM
1463
CA
TYR
A
215
67.151
3.428
2.460
1.00
28.52
C

ATOM
1464
CB
TYR
A
215
65.931
2.983
1.642
1.00
28.63
C

ATOM
1465
CG
TYR
A
215
64.788
2.478
2.486
1.00
30.63
C

ATOM
1466
CD1
TYR
A
215
64.884
1.262
3.177
1.00
32.35
C

ATOM
1467
CE1
TYR
A
215
63.832
0.800
3.965
1.00
33.17
C

ATOM
1468
CZ
TYR
A
215
62.674
1.560
4.063
1.00
34.20
C

ATOM
1469
OH
TYR
A
215
61.625
1.121
4.834
1.00
36.84
O

ATOM
1470
CE2
TYR
A
215
62.556
2.764
3.390
1.00
33.32
C

ATOM
1471
CD2
TYR
A
215
63.610
3.217
2.607
1.00
32.43
C

ATOM
1472
C
TYR
A
215
68.143
4.128
1.539
1.00
28.30
C

ATOM
1473
O
TYR
A
215
68.551
3.558
0.531
1.00
28.64
O

ATOM
1474
N
HIS
A
216
68.520
5.360
1.870
1.00
27.98
N

ATOM
1475
CA
HIS
A
216
69.431
6.133
1.027
1.00
27.92
C

ATOM
1476
CB
HIS
A
216
70.866
5.574
1.125
1.00
28.78
C

ATOM
1477
CG
HIS
A
216
71.628
6.080
2.315
1.00
32.47
C

ATOM
1478
ND1
HIS
A
216
72.993
5.922
2.453
1.00
36.05
N

ATOM
1479
CE1
HIS
A
216
73.386
6.479
3.587
1.00
37.27
C

ATOM
1480
NE2
HIS
A
216
72.328
6.997
4.187
1.00
36.76
N

ATOM
1481
CD2
HIS
A
216
71.217
6.761
3.413
1.00
35.02
C

ATOM
1482
C
HIS
A
216
68.936
6.268
−0.435
1.00
26.74
C

ATOM
1483
O
HIS
A
216
69.728
6.295
−1.383
1.00
26.90
O

ATOM
1484
N
ARG
A
217
67.616
6.360
−0.592
1.00
25.13
N

ATOM
1485
CA
ARG
A
217
66.964
6.461
−1.892
1.00
24.20
C

ATOM
1486
CB
ARG
A
217
66.380
5.106
−2.341
1.00
24.35
C

ATOM
1487
CG
ARG
A
217
67.373
3.964
−2.525
1.00
27.36
C

ATOM
1488
CD
ARG
A
217
66.718
2.584
−2.668
1.00
31.36
C

ATOM
1489
NE
ARG
A
217
66.048
2.433
−3.958
1.00
34.40
N

ATOM
1490
CZ
ARG
A
217
66.633
1.967
−5.061
1.00
36.63
C

ATOM
1491
NH1
ARG
A
217
67.909
1.595
−5.043
1.00
36.66
N

ATOM
1492
NH2
ARG
A
217
65.943
1.879
−6.190
1.00
37.21
N

ATOM
1493
C
ARG
A
217
65.808
7.429
−1.749
1.00
22.74
C

ATOM
1494
O
ARG
A
217
65.124
7.420
−0.729
1.00
23.06
O

ATOM
1495
N
TYR
A
218
65.580
8.240
−2.777
1.00
20.60
N

ATOM
1496
CA
TYR
A
218
64.445
9.141
−2.824
1.00
18.74
C

ATOM
1497
CB
TYR
A
218
64.674
10.371
−1.917
1.00
18.22
C

ATOM
1498
CG
TYR
A
218
65.867
11.216
−2.299
1.00
16.94
C

ATOM
1499
CD1
TYR
A
218
67.160
10.880
−1.870
1.00
15.03
C

ATOM
1500
CE1
TYR
A
218
68.265
11.679
−2.220
1.00
14.80
C

ATOM
1501
CZ
TYR
A
218
68.064
12.802
−3.020
1.00
15.81
C

ATOM
1502
OH
TYR
A
218
69.125
13.594
−3.393
1.00
16.21
O

ATOM
1503
CE2
TYR
A
218
66.790
13.145
−3.453
1.00
15.34
C

ATOM
1504
CD2
TYR
A
218
65.705
12.355
−3.093
1.00
15.11
C

ATOM
1505
C
TYR
A
218
64.212
9.584
−4.267
1.00
18.07
C

ATOM
1506
O
TYR
A
218
65.112
9.486
−5.102
1.00
17.75
O

ATOM
1507
N
HIS
A
219
63.006
10.075
−4.545
1.00
17.04
N

ATOM
1508
CA
HIS
A
219
62.721
10.757
−5.811
1.00
16.74
C

ATOM
1509
CB
HIS
A
219
61.430
10.231
−6.440
1.00
16.49
C

ATOM
1510
CG
HIS
A
219
61.547
8.819
−6.917
1.00
18.35
C

ATOM
1511
ND1
HIS
A
219
61.677
8.489
−8.253
1.00
18.97
N

ATOM
1512
CE1
HIS
A
219
61.791
7.179
−8.368
1.00
17.84
C

ATOM
1513
NE2
HIS
A
219
61.763
6.650
−7.157
1.00
19.10
N

ATOM
1514
CD2
HIS
A
219
61.621
7.653
−6.230
1.00
16.82
C

ATOM
1515
C
HIS
A
219
62.651
12.255
−5.551
1.00
16.15
C

ATOM
1516
O
HIS
A
219
62.346
12.681
−4.438
1.00
15.76
O

ATOM
1517
N
GLY
A
220
62.938
13.048
−6.576
1.00
16.23
N

ATOM
1518
CA
GLY
A
220
63.172
14.462
−6.384
1.00
16.70
C

ATOM
1519
C
GLY
A
220
61.992
15.217
−5.807
1.00
16.87
C

ATOM
1520
O
GLY
A
220
62.110
15.886
−4.788
1.00
16.14
O

ATOM
1521
N
ARG
A
221
60.848
15.097
−6.469
1.00
17.28
N

ATOM
1522
CA
ARG
A
221
59.691
15.923
−6.150
1.00
17.64
C

ATOM
1523
CB
ARG
A
221
58.590
15.746
−7.185
1.00
18.45
C

ATOM
1524
CG
ARG
A
221
59.002
16.190
−8.578
1.00
23.24
C

ATOM
1525
CD
ARG
A
221
58.156
15.591
−9.697
1.00
28.55
C

ATOM
1526
NE
ARG
A
221
58.705
15.933
−11.013
1.00
32.56
N

ATOM
1527
CZ
ARG
A
221
59.512
15.147
−11.720
1.00
35.42
C

ATOM
1528
NH1
ARG
A
221
59.879
13.956
−11.241
1.00
36.89
N

ATOM
1529
NH2
ARG
A
221
59.943
15.539
−12.920
1.00
35.53
N

ATOM
1530
C
ARG
A
221
59.155
15.652
−4.764
1.00
16.82
C

ATOM
1531
O
ARG
A
221
58.922
16.596
−4.015
1.00
16.95
O

ATOM
1532
N
SER
A
222
58.981
14.374
−4.417
1.00
15.97
N

ATOM
1533
CA
SER
A
222
58.439
14.002
−3.111
1.00
15.37
C

ATOM
1534
CB
SER
A
222
58.036
12.510
−3.066
1.00
15.54
C

ATOM
1535
OG
SER
A
222
59.136
11.654
−3.333
1.00
15.91
O

ATOM
1536
C
SER
A
222
59.396
14.347
−1.971
1.00
14.74
C

ATOM
1537
O
SER
A
222
58.963
14.684
−0.874
1.00
14.86
O

ATOM
1538
N
ALA
A
223
60.694
14.270
−2.225
1.00
14.48
N

ATOM
1539
CA
ALA
A
223
61.686
14.738
−1.253
1.00
14.36
C

ATOM
1540
CB
ALA
A
223
63.081
14.313
−1.677
1.00
14.45
C

ATOM
1541
C
ALA
A
223
61.619
16.266
−1.091
1.00
14.53
C

ATOM
1542
O
ALA
A
223
61.718
16.779
0.030
1.00
14.59
O

ATOM
1543
N
ALA
A
224
61.441
16.982
−2.205
1.00
13.88
N

ATOM
1544
CA
ALA
A
224
61.310
18.444
−2.169
1.00
13.96
C

ATOM
1545
CB
ALA
A
224
61.174
19.032
−3.591
1.00
13.04
C

ATOM
1546
C
ALA
A
224
60.116
18.832
−1.296
1.00
13.72
C

ATOM
1547
O
ALA
A
224
60.220
19.713
−0.462
1.00
14.14
O

ATOM
1548
N
VAL
A
225
59.001
18.123
−1.470
1.00
14.13
N

ATOM
1549
CA
VAL
A
225
57.776
18.363
−0.704
1.00
13.34
C

ATOM
1550
CB
VAL
A
225
56.602
17.517
−1.301
1.00
13.99
C

ATOM
1551
CG1
VAL
A
225
55.370
17.457
−0.352
1.00
11.55
C

ATOM
1552
CG2
VAL
A
225
56.236
18.063
−2.701
1.00
12.97
C

ATOM
1553
C
VAL
A
225
57.986
18.076
0.778
1.00
14.00
C

ATOM
1554
O
VAL
A
225
57.513
18.820
1.650
1.00
14.66
O

ATOM
1555
N
TRP
A
226
58.695
16.996
1.087
1.00
13.82
N

ATOM
1556
CA
TRP
A
226
59.037
16.751
2.481
1.00
14.22
C

ATOM
1557
CB
TRP
A
226
59.908
15.501
2.626
1.00
14.10
C

ATOM
1558
CG
TRP
A
226
60.362
15.305
4.045
1.00
14.21
C

ATOM
1559
CD1
TRP
A
226
61.444
15.888
4.651
1.00
13.01
C

ATOM
1560
NE1
TRP
A
226
61.516
15.488
5.961
1.00
13.97
N

ATOM
1561
CE2
TRP
A
226
60.473
14.643
6.231
1.00
13.33
C

ATOM
1562
CD2
TRP
A
226
59.723
14.510
5.046
1.00
14.66
C

ATOM
1563
CE3
TRP
A
226
58.583
13.683
5.063
1.00
14.53
C

ATOM
1564
CZ3
TRP
A
226
58.254
13.024
6.238
1.00
14.25
C

ATOM
1565
CH2
TRP
A
226
59.020
13.173
7.395
1.00
14.22
C

ATOM
1566
CZ2
TRP
A
226
60.132
13.981
7.415
1.00
15.55
C

ATOM
1567
C
TRP
A
226
59.763
17.976
3.062
1.00
13.86
C

ATOM
1568
O
TRP
A
226
59.406
18.468
4.136
1.00
14.16
O

ATOM
1569
N
SER
A
227
60.764
18.485
2.349
1.00
13.20
N

ATOM
1570
CA
SER
A
227
61.522
19.610
2.875
1.00
13.52
C

ATOM
1571
CB
SER
A
227
62.793
19.886
2.043
1.00
13.28
C

ATOM
1572
OG
SER
A
227
62.448
20.474
0.803
1.00
12.96
O

ATOM
1573
C
SER
A
227
60.634
20.845
2.967
1.00
13.72
C

ATOM
1574
O
SER
A
227
60.848
21.702
3.816
1.00
13.60
O

ATOM
1575
N
LEU
A
228
59.614
20.917
2.110
1.00
13.17
N

ATOM
1576
CA
LEU
A
228
58.673
22.028
2.171
1.00
13.14
C

ATOM
1577
CB
LEU
A
228
57.807
22.105
0.891
1.00
12.32
C

ATOM
1578
CG
LEU
A
228
58.606
22.646
−0.297
1.00
11.69
C

ATOM
1579
CD1
LEU
A
228
57.931
22.321
−1.659
1.00
13.88
C

ATOM
1580
CD2
LEU
A
228
58.893
24.135
−0.171
1.00
10.58
C

ATOM
1581
C
LEU
A
228
57.801
21.968
3.427
1.00
12.15
C

ATOM
1582
O
LEU
A
228
57.489
22.990
4.020
1.00
12.32
O

ATOM
1583
N
GLY
A
229
57.405
20.766
3.811
1.00
12.02
N

ATOM
1584
CA
GLY
A
229
56.693
20.556
5.056
1.00
12.19
C

ATOM
1585
C
GLY
A
229
57.512
20.973
6.281
1.00
12.64
C

ATOM
1586
O
GLY
A
229
56.968
21.560
7.224
1.00
12.42
O

ATOM
1587
N
ILE
A
230
58.811
20.662
6.269
1.00
13.07
N

ATOM
1588
CA
ILE
A
230
59.718
21.050
7.357
1.00
13.99
C

ATOM
1589
CB
ILE
A
230
61.145
20.421
7.133
1.00
13.90
C

ATOM
1590
CG1
ILE
A
230
61.067
18.894
7.053
1.00
13.25
C

ATOM
1591
CD1
ILE
A
230
60.622
18.243
8.368
1.00
11.51
C

ATOM
1592
CG2
ILE
A
230
62.118
20.815
8.272
1.00
14.90
C

ATOM
1593
C
ILE
A
230
59.785
22.587
7.409
1.00
14.39
C

ATOM
1594
O
ILE
A
230
59.686
23.211
8.488
1.00
14.11
O

ATOM
1595
N
LEU
A
231
59.915
23.182
6.222
1.00
14.04
N

ATOM
1596
CA
LEU
A
231
59.961
24.620
6.083
1.00
14.10
C

ATOM
1597
CB
LEU
A
231
60.197
24.995
4.609
1.00
14.16
C

ATOM
1598
CG
LEU
A
231
60.121
26.508
4.330
1.00
15.24
C

ATOM
1599
CD1
LEU
A
231
61.292
27.224
4.967
1.00
15.13
C

ATOM
1600
CD2
LEU
A
231
60.075
26.778
2.838
1.00
15.78
C

ATOM
1601
C
LEU
A
231
58.688
25.299
6.615
1.00
14.01
C

ATOM
1602
O
LEU
A
231
58.775
26.270
7.382
1.00
13.50
O

ATOM
1603
N
LEU
A
232
57.515
24.796
6.217
1.00
13.22
N

ATOM
1604
CA
LEU
A
232
56.256
25.394
6.644
1.00
13.16
C

ATOM
1605
CB
LEU
A
232
55.031
24.750
5.949
1.00
13.56
C

ATOM
1606
CG
LEU
A
232
53.653
25.362
6.282
1.00
12.22
C

ATOM
1607
CD1
LEU
A
232
53.627
26.902
6.159
1.00
13.83
C

ATOM
1608
CD2
LEU
A
232
52.521
24.721
5.419
1.00
11.85
C

ATOM
1609
C
LEU
A
232
56.112
25.294
8.164
1.00
13.79
C

ATOM
1610
O
LEU
A
232
55.723
26.269
8.817
1.00
14.65
O

ATOM
1611
N
TYR
A
233
56.445
24.133
8.723
1.00
13.34
N

ATOM
1612
CA
TYR
A
233
56.407
23.940
10.175
1.00
13.68
C

ATOM
1613
CB
TYR
A
233
56.870
22.524
10.551
1.00
12.73
C

ATOM
1614
CG
TYR
A
233
56.786
22.263
12.044
1.00
14.51
C

ATOM
1615
CD1
TYR
A
233
57.791
22.713
12.908
1.00
14.02
C

ATOM
1616
CE1
TYR
A
233
57.728
22.487
14.266
1.00
13.74
C

ATOM
1617
CZ
TYR
A
233
56.647
21.796
14.798
1.00
15.95
C

ATOM
1618
OH
TYR
A
233
56.590
21.586
16.169
1.00
17.38
O

ATOM
1619
CE2
TYR
A
233
55.630
21.352
13.978
1.00
15.69
C

ATOM
1620
CD2
TYR
A
233
55.705
21.588
12.594
1.00
14.19
C

ATOM
1621
C
TYR
A
233
57.296
24.989
10.855
1.00
14.14
C

ATOM
1622
O
TYR
A
233
56.893
25.639
11.837
1.00
14.22
O

ATOM
1623
N
ASP
A
234
58.497
25.162
10.304
1.00
14.64
N

ATOM
1624
CA
ASP
A
234
59.462
26.128
10.820
1.00
14.70
C

ATOM
1625
CB
ASP
A
234
60.741
26.074
9.986
1.00
15.23
C

ATOM
1626
CG
ASP
A
234
61.806
27.031
10.482
1.00
17.95
C

ATOM
1627
OD1
ASP
A
234
62.134
27.038
11.693
1.00
17.66
O

ATOM
1628
OD2
ASP
A
234
62.372
27.815
9.707
1.00
23.64
O

ATOM
1629
C
ASP
A
234
58.902
27.550
10.842
1.00
15.14
C

ATOM
1630
O
ASP
A
234
59.130
28.304
11.808
1.00
14.44
O

ATOM
1631
N
MET
A
235
58.177
27.921
9.782
1.00
14.52
N

ATOM
1632
CA
MET
A
235
57.585
29.248
9.679
1.00
15.77
C

ATOM
1633
CB
MET
A
235
56.946
29.472
8.300
1.00
15.95
C

ATOM
1634
CG
MET
A
235
57.955
29.567
7.157
1.00
19.29
C

ATOM
1635
SD
MET
A
235
57.147
30.105
5.616
1.00
23.96
S

ATOM
1636
CE
MET
A
235
56.577
28.752
5.093
1.00
24.70
C

ATOM
1637
C
MET
A
235
56.535
29.503
10.756
1.00
15.44
C

ATOM
1638
O
MET
A
235
56.551
30.545
11.395
1.00
15.28
O

ATOM
1639
N
VAL
A
236
55.622
28.557
10.944
1.00
15.79
N

ATOM
1640
CA
VAL
A
236
54.480
28.780
11.845
1.00
16.11
C

ATOM
1641
CB
VAL
A
236
53.169
28.062
11.349
1.00
16.48
C

ATOM
1642
CG1
VAL
A
236
52.709
28.622
9.995
1.00
15.52
C

ATOM
1643
CG2
VAL
A
236
53.327
26.521
11.277
1.00
14.68
C

ATOM
1644
C
VAL
A
236
54.808
28.422
13.295
1.00
17.29
C

ATOM
1645
O
VAL
A
236
54.084
28.833
14.220
1.00
17.67
O

ATOM
1646
N
CYS
A
237
55.901
27.673
13.503
1.00
17.50
N

ATOM
1647
CA
CYS
A
237
56.276
27.261
14.863
1.00
18.98
C

ATOM
1648
CB
CYS
A
237
56.400
25.735
14.986
1.00
18.51
C

ATOM
1649
SG
CYS
A
237
54.825
24.891
14.842
1.00
22.03
S

ATOM
1650
C
CYS
A
237
57.548
27.914
15.366
1.00
18.98
C

ATOM
1651
O
CYS
A
237
57.788
27.936
16.562
1.00
18.75
O

ATOM
1652
N
GLY
A
238
58.359
28.443
14.452
1.00
19.38
N

ATOM
1653
CA
GLY
A
238
59.584
29.125
14.835
1.00
20.34
C

ATOM
1654
C
GLY
A
238
60.776
28.206
14.966
1.00
21.28
C

ATOM
1655
O
GLY
A
238
61.871
28.677
15.269
1.00
21.63
O

ATOM
1656
N
ASP
A
239
60.572
26.906
14.743
1.00
21.89
N

ATOM
1657
CA
ASP
A
239
61.662
25.904
14.741
1.00
23.14
C

ATOM
1658
CB
ASP
A
239
62.038
25.466
16.161
1.00
24.31
C

ATOM
1659
CG
ASP
A
239
63.557
25.367
16.363
1.00
28.93
C

ATOM
1660
OD1
ASP
A
239
64.268
24.729
15.530
1.00
31.83
O

ATOM
1661
OD2
ASP
A
239
64.126
25.919
17.333
1.00
34.08
O

ATOM
1662
C
ASP
A
239
61.271
24.671
13.918
1.00
22.10
C

ATOM
1663
O
ASP
A
239
60.110
24.508
13.582
1.00
22.05
O

ATOM
1664
N
ILE
A
240
62.241
23.823
13.590
1.00
21.41
N

ATOM
1665
CA
ILE
A
240
61.995
22.616
12.803
1.00
21.20
C

ATOM
1666
CB
ILE
A
240
63.299
22.130
12.119
1.00
21.27
C

ATOM
1667
CG1
ILE
A
240
64.418
21.934
13.162
1.00
22.95
C

ATOM
1668
CD1
ILE
A
240
65.727
21.359
12.604
1.00
24.55
C

ATOM
1669
CG2
ILE
A
240
63.711
23.113
11.020
1.00
22.14
C

ATOM
1670
C
ILE
A
240
61.390
21.516
13.687
1.00
21.05
C

ATOM
1671
O
ILE
A
240
61.628
21.507
14.896
1.00
20.43
O

ATOM
1672
N
PRO
A
241
60.596
20.610
13.112
1.00
21.20
N

ATOM
1673
CA
PRO
A
241
59.885
19.609
13.924
1.00
22.14
C

ATOM
1674
CB
PRO
A
241
58.818
19.070
12.967
1.00
22.34
C

ATOM
1675
CG
PRO
A
241
59.418
19.243
11.581
1.00
20.54
C

ATOM
1676
CD
PRO
A
241
60.303
20.461
11.670
1.00
21.11
C

ATOM
1677
C
PRO
A
241
60.762
18.466
14.413
1.00
23.21
C

ATOM
1678
O
PRO
A
241
60.432
17.885
15.443
1.00
23.48
O

ATOM
1679
N
PHE
A
242
61.843
18.143
13.699
1.00
24.34
N

ATOM
1680
CA
PHE
A
242
62.625
16.949
13.999
1.00
25.31
C

ATOM
1681
CB
PHE
A
242
62.503
15.894
12.881
1.00
24.74
C

ATOM
1682
CG
PHE
A
242
61.097
15.596
12.440
1.00
22.55
C

ATOM
1683
CD1
PHE
A
242
60.115
15.212
13.354
1.00
21.74
C

ATOM
1684
CE1
PHE
A
242
58.812
14.916
12.923
1.00
21.18
C

ATOM
1685
CZ
PHE
A
242
58.489
15.011
11.556
1.00
21.06
C

ATOM
1686
CE2
PHE
A
242
59.467
15.392
10.642
1.00
20.29
C

ATOM
1687
CD2
PHE
A
242
60.763
15.672
11.088
1.00
21.16
C

ATOM
1688
C
PHE
A
242
64.099
17.286
14.169
1.00
27.27
C

ATOM
1689
O
PHE
A
242
64.671
18.038
13.370
1.00
27.35
O

ATOM
1690
N
GLU
A
243
64.716
16.692
15.186
1.00
29.13
N

ATOM
1691
CA
GLU
A
243
66.149
16.849
15.428
1.00
31.65
C

ATOM
1692
CB
GLU
A
243
66.404
17.361
16.849
1.00
32.51
C

ATOM
1693
CG
GLU
A
243
65.779
18.723
17.153
1.00
37.83
C

ATOM
1694
CD
GLU
A
243
66.521
19.895
16.505
1.00
43.98
C

ATOM
1695
OE1
GLU
A
243
66.675
19.903
15.260
1.00
46.61
O

ATOM
1696
OE2
GLU
A
243
66.941
20.824
17.241
1.00
46.61
O

ATOM
1697
C
GLU
A
243
66.951
15.568
15.187
1.00
31.62
C

ATOM
1698
O
GLU
A
243
68.096
15.630
14.759
1.00
32.81
O

ATOM
1699
N
HIS
A
244
66.361
14.409
15.454
1.00
31.55
N

ATOM
1700
CA
HIS
A
244
67.089
13.146
15.307
1.00
31.42
C

ATOM
1701
CB
HIS
A
244
67.187
12.423
16.650
1.00
32.01
C

ATOM
1702
CG
HIS
A
244
67.774
13.265
17.738
1.00
34.56
C

ATOM
1703
ND1
HIS
A
244
67.014
13.790
18.763
1.00
36.67
N

ATOM
1704
CE1
HIS
A
244
67.791
14.502
19.561
1.00
37.86
C

ATOM
1705
NE2
HIS
A
244
69.026
14.462
19.087
1.00
37.93
N

ATOM
1706
CD2
HIS
A
244
69.041
13.697
17.945
1.00
36.34
C

ATOM
1707
C
HIS
A
244
66.482
12.235
14.243
1.00
30.37
C

ATOM
1708
O
HIS
A
244
65.279
12.327
13.941
1.00
29.56
O

ATOM
1709
N
ASP
A
245
67.326
11.360
13.689
1.00
29.19
N

ATOM
1710
CA
ASP
A
245
66.909
10.373
12.691
1.00
28.54
C

ATOM
1711
CB
ASP
A
245
68.005
9.315
12.473
1.00
28.34
C

ATOM
1712
CG
ASP
A
245
69.208
9.853
11.726
1.00
28.71
C

ATOM
1713
OD1
ASP
A
245
69.183
11.016
11.252
1.00
28.60
O

ATOM
1714
OD2
ASP
A
245
70.242
9.174
11.572
1.00
30.07
O

ATOM
1715
C
ASP
A
245
65.624
9.670
13.103
1.00
28.04
C

ATOM
1716
O
ASP
A
245
64.724
9.485
12.284
1.00
27.65
O

ATOM
1717
N
GLU
A
246
65.566
9.292
14.381
1.00
27.40
N

ATOM
1718
CA
GLU
A
246
64.451
8.563
14.978
1.00
27.37
C

ATOM
1719
CB
GLU
A
246
64.743
8.286
16.468
1.00
28.11
C

ATOM
1720
CG
GLU
A
246
65.942
7.369
16.736
1.00
32.49
C

ATOM
1721
CD
GLU
A
246
67.302
8.072
16.650
1.00
37.16
C

ATOM
1722
OE1
GLU
A
246
67.413
9.255
17.037
1.00
39.44
O

ATOM
1723
OE2
GLU
A
246
68.276
7.434
16.191
1.00
40.05
O

ATOM
1724
C
GLU
A
246
63.128
9.318
14.844
1.00
26.19
C

ATOM
1725
O
GLU
A
246
62.087
8.720
14.570
1.00
25.74
O

ATOM
1726
N
GLU
A
247
63.178
10.630
15.054
1.00
24.84
N

ATOM
1727
CA
GLU
A
247
61.997
11.473
14.925
1.00
24.64
C

ATOM
1728
CB
GLU
A
247
62.228
12.861
15.550
1.00
24.76
C

ATOM
1729
CG
GLU
A
247
62.600
12.823
17.029
1.00
27.07
C

ATOM
1730
CD
GLU
A
247
63.106
14.164
17.539
1.00
31.82
C

ATOM
1731
OE1
GLU
A
247
63.956
14.804
16.873
1.00
31.23
O

ATOM
1732
OE2
GLU
A
247
62.653
14.582
18.623
1.00
35.62
O

ATOM
1733
C
GLU
A
247
61.573
11.592
13.458
1.00
23.43
C

ATOM
1734
O
GLU
A
247
60.388
11.491
13.151
1.00
22.84
O

ATOM
1735
N
ILE
A
248
62.546
11.782
12.563
1.00
22.82
N

ATOM
1736
CA
ILE
A
248
62.269
11.827
11.119
1.00
22.09
C

ATOM
1737
CB
ILE
A
248
63.555
12.106
10.284
1.00
22.33
C

ATOM
1738
CG1
ILE
A
248
64.103
13.506
10.594
1.00
21.24
C

ATOM
1739
CD1
ILE
A
248
65.557
13.692
10.191
1.00
23.01
C

ATOM
1740
CG2
ILE
A
248
63.273
11.965
8.767
1.00
21.11
C

ATOM
1741
C
ILE
A
248
61.567
10.547
10.665
1.00
22.18
C

ATOM
1742
O
ILE
A
248
60.512
10.608
10.038
1.00
21.20
O

ATOM
1743
N
ILE
A
249
62.144
9.396
11.016
1.00
22.55
N

ATOM
1744
CA
ILE
A
249
61.595
8.083
10.646
1.00
23.21
C

ATOM
1745
CB
ILE
A
249
62.539
6.943
11.136
1.00
23.49
C

ATOM
1746
CG1
ILE
A
249
63.856
6.947
10.348
1.00
24.43
C

ATOM
1747
CD1
ILE
A
249
64.971
6.114
11.041
1.00
26.84
C

ATOM
1748
CG2
ILE
A
249
61.853
5.562
11.051
1.00
24.03
C

ATOM
1749
C
ILE
A
249
60.175
7.875
11.200
1.00
23.18
C

ATOM
1750
O
ILE
A
249
59.312
7.314
10.520
1.00
22.99
O

ATOM
1751
N
ARG
A
250
59.943
8.318
12.435
1.00
23.13
N

ATOM
1752
CA
ARG
A
250
58.614
8.204
13.044
1.00
23.60
C

ATOM
1753
CB
ARG
A
250
58.679
8.421
14.562
1.00
23.56
C

ATOM
1754
CG
ARG
A
250
57.356
8.162
15.290
1.00
24.55
C

ATOM
1755
CD
ARG
A
250
57.504
7.770
16.760
1.00
24.93
C

ATOM
1756
NE
ARG
A
250
56.208
7.638
17.430
1.00
25.45
N

ATOM
1757
CZ
ARG
A
250
55.636
8.594
18.168
1.00
25.98
C

ATOM
1758
NH1
ARG
A
250
56.234
9.770
18.349
1.00
24.37
N

ATOM
1759
NH2
ARG
A
250
54.459
8.373
18.733
1.00
26.41
N

ATOM
1760
C
ARG
A
250
57.621
9.159
12.375
1.00
23.56
C

ATOM
1761
O
ARG
A
250
56.468
8.802
12.165
1.00
23.53
O

ATOM
1762
N
GLY
A
251
58.089
10.357
12.022
1.00
23.63
N

ATOM
1763
CA
GLY
A
251
57.282
11.334
11.314
1.00
24.56
C

ATOM
1764
C
GLY
A
251
56.082
11.864
12.096
1.00
25.30
C

ATOM
1765
O
GLY
A
251
55.074
12.248
11.496
1.00
25.76
O

ATOM
1766
N
GLN
A
252
56.177
11.877
13.423
1.00
25.26
N

ATOM
1767
CA
GLN
A
252
55.082
12.373
14.263
1.00
25.84
C

ATOM
1768
CB
GLN
A
252
55.005
11.603
15.593
1.00
26.06
C

ATOM
1769
CG
GLN
A
252
53.796
11.937
16.488
1.00
29.12
C

ATOM
1770
CD
GLN
A
252
52.439
11.649
15.837
1.00
32.13
C

ATOM
1771
OE1
GLN
A
252
51.537
12.506
15.854
1.00
31.35
O

ATOM
1772
NE2
GLN
A
252
52.292
10.448
15.264
1.00
32.42
N

ATOM
1773
C
GLN
A
252
55.271
13.863
14.504
1.00
25.11
C

ATOM
1774
O
GLN
A
252
56.310
14.303
15.008
1.00
24.98
O

ATOM
1775
N
VAL
A
253
54.265
14.634
14.123
1.00
24.33
N

ATOM
1776
CA
VAL
A
253
54.351
16.085
14.196
1.00
24.36
C

ATOM
1777
CB
VAL
A
253
53.751
16.750
12.922
1.00
24.24
C

ATOM
1778
CG1
VAL
A
253
53.971
18.240
12.948
1.00
24.73
C

ATOM
1779
CG2
VAL
A
253
54.356
16.124
11.647
1.00
24.87
C

ATOM
1780
C
VAL
A
253
53.601
16.576
15.431
1.00
23.69
C

ATOM
1781
O
VAL
A
253
52.427
16.275
15.602
1.00
23.22
O

ATOM
1782
N
PHE
A
254
54.297
17.321
16.278
1.00
23.14
N

ATOM
1783
CA
PHE
A
254
53.683
17.993
17.403
1.00
23.19
C

ATOM
1784
CB
PHE
A
254
54.295
17.481
18.702
1.00
22.64
C

ATOM
1785
CG
APHE
A
254
53.868
18.247
19.912
0.70
21.91
C

ATOM
1786
CG
BPHE
A
254
53.915
16.067
18.997
0.30
22.47
C

ATOM
1787
CD1
APHE
A
254
52.711
17.897
20.596
0.70
20.57
C

ATOM
1788
CD1
BPHE
A
254
54.877
15.073
19.055
0.30
21.39
C

ATOM
1789
CE1
APHE
A
254
52.308
18.608
21.724
0.70
18.82
C

ATOM
1790
CE1
BPHE
A
254
54.517
13.772
19.304
0.30
20.97
C

ATOM
1791
CZ
APHE
A
254
53.054
19.677
22.163
0.70
20.33
C

ATOM
1792
CZ
BPHE
A
254
53.180
13.445
19.476
0.30
21.52
C

ATOM
1793
CE2
APHE
A
254
54.214
20.045
21.486
0.70
20.58
C

ATOM
1794
CE2
BPHE
A
254
52.207
14.421
19.400
0.30
21.67
C

ATOM
1795
CD2
APHE
A
254
54.615
19.333
20.369
0.70
21.56
C

ATOM
1796
CD2
BPHE
A
254
52.574
15.720
19.157
0.30
21.61
C

ATOM
1797
C
PHE
A
254
53.789
19.507
17.295
1.00
23.65
C

ATOM
1798
O
PHE
A
254
54.876
20.055
17.059
1.00
23.03
O

ATOM
1799
N
PHE
A
255
52.652
20.173
17.475
1.00
24.25
N

ATOM
1800
CA
PHE
A
255
52.600
21.636
17.448
1.00
24.57
C

ATOM
1801
CB
PHE
A
255
51.367
22.117
16.705
1.00
24.07
C

ATOM
1802
CG
PHE
A
255
51.421
21.819
15.250
1.00
22.93
C

ATOM
1803
CD1
PHE
A
255
51.972
22.743
14.368
1.00
20.88
C

ATOM
1804
CE1
PHE
A
255
52.048
22.466
13.018
1.00
18.91
C

ATOM
1805
CZ
PHE
A
255
51.585
21.254
12.540
1.00
20.61
C

ATOM
1806
CE2
PHE
A
255
51.047
20.307
13.426
1.00
19.19
C

ATOM
1807
CD2
PHE
A
255
50.974
20.595
14.762
1.00
19.54
C

ATOM
1808
C
PHE
A
255
52.668
22.239
18.830
1.00
25.43
C

ATOM
1809
O
PHE
A
255
51.839
21.958
19.691
1.00
25.30
O

ATOM
1810
N
ARG
A
256
53.701
23.057
19.015
1.00
26.64
N

ATOM
1811
CA
ARG
A
256
54.026
23.713
20.274
1.00
27.50
C

ATOM
1812
CB
ARG
A
256
55.556
23.791
20.412
1.00
28.35
C

ATOM
1813
CG
ARG
A
256
56.282
24.268
19.116
1.00
31.19
C

ATOM
1814
CD
ARG
A
256
57.825
24.203
19.164
1.00
35.66
C

ATOM
1815
NE
ARG
A
256
58.346
23.171
18.257
1.00
38.13
N

ATOM
1816
CZ
ARG
A
256
59.580
22.660
18.298
1.00
40.12
C

ATOM
1817
NH1
ARG
A
256
60.466
23.080
19.204
1.00
40.47
N

ATOM
1818
NH2
ARG
A
256
59.930
21.716
17.431
1.00
38.85
N

ATOM
1819
C
ARG
A
256
53.444
25.122
20.255
1.00
27.08
C

ATOM
1820
O
ARG
A
256
53.389
25.807
21.279
1.00
27.90
O

ATOM
1821
N
GLN
A
257
53.023
25.546
19.068
1.00
26.07
N

ATOM
1822
CA
GLN
A
257
52.369
26.834
18.871
1.00
25.36
C

ATOM
1823
CB
GLN
A
257
53.126
27.643
17.803
1.00
25.81
C

ATOM
1824
CG
GLN
A
257
54.514
28.095
18.215
1.00
29.91
C

ATOM
1825
CD
GLN
A
257
54.493
29.381
19.019
1.00
35.63
C

ATOM
1826
OE1
GLN
A
257
53.596
30.222
18.846
1.00
37.93
O

ATOM
1827
NE2
GLN
A
257
55.480
29.545
19.901
1.00
37.58
N

ATOM
1828
C
GLN
A
257
50.931
26.611
18.399
1.00
23.15
C

ATOM
1829
O
GLN
A
257
50.618
25.574
17.821
1.00
22.57
O

ATOM
1830
N
ARG
A
258
50.072
27.593
18.633
1.00
21.04
N

ATOM
1831
CA
ARG
A
258
48.726
27.571
18.079
1.00
19.58
C

ATOM
1832
CB
ARG
A
258
47.862
28.674
18.683
1.00
19.69
C

ATOM
1833
CG
ARG
A
258
46.355
28.438
18.509
1.00
21.79
C

ATOM
1834
CD
ARG
A
258
45.834
28.809
17.134
1.00
24.81
C

ATOM
1835
NE
ARG
A
258
44.538
28.195
16.847
1.00
26.49
N

ATOM
1836
CZ
ARG
A
258
43.844
28.395
15.725
1.00
27.04
C

ATOM
1837
NH1
ARG
A
258
44.316
29.200
14.757
1.00
27.33
N

ATOM
1838
NH2
ARG
A
258
42.677
27.789
15.570
1.00
25.64
N

ATOM
1839
C
ARG
A
258
48.811
27.738
16.564
1.00
18.78
C

ATOM
1840
O
ARG
A
258
49.282
28.759
16.074
1.00
18.29
O

ATOM
1841
N
VAL
A
259
48.367
26.716
15.843
1.00
17.49
N

ATOM
1842
CA
VAL
A
259
48.404
26.682
14.389
1.00
17.02
C

ATOM
1843
CB
VAL
A
259
49.533
25.733
13.879
1.00
16.57
C

ATOM
1844
CG1
VAL
A
259
49.472
25.544
12.361
1.00
15.19
C

ATOM
1845
CG2
VAL
A
259
50.929
26.259
14.310
1.00
17.98
C

ATOM
1846
C
VAL
A
259
47.043
26.171
13.920
1.00
16.99
C

ATOM
1847
O
VAL
A
259
46.541
25.190
14.460
1.00
16.43
O

ATOM
1848
N
SER
A
260
46.451
26.843
12.930
1.00
17.02
N

ATOM
1849
CA
SER
A
260
45.141
26.451
12.398
1.00
17.31
C

ATOM
1850
CB
SER
A
260
44.687
27.398
11.273
1.00
17.29
C

ATOM
1851
OG
SER
A
260
45.399
27.137
10.073
1.00
17.50
O

ATOM
1852
C
SER
A
260
45.145
25.005
11.916
1.00
17.62
C

ATOM
1853
O
SER
A
260
46.182
24.484
11.518
1.00
17.40
O

ATOM
1854
N
SER
A
261
43.974
24.367
11.957
1.00
17.98
N

ATOM
1855
CA
SER
A
261
43.820
22.972
11.559
1.00
18.43
C

ATOM
1856
CB
SER
A
261
42.398
22.499
11.855
1.00
18.46
C

ATOM
1857
OG
SER
A
261
42.169
22.473
13.254
1.00
19.59
O

ATOM
1858
C
SER
A
261
44.118
22.748
10.082
1.00
18.64
C

ATOM
1859
O
SER
A
261
44.630
21.694
9.701
1.00
18.31
O

ATOM
1860
N
GLU
A
262
43.780
23.729
9.256
1.00
19.27
N

ATOM
1861
CA
GLU
A
262
44.102
23.659
7.829
1.00
20.49
C

ATOM
1862
CB
GLU
A
262
43.461
24.807
7.058
1.00
21.45
C

ATOM
1863
CG
GLU
A
262
42.033
24.525
6.627
1.00
27.18
C

ATOM
1864
CD
GLU
A
262
41.304
25.782
6.184
1.00
35.25
C

ATOM
1865
OE1
GLU
A
262
41.928
26.645
5.498
1.00
38.82
O

ATOM
1866
OE2
GLU
A
262
40.101
25.915
6.522
1.00
39.29
O

ATOM
1867
C
GLU
A
262
45.615
23.663
7.614
1.00
19.31
C

ATOM
1868
O
GLU
A
262
46.131
22.851
6.853
1.00
18.98
O

ATOM
1869
N
CYS
A
263
46.318
24.561
8.297
1.00
18.97
N

ATOM
1870
CA
CYS
A
263
47.785
24.596
8.196
1.00
18.66
C

ATOM
1871
CB
CYS
A
263
48.359
25.805
8.937
1.00
18.56
C

ATOM
1872
SG
CYS
A
263
50.133
26.031
8.731
1.00
18.69
S

ATOM
1873
C
CYS
A
263
48.385
23.275
8.703
1.00
18.45
C

ATOM
1874
O
CYS
A
263
49.223
22.664
8.024
1.00
18.06
O

ATOM
1875
N
GLN
A
264
47.932
22.827
9.873
1.00
18.01
N

ATOM
1876
CA
GLN
A
264
48.389
21.553
10.434
1.00
18.32
C

ATOM
1877
CB
GLN
A
264
47.650
21.210
11.748
1.00
17.97
C

ATOM
1878
CG
GLN
A
264
48.085
22.034
12.955
1.00
18.25
C

ATOM
1879
CD
GLN
A
264
47.598
21.447
14.282
1.00
20.77
C

ATOM
1880
OE1
GLN
A
264
47.359
20.240
14.382
1.00
19.45
O

ATOM
1881
NE2
GLN
A
264
47.464
22.299
15.304
1.00
19.10
N

ATOM
1882
C
GLN
A
264
48.191
20.419
9.424
1.00
18.18
C

ATOM
1883
O
GLN
A
264
49.068
19.581
9.252
1.00
18.03
O

ATOM
1884
N
HIS
A
265
47.033
20.405
8.768
1.00
18.36
N

ATOM
1885
CA
HIS
A
265
46.712
19.366
7.805
1.00
19.15
C

ATOM
1886
CB
HIS
A
265
45.269
19.505
7.310
1.00
19.80
C

ATOM
1887
CG
HIS
A
265
44.890
18.474
6.295
1.00
23.71
C

ATOM
1888
ND1
HIS
A
265
45.147
18.627
4.948
1.00
27.52
N

ATOM
1889
CE1
HIS
A
265
44.712
17.562
4.294
1.00
28.98
C

ATOM
1890
NE2
HIS
A
265
44.190
16.720
5.170
1.00
29.95
N

ATOM
1891
CD2
HIS
A
265
44.294
17.264
6.430
1.00
27.50
C

ATOM
1892
C
HIS
A
265
47.701
19.383
6.624
1.00
18.47
C

ATOM
1893
O
HIS
A
265
48.219
18.340
6.236
1.00
17.33
O

ATOM
1894
N
LEU
A
266
47.973
20.577
6.089
1.00
17.86
N

ATOM
1895
CA
LEU
A
266
48.891
20.717
4.968
1.00
17.70
C

ATOM
1896
CB
LEU
A
266
48.925
22.167
4.440
1.00
17.79
C

ATOM
1897
CG
LEU
A
266
49.889
22.490
3.277
1.00
16.98
C

ATOM
1898
CD1
LEU
A
266
49.700
21.533
2.080
1.00
16.25
C

ATOM
1899
CD2
LEU
A
266
49.731
23.941
2.832
1.00
16.33
C

ATOM
1900
C
LEU
A
266
50.282
20.225
5.372
1.00
17.61
C

ATOM
1901
O
LEU
A
266
50.906
19.443
4.642
1.00
17.30
O

ATOM
1902
N
ILE
A
267
50.741
20.639
6.555
1.00
17.19
N

ATOM
1903
CA
ILE
A
267
52.072
20.263
7.023
1.00
16.80
C

ATOM
1904
CB
ILE
A
267
52.425
20.934
8.385
1.00
16.67
C

ATOM
1905
CG1
ILE
A
267
52.702
22.433
8.196
1.00
15.36
C

ATOM
1906
CD1
ILE
A
267
52.656
23.273
9.494
1.00
14.12
C

ATOM
1907
CG2
ILE
A
267
53.626
20.245
9.024
1.00
15.66
C

ATOM
1908
C
ILE
A
267
52.173
18.753
7.137
1.00
17.49
C

ATOM
1909
O
ILE
A
267
53.119
18.156
6.618
1.00
16.97
O

ATOM
1910
N
ARG
A
268
51.178
18.140
7.783
1.00
17.52
N

ATOM
1911
CA
ARG
A
268
51.165
16.692
7.997
1.00
18.02
C

ATOM
1912
CB
ARG
A
268
49.990
16.302
8.907
1.00
18.56
C

ATOM
1913
CG
ARG
A
268
50.240
16.587
10.386
1.00
20.63
C

ATOM
1914
CD
ARG
A
268
49.234
15.899
11.331
1.00
25.57
C

ATOM
1915
NE
ARG
A
268
48.912
16.743
12.487
1.00
29.85
N

ATOM
1916
CZ
ARG
A
268
49.629
16.737
13.585
1.00
31.14
C

ATOM
1917
NH1
ARG
A
268
50.663
15.929
13.648
1.00
34.34
N

ATOM
1918
NH2
ARG
A
268
49.331
17.507
14.615
1.00
30.34
N

ATOM
1919
C
ARG
A
268
51.104
15.910
6.668
1.00
17.59
C

ATOM
1920
O
ARG
A
268
51.676
14.833
6.544
1.00
16.65
O

ATOM
1921
N
TRP
A
269
50.397
16.470
5.693
1.00
17.56
N

ATOM
1922
CA
TRP
A
269
50.336
15.913
4.341
1.00
18.04
C

ATOM
1923
CB
TRP
A
269
49.340
16.717
3.490
1.00
18.77
C

ATOM
1924
CG
TRP
A
269
48.810
15.979
2.265
1.00
21.08
C

ATOM
1925
CD1
TRP
A
269
49.030
14.662
1.914
1.00
22.56
C

ATOM
1926
NE1
TRP
A
269
48.387
14.372
0.730
1.00
24.35
N

ATOM
1927
CE2
TRP
A
269
47.716
15.491
0.301
1.00
23.34
C

ATOM
1928
CD2
TRP
A
269
47.957
16.522
1.248
1.00
22.70
C

ATOM
1929
CE3
TRP
A
269
47.377
17.781
1.033
1.00
23.10
C

ATOM
1930
CZ3
TRP
A
269
46.576
17.970
−0.102
1.00
24.93
C

ATOM
1931
CH2
TRP
A
269
46.351
16.922
−1.014
1.00
24.84
C

ATOM
1932
CZ2
TRP
A
269
46.911
15.679
−0.829
1.00
23.75
C

ATOM
1933
C
TRP
A
269
51.711
15.906
3.667
1.00
17.27
C

ATOM
1934
O
TRP
A
269
52.137
14.870
3.149
1.00
16.99
O

ATOM
1935
N
CYS
A
270
52.400
17.056
3.687
1.00
16.34
N

ATOM
1936
CA
CYS
A
270
53.759
17.173
3.134
1.00
16.21
C

ATOM
1937
CB
CYS
A
270
54.294
18.607
3.275
1.00
15.97
C

ATOM
1938
SG
CYS
A
270
53.427
19.842
2.287
1.00
16.89
S

ATOM
1939
C
CYS
A
270
54.742
16.241
3.824
1.00
16.04
C

ATOM
1940
O
CYS
A
270
55.711
15.774
3.195
1.00
15.33
O

ATOM
1941
N
LEU
A
271
54.488
15.978
5.112
1.00
15.59
N

ATOM
1942
CA
LEU
A
271
55.357
15.124
5.907
1.00
16.36
C

ATOM
1943
CB
LEU
A
271
55.574
15.727
7.304
1.00
15.90
C

ATOM
1944
CG
LEU
A
271
56.248
17.116
7.361
1.00
16.31
C

ATOM
1945
CD1
LEU
A
271
56.473
17.592
8.793
1.00
13.91
C

ATOM
1946
CD2
LEU
A
271
57.590
17.113
6.570
1.00
14.64
C

ATOM
1947
C
LEU
A
271
54.861
13.667
6.010
1.00
16.92
C

ATOM
1948
O
LEU
A
271
55.190
12.969
6.976
1.00
17.11
O

ATOM
1949
N
ALA
A
272
54.085
13.217
5.021
1.00
17.22
N

ATOM
1950
CA
ALA
A
272
53.627
11.819
4.971
1.00
18.16
C

ATOM
1951
CB
ALA
A
272
52.691
11.581
3.798
1.00
18.05
C

ATOM
1952
C
ALA
A
272
54.839
10.921
4.852
1.00
18.59
C

ATOM
1953
O
ALA
A
272
55.768
11.216
4.083
1.00
18.17
O

ATOM
1954
N
LEU
A
273
54.835
9.835
5.621
1.00
19.19
N

ATOM
1955
CA
LEU
A
273
55.953
8.894
5.630
1.00
19.94
C

ATOM
1956
CB
LEU
A
273
55.754
7.832
6.728
1.00
20.56
C

ATOM
1957
CG
LEU
A
273
56.079
8.298
8.162
1.00
21.18
C

ATOM
1958
CD1
LEU
A
273
55.894
7.176
9.193
1.00
21.79
C

ATOM
1959
CD2
LEU
A
273
57.491
8.889
8.262
1.00
20.34
C

ATOM
1960
C
LEU
A
273
56.178
8.254
4.258
1.00
20.58
C

ATOM
1961
O
LEU
A
273
57.322
8.138
3.800
1.00
20.82
O

ATOM
1962
N
ARG
A
274
55.090
7.849
3.605
1.00
20.78
N

ATOM
1963
CA
ARG
A
274
55.164
7.292
2.259
1.00
21.86
C

ATOM
1964
CB
ARG
A
274
53.968
6.373
1.955
1.00
22.23
C

ATOM
1965
CG
ARG
A
274
53.714
5.266
2.975
1.00
27.91
C

ATOM
1966
CD
ARG
A
274
52.588
4.263
2.576
1.00
35.10
C

ATOM
1967
NE
ARG
A
274
52.637
3.917
1.150
1.00
40.44
N

ATOM
1968
CZ
ARG
A
274
51.914
2.962
0.564
1.00
44.04
C

ATOM
1969
NH1
ARG
A
274
51.061
2.223
1.275
1.00
45.20
N

ATOM
1970
NH2
ARG
A
274
52.047
2.741
−0.742
1.00
44.81
N

ATOM
1971
C
ARG
A
274
55.226
8.418
1.227
1.00
20.85
C

ATOM
1972
O
ARG
A
274
54.312
9.249
1.157
1.00
20.77
O

ATOM
1973
N
PRO
A
275
56.297
8.452
0.435
1.00
20.06
N

ATOM
1974
CA
PRO
A
275
56.479
9.502
−0.576
1.00
20.15
C

ATOM
1975
CB
PRO
A
275
57.684
9.007
−1.384
1.00
19.41
C

ATOM
1976
CG
PRO
A
275
58.448
8.169
−0.409
1.00
19.87
C

ATOM
1977
CD
PRO
A
275
57.432
7.509
0.469
1.00
20.03
C

ATOM
1978
C
PRO
A
275
55.245
9.709
−1.474
1.00
20.50
C

ATOM
1979
O
PRO
A
275
54.842
10.860
−1.692
1.00
20.44
O

ATOM
1980
N
SER
A
276
54.650
8.618
−1.966
1.00
20.58
N

ATOM
1981
CA
SER
A
276
53.454
8.693
−2.811
1.00
20.56
C

ATOM
1982
CB
SER
A
276
53.146
7.323
−3.430
1.00
20.69
C

ATOM
1983
OG
SER
A
276
52.516
6.487
−2.479
1.00
22.25
O

ATOM
1984
C
SER
A
276
52.219
9.234
−2.067
1.00
20.21
C

ATOM
1985
O
SER
A
276
51.232
9.612
−2.697
1.00
20.43
O

ATOM
1986
N
ASP
A
277
52.264
9.266
−0.737
1.00
19.88
N

ATOM
1987
CA
ASP
A
277
51.173
9.875
0.027
1.00
19.72
C

ATOM
1988
CB
ASP
A
277
51.093
9.311
1.443
1.00
19.57
C

ATOM
1989
CG
ASP
A
277
50.404
7.945
1.501
1.00
21.58
C

ATOM
1990
OD1
ASP
A
277
49.751
7.540
0.504
1.00
20.40
O

ATOM
1991
OD2
ASP
A
277
50.470
7.222
2.522
1.00
21.84
O

ATOM
1992
C
ASP
A
277
51.266
11.407
0.085
1.00
19.39
C

ATOM
1993
O
ASP
A
277
50.295
12.068
0.483
1.00
20.39
O

ATOM
1994
N
ARG
A
278
52.413
11.962
−0.308
1.00
18.14
N

ATOM
1995
CA
ARG
A
278
52.633
13.408
−0.252
1.00
17.60
C

ATOM
1996
CB
ARG
A
278
54.137
13.740
−0.277
1.00
17.19
C

ATOM
1997
CG
ARG
A
278
54.859
13.330
1.009
1.00
16.29
C

ATOM
1998
CD
ARG
A
278
56.388
13.456
0.995
1.00
15.61
C

ATOM
1999
NE
ARG
A
278
56.954
12.458
1.908
1.00
15.33
N

ATOM
2000
CZ
ARG
A
278
58.152
11.885
1.769
1.00
15.76
C

ATOM
2001
NH1
ARG
A
278
58.965
12.239
0.770
1.00
13.75
N

ATOM
2002
NH2
ARG
A
278
58.541
10.966
2.649
1.00
13.90
N

ATOM
2003
C
ARG
A
278
51.908
14.104
−1.391
1.00
17.58
C

ATOM
2004
O
ARG
A
278
51.716
13.506
−2.466
1.00
17.77
O

ATOM
2005
N
PRO
A
279
51.508
15.357
−1.166
1.00
16.97
N

ATOM
2006
CA
PRO
A
279
50.820
16.142
−2.192
1.00
16.86
C

ATOM
2007
CB
PRO
A
279
50.364
17.387
−1.415
1.00
17.33
C

ATOM
2008
CG
PRO
A
279
51.426
17.533
−0.313
1.00
16.46
C

ATOM
2009
CD
PRO
A
279
51.685
16.125
0.088
1.00
16.42
C

ATOM
2010
C
PRO
A
279
51.768
16.573
−3.290
1.00
17.64
C

ATOM
2011
O
PRO
A
279
52.967
16.757
−3.021
1.00
17.91
O

ATOM
2012
N
THR
A
280
51.245
16.735
−4.507
1.00
17.35
N

ATOM
2013
CA
THR
A
280
51.998
17.353
−5.593
1.00
17.56
C

ATOM
2014
CB
THR
A
280
51.284
17.108
−6.937
1.00
17.70
C

ATOM
2015
OG1
THR
A
280
49.989
17.716
−6.885
1.00
18.13
O

ATOM
2016
CG2
THR
A
280
50.976
15.600
−7.152
1.00
18.27
C

ATOM
2017
C
THR
A
280
52.048
18.864
−5.326
1.00
18.09
C

ATOM
2018
O
THR
A
280
51.342
19.358
−4.427
1.00
18.12
O

ATOM
2019
N
PHE
A
281
52.838
19.600
−6.113
1.00
18.50
N

ATOM
2020
CA
PHE
A
281
52.870
21.066
−6.000
1.00
19.56
C

ATOM
2021
CB
PHE
A
281
53.863
21.702
−6.994
1.00
19.97
C

ATOM
2022
CG
PHE
A
281
55.322
21.369
−6.721
1.00
22.52
C

ATOM
2023
CD1
PHE
A
281
55.834
21.383
−5.433
1.00
25.27
C

ATOM
2024
CE1
PHE
A
281
57.198
21.070
−5.177
1.00
26.96
C

ATOM
2025
CZ
PHE
A
281
58.040
20.748
−6.235
1.00
29.27
C

ATOM
2026
CE2
PHE
A
281
57.535
20.748
−7.553
1.00
28.17
C

ATOM
2027
CD2
PHE
A
281
56.183
21.061
−7.781
1.00
26.44
C

ATOM
2028
C
PHE
A
281
51.474
21.656
−6.211
1.00
19.44
C

ATOM
2029
O
PHE
A
281
51.064
22.559
−5.481
1.00
19.75
O

ATOM
2030
N
GLU
A
282
50.742
21.119
−7.188
1.00
18.94
N

ATOM
2031
CA
GLU
A
282
49.396
21.592
−7.492
1.00
19.12
C

ATOM
2032
CB
GLU
A
282
48.851
20.940
−8.787
1.00
19.45
C

ATOM
2033
CG
GLU
A
282
47.360
21.133
−9.034
1.00
21.47
C

ATOM
2034
CD
GLU
A
282
46.874
20.578
−10.387
1.00
26.22
C

ATOM
2035
OE1
GLU
A
282
47.449
19.584
−10.886
1.00
26.51
O

ATOM
2036
OE2
GLU
A
282
45.901
21.136
−10.951
1.00
25.95
O

ATOM
2037
C
GLU
A
282
48.454
21.369
−6.307
1.00
18.61
C

ATOM
2038
O
GLU
A
282
47.648
22.248
−5.986
1.00
18.93
O

ATOM
2039
N
GLU
A
283
48.558
20.219
−5.640
1.00
17.63
N

ATOM
2040
CA
GLU
A
283
47.693
19.956
−4.485
1.00
17.55
C

ATOM
2041
CB
GLU
A
283
47.744
18.489
−4.076
1.00
17.90
C

ATOM
2042
CG
GLU
A
283
46.951
17.556
−4.989
1.00
18.94
C

ATOM
2043
CD
GLU
A
283
47.298
16.099
−4.752
1.00
21.25
C

ATOM
2044
OE1
GLU
A
283
48.463
15.806
−4.453
1.00
21.74
O

ATOM
2045
OE2
GLU
A
283
46.399
15.240
−4.852
1.00
26.34
O

ATOM
2046
C
GLU
A
283
47.994
20.850
−3.277
1.00
16.99
C

ATOM
2047
O
GLU
A
283
47.090
21.208
−2.519
1.00
16.78
O

ATOM
2048
N
ILE
A
284
49.260
21.208
−3.109
1.00
16.34
N

ATOM
2049
CA
ILE
A
284
49.645
22.147
−2.057
1.00
16.23
C

ATOM
2050
CB
ILE
A
284
51.182
22.296
−1.977
1.00
15.68
C

ATOM
2051
CG1
ILE
A
284
51.837
20.997
−1.492
1.00
15.14
C

ATOM
2052
CD1
ILE
A
284
53.373
20.968
−1.576
1.00
13.98
C

ATOM
2053
CG2
ILE
A
284
51.552
23.488
−1.074
1.00
15.67
C

ATOM
2054
C
ILE
A
284
49.003
23.507
−2.320
1.00
16.48
C

ATOM
2055
O
ILE
A
284
48.371
24.076
−1.447
1.00
16.43
O

ATOM
2056
N
GLN
A
285
49.162
24.009
−3.539
1.00
16.57
N

ATOM
2057
CA
GLN
A
285
48.677
25.335
−3.872
1.00
17.32
C

ATOM
2058
CB
GLN
A
285
49.376
25.867
−5.124
1.00
16.61
C

ATOM
2059
CG
GLN
A
285
50.848
26.173
−4.858
1.00
16.82
C

ATOM
2060
CD
GLN
A
285
51.485
26.941
−5.984
1.00
16.61
C

ATOM
2061
OE1
GLN
A
285
51.643
26.408
−7.087
1.00
16.49
O

ATOM
2062
NE2
GLN
A
285
51.822
28.204
−5.731
1.00
12.74
N

ATOM
2063
C
GLN
A
285
47.153
25.426
−3.998
1.00
17.59
C

ATOM
2064
O
GLN
A
285
46.596
26.520
−3.882
1.00
17.62
O

ATOM
2065
N
ASN
A
286
46.495
24.292
−4.231
1.00
17.76
N

ATOM
2066
CA
ASN
A
286
45.038
24.227
−4.189
1.00
18.67
C

ATOM
2067
CB
ASN
A
286
44.507
23.196
−5.199
1.00
19.01
C

ATOM
2068
CG
ASN
A
286
44.599
23.683
−6.644
1.00
20.31
C

ATOM
2069
OD1
ASN
A
286
44.581
24.890
−6.923
1.00
21.12
O

ATOM
2070
ND2
ASN
A
286
44.697
22.746
−7.566
1.00
21.21
N

ATOM
2071
C
ASN
A
286
44.473
23.948
−2.787
1.00
19.15
C

ATOM
2072
O
ASN
A
286
43.253
23.959
−2.585
1.00
18.66
O

ATOM
2073
N
HIS
A
287
45.362
23.711
−1.820
1.00
19.57
N

ATOM
2074
CA
HIS
A
287
44.943
23.402
−0.455
1.00
19.96
C

ATOM
2075
CB
HIS
A
287
46.161
23.008
0.398
1.00
20.42
C

ATOM
2076
CG
HIS
A
287
45.811
22.535
1.776
1.00
20.16
C

ATOM
2077
ND1
HIS
A
287
45.771
21.201
2.120
1.00
21.24
N

ATOM
2078
CE1
HIS
A
287
45.417
21.085
3.388
1.00
20.50
C

ATOM
2079
NE2
HIS
A
287
45.224
22.298
3.878
1.00
21.14
N

ATOM
2080
CD2
HIS
A
287
45.469
23.220
2.891
1.00
19.59
C

ATOM
2081
C
HIS
A
287
44.212
24.613
0.140
1.00
20.17
C

ATOM
2082
O
HIS
A
287
44.585
25.753
−0.140
1.00
20.09
O

ATOM
2083
N
PRO
A
288
43.154
24.375
0.921
1.00
20.64
N

ATOM
2084
CA
PRO
A
288
42.399
25.468
1.540
1.00
20.94
C

ATOM
2085
CB
PRO
A
288
41.409
24.741
2.463
1.00
21.25
C

ATOM
2086
CG
PRO
A
288
41.229
23.429
1.836
1.00
21.49
C

ATOM
2087
CD
PRO
A
288
42.549
23.063
1.215
1.00
20.84
C

ATOM
2088
C
PRO
A
288
43.263
26.449
2.323
1.00
20.62
C

ATOM
2089
O
PRO
A
288
42.995
27.641
2.242
1.00
21.00
O

ATOM
2090
N
TRP
A
289
44.290
25.982
3.027
1.00
20.44
N

ATOM
2091
CA
TRP
A
289
45.144
26.903
3.785
1.00
20.73
C

ATOM
2092
CB
TRP
A
289
46.165
26.169
4.668
1.00
19.78
C

ATOM
2093
CG
TRP
A
289
46.932
27.139
5.535
1.00
18.93
C

ATOM
2094
CD1
TRP
A
289
46.469
27.795
6.646
1.00
17.79
C

ATOM
2095
NE1
TRP
A
289
47.450
28.617
7.152
1.00
17.69
N

ATOM
2096
CE2
TRP
A
289
48.560
28.535
6.348
1.00
17.45
C

ATOM
2097
CD2
TRP
A
289
48.265
27.614
5.316
1.00
16.35
C

ATOM
2098
CE3
TRP
A
289
49.252
27.348
4.352
1.00
16.19
C

ATOM
2099
CZ3
TRP
A
289
50.488
27.992
4.453
1.00
14.25
C

ATOM
2100
CH2
TRP
A
289
50.753
28.894
5.498
1.00
15.51
C

ATOM
2101
CZ2
TRP
A
289
49.805
29.181
6.453
1.00
16.21
C

ATOM
2102
C
TRP
A
289
45.868
27.924
2.897
1.00
21.43
C

ATOM
2103
O
TRP
A
289
46.219
29.005
3.371
1.00
21.35
O

ATOM
2104
N
MET
A
290
46.081
27.575
1.627
1.00
22.16
N

ATOM
2105
CA
MET
A
290
46.795
28.432
0.672
1.00
23.41
C

ATOM
2106
CB
MET
A
290
47.570
27.561
−0.328
1.00
23.44
C

ATOM
2107
CG
MET
A
290
48.631
26.687
0.341
1.00
23.18
C

ATOM
2108
SD
MET
A
290
50.289
27.282
−0.016
1.00
24.31
S

ATOM
2109
CE
MET
A
290
50.282
28.805
0.810
1.00
21.67
C

ATOM
2110
C
MET
A
290
45.935
29.456
−0.093
1.00
24.66
C

ATOM
2111
O
MET
A
290
46.465
30.229
−0.901
1.00
24.82
O

ATOM
2112
N
GLN
A
291
44.627
29.472
0.161
1.00
25.63
N

ATOM
2113
CA
GLN
A
291
43.725
30.390
−0.541
1.00
27.47
C

ATOM
2114
CB
GLN
A
291
42.263
29.932
−0.399
1.00
28.12
C

ATOM
2115
CG
GLN
A
291
41.931
28.612
−1.133
1.00
30.95
C

ATOM
2116
CD
GLN
A
291
42.797
28.376
−2.378
1.00
35.68
C

ATOM
2117
OE1
GLN
A
291
42.599
29.038
−3.414
1.00
37.06
O

ATOM
2118
NE2
GLN
A
291
43.766
27.441
−2.277
1.00
34.40
N

ATOM
2119
C
GLN
A
291
43.879
31.844
−0.094
1.00
27.73
C

ATOM
2120
O
GLN
A
291
44.222
32.122
1.059
1.00
28.09
O

ATOM
2121
N
ASP
A
292
43.651
32.765
−1.026
1.00
28.22
N

ATOM
2122
CA
ASP
A
292
43.678
34.207
−0.750
1.00
28.34
C

ATOM
2123
CB
ASP
A
292
42.553
34.596
0.224
1.00
29.02
C

ATOM
2124
CG
ASP
A
292
41.176
34.236
−0.308
1.00
31.45
C

ATOM
2125
OD1
ASP
A
292
40.817
34.731
−1.402
1.00
33.30
O

ATOM
2126
OD2
ASP
A
292
40.400
33.452
0.291
1.00
34.49
O

ATOM
2127
C
ASP
A
292
45.027
34.718
−0.245
1.00
27.65
C

ATOM
2128
O
ASP
A
292
45.098
35.446
0.761
1.00
27.28
O

ATOM
2129
N
VAL
A
293
46.094
34.334
−0.946
1.00
26.88
N

ATOM
2130
CA
VAL
A
293
47.429
34.808
−0.622
1.00
25.72
C

ATOM
2131
CB
VAL
A
293
48.538
34.025
−1.396
1.00
26.36
C

ATOM
2132
CG1
VAL
A
293
48.546
34.374
−2.881
1.00
26.33
C

ATOM
2133
CG2
VAL
A
293
49.912
34.299
−0.799
1.00
24.82
C

ATOM
2134
C
VAL
A
293
47.550
36.311
−0.877
1.00
25.50
C

ATOM
2135
O
VAL
A
293
47.007
36.824
−1.848
1.00
24.70
O

ATOM
2136
N
LEU
A
294
48.261
37.004
0.009
1.00
25.07
N

ATOM
2137
CA
LEU
A
294
48.630
38.392
−0.226
1.00
25.15
C

ATOM
2138
CB
LEU
A
294
49.280
38.998
1.017
1.00
24.83
C

ATOM
2139
CG
LEU
A
294
48.500
39.140
2.329
1.00
24.86
C

ATOM
2140
CD1
LEU
A
294
49.412
39.783
3.371
1.00
22.85
C

ATOM
2141
CD2
LEU
A
294
47.199
39.941
2.148
1.00
24.42
C

ATOM
2142
C
LEU
A
294
49.621
38.487
−1.384
1.00
25.66
C

ATOM
2143
O
LEU
A
294
50.437
37.585
−1.598
1.00
25.15
O

ATOM
2144
N
LEU
A
295
49.539
39.585
−2.128
1.00
26.06
N

ATOM
2145
CA
LEU
A
295
50.587
39.950
−3.071
1.00
26.73
C

ATOM
2146
CB
LEU
A
295
50.122
41.106
−3.981
1.00
27.23
C

ATOM
2147
CG
LEU
A
295
48.775
40.944
−4.717
1.00
29.21
C

ATOM
2148
CD1
LEU
A
295
48.330
42.237
−5.412
1.00
31.53
C

ATOM
2149
CD2
LEU
A
295
48.829
39.801
−5.721
1.00
31.44
C

ATOM
2150
C
LEU
A
295
51.841
40.337
−2.265
1.00
26.44
C

ATOM
2151
O
LEU
A
295
51.729
40.733
−1.103
1.00
25.11
O

ATOM
2152
N
PRO
A
296
53.028
40.170
−2.851
1.00
27.04
N

ATOM
2153
CA
PRO
A
296
54.277
40.535
−2.164
1.00
27.59
C

ATOM
2154
CB
PRO
A
296
55.331
40.358
−3.250
1.00
27.65
C

ATOM
2155
CG
PRO
A
296
54.772
39.247
−4.091
1.00
27.68
C

ATOM
2156
CD
PRO
A
296
53.292
39.564
−4.171
1.00
26.80
C

ATOM
2157
C
PRO
A
296
54.265
41.964
−1.623
1.00
28.49
C

ATOM
2158
O
PRO
A
296
54.608
42.151
−0.459
1.00
28.36
O

ATOM
2159
N
GLN
A
297
53.854
42.942
−2.430
1.00
29.34
N

ATOM
2160
CA
GLN
A
297
53.801
44.328
−1.960
1.00
30.65
C

ATOM
2161
CB
GLN
A
297
53.467
45.305
−3.102
1.00
31.10
C

ATOM
2162
CG
GLN
A
297
53.783
46.766
−2.787
1.00
33.83
C

ATOM
2163
CD
GLN
A
297
55.239
46.993
−2.374
1.00
37.47
C

ATOM
2164
OE1
GLN
A
297
56.158
46.742
−3.153
1.00
38.85
O

ATOM
2165
NE2
GLN
A
297
55.444
47.468
−1.147
1.00
39.03
N

ATOM
2166
C
GLN
A
297
52.830
44.490
−0.782
1.00
30.41
C

ATOM
2167
O
GLN
A
297
53.174
45.125
0.210
1.00
30.58
O

ATOM
2168
N
GLU
A
298
51.640
43.900
−0.891
1.00
30.38
N

ATOM
2169
CA
GLU
A
298
50.699
43.839
0.235
1.00
30.73
C

ATOM
2170
CB
GLU
A
298
49.479
42.981
−0.103
1.00
31.10
C

ATOM
2171
CG
GLU
A
298
48.534
43.558
−1.141
1.00
33.59
C

ATOM
2172
CD
GLU
A
298
47.270
42.722
−1.289
1.00
37.83
C

ATOM
2173
OE1
GLU
A
298
47.369
41.480
−1.435
1.00
36.99
O

ATOM
2174
OE2
GLU
A
298
46.166
43.313
−1.272
1.00
40.82
O

ATOM
2175
C
GLU
A
298
51.378
43.269
1.485
1.00
30.06
C

ATOM
2176
O
GLU
A
298
51.258
43.837
2.577
1.00
30.09
O

ATOM
2177
N
THR
A
299
52.096
42.156
1.301
1.00
28.83
N

ATOM
2178
CA
THR
A
299
52.857
41.496
2.360
1.00
27.61
C

ATOM
2179
CB
THR
A
299
53.619
40.265
1.782
1.00
27.45
C

ATOM
2180
OG1
THR
A
299
52.690
39.346
1.192
1.00
25.03
O

ATOM
2181
CG2
THR
A
299
54.269
39.447
2.897
1.00
26.87
C

ATOM
2182
C
THR
A
299
53.840
42.442
3.062
1.00
27.70
C

ATOM
2183
O
THR
A
299
53.890
42.487
4.289
1.00
27.42
O

ATOM
2184
N
ALA
A
300
54.626
43.177
2.278
1.00
27.78
N

ATOM
2185
CA
ALA
A
300
55.622
44.093
2.819
1.00
28.26
C

ATOM
2186
CB
ALA
A
300
56.517
44.627
1.706
1.00
28.09
C

ATOM
2187
C
ALA
A
300
54.972
45.250
3.588
1.00
28.73
C

ATOM
2188
O
ALA
A
300
55.444
45.636
4.658
1.00
28.08
O

ATOM
2189
N
GLU
A
301
53.884
45.785
3.040
1.00
29.58
N

ATOM
2190
CA
GLU
A
301
53.169
46.894
3.668
1.00
31.18
C

ATOM
2191
CB
GLU
A
301
52.063
47.433
2.738
1.00
31.45
C

ATOM
2192
CG
GLU
A
301
52.592
48.250
1.555
1.00
34.28
C

ATOM
2193
CD
GLU
A
301
51.553
48.517
0.460
1.00
37.15
C

ATOM
2194
OE1
GLU
A
301
50.659
47.668
0.219
1.00
37.47
O

ATOM
2195
OE2
GLU
A
301
51.642
49.589
−0.177
1.00
38.55
O

ATOM
2196
C
GLU
A
301
52.610
46.488
5.042
1.00
31.10
C

ATOM
2197
O
GLU
A
301
52.779
47.211
6.019
1.00
31.18
O

ATOM
2198
N
ILE
A
302
51.989
45.311
5.107
1.00
31.28
N

ATOM
2199
CA
ILE
A
302
51.371
44.823
6.340
1.00
31.59
C

ATOM
2200
CB
ILE
A
302
50.284
43.767
6.019
1.00
31.30
C

ATOM
2201
CG1
ILE
A
302
49.201
44.378
5.115
1.00
31.02
C

ATOM
2202
CD1
ILE
A
302
48.293
43.357
4.435
1.00
29.87
C

ATOM
2203
CG2
ILE
A
302
49.673
43.195
7.311
1.00
30.80
C

ATOM
2204
C
ILE
A
302
52.384
44.286
7.373
1.00
32.02
C

ATOM
2205
O
ILE
A
302
52.263
44.577
8.560
1.00
31.80
O

ATOM
2206
N
HIS
A
303
53.391
43.544
6.909
1.00
32.60
N

ATOM
2207
CA
HIS
A
303
54.253
42.750
7.790
1.00
33.26
C

ATOM
2208
CB
HIS
A
303
54.176
41.282
7.379
1.00
32.20
C

ATOM
2209
CG
HIS
A
303
52.832
40.662
7.606
1.00
29.68
C

ATOM
2210
ND1
HIS
A
303
52.385
40.293
8.857
1.00
27.26
N

ATOM
2211
CE1
HIS
A
303
51.171
39.780
8.755
1.00
27.29
C

ATOM
2212
NE2
HIS
A
303
50.819
39.796
7.481
1.00
26.60
N

ATOM
2213
CD2
HIS
A
303
51.839
40.346
6.743
1.00
26.43
C

ATOM
2214
C
HIS
A
303
55.723
43.174
7.849
1.00
35.09
C

ATOM
2215
O
HIS
A
303
56.435
42.838
8.796
1.00
34.73
O

ATOM
2216
N
LEU
A
304
56.181
43.889
6.827
1.00
37.42
N

ATOM
2217
CA
LEU
A
304
57.588
44.256
6.724
1.00
40.17
C

ATOM
2218
CB
LEU
A
304
58.187
43.707
5.421
1.00
39.43
C

ATOM
2219
CG
LEU
A
304
58.574
42.224
5.234
1.00
38.74
C

ATOM
2220
CD1
LEU
A
304
57.830
41.238
6.125
1.00
34.54
C

ATOM
2221
CD2
LEU
A
304
58.465
41.807
3.760
1.00
35.74
C

ATOM
2222
C
LEU
A
304
57.751
45.774
6.796
1.00
42.83
C

ATOM
2223
O
LEU
A
304
58.861
46.286
6.661
1.00
43.07
O

ATOM
2224
N
HIS
A
305
56.629
46.462
7.033
1.00
46.30
N

ATOM
2225
CA
HIS
A
305
56.516
47.933
7.107
1.00
49.71
C

ATOM
2226
CB
HIS
A
305
56.747
48.459
8.545
1.00
50.37
C

ATOM
2227
CG
HIS
A
305
58.085
48.106
9.125
1.00
53.30
C

ATOM
2228
ND1
HIS
A
305
58.344
46.886
9.716
1.00
56.26
N

ATOM
2229
CE1
HIS
A
305
59.597
46.860
10.138
1.00
57.48
C

ATOM
2230
NE2
HIS
A
305
60.159
48.022
9.847
1.00
57.58
N

ATOM
2231
CD2
HIS
A
305
59.234
48.820
9.216
1.00
56.22
C

ATOM
2232
C
HIS
A
305
57.339
48.707
6.063
1.00
50.97
C

ATOM
2233
O
HIS
A
305
58.423
49.221
6.359
1.00
51.59
O

ATOM
2234
N
SER
A
306
56.795
48.799
4.850
1.00
52.46
N

ATOM
2235
CA
SER
A
306
57.518
49.345
3.693
1.00
53.65
C

ATOM
2236
CB
SER
A
306
56.768
49.009
2.401
1.00
53.75
C

ATOM
2237
OG
SER
A
306
57.340
47.873
1.784
1.00
54.33
O

ATOM
2238
C
SER
A
306
57.820
50.851
3.763
1.00
54.12
C

ATOM
2239
O
SER
A
306
58.964
51.291
3.600
1.00
54.51
O

ATOM
2240
OXT
SER
A
306
56.943
51.696
3.974
1.00
54.48
O

ATOM
2241
O1A
ANP
L
1
74.739
30.562
−0.833
1.00
18.02
O

ATOM
2242
PA
ANP
L
1
74.774
30.444
0.630
1.00
19.01
P

ATOM
2243
O2A
ANP
L
1
73.576
29.828
1.256
1.00
17.67
O

ATOM
2244
O3A
ANP
L
1
76.090
29.652
0.938
1.00
19.50
O

ATOM
2245
PB
ANP
L
1
76.391
28.426
1.887
1.00
21.38
P

ATOM
2246
O1B
ANP
L
1
77.321
27.642
1.069
1.00
18.82
O

ATOM
2247
O2B
ANP
L
1
77.348
29.007
2.991
1.00
24.75
O

ATOM
2248
N3B
ANP
L
1
75.190
27.617
2.664
1.00
20.02
N

ATOM
2249
PG
ANP
L
1
73.526
27.764
2.959
1.00
31.62
P

ATOM
2250
O3G
ANP
L
1
73.022
29.016
3.938
1.00
19.18
O

ATOM
2251
O2G
ANP
L
1
73.054
27.935
1.600
1.00
20.72
O

ATOM
2252
O1G
ANP
L
1
72.907
26.389
3.404
1.00
20.30
O

ATOM
2253
O5*
ANP
L
1
74.945
31.880
1.324
1.00
18.06
O

ATOM
2254
C5*
ANP
L
1
75.248
31.923
2.714
1.00
17.09
C

ATOM
2255
C4*
ANP
L
1
74.482
33.091
3.324
1.00
18.01
C

ATOM
2256
O4*
ANP
L
1
74.771
34.292
2.621
1.00
19.09
O

ATOM
2257
C1*
ANP
L
1
73.660
35.124
2.442
1.00
17.31
C

ATOM
2258
C2*
ANP
L
1
72.535
34.397
3.160
1.00
18.01
C

ATOM
2259
O2*
ANP
L
1
72.451
34.900
4.487
1.00
19.01
O

ATOM
2260
C3*
ANP
L
1
72.983
32.937
3.178
1.00
17.74
C

ATOM
2261
O3*
ANP
L
1
72.429
32.083
4.163
1.00
17.16
O

ATOM
2262
N9
ANP
L
1
73.486
35.319
0.979
1.00
17.49
N

ATOM
2263
C8
ANP
L
1
73.739
34.403
−0.019
1.00
15.85
C

ATOM
2264
N7
ANP
L
1
73.458
34.943
−1.228
1.00
14.30
N

ATOM
2265
C5
ANP
L
1
73.025
36.193
−1.045
1.00
15.53
C

ATOM
2266
C6
ANP
L
1
72.607
37.177
−1.929
1.00
16.13
C

ATOM
2267
N6
ANP
L
1
72.542
36.951
−3.254
1.00
14.38
N

ATOM
2268
C4
ANP
L
1
73.039
36.448
0.334
1.00
15.81
C

ATOM
2269
N3
ANP
L
1
72.632
37.646
0.795
1.00
17.04
N

ATOM
2270
C2
ANP
L
1
72.219
38.650
−0.068
1.00
17.00
C

ATOM
2271
N1
ANP
L
1
72.213
38.406
−1.417
1.00
16.49
N

ATOM
2272
O
HOH
W
1
63.572
15.756
8.058
1.00
26.33
O

ATOM
2273
O
HOH
W
2
61.017
10.214
−2.362
1.00
24.27
O

ATOM
2274
O
HOH
W
3
54.457
23.038
−11.444
1.00
30.92
O

ATOM
2275
O
HOH
W
4
63.756
21.549
−5.585
1.00
27.71
O

ATOM
2276
O
HOH
W
5
63.196
11.516
−9.068
1.00
26.46
O

ATOM
2277
O
HOH
W
6
58.424
12.040
−6.552
1.00
34.61
O

ATOM
2278
O
HOH
W
7
54.593
37.425
12.022
1.00
32.21
O

ATOM
2279
O
HOH
W
8
71.368
23.298
−3.142
1.00
29.05
O

ATOM
2280
O
HOH
W
9
64.911
20.478
−0.663
1.00
26.42
O

ATOM
2281
O
HOH
W
10
43.132
26.500
18.254
1.00
34.21
O

ATOM
2282
O
HOH
W
11
64.667
17.153
−3.465
1.00
26.68
O

ATOM
2283
O
HOH
W
12
75.478
24.941
1.494
1.00
29.16
O

ATOM
2284
O
HOH
W
13
63.267
18.804
11.098
1.00
24.60
O

ATOM
2285
O
HOH
W
14
47.333
35.497
10.172
1.00
39.07
O

ATOM
2286
O
HOH
W
15
41.592
25.798
13.188
1.00
29.60
O

ATOM
2287
O
HOH
W
16
46.216
35.678
3.186
1.00
30.38
O

ATOM
2288
O
HOH
W
17
73.656
23.760
−0.205
1.00
33.83
O

ATOM
2289
O
HOH
W
18
54.975
14.884
−3.637
1.00
27.43
O

ATOM
2290
O
HOH
W
19
58.350
33.360
−6.094
1.00
29.01
O

ATOM
2291
O
HOH
W
20
58.458
11.832
15.075
1.00
34.06
O

ATOM
2292
O
HOH
W
21
48.299
24.286
17.311
1.00
29.81
O

ATOM
2293
O
HOH
W
22
67.356
21.562
3.234
1.00
31.16
O

ATOM
2294
O
HOH
W
23
84.186
28.990
2.689
1.00
31.81
O

ATOM
2295
O
HOH
W
24
43.050
31.228
3.507
1.00
47.48
O

ATOM
2296
O
HOH
W
25
88.316
32.615
−4.360
1.00
32.51
O

ATOM
2297
O
HOH
W
26
71.447
43.185
−7.672
1.00
43.19
O

ATOM
2298
O
HOH
W
27
64.646
19.993
−3.620
1.00
28.98
O

ATOM
2299
O
HOH
W
28
71.618
43.781
0.688
1.00
40.30
O

ATOM
2300
O
HOH
W
29
70.325
37.710
6.677
1.00
31.97
O

ATOM
2301
O
HOH
W
30
71.184
18.590
9.525
1.00
35.40
O

ATOM
2302
O
HOH
W
31
53.890
12.402
−3.734
1.00
32.44
O

ATOM
2303
O
HOH
W
32
52.246
19.524
−9.419
1.00
35.84
O

ATOM
2304
O
HOH
W
33
40.639
26.398
16.837
1.00
35.65
O

ATOM
2305
O
HOH
W
34
60.620
13.344
−8.811
1.00
44.92
O

ATOM
2306
O
HOH
W
35
75.110
44.117
2.424
1.00
40.04
O

ATOM
2307
O
HOH
W
36
74.471
37.990
7.461
1.00
40.83
O

ATOM
2308
O
HOH
W
37
59.228
35.799
−5.068
1.00
33.92
O

ATOM
2309
O
HOH
W
38
57.123
17.309
16.065
1.00
40.82
O

ATOM
2310
O
HOH
W
39
73.994
32.523
−2.675
1.00
33.30
O

ATOM
2311
O
HOH
W
40
69.993
44.693
3.957
1.00
50.42
O

ATOM
2312
O
HOH
W
41
65.864
18.120
0.377
1.00
37.77
O

ATOM
2313
O
HOH
W
42
48.834
35.741
2.440
1.00
31.77
O

ATOM
2314
O
HOH
W
43
52.185
7.956
4.576
1.00
38.71
O

ATOM
2315
O
HOH
W
44
64.765
11.133
−15.777
1.00
33.65
O

ATOM
2316
O
HOH
W
45
48.197
17.129
−9.023
1.00
35.25
O

ATOM
2317
O
HOH
W
46
71.559
9.704
−7.782
1.00
42.63
O

ATOM
2318
O
HOH
W
47
72.838
31.092
−4.833
1.00
32.07
O

ATOM
2319
O
HOH
W
48
54.340
33.741
−9.311
1.00
38.01
O

ATOM
2320
O
HOH
W
49
54.223
11.905
9.111
1.00
33.22
O

ATOM
2321
O
HOH
W
50
52.887
36.641
−1.776
1.00
38.05
O

ATOM
2322
O
HOH
W
51
58.033
32.102
18.276
1.00
41.20
O

ATOM
2323
O
HOH
W
52
58.764
11.092
17.987
1.00
35.48
O

ATOM
2324
O
HOH
W
53
56.210
29.247
−10.737
1.00
40.52
O

ATOM
2325
O
HOH
W
54
75.583
29.566
5.684
1.00
42.12
O

ATOM
2326
O
HOH
W
55
82.299
27.704
4.152
1.00
43.41
O

ATOM
2327
O
HOH
W
56
61.670
6.087
15.210
1.00
42.46
O

ATOM
2328
O
HOH
W
57
41.909
26.005
9.492
1.00
38.52
O

ATOM
2329
O
HOH
W
58
72.941
15.417
4.788
1.00
53.05
O

ATOM
2330
O
HOH
W
59
56.478
27.573
−12.787
1.00
37.09
O

ATOM
2331
O
HOH
W
60
83.158
40.743
6.932
1.00
41.95
O

ATOM
2332
O
HOH
W
61
44.574
20.141
−2.416
1.00
38.16
O

ATOM
2333
O
HOH
W
62
51.818
13.854
13.409
1.00
36.87
O

ATOM
2334
O
HOH
W
63
56.901
22.491
−11.879
1.00
46.71
O

ATOM
2335
O
HOH
W
64
46.066
31.890
−3.335
1.00
46.54
O

ATOM
2336
O
HOH
W
65
46.390
17.471
11.120
1.00
41.50
O

ATOM
2337
O
HOH
W
66
73.021
18.047
7.679
1.00
45.56
O

ATOM
2338
O
HOH
W
67
56.272
6.117
−3.207
1.00
47.16
O

ATOM
2339
O
HOH
W
68
78.807
46.222
0.194
1.00
43.86
O

ATOM
2340
O
HOH
W
69
70.343
14.512
−11.989
1.00
41.06
O

ATOM
2341
O
HOH
W
70
43.908
38.440
0.670
1.00
53.02
O

ATOM
2342
O
HOH
W
71
40.352
28.430
2.051
1.00
45.97
O

ATOM
2343
O
HOH
W
72
44.496
19.095
11.235
1.00
54.47
O

ATOM
2344
O
HOH
W
73
47.165
15.788
6.720
1.00
41.01
O

ATOM
2345
O
HOH
W
74
56.445
43.287
−5.157
1.00
44.15
O

ATOM
2346
O
HOH
W
75
73.363
25.539
−17.736
1.00
50.03
O

ATOM
2347
O
HOH
W
76
67.665
14.838
−15.990
1.00
47.37
O

ATOM
2348
O
HOH
W
77
77.512
31.796
8.477
1.00
43.71
O

ATOM
2349
O
HOH
W
78
64.562
45.570
−0.458
1.00
42.82
O

ATOM
2350
O
HOH
W
79
72.601
12.906
5.087
1.00
41.65
O

ATOM
2351
O
HOH
W
80
64.569
29.017
13.834
1.00
46.57
O

ATOM
2352
O
HOH
W
81
58.851
5.715
−3.038
1.00
36.10
O

ATOM
2353
O
HOH
W
82
66.378
16.370
−1.785
1.00
36.18
O

ATOM
2354
O
HOH
W
83
52.161
13.315
8.870
1.00
38.72
O

ATOM
2355
O
HOH
W
84
84.302
27.201
−0.028
1.00
44.09
O

ATOM
2356
O
HOH
W
85
49.501
13.263
−4.243
1.00
40.50
O

ATOM
2357
O
HOH
W
86
63.118
41.154
−5.640
1.00
44.61
O

ATOM
2358
O
HOH
W
87
75.334
10.847
−0.667
1.00
41.03
O

ATOM
2359
O
HOH
W
88
51.946
9.440
7.089
1.00
44.13
O

ATOM
2360
O
HOH
W
89
46.051
15.476
9.731
1.00
44.74
O

ATOM
2361
O
HOH
W
90
60.662
7.651
−3.345
1.00
33.21
O

ATOM
2362
O
HOH
W
91
78.926
37.602
8.589
1.00
45.81
O

ATOM
2363
O
HOH
W
92
83.687
38.788
8.645
1.00
42.46
O

ATOM
2364
O
HOH
W
93
65.774
37.305
−9.200
1.00
42.61
O

ATOM
2365
O
HOH
W
94
48.890
32.798
13.190
1.00
44.81
O

ATOM
2366
O
HOH
W
95
71.057
6.982
7.124
1.00
46.01
O

ATOM
2367
O
HOH
W
96
73.156
42.259
2.367
1.00
41.64
O

ATOM
2368
O
HOH
W
97
56.031
35.393
16.920
1.00
47.09
O

ATOM
2369
O
HOH
W
98
90.130
23.863
−3.527
1.00
56.29
O

ATOM
2370
O
HOH
W
99
64.199
16.375
1.499
1.00
32.31
O

ATOM
2371
O
HOH
W
100
52.185
30.882
13.804
1.00
45.03
O

ATOM
2372
O
HOH
W
101
78.245
25.957
−3.060
1.00
37.82
O

ATOM
2373
O
HOH
W
102
70.395
32.498
−12.472
1.00
40.91
O

ATOM
2374
O
HOH
W
103
76.497
26.635
−1.230
1.00
45.90
O

ATOM
2375
O
HOH
W
104
53.869
39.933
10.992
1.00
48.40
O

ATOM
2376
O
HOH
W
105
52.957
42.953
−5.317
1.00
43.64
O

ATOM
2377
O
HOH
W
106
81.062
46.768
−1.405
1.00
51.11
O

ATOM
2378
O
HOH
W
107
85.023
38.607
−2.261
1.00
44.62
O

ATOM
2379
O
HOH
W
108
55.351
15.949
−6.982
1.00
56.30
O

ATOM
2380
O
HOH
W
109
72.893
16.276
−11.510
1.00
40.24
O

ATOM
2381
O
HOH
W
110
64.150
29.039
11.361
1.00
44.87
O

ATOM
2382
O
HOH
W
111
70.497
11.613
14.584
1.00
42.70
O

ATOM
2383
O
HOH
W
112
47.743
30.590
14.200
1.00
41.84
O

ATOM
2384
O
HOH
W
113
67.986
19.239
2.487
1.00
45.28
O

ATOM
2385
O
HOH
W
114
66.956
9.523
−15.205
1.00
44.06
O

ATOM
2386
O
HOH
W
115
71.948
39.028
3.510
1.00
48.92
O

ATOM
2387
O
HOH
W
116
73.384
36.583
9.395
1.00
49.46
O

ATOM
2388
O
HOH
W
117
69.213
13.943
11.885
1.00
43.79
O

ATOM
2389
O
HOH
W
118
92.376
29.991
−13.421
1.00
50.66
O

ATOM
2390
O
HOH
W
119
71.748
33.616
8.364
1.00
44.60
O

ATOM
2391
O
HOH
W
120
72.751
30.625
9.138
1.00
54.54
O

ATOM
2392
O
HOH
W
121
44.373
14.896
1.763
1.00
54.90
O

ATOM
2393
O
HOH
W
122
72.331
37.663
5.252
1.00
54.91
O

ATOM
2394
O
HOH
W
123
85.766
37.929
7.966
1.00
45.42
O

ATOM
2395
O
HOH
W
124
82.375
46.624
−12.952
1.00
49.98
O

ATOM
2396
O
HOH
W
125
69.185
5.514
−10.117
1.00
57.15
O

ATOM
2397
O
HOH
W
126
72.843
16.943
−2.415
1.00
48.35
O

ATOM
2398
O
HOH
W
127
58.459
18.549
−11.193
1.00
68.47
O

ATOM
2399
O
HOH
W
128
64.272
33.293
−12.839
1.00
48.86
O

ATOM
2400
O
HOH
W
129
59.782
37.121
−16.253
1.00
59.29
O

[0512]

4

TABLE 4

REMARK Written by DEALPDB Version 1.13 (06/02)

REMARK Thu Jan 23 14:56:07 2003

HEADER
----
XX-XXX-XX xxxx

COMPND
---

REMARK
3

REMARK
3
REFINEMENT.

REMARK
3
PROGRAM
REFMAC 5.1.25

REMARK
3
AUTHORS
MURSHUDOV, VAGIN, DODSON

REMARK
3

REMARK
3
REFINEMENT TARGET
MAXIMUM LIKELIHOOD

REMARK
3

REMARK
3
DATA USED IN REFINEMENT.

REMARK
3
RESOLUTION RANGE HIGH (ANGSTROMS)
1.80

REMARK
3
RESOLUTION RANGE LOW (ANGSTROMS)
81.65

REMARK
3
DATA CUTOFF (SIGMA(F))
NONE

REMARK
3
COMPLETENESS FOR RANGE (%)
99.77

REMARK
3
NUMBER OF REFLECTIONS
24820

REMARK
3

REMARK
3
FIT TO DATA USED IN REFINEMENT.

REMARK
3
CROSS-VALIDATION METHOD
THROUGHOUT

REMARK
3
FREE R VALUE TEST SET SELECTION
RANDOM

REMARK
3
R VALUE (WORKING + TEST SET)
0.18829

REMARK
3
R VALUE (WORKING SET)
0.18620

REMARK
3
FREE R VALUE
0.22809

REMARK
3
FREE R VALUE TEST SET SIZE (%)
5.1

REMARK
3
FREE R VALUE TEST SET COUNT
1327

REMARK
3

REMARK
3
FIT IN THE HIGHEST RESOLUTION BIN.

REMARK
3
TOTAL NUMBER OF BINS USED
20

REMARK
3
BIN RESOLUTION RANGE HIGH
1.800

REMARK
3
BIN RESOLUTION RANGE LOW
1.847

REMARK
3
REFLECTION IN BIN (WORKING SET)
1749

REMARK
3
BIN R VALUE (WORKING SET)
0.242

REMARK
3
BIN FREE R VALUE SET COUNT
90

REMARK
3
BIN FREE R VALUE
0.288

REMARK
3

REMARK
3
NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.

REMARK
3
ALL ATOMS
2507

REMARK
3

REMARK
3
B VALUES.

REMARK
3
FROM WILSON PLOT (A**2)
NULL

REMARK
3
MEAN B VALUE (OVERALL, A**2)
17.218

REMARK
3
OVERALL ANISOTROPIC B VALUE.

REMARK
3
B11 (A**2)
−0.09

REMARK
3
B22 (A**2)
0.14

REMARK
3
B33 (A**2)
−0.04

REMARK
3
B12 (A**2)
0.00

REMARK
3
B13 (A**2)
−0.02

REMARK
3
B23 (A**2)
0.00

REMARK
3

REMARK
3
ESTIMATED OVERALL COORDINATE ERROR.

REMARK
3
ESU BASED ON R VALUE (A)
0.141

REMARK
3
ESU BASED ON FREE R VALUE (A)
0.133

REMARK
3
ESU BASED ON MAXIMUM LIKELIHOOD (A)
0.082

REMARK
3
ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2)
2.620

REMARK
3

REMARK
3
CORRELATION COEFFICIENTS.

REMARK
3
CORRELATION COEFFICIENT FO-FC
0.948

REMARK
3
CORRELATION COEFFICIENT FO-FC FREE
0.929

REMARK
3

REMARK
3
RMS DEVIATIONS FROM IDEAL VALUES
COUNT
RMS
WEIGHT

REMARK
3
BOND LENGTHS REFINED ATOMS (A)
2310
0.010
0.022

REMARK
3
BOND LENGTHS OTHERS (A)
2097
0.002
0.020

REMARK
3
BOND ANGLES REFINED ATOMS (DEGREES)
3134
1.372
1.981

REMARK
3
BOND ANGLES OTHERS (DEGREES)
4890
0.790
3.000

REMARK
3
TORSION ANGLES, PERIOD 1 (DEGREES)
272
5.281
5.000

REMARK
3
CHIRAL-CENTER RESTRAINTS (A**3)
344
0.076
0.200

REMARK
3
GENERAL PLANES REFINED ATOMS (A)
2489
0.005
0.020

REMARK
3
GENERAL PLANES OTHERS (A)
465
0.002
0.020

REMARK
3
NON-BONDED CONTACTS REFINED ATOMS (A)
475
0.205
0.200

REMARK
3
NON-BONDED CONTACTS OTHERS (A)
2364
0.223
0.200

REMARK
3
NON-BONDED TORSION OTHERS (A)
1222
0.081
0.200

REMARK
3
H-BOND (X...Y) REFINED ATOMS (A)
147
0.162
0.200

REMARK
3
SYMMETRY VDW REFINED ATOMS (A)
21
0.168
0.200

REMARK
3
SYMMETRY VDW OTHERS (A)
86
0.250
0.200

REMARK
3
SYMMETRY H-BOND REFINED ATOMS (A)
14
0.111
0.200

REMARK
3

REMARK
3
ISOTROPIC THERMAL FACTOR RESTRAINTS.
COUNT
RMS
WEIGHT

REMARK
3
MAIN-CHAIN BOND REFINED ATOMS (A**2)
1365
0.818
1.500

REMARK
3
MAIN-CHAIN ANGLE REFINED ATOMS (A**2)
2224
1.568
2.000

REMARK
3
SIDE-CHAIN BOND REFINED ATOMS (A**2)
945
2.206
3.000

REMARK
3
SIDE-CHAIN ANGLE REFINED ATOMS (A**2)
910
3.668
4.500

REMARK
3

REMARK
3
NCS RESTRAINTS STATISTICS

REMARK
3
NUMBER OF NCS GROUPS
NULL

REMARK
3

REMARK
3

REMARK
3
TLS DETAILS

REMARK
3
NUMBER OF TLS GROUPS
1

REMARK
3

REMARK
3
TLS GROUP
1

REMARK
3
NUMBER OF COMPONENTS GROUP
1

REMARK
3
COMPONENTS C SSSEQI TO C SSSEQI

REMARK
3
RESIDUE RANGE A 419 A 691

REMARK
3
ORIGIN FOR THE GROUP (A) 6.9620 1.7680 19.1340

REMARK
3
T TENSOR

REMARK
3
T11
0.0048
T22
0.0352

REMARK
3
T33
0.0580
T12
−0.0119

REMARK
3
T13
−0.0081
T23
0.0084

REMARK
3
L TENSOR

REMARK
3
L11
0.3962
L22
0.3784

REMARK
3
L33
0.2902
L12
−0.1647

REMARK
3
L13
0.0731
L23
0.0592

REMARK
3
S TENSOR

REMARK
3
S11
−0.0145
S12
0.0246
S13
0.0170

REMARK
3
S21
0.0077
S22
0.0410
S23
0.0381

REMARK
3
S31
−0.0159
S32
0.0355
S33
−0.0265

REMARK
3

REMARK
3

REMARK
3
BULK SOLVENT MODELLING.

REMARK
3
METHOD USED
BABINET MODEL WITH MASK

REMARK
3
PARAMETERS FOR MASK CALCULATION

REMARK
3
VDW PROBE RADIUS
1.40

REMARK
3
ION PROBE RADIUS
0.80

REMARK
3
SHRINKAGE RADIUS
0.80

REMARK
3

REMARK
3
OTHER REFINEMENT REMARKS

REMARK
3
HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS

REMARK
3

CRYST1
37.316 46.978 81.109 90.00 92.83 90.00 P 1 21 1

SCALE1
0.026798 0.000000 0.001323 0.00000

SCALE2
0.000000 0.021287 0.000000 0.00000

SCALE3
0.000000 0.000000 0.012344 0.00000

ATOM
1
N
MET
A
419
−17.724
15.274
26.545
1.00
41.92
A
N

ATOM
3
CA
MET
A
419
−16.798
15.014
25.404
1.00
41.87
A
C

ATOM
5
CB
MET
A
419
−17.513
15.303
24.075
1.00
42.37
A
C

ATOM
8
CG
MET
A
419
−18.905
14.692
23.955
1.00
44.21
A
C

ATOM
11
SD
MET
A
419
−18.872
12.884
23.783
1.00
48.64
A
S

ATOM
12
CE
MET
A
419
−19.036
12.354
25.521
1.00
47.82
A
C

ATOM
16
C
MET
A
419
−15.527
15.875
25.505
1.00
40.85
A
C

ATOM
17
O
MET
A
419
−14.857
16.115
24.495
1.00
41.39
A
O

ATOM
20
N
ILE
A
420
−15.200
16.322
26.719
1.00
39.21
A
N

ATOM
22
CA
ILE
A
420
−14.050
17.208
26.982
1.00
37.79
A
C

ATOM
24
CB
ILE
A
420
−12.697
16.519
26.689
1.00
37.82
A
C

ATOM
26
CG1
ILE
A
420
−12.557
15.240
27.512
1.00
38.41
A
C

ATOM
29
CD1
ILE
A
420
−11.209
14.556
27.348
1.00
38.81
A
C

ATOM
33
CG2
ILE
A
420
−11.539
17.494
26.996
1.00
37.64
A
C

ATOM
37
C
ILE
A
420
−14.081
18.526
26.218
1.00
36.12
A
C

ATOM
38
O
ILE
A
420
−13.850
18.561
25.013
1.00
36.25
A
O

ATOM
39
N
ALA
A
421
−14.316
19.613
26.935
1.00
34.13
A
N

ATOM
41
CA
ALA
A
421
−14.207
20.936
26.356
1.00
32.57
A
C

ATOM
43
CB
ALA
A
421
−15.126
21.909
27.076
1.00
32.58
A
C

ATOM
47
C
ALA
A
421
−12.762
21.394
26.457
1.00
31.11
A
C

ATOM
48
O
ALA
A
421
−12.009
20.935
27.315
1.00
30.48
A
O

ATOM
49
N
ARG
A
422
−12.385
22.305
25.572
1.00
29.35
A
N

ATOM
51
CA
ARG
A
422
−11.069
22.917
25.610
1.00
28.21
A
C

ATOM
53
CB
ARG
A
422
−10.957
23.974
24.506
1.00
28.08
A
C

ATOM
56
CG
ARG
A
422
−9.542
24.501
24.279
1.00
27.30
A
C

ATOM
59
CD
ARG
A
422
−9.471
25.640
23.289
1.00
25.94
A
C

ATOM
62
NE
ARG
A
422
−10.069
25.288
22.005
1.00
25.59
A
N

ATOM
64
CZ
ARG
A
422
−9.474
24.572
21.057
1.00
24.52
A
C

ATOM
65
NH1
ARG
A
422
−8.241
24.095
21.225
1.00
22.64
A
N

ATOM
68
NH2
ARG
A
422
−10.124
24.320
19.932
1.00
24.29
A
N

ATOM
71
C
ARG
A
422
−10.773
23.535
26.985
1.00
27.22
A
C

ATOM
72
O
ARG
A
422
−9.632
23.519
27.435
1.00
26.74
A
O

ATOM
73
N
GLU
A
423
−11.808
24.051
27.652
1.00
26.08
A
N

ATOM
75
CA
GLU
A
423
−11.674
24.666
28.979
1.00
25.78
A
C

ATOM
77
CB
GLU
A
423
−13.012
25.237
29.474
1.00
26.29
A
C

ATOM
80
CG
GLU
A
423
−13.662
26.233
28.552
1.00
28.01
A
C

ATOM
83
CD
GLU
A
423
−14.629
25.584
27.583
1.00
29.62
A
C

ATOM
84
OE1
GLU
A
423
−14.183
25.287
26.450
1.00
28.40
A
O

ATOM
85
OE2
GLU
A
423
−15.823
25.382
27.960
1.00
30.82
A
O

ATOM
86
C
GLU
A
423
−11.224
23.675
30.040
1.00
24.55
A
C

ATOM
87
O
GLU
A
423
−10.636
24.070
31.034
1.00
24.25
A
O

ATOM
88
N
ASP
A
424
−11.550
22.401
29.843
1.00
23.65
A
N

ATOM
90
CA
ASP
A
424
−11.151
21.351
30.778
1.00
23.18
A
C

ATOM
92
CB
ASP
A
424
−11.925
20.056
30.503
1.00
23.13
A
C

ATOM
95
CG
ASP
A
424
−13.436
20.219
30.670
1.00
25.17
A
C

ATOM
96
OD1
ASP
A
424
−13.848
21.127
31.427
1.00
26.20
A
O

ATOM
97
OD2
ASP
A
424
−14.276
19.481
30.095
1.00
26.16
A
O

ATOM
98
C
ASP
A
424
−9.639
21.067
30.742
1.00
22.42
A
C

ATOM
99
O
ASP
A
424
−9.148
20.360
31.606
1.00
21.99
A
O

ATOM
100
N
VAL
A
425
−8.920
21.606
29.752
1.00
21.44
A
N

ATOM
102
CA
VAL
A
425
−7.488
21.342
29.592
1.00
21.23
A
C

ATOM
104
CB
VAL
A
425
−7.184
20.639
28.249
1.00
21.09
A
C

ATOM
106
CG1
VAL
A
425
−5.678
20.393
28.092
1.00
21.37
A
C

ATOM
110
CG2
VAL
A
425
−7.963
19.337
28.133
1.00
20.93
A
C

ATOM
114
C
VAL
A
425
−6.715
22.641
29.649
1.00
21.24
A
C

ATOM
115
O
VAL
A
425
−6.957
23.541
28.836
1.00
21.03
A
O

ATOM
116
N
VAL
A
426
−5.824
22.742
30.631
1.00
20.75
A
N

ATOM
118
CA
VAL
A
426
−4.965
23.894
30.830
1.00
21.32
A
C

ATOM
120
CB
VAL
A
426
−4.992
24.367
32.300
1.00
21.30
A
C

ATOM
122
CG1
VAL
A
426
−4.044
25.545
32.514
1.00
22.52
A
C

ATOM
126
CG2
VAL
A
426
−6.415
24.743
32.718
1.00
21.78
A
C

ATOM
130
C
VAL
A
426
−3.522
23.530
30.466
1.00
21.27
A
C

ATOM
131
O
VAL
A
426
−2.931
22.621
31.046
1.00
20.65
A
O

ATOM
132
N
LEU
A
427
−2.960
24.253
29.509
1.00
21.37
A
N

ATOM
134
CA
LEU
A
427
−1.585
24.024
29.079
1.00
21.38
A
C

ATOM
136
CB
LEU
A
427
−1.413
24.387
27.593
1.00
21.39
A
C

ATOM
139
CG
LEU
A
427
−2.428
23.797
26.603
1.00
21.09
A
C

ATOM
141
CD1
LEU
A
427
−2.214
24.341
25.191
1.00
21.00
A
C

ATOM
145
CD2
LEU
A
427
−2.399
22.267
26.592
1.00
20.75
A
C

ATOM
149
C
LEU
A
427
−0.626
24.841
29.931
1.00
22.15
A
C

ATOM
150
O
LEU
A
427
−0.819
26.043
30.102
1.00
21.62
A
O

ATOM
151
N
ASN
A
428
0.413
24.189
30.448
1.00
22.43
A
N

ATOM
153
CA
ASN
A
428
1.416
24.834
31.311
1.00
23.45
A
C

ATOM
155
CB
ASN
A
428
1.710
23.923
32.508
1.00
23.76
A
C

ATOM
158
CG
ASN
A
428
0.458
23.579
33.293
1.00
26.13
A
C

ATOM
159
OD1
ASN
A
428
0.301
22.454
33.774
1.00
30.61
A
O

ATOM
160
ND2
ASN
A
428
−0.455
24.536
33.400
1.00
28.03
A
N

ATOM
163
C
ASN
A
428
2.728
25.192
30.611
1.00
23.29
A
C

ATOM
164
O
ASN
A
428
3.316
26.231
30.907
1.00
23.11
A
O

ATOM
165
N
ARG
A
429
3.217
24.316
29.732
1.00
23.23
A
N

ATOM
167
CA
ARG
A
429
4.438
24.593
28.965
1.00
23.80
A
C

ATOM
169
CB
ARG
A
429
5.678
24.419
29.846
1.00
24.47
A
C

ATOM
172
CG
ARG
A
429
5.945
22.999
30.298
1.00
26.49
A
C

ATOM
175
CD
ARG
A
429
7.254
22.845
31.078
1.00
30.54
A
C

ATOM
178
NE
ARG
A
429
7.866
21.544
30.824
1.00
34.08
A
N

ATOM
180
CZ
ARG
A
429
8.873
21.315
29.980
1.00
35.96
A
C

ATOM
181
NH1
ARG
A
429
9.438
22.308
29.290
1.00
36.94
A
N

ATOM
184
NH2
ARG
A
429
9.330
20.077
29.838
1.00
36.82
A
N

ATOM
187
C
ARG
A
429
4.596
23.731
27.715
1.00
23.63
A
C

ATOM
188
O
ARG
A
429
3.847
22.785
27.506
1.00
22.57
A
O

ATOM
189
N
ILE
A
430
5.592
24.053
26.895
1.00
23.59
A
N

ATOM
191
CA
ILE
A
430
5.901
23.258
25.711
1.00
24.18
A
C

ATOM
193
CB
ILE
A
430
6.382
24.161
24.535
1.00
24.28
A
C

ATOM
195
CG1
ILE
A
430
5.211
25.021
24.046
1.00
24.59
A
C

ATOM
198
CD1
ILE
A
430
5.513
25.900
22.844
1.00
23.92
A
C

ATOM
202
CG2
ILE
A
430
6.967
23.305
23.398
1.00
24.51
A
C

ATOM
206
C
ILE
A
430
6.914
22.169
26.036
1.00
25.15
A
C

ATOM
207
O
ILE
A
430
7.978
22.435
26.594
1.00
25.52
A
O

ATOM
208
N
LEU
A
431
6.555
20.940
25.683
1.00
26.06
A
N

ATOM
210
CA
LEU
A
431
7.351
19.745
25.935
1.00
27.29
A
C

ATOM
212
CB
LEU
A
431
6.411
18.533
25.929
1.00
27.83
A
C

ATOM
215
CG
LEU
A
431
6.627
17.314
26.814
1.00
29.05
A
C

ATOM
217
CD1
LEU
A
431
7.002
17.675
28.242
1.00
29.90
A
C

ATOM
221
CD2
LEU
A
431
5.346
16.505
26.789
1.00
29.38
A
C

ATOM
225
C
LEU
A
431
8.423
19.572
24.863
1.00
28.18
A
C

ATOM
226
O
LEU
A
431
9.582
19.243
25.149
1.00
28.38
A
O

ATOM
227
N
GLY
A
432
8.024
19.793
23.620
1.00
28.92
A
N

ATOM
229
CA
GLY
A
432
8.932
19.691
22.500
1.00
29.66
A
C

ATOM
232
C
GLY
A
432
8.267
19.963
21.166
1.00
30.32
A
C

ATOM
233
O
GLY
A
432
7.040
20.023
21.065
1.00
29.86
A
O

ATOM
234
N
GLU
A
433
9.096
20.144
20.144
1.00
31.32
A
N

ATOM
236
CA
GLU
A
433
8.636
20.260
18.767
1.00
32.42
A
C

ATOM
238
CB
GLU
A
433
9.600
21.120
17.946
1.00
33.03
A
C

ATOM
241
CG
GLU
A
433
9.426
21.056
16.433
1.00
35.97
A
C

ATOM
244
CD
GLU
A
433
8.136
21.696
15.966
1.00
39.52
A
C

ATOM
245
OE1
GLU
A
433
7.078
21.062
16.142
1.00
41.45
A
O

ATOM
246
OE2
GLU
A
433
8.178
22.828
15.417
1.00
43.45
A
O

ATOM
247
C
GLU
A
433
8.559
18.853
18.200
1.00
32.62
A
C

ATOM
248
O
GLU
A
433
9.584
18.218
17.959
1.00
33.07
A
O

ATOM
249
N
GLY
A
434
7.341
18.364
18.027
1.00
32.46
A
N

ATOM
251
CA
GLY
A
434
7.110
17.080
17.411
1.00
32.53
A
C

ATOM
254
C
GLY
A
434
6.926
17.141
15.904
1.00
32.66
A
C

ATOM
255
O
GLY
A
434
7.033
18.193
15.266
1.00
32.19
A
O

ATOM
256
N
PHE
A
435
6.619
15.974
15.353
1.00
32.83
A
N

ATOM
258
CA
PHE
A
435
6.413
15.765
13.926
1.00
32.68
A
C

ATOM
260
CB
PHE
A
435
6.032
14.294
13.703
1.00
33.30
A
C

ATOM
263
CG
PHE
A
435
6.016
13.890
12.267
1.00
35.29
A
C

ATOM
264
CD1
PHE
A
435
7.202
13.628
11.601
1.00
37.64
A
C

ATOM
266
CE1
PHE
A
435
7.197
13.260
10.263
1.00
38.62
A
C

ATOM
268
CZ
PHE
A
435
6.000
13.162
9.582
1.00
38.93
A
C

ATOM
270
CE2
PHE
A
435
4.807
13.434
10.236
1.00
38.98
A
C

ATOM
272
CD2
PHE
A
435
4.821
13.794
11.575
1.00
36.99
A
C

ATOM
274
C
PHE
A
435
5.330
16.662
13.319
1.00
31.77
A
C

ATOM
275
O
PHE
A
435
5.533
17.269
12.262
1.00
31.44
A
O

ATOM
276
N
PHE
A
436
4.178
16.734
13.982
1.00
30.64
A
N

ATOM
278
CA
PHE
A
436
3.030
17.476
13.465
1.00
29.83
A
C

ATOM
280
CB
PHE
A
436
1.716
16.792
13.880
1.00
30.65
A
C

ATOM
283
CG
PHE
A
436
1.425
15.511
13.114
1.00
33.59
A
C

ATOM
284
CD1
PHE
A
436
0.993
15.554
11.791
1.00
36.89
A
C

ATOM
286
CE1
PHE
A
436
0.731
14.368
11.076
1.00
38.35
A
C

ATOM
288
CZ
PHE
A
436
0.917
13.136
11.692
1.00
38.06
A
C

ATOM
290
CE2
PHE
A
436
1.354
13.086
13.006
1.00
37.74
A
C

ATOM
292
CD2
PHE
A
436
1.608
14.268
13.709
1.00
36.81
A
C

ATOM
294
C
PHE
A
436
3.036
18.949
13.904
1.00
27.92
A
C

ATOM
295
O
PHE
A
436
2.435
19.783
13.242
1.00
26.90
A
O

ATOM
296
N
GLY
A
437
3.713
19.242
15.021
1.00
25.85
A
N

ATOM
298
CA
GLY
A
437
3.773
20.582
15.598
1.00
24.35
A
C

ATOM
301
C
GLY
A
437
4.152
20.555
17.076
1.00
23.03
A
C

ATOM
302
O
GLY
A
437
4.635
19.549
17.596
1.00
22.52
A
O

ATOM
303
N
GLU
A
438
3.912
21.660
17.774
1.00
21.56
A
N

ATOM
305
CA
GLU
A
438
4.295
21.761
19.176
1.00
20.35
A
C

ATOM
307
CB
GLU
A
438
4.114
23.191
19.694
1.00
20.82
A
C

ATOM
310
CG
GLU
A
438
4.921
24.235
18.922
1.00
23.31
A
C

ATOM
313
CD
GLU
A
438
6.325
24.443
19.459
1.00
26.75
A
C

ATOM
314
OE1
GLU
A
438
6.960
23.454
19.896
1.00
24.49
A
O

ATOM
315
OE2
GLU
A
438
6.792
25.611
19.446
1.00
29.56
A
O

ATOM
316
C
GLU
A
438
3.473
20.781
20.016
1.00
18.49
A
C

ATOM
317
O
GLU
A
438
2.306
20.552
19.744
1.00
17.45
A
O

ATOM
318
N
VAL
A
439
4.124
20.199
21.017
1.00
17.29
A
N

ATOM
320
CA
VAL
A
439
3.498
19.315
21.986
1.00
16.28
A
C

ATOM
322
CB
VAL
A
439
4.183
17.933
22.024
1.00
16.57
A
C

ATOM
324
CG1
VAL
A
439
3.516
17.038
23.065
1.00
17.25
A
C

ATOM
328
CG2
VAL
A
439
4.141
17.301
20.643
1.00
16.55
A
C

ATOM
332
C
VAL
A
439
3.623
19.974
23.350
1.00
15.68
A
C

ATOM
333
O
VAL
A
439
4.705
20.380
23.732
1.00
14.39
A
O

ATOM
334
N
TYR
A
440
2.508
20.084
24.068
1.00
14.79
A
N

ATOM
336
CA
TYR
A
440
2.447
20.789
25.345
1.00
14.71
A
C

ATOM
338
CB
TYR
A
440
1.269
21.749
25.334
1.00
14.65
A
C

ATOM
341
CG
TYR
A
440
1.348
22.842
24.301
1.00
15.25
A
C

ATOM
342
CD1
TYR
A
440
1.809
24.110
24.639
1.00
16.36
A
C

ATOM
344
CE1
TYR
A
440
1.860
25.135
23.691
1.00
16.17
A
C

ATOM
346
CZ
TYR
A
440
1.436
24.895
22.395
1.00
18.28
A
C

ATOM
347
OH
TYR
A
440
1.490
25.905
21.453
1.00
20.25
A
O

ATOM
349
CE2
TYR
A
440
0.967
23.644
22.038
1.00
16.17
A
C

ATOM
351
CD2
TYR
A
440
0.916
22.630
22.994
1.00
14.61
A
C

ATOM
353
C
TYR
A
440
2.228
19.817
26.479
1.00
15.34
A
C

ATOM
354
O
TYR
A
440
1.608
18.765
26.270
1.00
15.00
A
O

ATOM
355
N
GLU
A
441
2.723
20.168
27.669
1.00
15.04
A
N

ATOM
357
CA
GLU
A
441
2.340
19.514
28.921
1.00
16.43
A
C

ATOM
359
CB
GLU
A
441
3.513
19.470
29.916
1.00
17.43
A
C

ATOM
362
CG
GLU
A
441
3.244
18.575
31.117
1.00
21.96
A
C

ATOM
365
CD
GLU
A
441
4.331
18.631
32.173
1.00
28.06
A
C

ATOM
366
OE1
GLU
A
441
5.533
18.478
31.828
1.00
31.85
A
O

ATOM
367
OE2
GLU
A
441
3.975
18.829
33.361
1.00
32.28
A
O

ATOM
368
C
GLU
A
441
1.196
20.317
29.514
1.00
15.91
A
C

ATOM
369
O
GLU
A
441
1.205
21.549
29.457
1.00
15.73
A
O

ATOM
370
N
GLY
A
442
0.214
19.627
30.074
1.00
15.38
A
N

ATOM
372
CA
GLY
A
442
−0.938
20.279
30.679
1.00
15.56
A
C

ATOM
375
C
GLY
A
442
−1.686
19.408
31.671
1.00
15.46
A
C

ATOM
376
O
GLY
A
442
−1.266
18.295
31.998
1.00
14.91
A
O

ATOM
377
N
VAL
A
443
−2.799
19.937
32.159
1.00
15.90
A
N

ATOM
379
CA
VAL
A
443
−3.655
19.250
33.120
1.00
15.95
A
C

ATOM
381
CB
VAL
A
443
−3.585
19.926
34.515
1.00
15.99
A
C

ATOM
383
CG1
VAL
A
443
−4.535
19.256
35.486
1.00
16.92
A
C

ATOM
387
CG2
VAL
A
443
−2.159
19.901
35.054
1.00
16.66
A
C

ATOM
391
C
VAL
A
443
−5.088
19.235
32.606
1.00
16.11
A
C

ATOM
392
O
VAL
A
443
−5.677
20.280
32.328
1.00
16.39
A
O

ATOM
393
N
TYR
A
444
−5.645
18.039
32.474
1.00
16.07
A
N

ATOM
395
CA
TYR
A
444
−7.053
17.833
32.189
1.00
16.30
A
C

ATOM
397
CB
TYR
A
444
−7.210
16.696
31.179
1.00
16.55
A
C

ATOM
400
CG
TYR
A
444
−8.608
16.106
31.085
1.00
16.49
A
C

ATOM
401
CD1
TYR
A
444
−9.735
16.925
30.992
1.00
17.40
A
C

ATOM
403
CE1
TYR
A
444
−11.002
16.376
30.907
1.00
18.98
A
C

ATOM
405
CZ
TYR
A
444
−11.159
15.013
30.900
1.00
19.67
A
C

ATOM
406
OH
TYR
A
444
−12.417
14.454
30.818
1.00
22.12
A
O

ATOM
408
CE2
TYR
A
444
−10.066
14.189
30.992
1.00
18.71
A
C

ATOM
410
CD2
TYR
A
444
−8.801
14.737
31.070
1.00
18.30
A
C

ATOM
412
C
TYR
A
444
−7.828
17.530
33.495
1.00
16.91
A
C

ATOM
413
O
TYR
A
444
−7.500
16.593
34.223
1.00
16.06
A
O

ATOM
414
N
THR
A
445
−8.845
18.338
33.779
1.00
17.53
A
N

ATOM
416
CA
THR
A
445
−9.703
18.146
34.944
1.00
18.31
A
C

ATOM
418
CB
THR
A
445
−9.911
19.475
35.684
1.00
18.17
A
C

ATOM
420
OG1
THR
A
445
−8.651
20.045
36.030
1.00
19.23
A
O

ATOM
422
CG2
THR
A
445
−10.578
19.262
37.044
1.00
18.29
A
C

ATOM
426
C
THR
A
445
−11.032
17.632
34.430
1.00
19.18
A
C

ATOM
427
O
THR
A
445
−11.702
18.345
33.694
1.00
19.17
A
O

ATOM
428
N
ASN
A
446
−11.402
16.403
34.791
1.00
19.93
A
N

ATOM
430
CA
ASN
A
446
−12.665
15.825
34.351
1.00
21.09
A
C

ATOM
432
CB
ASN
A
446
−12.617
14.266
34.318
1.00
21.05
A
C

ATOM
435
CG
ASN
A
446
−12.502
13.602
35.704
1.00
21.28
A
C

ATOM
436
OD1
ASN
A
446
−12.158
12.407
35.796
1.00
22.39
A
O

ATOM
437
ND2
ASN
A
446
−12.778
14.345
36.766
1.00
18.07
A
N

ATOM
440
C
ASN
A
446
−13.831
16.414
35.163
1.00
22.07
A
C

ATOM
441
O
ASN
A
446
−13.646
17.396
35.907
1.00
22.06
A
O

ATOM
442
N
HIS
A
447
−15.025
15.861
34.999
1.00
23.22
A
N

ATOM
444
CA
HIS
A
447
−16.215
16.446
35.621
1.00
24.56
A
C

ATOM
446
CB
HIS
A
447
−17.479
16.009
34.878
1.00
25.52
A
C

ATOM
449
CG
HIS
A
447
−17.560
16.535
33.474
1.00
28.90
A
C

ATOM
450
ND1
HIS
A
447
−17.485
17.879
33.177
1.00
32.01
A
N

ATOM
452
CE1
HIS
A
447
−17.581
18.047
31.869
1.00
32.90
A
C

ATOM
454
NE2
HIS
A
447
−17.712
16.859
31.306
1.00
33.63
A
N

ATOM
456
CD2
HIS
A
447
−17.703
15.896
32.289
1.00
32.36
A
C

ATOM
458
C
HIS
A
447
−16.323
16.121
37.113
1.00
24.17
A
C

ATOM
459
O
HIS
A
447
−17.141
16.715
37.819
1.00
24.60
A
O

ATOM
460
N
LYS
A
448
−15.513
15.168
37.575
1.00
23.56
A
N

ATOM
462
CA
LYS
A
448
−15.440
14.802
38.994
1.00
23.13
A
C

ATOM
464
CB
LYS
A
448
−15.188
13.302
39.137
1.00
23.02
A
C

ATOM
467
CG
LYS
A
448
−16.354
12.461
38.679
1.00
23.56
A
C

ATOM
470
CD
LYS
A
448
−15.916
11.043
38.364
1.00
24.68
A
C

ATOM
473
CE
LYS
A
448
−17.090
10.180
37.907
1.00
25.53
A
C

ATOM
476
NZ
LYS
A
448
−16.689
8.742
37.931
1.00
23.92
A
N

ATOM
480
C
LYS
A
448
−14.353
15.561
39.758
1.00
22.72
A
C

ATOM
481
O
LYS
A
448
−14.197
15.369
40.974
1.00
23.18
A
O

ATOM
482
N
GLY
A
449
−13.606
16.401
39.048
1.00
21.47
A
N

ATOM
484
CA
GLY
A
449
−12.580
17.234
39.648
1.00
21.53
A
C

ATOM
487
C
GLY
A
449
−11.237
16.542
39.729
1.00
21.19
A
C

ATOM
488
O
GLY
A
449
−10.319
17.047
40.366
1.00
20.74
A
O

ATOM
489
N
GLU
A
450
−11.127
15.386
39.080
1.00
20.98
A
N

ATOM
491
CA
GLU
A
450
−9.879
14.630
39.054
1.00
21.35
A
C

ATOM
493
CB
GLU
A
450
−10.150
13.172
38.691
1.00
21.63
A
C

ATOM
496
CG
GLU
A
450
−11.186
12.486
39.565
1.00
23.33
A
C

ATOM
499
CD
GLU
A
450
−11.347
11.024
39.214
1.00
26.08
A
C

ATOM
500
OE1
GLU
A
450
−10.821
10.178
39.963
1.00
26.94
A
O

ATOM
501
OE2
GLU
A
450
−12.024
10.726
38.201
1.00
28.51
A
O

ATOM
502
C
GLU
A
450
−8.955
15.232
38.019
1.00
21.24
A
C

ATOM
503
O
GLU
A
450
−9.376
15.478
36.902
1.00
20.28
A
O

ATOM
504
N
LYS
A
451
−7.691
15.436
38.388
1.00
21.76
A
N

ATOM
506
CA
LYS
A
451
−6.694
16.059
37.507
1.00
21.92
A
C

ATOM
508
CB
LYS
A
451
−5.963
17.166
38.254
1.00
22.51
A
C

ATOM
511
CG
LYS
A
451
−6.919
18.230
38.784
1.00
23.99
A
C

ATOM
514
CD
LYS
A
451
−6.239
19.546
39.068
1.00
26.30
A
C

ATOM
517
CE
LYS
A
451
−7.250
20.582
39.558
1.00
27.02
A
C

ATOM
520
NZ
LYS
A
451
−7.947
21.286
38.459
1.00
26.84
A
N

ATOM
524
C
LYS
A
451
−5.707
15.026
36.956
1.00
21.70
A
C

ATOM
525
O
LYS
A
451
−5.111
14.249
37.707
1.00
22.12
A
O

ATOM
526
N
ILE
A
452
−5.586
15.005
35.633
1.00
20.88
A
N

ATOM
528
CA
ILE
A
452
−4.729
14.074
34.923
1.00
20.89
A
C

ATOM
530
CB
ILE
A
452
−5.587
13.104
34.051
1.00
21.84
A
C

ATOM
532
CG1
ILE
A
452
−4.773
11.937
33.512
1.00
24.27
A
C

ATOM
535
CD1
ILE
A
452
−4.557
10.839
34.539
1.00
27.03
A
C

ATOM
539
CG2
ILE
A
452
−6.222
13.783
32.894
1.00
23.92
A
C

ATOM
543
C
ILE
A
452
−3.743
14.883
34.086
1.00
19.23
A
C

ATOM
544
O
ILE
A
452
−4.127
15.801
33.366
1.00
17.19
A
O

ATOM
545
N
ASN
A
453
−2.468
14.561
34.227
1.00
18.03
A
N

ATOM
547
CA
ASN
A
453
−1.427
15.173
33.421
1.00
16.96
A
C

ATOM
549
CB
ASN
A
453
−0.039
14.893
34.019
1.00
17.63
A
C

ATOM
552
CG
ASN
A
453
0.144
15.546
35.375
1.00
19.82
A
C

ATOM
553
OD1
ASN
A
453
−0.283
16.675
35.581
1.00
20.59
A
O

ATOM
554
ND2
ASN
A
453
0.782
14.835
36.307
1.00
22.47
A
N

ATOM
557
C
ASN
A
453
−1.537
14.640
32.002
1.00
15.39
A
C

ATOM
558
O
ASN
A
453
−1.741
13.432
31.792
1.00
13.98
A
O

ATOM
559
N
VAL
A
454
−1.442
15.553
31.040
1.00
13.24
A
N

ATOM
561
CA
VAL
A
454
−1.609
15.230
29.630
1.00
12.28
A
C

ATOM
563
CB
VAL
A
454
−3.001
15.671
29.107
1.00
11.15
A
C

ATOM
565
CG1
VAL
A
454
−4.107
14.882
29.798
1.00
11.44
A
C

ATOM
569
CG2
VAL
A
454
−3.210
17.193
29.273
1.00
10.74
A
C

ATOM
573
C
VAL
A
454
−0.515
15.843
28.752
1.00
12.12
A
C

ATOM
574
O
VAL
A
454
0.128
16.843
29.123
1.00
11.68
A
O

ATOM
575
N
ALA
A
455
−0.276
15.196
27.615
1.00
11.65
A
N

ATOM
577
CA
ALA
A
455
0.496
15.770
26.521
1.00
11.60
A
C

ATOM
579
CB
ALA
A
455
1.493
14.785
25.979
1.00
12.08
A
C

ATOM
583
C
ALA
A
455
−0.511
16.142
25.435
1.00
12.46
A
C

ATOM
584
O
ALA
A
455
−1.331
15.327
25.055
1.00
12.88
A
O

ATOM
585
N
VAL
A
456
−0.459
17.384
24.968
1.00
11.82
A
N

ATOM
587
CA
VAL
A
456
−1.368
17.858
23.960
1.00
12.46
A
C

ATOM
589
CB
VAL
A
456
−2.073
19.125
24.456
1.00
12.62
A
C

ATOM
591
CG1
VAL
A
456
−2.956
19.704
23.364
1.00
13.07
A
C

ATOM
595
CG2
VAL
A
456
−2.883
18.786
25.679
1.00
12.74
A
C

ATOM
599
C
VAL
A
456
−0.622
18.148
22.668
1.00
13.13
A
C

ATOM
600
O
VAL
A
456
0.252
19.006
22.631
1.00
12.69
A
O

ATOM
601
N
LYS
A
457
−0.958
17.415
21.616
1.00
13.43
A
N

ATOM
603
CA
LYS
A
457
−0.324
17.577
20.322
1.00
14.66
A
C

ATOM
605
CB
LYS
A
457
−0.214
16.220
19.615
1.00
15.55
A
C

ATOM
608
CG
LYS
A
457
0.694
15.217
20.350
1.00
18.42
A
C

ATOM
611
CD
LYS
A
457
0.840
13.874
19.626
1.00
22.96
A
C

ATOM
614
CE
LYS
A
457
1.221
14.008
18.151
1.00
26.16
A
C

ATOM
617
NZ
LYS
A
457
1.738
12.702
17.608
1.00
29.52
A
N

ATOM
621
C
LYS
A
457
−1.123
18.569
19.480
1.00
14.79
A
C

ATOM
622
O
LYS
A
457
−2.350
18.553
19.483
1.00
14.94
A
O

ATOM
623
N
THR
A
458
−0.421
19.452
18.787
1.00
16.01
A
N

ATOM
625
CA
THR
A
458
−1.056
20.426
17.902
1.00
17.14
A
C

ATOM
627
CB
THR
A
458
−0.974
21.856
18.470
1.00
17.23
A
C

ATOM
629
OG1
THR
A
458
0.390
22.295
18.492
1.00
16.75
A
O

ATOM
631
CG2
THR
A
458
−1.437
21.907
19.927
1.00
18.01
A
C

ATOM
635
C
THR
A
458
−0.380
20.398
16.541
1.00
18.40
A
C

ATOM
636
O
THR
A
458
0.705
19.846
16.397
1.00
18.01
A
O

ATOM
637
N
CYS
A
459
−1.032
21.017
15.561
1.00
20.44
A
N

ATOM
639
CA
CYS
A
459
−0.512
21.123
14.195
1.00
22.30
A
C

ATOM
641
CB
CYS
A
459
−1.643
20.944
13.189
1.00
22.75
A
C

ATOM
644
SG
CYS
A
459
−2.097
19.219
12.971
1.00
27.79
A
S

ATOM
645
C
CYS
A
459
0.174
22.470
13.959
1.00
22.93
A
C

ATOM
646
O
CYS
A
459
−0.344
23.509
14.347
1.00
22.16
A
O

ATOM
647
N
LYS
A
460
1.347
22.426
13.337
1.00
24.00
A
N

ATOM
649
CA
LYS
A
460
2.082
23.624
12.970
1.00
25.15
A
C

ATOM
651
CB
LYS
A
460
3.487
23.276
12.461
1.00
25.42
A
C

ATOM
654
CG
LYS
A
460
3.540
22.407
11.195
1.00
27.60
A
C

ATOM
657
CD
LYS
A
460
4.982
22.089
10.797
1.00
31.10
A
C

ATOM
660
CE
LYS
A
460
5.641
21.091
11.756
1.00
33.59
A
C

ATOM
663
NZ
LYS
A
460
6.879
20.456
11.191
1.00
35.01
A
N

ATOM
667
C
LYS
A
460
1.301
24.390
11.917
1.00
25.65
A
C

ATOM
668
O
LYS
A
460
0.444
23.818
11.226
1.00
25.83
A
O

ATOM
669
N
LYS
A
461
1.574
25.687
11.808
1.00
25.80
A
N

ATOM
671
CA
LYS
A
461
0.826
26.538
10.882
1.00
26.62
A
C

ATOM
673
CB
LYS
A
461
1.252
28.006
11.008
1.00
26.88
A
C

ATOM
676
CG
LYS
A
461
2.713
28.253
10.821
1.00
27.10
A
C

ATOM
679
CD
LYS
A
461
2.998
29.749
10.885
1.00
26.75
A
C

ATOM
682
CE
LYS
A
461
4.299
30.069
10.215
1.00
26.14
A
C

ATOM
685
NZ
LYS
A
461
4.520
31.513
10.213
1.00
24.09
A
N

ATOM
689
C
LYS
A
461
0.920
26.065
9.424
1.00
26.93
A
C

ATOM
690
O
LYS
A
461
−0.036
26.221
8.675
1.00
27.53
A
O

ATOM
691
N
ASP
A
462
2.046
25.462
9.044
1.00
27.62
A
N

ATOM
693
CA
ASP
A
462
2.260
24.961
7.678
1.00
28.08
A
C

ATOM
695
CB
ASP
A
462
3.747
25.062
7.309
1.00
28.77
A
C

ATOM
698
CG
ASP
A
462
4.025
24.701
5.853
1.00
30.67
A
C

ATOM
699
OD1
ASP
A
462
3.273
25.156
4.964
1.00
33.53
A
O

ATOM
700
OD2
ASP
A
462
4.973
23.959
5.506
1.00
34.82
A
O

ATOM
701
C
ASP
A
462
1.772
23.509
7.560
1.00
27.68
A
C

ATOM
702
O
ASP
A
462
2.542
22.601
7.211
1.00
28.33
A
O

ATOM
703
N
CYS
A
463
0.500
23.302
7.891
1.00
26.54
A
N

ATOM
705
CA
CYS
A
463
−0.123
21.991
7.824
1.00
25.64
A
C

ATOM
707
CB
CYS
A
463
−0.529
21.522
9.217
1.00
25.87
A
C

ATOM
710
SG
CYS
A
463
−1.141
19.833
9.252
1.00
28.94
A
S

ATOM
711
C
CYS
A
463
−1.350
22.104
6.918
1.00
23.92
A
C

ATOM
712
O
CYS
A
463
−2.319
22.772
7.251
1.00
23.05
A
O

ATOM
713
N
THR
A
464
−1.277
21.480
5.751
1.00
22.41
A
N

ATOM
715
CA
THR
A
464
−2.385
21.500
4.800
1.00
21.51
A
C

ATOM
717
CB
THR
A
464
−1.947
20.928
3.435
1.00
21.47
A
C

ATOM
719
OG1
THR
A
464
−1.405
19.607
3.600
1.00
19.22
A
O

ATOM
721
CG2
THR
A
464
−0.804
21.743
2.823
1.00
21.55
A
C

ATOM
725
C
THR
A
464
−3.571
20.689
5.316
1.00
21.41
A
C

ATOM
726
O
THR
A
464
−3.414
19.755
6.111
1.00
19.82
A
O

ATOM
727
N
LEU
A
465
−4.758
21.040
4.832
1.00
21.68
A
N

ATOM
729
CA
LEU
A
465
−5.969
20.261
5.090
1.00
22.10
A
C

ATOM
731
CB
LEU
A
465
−7.165
20.906
4.378
1.00
22.26
A
C

ATOM
734
CG
LEU
A
465
−7.631
22.229
4.986
1.00
22.45
A
C

ATOM
736
CD1
LEU
A
465
−8.763
22.808
4.170
1.00
24.00
A
C

ATOM
740
CD2
LEU
A
465
−8.079
22.028
6.446
1.00
23.54
A
C

ATOM
744
C
LEU
A
465
−5.798
18.821
4.624
1.00
22.80
A
C

ATOM
745
O
LEU
A
465
−6.322
17.892
5.234
1.00
22.69
A
O

ATOM
746
N
ASP
A
466
−5.073
18.665
3.524
1.00
23.58
A
N

ATOM
748
CA
ASP
A
466
−4.666
17.367
3.004
1.00
25.03
A
C

ATOM
750
CB
ASP
A
466
−3.709
17.593
1.820
1.00
25.18
A
C

ATOM
753
CG
ASP
A
466
−3.414
16.332
1.038
1.00
27.16
A
C

ATOM
754
OD1
ASP
A
466
−3.623
15.216
1.570
1.00
26.35
A
O

ATOM
755
OD2
ASP
A
466
−2.966
16.376
−0.139
1.00
29.99
A
O

ATOM
756
C
ASP
A
466
−3.993
16.539
4.101
1.00
25.88
A
C

ATOM
757
O
ASP
A
466
−4.460
15.448
4.445
1.00
25.28
A
O

ATOM
758
N
ASN
A
467
−2.900
17.063
4.656
1.00
27.10
A
N

ATOM
760
CA
ASN
A
467
−2.161
16.350
5.702
1.00
28.05
A
C

ATOM
762
CB
ASN
A
467
−0.772
16.985
5.916
1.00
28.48
A
C

ATOM
765
CG
ASN
A
467
0.134
16.866
4.684
1.00
29.52
A
C

ATOM
766
OD1
ASN
A
467
0.992
17.713
4.447
1.00
31.12
A
O

ATOM
767
ND2
ASN
A
467
−0.059
15.816
3.901
1.00
33.05
A
N

ATOM
770
C
ASN
A
467
−2.920
16.263
7.037
1.00
28.75
A
C

ATOM
771
O
ASN
A
467
−2.724
15.322
7.806
1.00
28.72
A
O

ATOM
772
N
LYS
A
468
−3.794
17.232
7.296
1.00
29.65
A
N

ATOM
774
CA
LYS
A
468
−4.560
17.300
8.544
1.00
30.66
A
C

ATOM
776
CB
LYS
A
468
−5.273
18.642
8.639
1.00
30.86
A
C

ATOM
779
CG
LYS
A
468
−5.702
19.038
10.031
1.00
32.87
A
C

ATOM
782
CD
LYS
A
468
−4.950
20.278
10.513
1.00
35.25
A
C

ATOM
785
CE
LYS
A
468
−5.304
21.521
9.671
1.00
36.51
A
C

ATOM
788
NZ
LYS
A
468
−4.860
22.805
10.300
1.00
37.11
A
N

ATOM
792
C
LYS
A
468
−5.604
16.186
8.644
1.00
31.56
A
C

ATOM
793
O
LYS
A
468
−5.905
15.716
9.740
1.00
31.30
A
O

ATOM
794
N
GLU
A
469
−6.159
15.779
7.504
1.00
32.55
A
N

ATOM
796
CA
GLU
A
469
−7.144
14.694
7.473
1.00
33.52
A
C

ATOM
798
CB
GLU
A
469
−7.866
14.646
6.117
1.00
33.78
A
C

ATOM
801
CG
GLU
A
469
−8.835
13.476
5.924
1.00
34.57
A
C

ATOM
804
CD
GLU
A
469
−9.939
13.398
6.975
1.00
36.41
A
C

ATOM
805
OE1
GLU
A
469
−10.241
14.421
7.638
1.00
36.96
A
O

ATOM
806
OE2
GLU
A
469
−10.527
12.301
7.131
1.00
38.63
A
O

ATOM
807
C
GLU
A
469
−6.471
13.355
7.789
1.00
34.36
A
C

ATOM
808
O
GLU
A
469
−7.067
12.508
8.436
1.00
33.99
A
O

ATOM
809
N
LYS
A
470
−5.226
13.185
7.344
1.00
35.36
A
N

ATOM
811
CA
LYS
A
470
−4.441
11.983
7.651
1.00
36.27
A
C

ATOM
813
CB
LYS
A
470
−3.087
12.022
6.942
1.00
36.53
A
C

ATOM
816
CG
LYS
A
470
−3.155
12.204
5.444
1.00
37.48
A
C

ATOM
819
CD
LYS
A
470
−1.766
12.076
4.833
1.00
38.99
A
C

ATOM
822
CE
LYS
A
470
−1.822
11.889
3.334
1.00
39.11
A
C

ATOM
825
NZ
LYS
A
470
−0.566
11.286
2.828
1.00
39.24
A
N

ATOM
829
C
LYS
A
470
−4.184
11.839
9.144
1.00
36.64
A
C

ATOM
830
O
LYS
A
470
−4.342
10.758
9.709
1.00
37.23
A
O

ATOM
831
N
PHE
A
471
−3.773
12.938
9.763
1.00
36.96
A
N

ATOM
833
CA
PHE
A
471
−3.512
13.023
11.201
1.00
37.25
A
C

ATOM
835
CB
PHE
A
471
−2.955
14.420
11.517
1.00
37.75
A
C

ATOM
838
CG
PHE
A
471
−2.489
14.615
12.947
1.00
40.27
A
C

ATOM
839
CD1
PHE
A
471
−1.834
13.605
13.650
1.00
42.26
A
C

ATOM
841
CE1
PHE
A
471
−1.407
13.815
14.958
1.00
43.12
A
C

ATOM
843
CZ
PHE
A
471
−1.611
15.056
15.572
1.00
43.43
A
C

ATOM
845
CE2
PHE
A
471
−2.243
16.066
14.883
1.00
42.92
A
C

ATOM
847
CD2
PHE
A
471
−2.680
15.847
13.578
1.00
42.50
A
C

ATOM
849
C
PHE
A
471
−4.770
12.764
12.031
1.00
36.80
A
C

ATOM
850
O
PHE
A
471
−4.725
12.035
13.017
1.00
36.85
A
O

ATOM
851
N
MET
A
472
−5.885
13.369
11.630
1.00
36.07
A
N

ATOM
853
CA
MET
A
472
−7.154
13.199
12.338
1.00
36.08
A
C

ATOM
855
CB
MET
A
472
−8.246
14.103
11.761
1.00
36.21
A
C

ATOM
858
CG
MET
A
472
−8.083
15.565
12.091
1.00
38.47
A
C

ATOM
861
SD
MET
A
472
−7.642
15.859
13.819
1.00
42.21
A
S

ATOM
862
CE
MET
A
472
−5.860
15.966
13.721
1.00
42.25
A
C

ATOM
866
C
MET
A
472
−7.626
11.758
12.262
1.00
35.10
A
C

ATOM
867
O
MET
A
472
−8.011
11.176
13.278
1.00
34.68
A
O

ATOM
868
N
SER
A
473
−7.599
11.200
11.056
1.00
34.38
A
N

ATOM
870
CA
SER
A
473
−8.067
9.836
10.838
1.00
34.10
A
C

ATOM
872
CB
SER
A
473
−8.111
9.481
9.341
1.00
34.17
A
C

ATOM
875
OG
SER
A
473
−6.876
9.725
8.700
1.00
35.90
A
O

ATOM
877
C
SER
A
473
−7.194
8.870
11.619
1.00
33.23
A
C

ATOM
878
O
SER
A
473
−7.681
7.877
12.146
1.00
33.23
A
O

ATOM
879
N
GLU
A
474
−5.909
9.196
11.728
1.00
32.29
A
N

ATOM
881
CA
GLU
A
474
−4.957
8.405
12.504
1.00
31.53
A
C

ATOM
883
CB
GLU
A
474
−3.532
8.889
12.235
1.00
32.06
A
C

ATOM
886
CG
GLU
A
474
−2.462
8.083
12.940
1.00
35.27
A
C

ATOM
889
CD
GLU
A
474
−1.059
8.482
12.520
1.00
38.82
A
C

ATOM
890
OE1
GLU
A
474
−0.125
7.684
12.765
1.00
41.03
A
O

ATOM
891
OE2
GLU
A
474
−0.896
9.590
11.945
1.00
41.72
A
O

ATOM
892
C
GLU
A
474
−5.252
8.474
13.999
1.00
29.52
A
C

ATOM
893
O
GLU
A
474
−5.194
7.463
14.689
1.00
28.59
A
O

ATOM
894
N
ALA
A
475
−5.583
9.664
14.486
1.00
27.61
A
N

ATOM
896
CA
ALA
A
475
−5.852
9.876
15.908
1.00
26.39
A
C

ATOM
898
CB
ALA
A
475
−5.991
11.361
16.196
1.00
26.28
A
C

ATOM
902
C
ALA
A
475
−7.117
9.144
16.379
1.00
25.41
A
C

ATOM
903
O
ALA
A
475
−7.186
8.717
17.521
1.00
24.68
A
O

ATOM
904
N
VAL
A
476
−8.111
9.024
15.501
1.00
24.57
A
N

ATOM
906
CA
VAL
A
476
−9.364
8.342
15.837
1.00
24.02
A
C

ATOM
908
CB
VAL
A
476
−10.457
8.593
14.764
1.00
24.14
A
C

ATOM
910
CG1
VAL
A
476
−11.668
7.695
14.975
1.00
24.34
A
C

ATOM
914
CG2
VAL
A
476
−10.910
10.051
14.786
1.00
24.76
A
C

ATOM
918
C
VAL
A
476
−9.096
6.840
16.010
1.00
23.50
A
C

ATOM
919
O
VAL
A
476
−9.673
6.207
16.889
1.00
22.85
A
O

ATOM
920
N
ILE
A
477
−8.191
6.283
15.197
1.00
23.32
A
N

ATOM
922
CA
ILE
A
477
−7.794
4.880
15.366
1.00
23.29
A
C

ATOM
924
CB
ILE
A
477
−6.857
4.392
14.232
1.00
23.54
A
C

ATOM
926
CG1
ILE
A
477
−7.579
4.420
12.883
1.00
25.55
A
C

ATOM
929
CD1
ILE
A
477
−6.693
4.070
11.676
1.00
26.07
A
C

ATOM
933
CG2
ILE
A
477
−6.357
2.978
14.550
1.00
24.90
A
C

ATOM
937
C
ILE
A
477
−7.126
4.693
16.729
1.00
22.19
A
C

ATOM
938
O
ILE
A
477
−7.505
3.833
17.502
1.00
20.75
A
O

ATOM
939
N
MET
A
478
−6.126
5.518
17.025
1.00
22.05
A
N

ATOM
941
CA
MET
A
478
−5.479
5.507
18.341
1.00
21.67
A
C

ATOM
943
CB
MET
A
478
−4.401
6.603
18.421
1.00
22.21
A
C

ATOM
946
CG
MET
A
478
−3.172
6.370
17.537
1.00
23.35
A
C

ATOM
949
SD
MET
A
478
−2.324
4.761
17.784
1.00
27.04
A
S

ATOM
950
CE
MET
A
478
−1.687
4.917
19.390
1.00
24.74
A
C

ATOM
954
C
MET
A
478
−6.463
5.660
19.508
1.00
21.22
A
C

ATOM
955
O
MET
A
478
−6.280
5.042
20.541
1.00
20.80
A
O

ATOM
956
N
LYS
A
479
−7.517
6.461
19.336
1.00
21.22
A
N

ATOM
958
CA
LYS
A
479
−8.521
6.681
20.381
1.00
21.07
A
C

ATOM
960
CB
LYS
A
479
−9.550
7.727
19.910
1.00
21.83
A
C

ATOM
963
CG
LYS
A
479
−10.728
7.940
20.864
1.00
25.29
A
C

ATOM
966
CD
LYS
A
479
−11.616
9.074
20.401
1.00
28.79
A
C

ATOM
969
CE
LYS
A
479
−12.585
9.512
21.494
1.00
30.50
A
C

ATOM
972
NZ
LYS
A
479
−13.545
8.454
21.868
1.00
31.90
A
N

ATOM
976
C
LYS
A
479
−9.251
5.394
20.752
1.00
20.32
A
C

ATOM
977
O
LYS
A
479
−9.653
5.195
21.906
1.00
20.37
A
O

ATOM
978
N
ASN
A
480
−9.447
4.529
19.761
1.00
18.51
A
N

ATOM
980
CA
ASN
A
480
−10.168
3.284
19.980
1.00
18.01
A
C

ATOM
982
CB
ASN
A
480
−10.851
2.841
18.692
1.00
17.94
A
C

ATOM
985
CG
ASN
A
480
−12.098
3.625
18.410
1.00
16.43
A
C

ATOM
986
OD1
ASN
A
480
−13.135
3.388
19.038
1.00
14.27
A
O

ATOM
987
ND2
ASN
A
480
−12.016
4.574
17.481
1.00
13.64
A
N

ATOM
990
C
ASN
A
480
−9.277
2.174
20.512
1.00
17.93
A
C

ATOM
991
O
ASN
A
480
−9.768
1.196
21.049
1.00
17.90
A
O

ATOM
992
N
LEU
A
481
−7.969
2.305
20.345
1.00
18.54
A
N

ATOM
994
CA
LEU
A
481
−7.052
1.344
20.933
1.00
19.58
A
C

ATOM
996
CB
LEU
A
481
−5.647
1.510
20.375
1.00
19.65
A
C

ATOM
999
CG
LEU
A
481
−5.418
0.995
18.958
1.00
19.49
A
C

ATOM
1001
CD1
LEU
A
481
−4.028
1.362
18.492
1.00
20.75
A
C

ATOM
1005
CD2
LEU
A
481
−5.645
−0.497
18.891
1.00
19.12
A
C

ATOM
1009
C
LEU
A
481
−7.028
1.560
22.430
1.00
20.27
A
C

ATOM
1010
O
LEU
A
481
−6.658
2.630
22.899
1.00
22.42
A
O

ATOM
1011
N
ASP
A
482
−7.411
0.543
23.177
1.00
20.28
A
N

ATOM
1013
CA
ASP
A
482
−7.360
0.583
24.626
1.00
20.20
A
C

ATOM
1015
CB
ASP
A
482
−8.781
0.626
25.196
1.00
21.36
A
C

ATOM
1018
CG
ASP
A
482
−8.815
0.831
26.702
1.00
24.17
A
C

ATOM
1019
OD1
ASP
A
482
−9.901
0.603
27.288
1.00
31.84
A
O

ATOM
1020
OD2
ASP
A
482
−7.843
1.228
27.382
1.00
28.34
A
O

ATOM
1021
C
ASP
A
482
−6.625
−0.664
25.080
1.00
19.09
A
C

ATOM
1022
O
ASP
A
482
−7.178
−1.765
25.073
1.00
19.88
A
O

ATOM
1023
N
HIS
A
483
−5.349
−0.490
25.413
1.00
16.36
A
N

ATOM
1025
CA
HIS
A
483
−4.508
−1.572
25.890
1.00
15.18
A
C

ATOM
1027
CB
HIS
A
483
−3.723
−2.178
24.727
1.00
14.01
A
C

ATOM
1030
CG
HIS
A
483
−3.068
−3.474
25.069
1.00
13.88
A
C

ATOM
1031
ND1
HIS
A
483
−1.872
−3.542
25.755
1.00
13.01
A
N

ATOM
1033
CE1
HIS
A
483
−1.569
−4.812
25.969
1.00
13.34
A
C

ATOM
1035
NE2
HIS
A
483
−2.515
−5.566
25.429
1.00
12.59
A
N

ATOM
1037
CD2
HIS
A
483
−3.465
−4.752
24.867
1.00
12.02
A
C

ATOM
1039
C
HIS
A
483
−3.553
−1.015
26.964
1.00
14.57
A
C

ATOM
1040
O
HIS
A
483
−3.092
0.118
26.840
1.00
14.09
A
O

ATOM
1041
N
PRO
A
484
−3.278
−1.775
28.023
1.00
14.32
A
N

ATOM
1042
CA
PRO
A
484
−2.360
−1.310
29.080
1.00
13.52
A
C

ATOM
1044
CB
PRO
A
484
−2.254
−2.519
30.037
1.00
14.18
A
C

ATOM
1047
CG
PRO
A
484
−3.355
−3.429
29.700
1.00
15.62
A
C

ATOM
1050
CD
PRO
A
484
−3.866
−3.091
28.339
1.00
14.94
A
C

ATOM
1053
C
PRO
A
484
−0.956
−0.924
28.610
1.00
12.37
A
C

ATOM
1054
O
PRO
A
484
−0.285
−0.173
29.308
1.00
12.09
A
O

ATOM
1055
N
HIS
A
485
−0.532
−1.423
27.448
1.00
11.71
A
N

ATOM
1057
CA
HIS
A
485
0.790
−1.148
26.915
1.00
10.90
A
C

ATOM
1059
CB
HIS
A
485
1.606
−2.438
26.948
1.00
11.48
A
C

ATOM
1062
CG
HIS
A
485
1.687
−2.999
28.326
1.00
11.67
A
C

ATOM
1063
ND1
HIS
A
485
2.263
−2.293
29.357
1.00
10.00
A
N

ATOM
1065
CE1
HIS
A
485
2.139
−2.984
30.478
1.00
13.83
A
C

ATOM
1067
NE2
HIS
A
485
1.496
−4.105
30.211
1.00
13.41
A
N

ATOM
1069
CD2
HIS
A
485
1.179
−4.129
28.873
1.00
13.59
A
C

ATOM
1071
C
HIS
A
485
0.786
−0.514
25.549
1.00
10.49
A
C

ATOM
1072
O
HIS
A
485
1.722
−0.706
24.795
1.00
9.78
A
O

ATOM
1073
N
ILE
A
486
−0.267
0.258
25.260
1.00
9.75
A
N

ATOM
1075
CA
ILE
A
486
−0.313
1.165
24.107
1.00
9.72
A
C

ATOM
1077
CB
ILE
A
486
−1.352
0.675
23.077
1.00
9.49
A
C

ATOM
1079
CG1
ILE
A
486
−0.941
−0.698
22.509
1.00
9.88
A
C

ATOM
1082
CD1
ILE
A
486
−1.944
−1.282
21.569
1.00
11.12
A
C

ATOM
1086
CG2
ILE
A
486
−1.516
1.670
21.927
1.00
10.54
A
C

ATOM
1090
C
ILE
A
486
−0.683
2.561
24.617
1.00
10.03
A
C

ATOM
1091
O
ILE
A
486
−1.500
2.684
25.533
1.00
9.12
A
O

ATOM
1092
N
VAL
A
487
−0.079
3.585
24.034
1.00
10.75
A
N

ATOM
1094
CA
VAL
A
487
−0.294
4.958
24.477
1.00
11.70
A
C

ATOM
1096
CB
VAL
A
487
0.535
6.007
23.674
1.00
11.46
A
C

ATOM
1098
CG1
VAL
A
487
2.006
5.849
23.946
1.00
11.31
A
C

ATOM
1102
CG2
VAL
A
487
0.242
5.925
22.175
1.00
12.24
A
C

ATOM
1106
C
VAL
A
487
−1.782
5.278
24.394
1.00
12.42
A
C

ATOM
1107
O
VAL
A
487
−2.479
4.824
23.481
1.00
10.87
A
O

ATOM
1108
N
LYS
A
488
−2.269
6.010
25.386
1.00
14.04
A
N

ATOM
1110
CA
LYS
A
488
−3.699
6.252
25.531
1.00
15.40
A
C

ATOM
1112
CB
LYS
A
488
−4.147
6.081
26.979
1.00
16.29
A
C

ATOM
1115
CG
LYS
A
488
−5.648
6.355
27.161
1.00
18.92
A
C

ATOM
1118
CD
LYS
A
488
−6.109
6.153
28.588
1.00
22.97
A
C

ATOM
1121
CE
LYS
A
488
−7.638
6.269
28.693
1.00
26.06
A
C

ATOM
1124
NZ
LYS
A
488
−8.179
5.734
29.994
1.00
28.52
A
N

ATOM
1128
C
LYS
A
488
−4.019
7.663
25.090
1.00
16.61
A
C

ATOM
1129
O
LYS
A
488
−3.470
8.625
25.650
1.00
15.54
A
O

ATOM
1130
N
LEU
A
489
−4.879
7.760
24.079
1.00
18.15
A
N

ATOM
1132
CA
LEU
A
489
−5.458
9.028
23.644
1.00
20.47
A
C

ATOM
1134
CB
LEU
A
489
−5.707
9.035
22.135
1.00
20.96
A
C

ATOM
1137
CG
LEU
A
489
−6.318
10.312
21.519
1.00
22.08
A
C

ATOM
1139
CD1
LEU
A
489
−6.157
10.316
20.034
1.00
23.52
A
C

ATOM
1143
CD2
LEU
A
489
−7.776
10.472
21.876
1.00
24.93
A
C

ATOM
1147
C
LEU
A
489
−6.734
9.229
24.426
1.00
22.11
A
C

ATOM
1148
O
LEU
A
489
−7.625
8.370
24.402
1.00
23.38
A
O

ATOM
1149
N
ILE
A
490
−6.813
10.361
25.125
1.00
22.70
A
N

ATOM
1151
CA
ILE
A
490
−7.920
10.685
26.016
1.00
23.88
A
C

ATOM
1153
CB
ILE
A
490
−7.400
11.539
27.185
1.00
24.15
A
C

ATOM
1155
CG1
ILE
A
490
−6.437
10.714
28.049
1.00
25.63
A
C

ATOM
1158
CD1
ILE
A
490
−5.849
11.484
29.192
1.00
25.52
A
C

ATOM
1162
CG2
ILE
A
490
−8.558
12.096
28.022
1.00
25.12
A
C

ATOM
1166
C
ILE
A
490
−9.047
11.420
25.274
1.00
23.99
A
C

ATOM
1167
O
ILE
A
490
−10.232
11.098
25.448
1.00
24.52
A
O

ATOM
1168
N
GLY
A
491
−8.685
12.413
24.468
1.00
23.22
A
N

ATOM
1170
CA
GLY
A
491
−9.677
13.139
23.681
1.00
23.44
A
C

ATOM
1173
C
GLY
A
491
−9.145
13.889
22.481
1.00
23.06
A
C

ATOM
1174
O
GLY
A
491
−7.944
14.066
22.320
1.00
21.24
A
O

ATOM
1175
N
ILE
A
492
−10.069
14.324
21.623
1.00
23.34
A
N

ATOM
1177
CA
ILE
A
492
−9.747
15.175
20.490
1.00
23.94
A
C

ATOM
1179
CB
ILE
A
492
−9.914
14.394
19.167
1.00
24.29
A
C

ATOM
1181
CG1
ILE
A
492
−9.044
13.128
19.175
1.00
24.89
A
C

ATOM
1184
CD1
ILE
A
492
−9.389
12.139
18.099
1.00
26.68
A
C

ATOM
1188
CG2
ILE
A
492
−9.539
15.252
17.986
1.00
24.59
A
C

ATOM
1192
C
ILE
A
492
−10.675
16.401
20.528
1.00
24.76
A
C

ATOM
1193
O
ILE
A
492
−11.891
16.254
20.639
1.00
23.89
A
O

ATOM
1194
N
ILE
A
493
−10.086
17.598
20.508
1.00
25.52
A
N

ATOM
1196
CA
ILE
A
493
−10.828
18.833
20.257
1.00
26.54
A
C

ATOM
1198
CB
ILE
A
493
−10.315
20.009
21.138
1.00
26.60
A
C

ATOM
1200
CG1
ILE
A
493
−10.215
19.614
22.613
1.00
26.82
A
C

ATOM
1203
CD1
ILE
A
493
−11.446
18.990
23.180
1.00
27.58
A
C

ATOM
1207
CG2
ILE
A
493
−11.217
21.249
20.961
1.00
26.95
A
C

ATOM
1211
C
ILE
A
493
−10.609
19.151
18.785
1.00
27.17
A
C

ATOM
1212
O
ILE
A
493
−9.531
19.576
18.404
1.00
26.34
A
O

ATOM
1213
N
GLU
A
494
−11.628
18.927
17.959
1.00
28.32
A
N

ATOM
1215
CA
GLU
A
494
−11.502
19.096
16.510
1.00
29.45
A
C

ATOM
1217
CB
GLU
A
494
−12.698
18.444
15.800
1.00
30.09
A
C

ATOM
1220
CG
GLU
A
494
−12.800
16.943
16.024
1.00
32.11
A
C

ATOM
1223
CD
GLU
A
494
−13.958
16.292
15.280
1.00
35.78
A
C

ATOM
1224
OE1
GLU
A
494
−14.108
16.531
14.058
1.00
38.41
A
O

ATOM
1225
OE2
GLU
A
494
−14.717
15.524
15.918
1.00
38.33
A
O

ATOM
1226
C
GLU
A
494
−11.390
20.567
16.098
1.00
29.72
A
C

ATOM
1227
O
GLU
A
494
−10.667
20.900
15.160
1.00
29.12
A
O

ATOM
1228
N
GLU
A
495
−12.073
21.432
16.846
1.00
30.47
A
N

ATOM
1230
CA
GLU
A
495
−12.259
22.853
16.505
1.00
31.12
A
C

ATOM
1232
CB
GLU
A
495
−13.324
23.465
17.435
1.00
31.66
A
C

ATOM
1235
CG
GLU
A
495
−14.759
23.024
17.203
1.00
34.10
A
C

ATOM
1238
CD
GLU
A
495
−14.995
21.541
17.444
1.00
36.85
A
C

ATOM
1239
OE1
GLU
A
495
−14.650
21.029
18.544
1.00
38.24
A
O

ATOM
1240
OE2
GLU
A
495
−15.521
20.885
16.517
1.00
39.02
A
O

ATOM
1241
C
GLU
A
495
−10.978
23.695
16.633
1.00
30.92
A
C

ATOM
1242
O
GLU
A
495
−9.950
23.203
17.113
1.00
30.08
A
O

ATOM
1243
N
GLU
A
496
−11.084
24.966
16.207
1.00
30.74
A
N

ATOM
1245
CA
GLU
A
496
−10.102
26.053
16.450
1.00
30.21
A
C

ATOM
1247
CB
GLU
A
496
−10.331
26.722
17.809
1.00
30.71
A
C

ATOM
1250
CG
GLU
A
496
−11.767
27.153
18.080
1.00
33.56
A
C

ATOM
1253
CD
GLU
A
496
−12.218
28.297
17.176
1.00
37.40
A
C

ATOM
1254
OE1
GLU
A
496
−11.734
29.442
17.368
1.00
39.71
A
O

ATOM
1255
OE2
GLU
A
496
−13.057
28.053
16.273
1.00
39.53
A
O

ATOM
1256
C
GLU
A
496
−8.688
25.536
16.214
1.00
28.69
A
C

ATOM
1257
O
GLU
A
496
−8.518
24.890
15.181
1.00
29.82
A
O

ATOM
1258
N
PRO
A
497
−7.673
25.765
17.068
1.00
26.40
A
N

ATOM
1259
CA
PRO
A
497
−6.463
24.955
16.914
1.00
24.97
A
C

ATOM
1261
CB
PRO
A
497
−5.435
25.650
17.812
1.00
25.01
A
C

ATOM
1264
CG
PRO
A
497
−6.217
26.352
18.819
1.00
25.48
A
C

ATOM
1267
CD
PRO
A
497
−7.508
26.726
18.176
1.00
26.20
A
C

ATOM
1270
C
PRO
A
497
−6.785
23.545
17.400
1.00
23.59
A
C

ATOM
1271
O
PRO
A
497
−7.238
23.365
18.525
1.00
21.60
A
O

ATOM
1272
N
THR
A
498
−6.593
22.562
16.533
1.00
22.37
A
N

ATOM
1274
CA
THR
A
498
−6.969
21.193
16.855
1.00
22.15
A
C

ATOM
1276
CB
THR
A
498
−6.918
20.363
15.580
1.00
22.32
A
C

ATOM
1278
OG1
THR
A
498
−7.958
20.826
14.700
1.00
25.57
A
O

ATOM
1280
CG2
THR
A
498
−7.252
18.924
15.840
1.00
22.92
A
C

ATOM
1284
C
THR
A
498
−6.022
20.654
17.922
1.00
20.09
A
C

ATOM
1285
O
THR
A
498
−4.835
20.874
17.821
1.00
19.92
A
O

ATOM
1286
N
TRP
A
499
−6.568
20.002
18.950
1.00
19.00
A
N

ATOM
1288
CA
TRP
A
499
−5.777
19.413
20.040
1.00
17.23
A
C

ATOM
1290
CB
TRP
A
499
−6.188
20.010
21.393
1.00
17.26
A
C

ATOM
1293
CG
TRP
A
499
−5.734
21.440
21.693
1.00
16.11
A
C

ATOM
1294
CD1
TRP
A
499
−5.098
22.301
20.851
1.00
16.58
A
C

ATOM
1296
NE1
TRP
A
499
−4.865
23.499
21.483
1.00
15.91
A
N

ATOM
1298
CE2
TRP
A
499
−5.342
23.431
22.760
1.00
13.91
A
C

ATOM
1299
CD2
TRP
A
499
−5.906
22.149
22.927
1.00
14.32
A
C

ATOM
1300
CE3
TRP
A
499
−6.474
21.825
24.167
1.00
14.41
A
C

ATOM
1302
CZ3
TRP
A
499
−6.466
22.789
25.187
1.00
15.48
A
C

ATOM
1304
CH2
TRP
A
499
−5.914
24.063
24.973
1.00
15.79
A
C

ATOM
1306
CZ2
TRP
A
499
−5.345
24.401
23.770
1.00
16.05
A
C

ATOM
1308
C
TRP
A
499
−6.011
17.891
20.113
1.00
16.56
A
C

ATOM
1309
O
TRP
A
499
−7.161
17.444
20.219
1.00
16.56
A
O

ATOM
1310
N
ILE
A
500
−4.933
17.111
20.082
1.00
15.45
A
N

ATOM
1312
CA
ILE
A
500
−4.987
15.696
20.427
1.00
15.58
A
C

ATOM
1314
CB
ILE
A
500
−4.126
14.870
19.461
1.00
16.46
A
C

ATOM
1316
CG1
ILE
A
500
−4.423
15.233
17.994
1.00
17.06
A
C

ATOM
1319
CD1
ILE
A
500
−5.887
15.183
17.626
1.00
18.75
A
C

ATOM
1323
CG2
ILE
A
500
−4.288
13.390
19.744
1.00
18.35
A
C

ATOM
1327
C
ILE
A
500
−4.467
15.555
21.863
1.00
14.87
A
C

ATOM
1328
O
ILE
A
500
−3.323
15.879
22.141
1.00
14.70
A
O

ATOM
1329
N
ILE
A
501
−5.318
15.096
22.765
1.00
13.73
A
N

ATOM
1331
CA
ILE
A
501
−4.998
14.985
24.178
1.00
13.36
A
C

ATOM
1333
CB
ILE
A
501
−6.190
15.451
25.034
1.00
12.71
A
C

ATOM
1335
CG1
ILE
A
501
−6.719
16.788
24.496
1.00
14.26
A
C

ATOM
1338
CD1
ILE
A
501
−7.978
17.256
25.129
1.00
15.07
A
C

ATOM
1342
CG2
ILE
A
501
−5.768
15.583
26.483
1.00
12.38
A
C

ATOM
1346
C
ILE
A
501
−4.629
13.546
24.539
1.00
13.36
A
C

ATOM
1347
O
ILE
A
501
−5.469
12.638
24.448
1.00
13.51
A
O

ATOM
1348
N
MET
A
502
−3.372
13.359
24.933
1.00
13.48
A
N

ATOM
1350
CA
MET
A
502
−2.836
12.061
25.353
1.00
13.96
A
C

ATOM
1352
CB
MET
A
502
−1.550
11.754
24.585
1.00
14.71
A
C

ATOM
1355
CG
MET
A
502
−1.634
11.957
23.074
1.00
18.44
A
C

ATOM
1358
SD
MET
A
502
−2.691
10.736
22.262
1.00
25.96
A
S

ATOM
1359
CE
MET
A
502
−1.705
9.251
22.464
1.00
24.95
A
C

ATOM
1363
C
MET
A
502
−2.498
12.057
26.845
1.00
13.14
A
C

ATOM
1364
O
MET
A
502
−2.200
13.092
27.436
1.00
11.75
A
O

ATOM
1365
N
GLU
A
503
−2.501
10.879
27.458
1.00
12.97
A
N

ATOM
1367
CA
GLU
A
503
−1.947
10.721
28.784
1.00
13.82
A
C

ATOM
1369
CB
GLU
A
503
−2.136
9.258
29.215
1.00
15.08
A
C

ATOM
1372
CG
GLU
A
503
−1.603
8.887
30.583
1.00
18.56
A
C

ATOM
1375
CD
GLU
A
503
−2.097
7.516
31.024
1.00
23.89
A
C

ATOM
1376
OE1
GLU
A
503
−2.315
6.636
30.153
1.00
26.84
A
O

ATOM
1377
OE2
GLU
A
503
−2.272
7.314
32.243
1.00
29.32
A
O

ATOM
1378
C
GLU
A
503
−0.457
11.112
28.747
1.00
13.19
A
C

ATOM
1379
O
GLU
A
503
0.230
10.778
27.787
1.00
13.15
A
O

ATOM
1380
N
LEU
A
504
0.020
11.836
29.760
1.00
12.59
A
N

ATOM
1382
CA
LEU
A
504
1.440
12.210
29.862
1.00
13.43
A
C

ATOM
1384
CB
LEU
A
504
1.635
13.449
30.746
1.00
13.57
A
C

ATOM
1387
CG
LEU
A
504
3.065
13.981
30.844
1.00
14.83
A
C

ATOM
1389
CD1
LEU
A
504
3.440
14.719
29.551
1.00
15.70
A
C

ATOM
1393
CD2
LEU
A
504
3.281
14.893
32.069
1.00
17.43
A
C

ATOM
1397
C
LEU
A
504
2.237
11.049
30.443
1.00
13.16
A
C

ATOM
1398
O
LEU
A
504
1.831
10.448
31.436
1.00
12.13
A
O

ATOM
1399
N
TYR
A
505
3.361
10.740
29.807
1.00
13.87
A
N

ATOM
1401
CA
TYR
A
505
4.261
9.682
30.247
1.00
14.37
A
C

ATOM
1403
CB
TYR
A
505
4.379
8.582
29.159
1.00
15.13
A
C

ATOM
1406
CG
TYR
A
505
3.034
7.948
28.815
1.00
14.57
A
C

ATOM
1407
CD1
TYR
A
505
2.254
7.352
29.802
1.00
16.24
A
C

ATOM
1409
CE1
TYR
A
505
0.996
6.804
29.506
1.00
15.83
A
C

ATOM
1411
CZ
TYR
A
505
0.517
6.853
28.221
1.00
13.11
A
C

ATOM
1412
OH
TYR
A
505
−0.713
6.332
27.933
1.00
15.41
A
O

ATOM
1414
CE2
TYR
A
505
1.255
7.455
27.229
1.00
13.32
A
C

ATOM
1416
CD2
TYR
A
505
2.506
8.017
27.532
1.00
14.19
A
C

ATOM
1418
C
TYR
A
505
5.566
10.408
30.557
1.00
14.61
A
C

ATOM
1419
O
TYR
A
505
6.379
10.672
29.675
1.00
13.90
A
O

ATOM
1420
N
PRO
A
506
5.707
10.836
31.812
1.00
15.51
A
N

ATOM
1421
CA
PRO
A
506
6.699
11.840
32.188
1.00
15.79
A
C

ATOM
1423
CB
PRO
A
506
6.291
12.186
33.616
1.00
16.40
A
C

ATOM
1426
CG
PRO
A
506
5.692
10.962
34.115
1.00
16.38
A
C

ATOM
1429
CD
PRO
A
506
4.903
10.414
32.974
1.00
16.03
A
C

ATOM
1432
C
PRO
A
506
8.168
11.364
32.119
1.00
15.41
A
C

ATOM
1433
O
PRO
A
506
9.055
12.186
32.029
1.00
15.80
A
O

ATOM
1434
N
TYR
A
507
8.406
10.062
32.106
1.00
14.60
A
N

ATOM
1436
CA
TYR
A
507
9.767
9.548
31.946
1.00
13.73
A
C

ATOM
1438
CB
TYR
A
507
9.872
8.143
32.516
1.00
13.74
A
C

ATOM
1441
CG
TYR
A
507
9.659
8.071
33.997
1.00
14.65
A
C

ATOM
1442
CD1
TYR
A
507
10.704
8.269
34.879
1.00
15.68
A
C

ATOM
1444
CE1
TYR
A
507
10.505
8.191
36.268
1.00
17.32
A
C

ATOM
1446
CZ
TYR
A
507
9.241
7.931
36.754
1.00
16.75
A
C

ATOM
1447
OH
TYR
A
507
9.002
7.873
38.099
1.00
19.60
A
O

ATOM
1449
CE2
TYR
A
507
8.198
7.737
35.895
1.00
15.81
A
C

ATOM
1451
CD2
TYR
A
507
8.408
7.807
34.521
1.00
14.55
A
C

ATOM
1453
C
TYR
A
507
10.276
9.550
30.491
1.00
13.31
A
C

ATOM
1454
O
TYR
A
507
11.451
9.268
30.268
1.00
13.27
A
O

ATOM
1455
N
GLY
A
508
9.411
9.838
29.516
1.00
12.24
A
N

ATOM
1457
CA
GLY
A
508
9.834
10.058
28.142
1.00
12.21
A
C

ATOM
1460
C
GLY
A
508
10.112
8.784
27.362
1.00
11.49
A
C

ATOM
1461
O
GLY
A
508
9.628
7.729
27.727
1.00
10.44
A
O

ATOM
1462
N
GLU
A
509
10.885
8.896
26.281
1.00
11.21
A
N

ATOM
1464
CA
GLU
A
509
11.183
7.744
25.416
1.00
11.54
A
C

ATOM
1466
CB
GLU
A
509
11.913
8.194
24.156
1.00
12.66
A
C

ATOM
1469
CG
GLU
A
509
11.143
9.164
23.279
1.00
15.29
A
C

ATOM
1472
CD
GLU
A
509
11.973
9.695
22.119
1.00
18.15
A
C

ATOM
1473
OE1
GLU
A
509
13.122
9.251
21.947
1.00
19.31
A
O

ATOM
1474
OE2
GLU
A
509
11.472
10.588
21.393
1.00
21.32
A
O

ATOM
1475
C
GLU
A
509
12.038
6.666
26.095
1.00
10.37
A
C

ATOM
1476
O
GLU
A
509
12.953
6.974
26.847
1.00
10.56
A
O

ATOM
1477
N
LEU
A
510
11.742
5.399
25.791
1.00
9.52
A
N

ATOM
1479
CA
LEU
A
510
12.447
4.275
26.392
1.00
9.25
A
C

ATOM
1481
CB
LEU
A
510
11.768
2.956
25.990
1.00
9.16
A
C

ATOM
1484
CG
LEU
A
510
12.395
1.682
26.566
1.00
8.82
A
C

ATOM
1486
CD1
LEU
A
510
12.453
1.737
28.081
1.00
9.86
A
C

ATOM
1490
CD2
LEU
A
510
11.596
0.465
26.104
1.00
9.45
A
C

ATOM
1494
C
LEU
A
510
13.948
4.249
26.057
1.00
9.51
A
C

ATOM
1495
O
LEU
A
510
14.772
3.937
26.925
1.00
9.34
A
O

ATOM
1496
N
GLY
A
511
14.322
4.610
24.824
1.00
9.82
A
N

ATOM
1498
CA
GLY
A
511
15.729
4.549
24.433
1.00
10.57
A
C

ATOM
1501
C
GLY
A
511
16.585
5.425
25.340
1.00
10.99
A
C

ATOM
1502
O
GLY
A
511
17.566
4.964
25.934
1.00
11.11
A
O

ATOM
1503
N
HIS
A
512
16.178
6.672
25.492
1.00
11.55
A
N

ATOM
1505
CA
HIS
A
512
16.875
7.608
26.374
1.00
12.69
A
C

ATOM
1507
CB
HIS
A
512
16.319
9.011
26.174
1.00
13.88
A
C

ATOM
1510
CG
HIS
A
512
16.559
9.541
24.795
1.00
17.28
A
C

ATOM
1511
ND1
HIS
A
512
17.678
9.214
24.061
1.00
22.03
A
N

ATOM
1513
CE1
HIS
A
512
17.618
9.808
22.882
1.00
22.98
A
C

ATOM
1515
NE2
HIS
A
512
16.508
10.518
22.831
1.00
21.48
A
N

ATOM
1517
CD2
HIS
A
512
15.821
10.360
24.011
1.00
20.94
A
C

ATOM
1519
C
HIS
A
512
16.810
7.196
27.840
1.00
11.73
A
C

ATOM
1520
O
HIS
A
512
17.795
7.308
28.560
1.00
11.30
A
O

ATOM
1521
N
TYR
A
513
15.664
6.682
28.269
1.00
10.95
A
N

ATOM
1523
CA
TYR
A
513
15.472
6.184
29.630
1.00
10.24
A
C

ATOM
1525
CB
TYR
A
513
14.034
5.677
29.797
1.00
10.11
A
C

ATOM
1528
CG
TYR
A
513
13.693
5.094
31.169
1.00
9.46
A
C

ATOM
1529
CD1
TYR
A
513
13.157
5.901
32.160
1.00
9.43
A
C

ATOM
1531
CE1
TYR
A
513
12.800
5.391
33.393
1.00
9.59
A
C

ATOM
1533
CZ
TYR
A
513
12.988
4.068
33.671
1.00
9.14
A
C

ATOM
1534
OH
TYR
A
513
12.628
3.617
34.912
1.00
12.42
A
O

ATOM
1536
CE2
TYR
A
513
13.533
3.214
32.708
1.00
8.34
A
C

ATOM
1538
CD2
TYR
A
513
13.854
3.735
31.452
1.00
8.09
A
C

ATOM
1540
C
TYR
A
513
16.469
5.068
29.965
1.00
10.47
A
C

ATOM
1541
O
TYR
A
513
17.110
5.099
31.009
1.00
10.13
A
O

ATOM
1542
N
LEU
A
514
16.623
4.102
29.058
1.00
10.69
A
N

ATOM
1544
CA
LEU
A
514
17.596
3.021
29.239
1.00
11.38
A
C

ATOM
1546
CB
LEU
A
514
17.478
1.997
28.115
1.00
11.46
A
C

ATOM
1549
CG
LEU
A
514
16.163
1.198
28.035
1.00
12.98
A
C

ATOM
1551
CD1
LEU
A
514
16.082
0.442
26.729
1.00
14.53
A
C

ATOM
1555
CD2
LEU
A
514
16.010
0.260
29.218
1.00
12.92
A
C

ATOM
1559
C
LEU
A
514
19.027
3.556
29.300
1.00
12.00
A
C

ATOM
1560
O
LEU
A
514
19.839
3.080
30.090
1.00
12.23
A
O

ATOM
1561
N
GLU
A
515
19.330
4.518
28.450
1.00
12.66
A
N

ATOM
1563
CA
GLU
A
515
20.650
5.160
28.447
1.00
14.53
A
C

ATOM
1565
CB
GLU
A
515
20.742
6.212
27.346
1.00
15.14
A
C

ATOM
1568
CG
GLU
A
515
20.701
5.656
25.929
1.00
19.10
A
C

ATOM
1571
CD
GLU
A
515
20.531
6.744
24.868
1.00
24.40
A
C

ATOM
1572
OE1
GLU
A
515
20.496
7.948
25.236
1.00
29.66
A
O

ATOM
1573
OE2
GLU
A
515
20.433
6.395
23.665
1.00
28.24
A
O

ATOM
1574
C
GLU
A
515
20.954
5.812
29.795
1.00
15.17
A
C

ATOM
1575
O
GLU
A
515
22.046
5.601
30.347
1.00
15.52
A
O

ATOM
1576
N
ARG
A
516
19.987
6.576
30.317
1.00
15.35
A
N

ATOM
1578
CA
ARG
A
516
20.114
7.306
31.595
1.00
16.48
A
C

ATOM
1580
CB
ARG
A
516
18.842
8.134
31.882
1.00
17.00
A
C

ATOM
1583
CG
ARG
A
516
18.722
9.407
31.115
1.00
19.06
A
C

ATOM
1586
CD
ARG
A
516
17.815
10.406
31.760
1.00
18.75
A
C

ATOM
1589
NE
ARG
A
516
16.482
9.894
32.079
1.00
17.60
A
N

ATOM
1591
CZ
ARG
A
516
15.500
9.702
31.197
1.00
17.67
A
C

ATOM
1592
NH1
ARG
A
516
15.669
9.969
29.909
1.00
17.37
A
N

ATOM
1595
NH2
ARG
A
516
14.323
9.248
31.612
1.00
20.07
A
N

ATOM
1598
C
ARG
A
516
20.298
6.382
32.790
1.00
16.29
A
C

ATOM
1599
O
ARG
A
516
21.032
6.702
33.743
1.00
15.28
A
O

ATOM
1600
N
ASN
A
517
19.609
5.245
32.745
1.00
16.03
A
N

ATOM
1602
CA
ASN
A
517
19.387
4.432
33.927
1.00
15.86
A
C

ATOM
1604
CB
ASN
A
517
17.876
4.249
34.155
1.00
15.83
A
C

ATOM
1607
CG
ASN
A
517
17.161
5.562
34.430
1.00
16.01
A
C

ATOM
1608
OD1
ASN
A
517
16.182
5.918
33.758
1.00
16.60
A
O

ATOM
1609
ND2
ASN
A
517
17.671
6.316
35.390
1.00
15.03
A
N

ATOM
1612
C
ASN
A
517
20.108
3.092
33.863
1.00
16.06
A
C

ATOM
1613
O
ASN
A
517
19.900
2.238
34.715
1.00
15.77
A
O

ATOM
1614
N
LYS
A
518
20.980
2.928
32.870
1.00
16.16
A
N

ATOM
1616
CA
LYS
A
518
21.613
1.641
32.606
1.00
17.63
A
C

ATOM
1618
CB
LYS
A
518
22.643
1.784
31.474
1.00
17.77
A
C

ATOM
1621
CG
LYS
A
518
23.632
0.636
31.368
1.00
20.82
A
C

ATOM
1624
CD
LYS
A
518
24.421
0.686
30.063
1.00
24.15
A
C

ATOM
1627
CE
LYS
A
518
25.172
1.979
29.909
1.00
26.03
A
C

ATOM
1630
NZ
LYS
A
518
24.304
3.106
29.435
1.00
28.18
A
N

ATOM
1634
C
LYS
A
518
22.254
1.017
33.849
1.00
18.11
A
C

ATOM
1635
O
LYS
A
518
22.126
−0.189
34.086
1.00
18.39
A
O

ATOM
1636
N
ASN
A
519
22.938
1.825
34.652
1.00
18.49
A
N

ATOM
1638
CA
ASN
A
519
23.671
1.287
35.802
1.00
19.30
A
C

ATOM
1640
CB
ASN
A
519
24.611
2.346
36.375
1.00
19.86
A
C

ATOM
1643
CG
ASN
A
519
25.664
2.759
35.382
1.00
21.38
A
C

ATOM
1644
OD1
ASN
A
519
26.149
1.930
34.612
1.00
26.70
A
O

ATOM
1645
ND2
ASN
A
519
26.012
4.042
35.372
1.00
28.25
A
N

ATOM
1648
C
ASN
A
519
22.823
0.691
36.922
1.00
19.78
A
C

ATOM
1649
O
ASN
A
519
23.344
−0.079
37.710
1.00
19.38
A
O

ATOM
1650
N
SER
A
520
21.531
1.029
36.985
1.00
19.92
A
N

ATOM
1652
CA
SER
A
520
20.647
0.503
38.031
1.00
20.71
A
C

ATOM
1654
CB
SER
A
520
20.044
1.663
38.834
1.00
21.31
A
C

ATOM
1657
OG
SER
A
520
19.120
2.400
38.069
1.00
23.80
A
O

ATOM
1659
C
SER
A
520
19.536
−0.435
37.536
1.00
20.17
A
C

ATOM
1660
O
SER
A
520
18.775
−0.953
38.335
1.00
21.79
A
O

ATOM
1661
N
LEU
A
521
19.456
−0.678
36.234
1.00
18.62
A
N

ATOM
1663
CA
LEU
A
521
18.417
−1.545
35.676
1.00
17.54
A
C

ATOM
1665
CB
LEU
A
521
18.209
−1.218
34.192
1.00
17.30
A
C

ATOM
1668
CG
LEU
A
521
17.417
0.046
33.909
1.00
17.34
A
C

ATOM
1670
CD1
LEU
A
521
17.651
0.555
32.493
1.00
17.37
A
C

ATOM
1674
CD2
LEU
A
521
15.950
−0.230
34.136
1.00
19.13
A
C

ATOM
1678
C
LEU
A
521
18.794
−3.014
35.804
1.00
16.93
A
C

ATOM
1679
O
LEU
A
521
19.938
−3.378
35.566
1.00
17.89
A
O

ATOM
1680
N
LYS
A
522
17.841
−3.863
36.164
1.00
15.75
A
N

ATOM
1682
CA
LYS
A
522
18.070
−5.314
36.231
1.00
15.93
A
C

ATOM
1684
CB
LYS
A
522
17.277
−5.944
37.385
1.00
16.21
A
C

ATOM
1687
CG
LYS
A
522
17.444
−5.237
38.719
1.00
18.79
A
C

ATOM
1690
CD
LYS
A
522
16.528
−5.804
39.802
1.00
21.17
A
C

ATOM
1693
CE
LYS
A
522
15.090
−5.353
39.648
1.00
23.90
A
C

ATOM
1696
NZ
LYS
A
522
14.842
−3.888
39.964
1.00
25.89
A
N

ATOM
1700
C
LYS
A
522
17.623
−5.956
34.915
1.00
14.75
A
C

ATOM
1701
O
LYS
A
522
16.727
−5.432
34.257
1.00
14.52
A
O

ATOM
1702
N
VAL
A
523
18.223
−7.096
34.556
1.00
13.60
A
N

ATOM
1704
CA
VAL
A
523
17.821
−7.845
33.349
1.00
13.60
A
C

ATOM
1706
CB
VAL
A
523
18.666
−9.113
33.137
1.00
13.75
A
C

ATOM
1708
CG1
VAL
A
523
18.182
−9.891
31.939
1.00
13.84
A
C

ATOM
1712
CG2
VAL
A
523
20.157
−8.741
32.968
1.00
14.55
A
C

ATOM
1716
C
VAL
A
523
16.344
−8.238
33.420
1.00
13.39
A
C

ATOM
1717
O
VAL
A
523
15.631
−8.222
32.427
1.00
12.33
A
O

ATOM
1718
N
LEU
A
524
15.887
−8.535
34.626
1.00
13.26
A
N

ATOM
1720
CA
LEU
A
524
14.512
−8.886
34.875
1.00
14.13
A
C

ATOM
1722
CB
LEU
A
524
14.392
−9.107
36.382
1.00
15.52
A
C

ATOM
1725
CG
LEU
A
524
13.090
−9.468
37.032
1.00
20.72
A
C

ATOM
1727
CD1
LEU
A
524
12.523
−10.698
36.358
1.00
22.55
A
C

ATOM
1731
CD2
LEU
A
524
13.407
−9.706
38.518
1.00
22.42
A
C

ATOM
1735
C
LEU
A
524
13.556
−7.804
34.362
1.00
12.61
A
C

ATOM
1736
O
LEU
A
524
12.528
−8.109
33.738
1.00
11.66
A
O

ATOM
1737
N
THR
A
525
13.909
−6.544
34.590
1.00
11.21
A
N

ATOM
1739
CA
THR
A
525
13.113
−5.402
34.123
1.00
11.25
A
C

ATOM
1741
CB
THR
A
525
13.650
−4.120
34.788
1.00
11.51
A
C

ATOM
1743
OG1
THR
A
525
13.552
−4.260
36.215
1.00
13.76
A
O

ATOM
1745
CG2
THR
A
525
12.815
−2.922
34.467
1.00
11.96
A
C

ATOM
1749
C
THR
A
525
13.124
−5.235
32.600
1.00
10.93
A
C

ATOM
1750
O
THR
A
525
12.114
−4.850
32.001
1.00
10.34
A
O

ATOM
1751
N
LEU
A
526
14.275
−5.482
31.987
1.00
9.76
A
N

ATOM
1753
CA
LEU
A
526
14.412
−5.405
30.523
1.00
9.91
A
C

ATOM
1755
CB
LEU
A
526
15.877
−5.597
30.105
1.00
9.71
A
C

ATOM
1758
CG
LEU
A
526
16.878
−4.621
30.717
1.00
10.00
A
C

ATOM
1760
CD1
LEU
A
526
18.268
−4.904
30.219
1.00
10.63
A
C

ATOM
1764
CD2
LEU
A
526
16.484
−3.208
30.422
1.00
10.98
A
C

ATOM
1768
C
LEU
A
526
13.520
−6.455
29.836
1.00
9.82
A
C

ATOM
1769
O
LEU
A
526
12.876
−6.176
28.822
1.00
8.11
A
O

ATOM
1770
N
VAL
A
527
13.475
−7.660
30.411
1.00
9.84
A
N

ATOM
1772
CA
VAL
A
527
12.588
−8.709
29.924
1.00
10.01
A
C

ATOM
1774
CB
VAL
A
527
12.910
−10.075
30.588
1.00
10.28
A
C

ATOM
1776
CG1
VAL
A
527
11.950
−11.157
30.103
1.00
12.12
A
C

ATOM
1780
CG2
VAL
A
527
14.326
−10.464
30.275
1.00
11.61
A
C

ATOM
1784
C
VAL
A
527
11.111
−8.316
30.132
1.00
9.91
A
C

ATOM
1785
O
VAL
A
527
10.286
−8.533
29.247
1.00
9.20
A
O

ATOM
1786
N
LEU
A
528
10.783
−7.715
31.277
1.00
9.17
A
N

ATOM
1788
CA
LEU
A
528
9.419
−7.239
31.548
1.00
9.55
A
C

ATOM
1790
CB
LEU
A
528
9.308
−6.582
32.940
1.00
10.47
A
C

ATOM
1793
CG
LEU
A
528
7.962
−5.908
33.230
1.00
11.24
A
C

ATOM
1795
CD1
LEU
A
528
6.855
−6.956
33.158
1.00
11.66
A
C

ATOM
1799
CD2
LEU
A
528
7.961
−5.179
34.544
1.00
12.72
A
C

ATOM
1803
C
LEU
A
528
8.976
−6.263
30.464
1.00
9.67
A
C

ATOM
1804
O
LEU
A
528
7.878
−6.389
29.928
1.00
8.64
A
O

ATOM
1805
N
TYR
A
529
9.825
−5.290
30.120
1.00
9.08
A
N

ATOM
1807
CA
TYR
A
529
9.447
−4.301
29.091
1.00
8.78
A
C

ATOM
1809
CB
TYR
A
529
10.522
−3.215
28.939
1.00
8.57
A
C

ATOM
1812
CG
TYR
A
529
10.744
−2.321
30.143
1.00
10.12
A
C

ATOM
1813
CD1
TYR
A
529
9.833
−2.257
31.193
1.00
10.85
A
C

ATOM
1815
CE1
TYR
A
529
10.057
−1.438
32.298
1.00
12.11
A
C

ATOM
1817
CZ
TYR
A
529
11.211
−0.677
32.365
1.00
13.84
A
C

ATOM
1818
OH
TYR
A
529
11.441
0.140
33.449
1.00
16.48
A
O

ATOM
1820
CE2
TYR
A
529
12.137
−0.737
31.354
1.00
11.18
A
C

ATOM
1822
CD2
TYR
A
529
11.903
−1.565
30.248
1.00
11.83
A
C

ATOM
1824
C
TYR
A
529
9.202
−4.967
27.734
1.00
8.22
A
C

ATOM
1825
O
TYR
A
529
8.255
−4.615
27.028
1.00
9.04
A
O

ATOM
1826
N
SER
A
530
10.036
−5.937
27.390
1.00
8.24
A
N

ATOM
1828
CA
SER
A
530
9.889
−6.722
26.154
1.00
7.83
A
C

ATOM
1830
CB
SER
A
530
11.052
−7.730
26.015
1.00
7.54
A
C

ATOM
1833
OG
SER
A
530
12.310
−7.077
25.839
1.00
10.28
A
O

ATOM
1835
C
SER
A
530
8.543
−7.458
26.137
1.00
7.48
A
C

ATOM
1836
O
SER
A
530
7.820
−7.443
25.141
1.00
7.17
A
O

ATOM
1837
N
LEU
A
531
8.199
−8.074
27.258
1.00
6.73
A
N

ATOM
1839
CA
LEU
A
531
6.931
−8.800
27.389
1.00
7.75
A
C

ATOM
1841
CB
LEU
A
531
6.912
−9.561
28.728
1.00
7.60
A
C

ATOM
1844
CG
LEU
A
531
5.618
−10.232
29.178
1.00
8.41
A
C

ATOM
1846
CD1
LEU
A
531
5.201
−11.263
28.153
1.00
9.01
A
C

ATOM
1850
CD2
LEU
A
531
5.776
−10.881
30.561
1.00
11.57
A
C

ATOM
1854
C
LEU
A
531
5.731
−7.876
27.280
1.00
7.08
A
C

ATOM
1855
O
LEU
A
531
4.745
−8.201
26.644
1.00
6.97
A
O

ATOM
1856
N
GLN
A
532
5.797
−6.711
27.911
1.00
7.33
A
N

ATOM
1858
CA
GLN
A
532
4.706
−5.735
27.831
1.00
7.02
A
C

ATOM
1860
CB
GLN
A
532
5.050
−4.514
28.702
1.00
6.93
A
C

ATOM
1863
CG
GLN
A
532
4.930
−4.815
30.195
1.00
7.50
A
C

ATOM
1866
CD
GLN
A
532
5.235
−3.632
31.101
1.00
9.98
A
C

ATOM
1867
OE1
GLN
A
532
5.756
−2.626
30.657
1.00
9.61
A
O

ATOM
1868
NE2
GLN
A
532
4.903
−3.772
32.393
1.00
8.99
A
N

ATOM
1871
C
GLN
A
532
4.439
−5.290
26.388
1.00
7.09
A
C

ATOM
1872
O
GLN
A
532
3.281
−5.223
25.942
1.00
6.73
A
O

ATOM
1873
N
ILE
A
533
5.505
−4.991
25.645
1.00
7.80
A
N

ATOM
1875
CA
ILE
A
533
5.341
−4.572
24.264
1.00
8.29
A
C

ATOM
1877
CB
ILE
A
533
6.663
−4.028
23.692
1.00
8.97
A
C

ATOM
1879
CG1
ILE
A
533
7.124
−2.779
24.445
1.00
8.38
A
C

ATOM
1882
CD1
ILE
A
533
6.158
−1.630
24.424
1.00
9.69
A
C

ATOM
1886
CG2
ILE
A
533
6.527
−3.760
22.221
1.00
9.41
A
C

ATOM
1890
C
ILE
A
533
4.825
−5.736
23.419
1.00
8.33
A
C

ATOM
1891
O
ILE
A
533
4.010
−5.548
22.512
1.00
8.38
A
O

ATOM
1892
N
CYS
A
534
5.305
−6.938
23.717
1.00
7.80
A
N

ATOM
1894
CA
CYS
A
534
4.829
−8.141
23.044
1.00
8.73
A
C

ATOM
1896
CB
CYS
A
534
5.588
−9.373
23.521
1.00
9.35
A
C

ATOM
1899
SG
CYS
A
534
5.440
−10.785
22.388
1.00
10.44
A
S

ATOM
1900
C
CYS
A
534
3.332
−8.326
23.234
1.00
8.30
A
C

ATOM
1901
O
CYS
A
534
2.638
−8.690
22.279
1.00
7.97
A
O

ATOM
1902
N
LYS
A
535
2.821
−8.083
24.451
1.00
8.09
A
N

ATOM
1904
CA
LYS
A
535
1.381
−8.179
24.685
1.00
8.26
A
C

ATOM
1906
CB
LYS
A
535
1.055
−8.053
26.169
1.00
8.37
A
C

ATOM
1909
CG
LYS
A
535
1.491
−9.239
26.965
1.00
10.48
A
C

ATOM
1912
CD
LYS
A
535
1.166
−9.072
28.438
1.00
13.12
A
C

ATOM
1915
CE
LYS
A
535
1.380
−10.378
29.159
1.00
15.75
A
C

ATOM
1918
NZ
LYS
A
535
1.022
−10.255
30.588
1.00
19.99
A
N

ATOM
1922
C
LYS
A
535
0.569
−7.160
23.880
1.00
8.96
A
C

ATOM
1923
O
LYS
A
535
−0.525
−7.471
23.383
1.00
8.89
A
O

ATOM
1924
N
ALA
A
536
1.079
−5.946
23.758
1.00
8.31
A
N

ATOM
1926
CA
ALA
A
536
0.461
−4.964
22.870
1.00
8.35
A
C

ATOM
1928
CB
ALA
A
536
1.208
−3.652
22.932
1.00
8.92
A
C

ATOM
1932
C
ALA
A
536
0.418
−5.463
21.434
1.00
8.28
A
C

ATOM
1933
O
ALA
A
536
−0.595
−5.288
20.745
1.00
8.64
A
O

ATOM
1934
N
MET
A
537
1.505
−6.073
20.973
1.00
7.09
A
N

ATOM
1936
CA
MET
A
537
1.578
−6.552
19.596
1.00
7.42
A
C

ATOM
1938
CB
MET
A
537
3.020
−6.875
19.183
1.00
7.57
A
C

ATOM
1941
CG
MET
A
537
3.879
−5.632
19.008
1.00
7.90
A
C

ATOM
1944
SD
MET
A
537
3.169
−4.342
17.962
1.00
11.76
A
S

ATOM
1945
CE
MET
A
537
2.724
−5.210
16.517
1.00
14.61
A
C

ATOM
1949
C
MET
A
537
0.679
−7.755
19.365
1.00
7.65
A
C

ATOM
1950
O
MET
A
537
0.122
−7.907
18.271
1.00
8.38
A
O

ATOM
1951
N
ALA
A
538
0.479
−8.576
20.386
1.00
7.79
A
N

ATOM
1953
CA
ALA
A
538
−0.451
−9.717
20.244
1.00
8.20
A
C

ATOM
1955
CB
ALA
A
538
−0.415
−10.622
21.450
1.00
8.47
A
C

ATOM
1959
C
ALA
A
538
−1.876
−9.203
20.011
1.00
8.12
A
C

ATOM
1960
O
ALA
A
538
−2.643
−9.800
19.251
1.00
8.25
A
O

ATOM
1961
N
TYR
A
539
−2.230
−8.116
20.670
1.00
8.11
A
N

ATOM
1963
CA
TYR
A
539
−3.542
−7.483
20.457
1.00
9.32
A
C

ATOM
1965
CB
TYR
A
539
−3.774
−6.365
21.469
1.00
9.99
A
C

ATOM
1968
CG
TYR
A
539
−5.068
−5.630
21.207
1.00
11.93
A
C

ATOM
1969
CD1
TYR
A
539
−6.271
−6.313
21.198
1.00
15.15
A
C

ATOM
1971
CE1
TYR
A
539
−7.490
−5.653
20.916
1.00
19.59
A
C

ATOM
1973
CZ
TYR
A
539
−7.490
−4.300
20.654
1.00
21.53
A
C

ATOM
1974
OH
TYR
A
539
−8.702
−3.667
20.376
1.00
25.74
A
O

ATOM
1976
CE2
TYR
A
539
−6.300
−3.595
20.656
1.00
19.80
A
C

ATOM
1978
CD2
TYR
A
539
−5.082
−4.267
20.928
1.00
17.80
A
C

ATOM
1980
C
TYR
A
539
−3.671
−6.953
19.013
1.00
9.25
A
C

ATOM
1981
O
TYR
A
539
−4.671
−7.228
18.327
1.00
10.22
A
O

ATOM
1982
N
LEU
A
540
−2.662
−6.226
18.534
1.00
8.68
A
N

ATOM
1984
CA
LEU
A
540
−2.681
−5.747
17.162
1.00
9.52
A
C

ATOM
1986
CB
LEU
A
540
−1.497
−4.781
16.902
1.00
9.52
A
C

ATOM
1989
CG
LEU
A
540
−1.503
−3.503
17.757
1.00
9.17
A
C

ATOM
1991
CD1
LEU
A
540
−0.301
−2.603
17.427
1.00
12.37
A
C

ATOM
1995
CD2
LEU
A
540
−2.795
−2.746
17.652
1.00
11.42
A
C

ATOM
1999
C
LEU
A
540
−2.765
−6.896
16.132
1.00
10.02
A
C

ATOM
2000
O
LEU
A
540
−3.496
−6.801
15.139
1.00
10.77
A
O

ATOM
2001
N
GLU
A
541
−2.053
−7.983
16.386
1.00
9.88
A
N

ATOM
2003
CA
GLU
A
541
−2.071
−9.173
15.534
1.00
10.37
A
C

ATOM
2005
CB
GLU
A
541
−1.081
−10.216
16.087
1.00
10.24
A
C

ATOM
2008
CG
GLU
A
541
−1.140
−11.612
15.478
1.00
11.36
A
C

ATOM
2011
CD
GLU
A
541
−0.136
−12.569
16.101
1.00
10.66
A
C

ATOM
2012
OE1
GLU
A
541
−0.448
−13.191
17.153
1.00
11.76
A
O

ATOM
2013
OE2
GLU
A
541
0.968
−12.704
15.543
1.00
11.66
A
O

ATOM
2014
C
GLU
A
541
−3.491
−9.739
15.437
1.00
10.85
A
C

ATOM
2015
O
GLU
A
541
−3.907
−10.192
14.378
1.00
11.81
A
O

ATOM
2016
N
SER
A
542
−4.243
−9.677
16.531
1.00
11.36
A
N

ATOM
2018
CA
SER
A
542
−5.608
−10.206
16.550
1.00
11.65
A
C

ATOM
2020
CB
SER
A
542
−6.160
−10.250
17.976
1.00
12.06
A
C

ATOM
2023
OG
SER
A
542
−6.549
−8.983
18.468
1.00
11.97
A
O

ATOM
2025
C
SER
A
542
−6.576
−9.458
15.641
1.00
12.56
A
C

ATOM
2026
O
SER
A
542
−7.631
−10.010
15.277
1.00
11.49
A
O

ATOM
2027
N
ILE
A
543
−6.260
−8.210
15.323
1.00
12.89
A
N

ATOM
2029
CA
ILE
A
543
−7.050
−7.424
14.358
1.00
13.67
A
C

ATOM
2031
CB
ILE
A
543
−7.562
−6.115
14.994
1.00
14.02
A
C

ATOM
2033
CG1
ILE
A
543
−6.433
−5.283
15.598
1.00
14.22
A
C

ATOM
2036
CD1
ILE
A
543
−6.826
−3.900
15.926
1.00
15.54
A
C

ATOM
2040
CG2
ILE
A
543
−8.591
−6.404
16.074
1.00
13.84
A
C

ATOM
2044
C
ILE
A
543
−6.317
−7.159
13.042
1.00
14.47
A
C

ATOM
2045
O
ILE
A
543
−6.732
−6.316
12.252
1.00
14.15
A
O

ATOM
2046
N
ASN
A
544
−5.235
−7.885
12.809
1.00
15.25
A
N

ATOM
2048
CA
ASN
A
544
−4.457
−7.780
11.575
1.00
17.01
A
C

ATOM
2050
CB
ASN
A
544
−5.260
−8.311
10.368
1.00
18.38
A
C

ATOM
2053
CG
ASN
A
544
−5.668
−9.758
10.523
1.00
22.26
A
C

ATOM
2054
OD1
ASN
A
544
−4.821
−10.644
10.660
1.00
28.79
A
O

ATOM
2055
ND2
ASN
A
544
−6.970
−10.012
10.491
1.00
27.53
A
N

ATOM
2058
C
ASN
A
544
−3.995
−6.353
11.302
1.00
17.05
A
C

ATOM
2059
O
ASN
A
544
−4.019
−5.878
10.162
1.00
18.03
A
O

ATOM
2060
N
CYS
A
545
−3.591
−5.672
12.365
1.00
16.00
A
N

ATOM
2062
CA
CYS
A
545
−3.103
−4.305
12.291
1.00
16.72
A
C

ATOM
2064
CB
CYS
A
545
−3.628
−3.544
13.494
1.00
16.76
A
C

ATOM
2067
SG
CYS
A
545
−3.019
−1.887
13.701
1.00
24.49
A
S

ATOM
2068
C
CYS
A
545
−1.586
−4.358
12.295
1.00
15.33
A
C

ATOM
2069
O
CYS
A
545
−0.994
−4.800
13.278
1.00
15.78
A
O

ATOM
2070
N
VAL
A
546
−0.969
−3.933
11.194
1.00
14.28
A
N

ATOM
2072
CA
VAL
A
546
0.498
−3.913
11.064
1.00
13.55
A
C

ATOM
2074
CB
VAL
A
546
0.939
−4.206
9.610
1.00
14.14
A
C

ATOM
2076
CG1
VAL
A
546
2.466
−4.261
9.507
1.00
15.81
A
C

ATOM
2080
CG2
VAL
A
546
0.296
−5.520
9.111
1.00
15.91
A
C

ATOM
2084
C
VAL
A
546
0.998
−2.542
11.524
1.00
13.04
A
C

ATOM
2085
O
VAL
A
546
0.606
−1.505
10.980
1.00
12.91
A
O

ATOM
2086
N
HIS
A
547
1.871
−2.540
12.533
1.00
11.11
A
N

ATOM
2088
CA
HIS
A
547
2.287
−1.318
13.227
1.00
10.91
A
C

ATOM
2090
CB
HIS
A
547
2.643
−1.668
14.683
1.00
10.19
A
C

ATOM
2093
CG
HIS
A
547
2.902
−0.475
15.544
1.00
10.34
A
C

ATOM
2094
ND1
HIS
A
547
4.081
0.228
15.491
1.00
11.48
A
N

ATOM
2096
CE1
HIS
A
547
4.038
1.226
16.361
1.00
10.70
A
C

ATOM
2098
NE2
HIS
A
547
2.864
1.199
16.967
1.00
9.34
A
N

ATOM
2100
CD2
HIS
A
547
2.140
0.138
16.481
1.00
10.35
A
C

ATOM
2102
C
HIS
A
547
3.431
−0.584
12.527
1.00
10.89
A
C

ATOM
2103
O
HIS
A
547
3.342
0.628
12.322
1.00
11.28
A
O

ATOM
2104
N
ARG
A
548
4.479
−1.321
12.157
1.00
10.62
A
N

ATOM
2106
CA
ARG
A
548
5.652
−0.819
11.406
1.00
10.76
A
C

ATOM
2108
CB
ARG
A
548
5.248
−0.092
10.114
1.00
11.42
A
C

ATOM
2111
CG
ARG
A
548
4.346
−0.845
9.128
1.00
12.89
A
C

ATOM
2114
CD
ARG
A
548
4.246
−0.093
7.781
1.00
15.96
A
C

ATOM
2117
NE
ARG
A
548
3.297
−0.686
6.841
1.00
16.19
A
N

ATOM
2119
CZ
ARG
A
548
3.236
−0.367
5.543
1.00
18.71
A
C

ATOM
2120
NH1
ARG
A
548
4.045
0.549
5.039
1.00
17.01
A
N

ATOM
2123
NH2
ARG
A
548
2.350
−0.948
4.752
1.00
19.52
A
N

ATOM
2126
C
ARG
A
548
6.616
0.100
12.165
1.00
10.94
A
C

ATOM
2127
O
ARG
A
548
7.610
0.540
11.585
1.00
11.17
A
O

ATOM
2128
N
ASP
A
549
6.345
0.423
13.421
1.00
10.64
A
N

ATOM
2130
CA
ASP
A
549
7.255
1.294
14.181
1.00
11.41
A
C

ATOM
2132
CB
ASP
A
549
6.824
2.767
14.120
1.00
11.59
A
C

ATOM
2135
CG
ASP
A
549
7.947
3.735
14.497
1.00
16.46
A
C

ATOM
2136
OD1
ASP
A
549
9.129
3.319
14.543
1.00
19.23
A
O

ATOM
2137
OD2
ASP
A
549
7.726
4.944
14.778
1.00
18.02
A
O

ATOM
2138
C
ASP
A
549
7.456
0.836
15.616
1.00
10.41
A
C

ATOM
2139
O
ASP
A
549
7.269
1.597
16.576
1.00
10.29
A
O

ATOM
2140
N
ILE
A
550
7.926
−0.400
15.743
1.00
10.29
A
N

ATOM
2142
CA
ILE
A
550
8.229
−0.986
17.046
1.00
10.14
A
C

ATOM
2144
CB
ILE
A
550
7.858
−2.490
17.037
1.00
10.18
A
C

ATOM
2146
CG1
ILE
A
550
6.440
−2.685
16.476
1.00
9.59
A
C

ATOM
2149
CD1
ILE
A
550
6.199
−4.070
15.917
1.00
12.93
A
C

ATOM
2153
CG2
ILE
A
550
7.936
−3.059
18.435
1.00
10.80
A
C

ATOM
2157
C
ILE
A
550
9.709
−0.791
17.310
1.00
10.07
A
C

ATOM
2158
O
ILE
A
550
10.517
−1.517
16.793
1.00
10.23
A
O

ATOM
2159
N
ALA
A
551
10.032
0.227
18.094
1.00
10.23
A
N

ATOM
2161
CA
ALA
A
551
11.403
0.671
18.312
1.00
9.79
A
C

ATOM
2163
CB
ALA
A
551
11.883
1.526
17.130
1.00
9.99
A
C

ATOM
2167
C
ALA
A
551
11.404
1.495
19.593
1.00
9.51
A
C

ATOM
2168
O
ALA
A
551
10.399
2.111
19.911
1.00
8.53
A
O

ATOM
2169
N
VAL
A
552
12.536
1.529
20.304
1.00
8.79
A
N

ATOM
2171
CA
VAL
A
552
12.595
2.169
21.630
1.00
9.71
A
C

ATOM
2173
CB
VAL
A
552
13.917
1.852
22.434
1.00
9.32
A
C

ATOM
2175
CG1
VAL
A
552
13.981
0.377
22.814
1.00
11.97
A
C

ATOM
2179
CG2
VAL
A
552
15.175
2.296
21.700
1.00
10.51
A
C

ATOM
2183
C
VAL
A
552
12.373
3.671
21.605
1.00
9.86
A
C

ATOM
2184
O
VAL
A
552
11.910
4.231
22.605
1.00
9.34
A
O

ATOM
2185
N
ARG
A
553
12.672
4.305
20.462
1.00
9.93
A
N

ATOM
2187
CA
ARG
A
553
12.381
5.715
20.233
1.00
11.22
A
C

ATOM
2189
CB
ARG
A
553
12.914
6.152
18.849
1.00
12.32
A
C

ATOM
2192
CG
ARG
A
553
12.746
7.598
18.520
1.00
18.30
A
C

ATOM
2195
CD
ARG
A
553
13.541
8.051
17.284
1.00
25.13
A
C

ATOM
2198
NE
ARG
A
553
13.202
9.422
16.907
1.00
30.79
A
N

ATOM
2200
CZ
ARG
A
553
13.974
10.246
16.190
1.00
34.09
A
C

ATOM
2201
NH1
ARG
A
553
15.161
9.865
15.721
1.00
35.69
A
N

ATOM
2204
NH2
ARG
A
553
13.536
11.475
15.928
1.00
35.84
A
N

ATOM
2207
C
ARG
A
553
10.873
5.962
20.295
1.00
10.85
A
C

ATOM
2208
O
ARG
A
553
10.427
7.061
20.646
1.00
9.83
A
O

ATOM
2209
N
ASN
A
554
10.101
4.948
19.911
1.00
8.85
A
N

ATOM
2211
CA
ASN
A
554
8.650
5.050
19.820
1.00
9.54
A
C

ATOM
2213
CB
ASN
A
554
8.173
4.595
18.434
1.00
8.92
A
C

ATOM
2216
CG
ASN
A
554
6.729
4.998
18.148
1.00
10.60
A
C

ATOM
2217
OD1
ASN
A
554
6.321
6.131
18.457
1.00
11.60
A
O

ATOM
2218
ND2
ASN
A
554
5.959
4.101
17.560
1.00
11.34
A
N

ATOM
2221
C
ASN
A
554
7.907
4.279
20.910
1.00
9.30
A
C

ATOM
2222
O
ASN
A
554
6.788
3.841
20.707
1.00
10.60
A
O

ATOM
2223
N
ILE
A
555
8.544
4.108
22.062
1.00
10.21
A
N

ATOM
2225
CA
ILE
A
555
7.935
3.514
23.235
1.00
9.86
A
C

ATOM
2227
CB
ILE
A
555
8.595
2.177
23.597
1.00
9.61
A
C

ATOM
2229
CG1
ILE
A
555
8.358
1.140
22.488
1.00
10.41
A
C

ATOM
2232
CD1
ILE
A
555
9.318
0.017
22.555
1.00
11.60
A
C

ATOM
2236
CG2
ILE
A
555
8.103
1.672
24.948
1.00
9.20
A
C

ATOM
2240
C
ILE
A
555
8.114
4.536
24.350
1.00
10.75
A
C

ATOM
2241
O
ILE
A
555
9.208
5.071
24.541
1.00
10.55
A
O

ATOM
2242
N
LEU
A
556
7.044
4.807
25.088
1.00
10.73
A
N

ATOM
2244
CA
LEU
A
556
7.084
5.751
26.209
1.00
11.14
A
C

ATOM
2246
CB
LEU
A
556
5.932
6.765
26.100
1.00
11.83
A
C

ATOM
2249
CG
LEU
A
556
6.005
7.814
24.986
1.00
14.83
A
C

ATOM
2251
CD1
LEU
A
556
7.308
8.567
24.986
1.00
18.18
A
C

ATOM
2255
CD2
LEU
A
556
5.770
7.191
23.644
1.00
19.54
A
C

ATOM
2259
C
LEU
A
556
7.001
5.052
27.535
1.00
10.30
A
C

ATOM
2260
O
LEU
A
556
6.353
4.017
27.670
1.00
9.91
A
O

ATOM
2261
N
VAL
A
557
7.636
5.660
28.529
1.00
9.82
A
N

ATOM
2263
CA
VAL
A
557
7.790
5.088
29.856
1.00
10.20
A
C

ATOM
2265
CB
VAL
A
557
9.244
5.235
30.379
1.00
9.42
A
C

ATOM
2267
CG1
VAL
A
557
9.382
4.662
31.776
1.00
9.30
A
C

ATOM
2271
CG2
VAL
A
557
10.274
4.537
29.435
1.00
10.82
A
C

ATOM
2275
C
VAL
A
557
6.809
5.808
30.788
1.00
10.92
A
C

ATOM
2276
O
VAL
A
557
6.990
6.979
31.126
1.00
10.29
A
O

ATOM
2277
N
ALA
A
558
5.744
5.103
31.149
1.00
11.83
A
N

ATOM
2279
CA
ALA
A
558
4.753
5.595
32.116
1.00
12.73
A
C

ATOM
2281
CB
ALA
A
558
3.474
4.716
32.040
1.00
12.91
A
C

ATOM
2285
C
ALA
A
558
5.291
5.615
33.542
1.00
13.27
A
C

ATOM
2286
O
ALA
A
558
5.043
6.550
34.330
1.00
14.71
A
O

ATOM
2287
N
SER
A
559
6.010
4.559
33.884
1.00
13.11
A
N

ATOM
2289
CA
SER
A
559
6.639
4.396
35.186
1.00
13.68
A
C

ATOM
2291
CB
SER
A
559
5.618
3.934
36.220
1.00
13.21
A
C

ATOM
2294
OG
SER
A
559
5.230
2.589
36.006
1.00
13.73
A
O

ATOM
2296
C
SER
A
559
7.719
3.352
35.030
1.00
13.54
A
C

ATOM
2297
O
SER
A
559
7.737
2.663
34.025
1.00
12.55
A
O

ATOM
2298
N
PRO
A
560
8.593
3.177
36.018
1.00
14.61
A
N

ATOM
2299
CA
PRO
A
560
9.559
2.069
35.950
1.00
15.41
A
C

ATOM
2301
CB
PRO
A
560
10.361
2.217
37.251
1.00
15.46
A
C

ATOM
2304
CG
PRO
A
560
10.251
3.662
37.572
1.00
15.49
A
C

ATOM
2307
CD
PRO
A
560
8.794
3.996
37.233
1.00
15.51
A
C

ATOM
2310
C
PRO
A
560
8.919
0.678
35.800
1.00
15.83
A
C

ATOM
2311
O
PRO
A
560
9.589
−0.279
35.390
1.00
16.34
A
O

ATOM
2312
N
GLU
A
561
7.626
0.579
36.070
1.00
16.53
A
N

ATOM
2314
CA
GLU
A
561
6.918
−0.689
35.993
1.00
16.63
A
C

ATOM
2316
CB
GLU
A
561
6.035
−0.834
37.234
1.00
18.01
A
C

ATOM
2319
CG
GLU
A
561
6.833
−0.946
38.529
1.00
22.37
A
C

ATOM
2322
CD
GLU
A
561
6.517
0.168
39.506
1.00
28.24
A
C

ATOM
2323
OE1
GLU
A
561
6.453
1.357
39.072
1.00
32.07
A
O

ATOM
2324
OE2
GLU
A
561
6.315
−0.152
40.707
1.00
33.30
A
O

ATOM
2325
C
GLU
A
561
6.059
−0.871
34.733
1.00
14.93
A
C

ATOM
2326
O
GLU
A
561
5.445
−1.916
34.574
1.00
14.59
A
O

ATOM
2327
N
CYS
A
562
6.025
0.111
33.835
1.00
13.75
A
N

ATOM
2329
CA
CYS
A
562
5.074
0.089
32.711
1.00
14.08
A
C

ATOM
2331
CB
CYS
A
562
3.692
0.541
33.159
1.00
14.16
A
C

ATOM
2334
SG
CYS
A
562
2.464
0.485
31.846
1.00
17.94
A
S

ATOM
2335
C
CYS
A
562
5.534
0.942
31.520
1.00
12.60
A
C

ATOM
2336
O
CYS
A
562
5.747
2.155
31.640
1.00
12.45
A
O

ATOM
2337
N
VAL
A
563
5.709
0.282
30.377
1.00
11.25
A
N

ATOM
2339
CA
VAL
A
563
5.979
0.962
29.125
1.00
10.38
A
C

ATOM
2341
CB
VAL
A
563
7.259
0.421
28.421
1.00
10.60
A
C

ATOM
2343
CG1
VAL
A
563
8.477
0.548
29.329
1.00
10.27
A
C

ATOM
2347
CG2
VAL
A
563
7.102
−1.020
27.949
1.00
10.55
A
C

ATOM
2351
C
VAL
A
563
4.748
0.912
28.184
1.00
10.67
A
C

ATOM
2352
O
VAL
A
563
3.867
0.058
28.336
1.00
10.13
A
O

ATOM
2353
N
LYS
A
564
4.723
1.806
27.202
1.00
9.96
A
N

ATOM
2355
CA
LYS
A
564
3.586
1.997
26.285
1.00
10.71
A
C

ATOM
2357
CB
LYS
A
564
2.835
3.290
26.642
1.00
10.90
A
C

ATOM
2360
CG
LYS
A
564
2.453
3.420
28.104
1.00
13.45
A
C

ATOM
2363
CD
LYS
A
564
1.102
2.850
28.403
1.00
14.37
A
C

ATOM
2366
CE
LYS
A
564
0.676
3.158
29.838
1.00
16.32
A
C

ATOM
2369
NZ
LYS
A
564
−0.589
2.458
30.221
1.00
17.26
A
N

ATOM
2373
C
LYS
A
564
4.050
2.148
24.828
1.00
9.71
A
C

ATOM
2374
O
LYS
A
564
4.814
3.069
24.502
1.00
9.88
A
O

ATOM
2375
N
LEU
A
565
3.615
1.238
23.964
1.00
8.95
A
N

ATOM
2377
CA
LEU
A
565
3.909
1.334
22.533
1.00
9.28
A
C

ATOM
2379
CB
LEU
A
565
3.418
0.094
21.802
1.00
9.45
A
C

ATOM
2382
CG
LEU
A
565
3.702
0.004
20.289
1.00
9.53
A
C

ATOM
2384
CD1
LEU
A
565
5.202
0.062
20.003
1.00
10.72
A
C

ATOM
2388
CD2
LEU
A
565
3.070
−1.258
19.781
1.00
12.45
A
C

ATOM
2392
C
LEU
A
565
3.245
2.565
21.928
1.00
9.46
A
C

ATOM
2393
O
LEU
A
565
2.054
2.825
22.167
1.00
9.53
A
O

ATOM
2394
N
GLY
A
566
4.007
3.302
21.131
1.00
10.94
A
N

ATOM
2396
CA
GLY
A
566
3.540
4.539
20.511
1.00
12.38
A
C

ATOM
2399
C
GLY
A
566
2.748
4.337
19.222
1.00
14.40
A
C

ATOM
2400
O
GLY
A
566
2.312
3.235
18.882
1.00
12.68
A
O

ATOM
2401
N
ASP
A
567
2.524
5.424
18.494
1.00
17.06
A
N

ATOM
2403
CA
ASP
A
567
1.644
5.322
17.327
1.00
19.73
A
C

ATOM
2405
CB
ASP
A
567
0.986
6.649
16.942
1.00
21.13
A
C

ATOM
2408
CG
ASP
A
567
1.917
7.779
16.889
1.00
24.80
A
C

ATOM
2409
OD1
ASP
A
567
2.981
7.672
16.231
1.00
32.54
A
O

ATOM
2410
OD2
ASP
A
567
1.623
8.856
17.439
1.00
29.95
A
O

ATOM
2411
C
ASP
A
567
2.257
4.622
16.108
1.00
20.41
A
C

ATOM
2412
O
ASP
A
567
3.467
4.413
16.011
1.00
17.31
A
O

ATOM
2413
N
PHE
A
568
1.368
4.262
15.196
1.00
22.78
A
N

ATOM
2415
CA
PHE
A
568
1.698
3.525
13.979
1.00
25.32
A
C

ATOM
2417
CB
PHE
A
568
0.428
3.274
13.152
1.00
26.08
A
C

ATOM
2420
CG
PHE
A
568
−0.619
2.555
13.894
1.00
27.54
A
C

ATOM
2421
CD1
PHE
A
568
−1.780
3.199
14.285
1.00
29.54
A
C

ATOM
2423
CE1
PHE
A
568
−2.745
2.522
14.983
1.00
29.57
A
C

ATOM
2425
CZ
PHE
A
568
−2.560
1.197
15.312
1.00
30.42
A
C

ATOM
2427
CE2
PHE
A
568
−1.412
0.548
14.935
1.00
30.12
A
C

ATOM
2429
CD2
PHE
A
568
−0.443
1.228
14.228
1.00
29.43
A
C

ATOM
2431
C
PHE
A
568
2.666
4.282
13.116
1.00
27.26
A
C

ATOM
2432
O
PHE
A
568
2.610
5.502
13.050
1.00
27.24
A
O

ATOM
2433
N
GLY
A
569
3.536
3.545
12.433
1.00
29.69
A
N

ATOM
2435
CA
GLY
A
569
4.511
4.124
11.531
1.00
32.08
A
C

ATOM
2438
C
GLY
A
569
3.937
5.058
10.482
1.00
34.61
A
C

ATOM
2439
O
GLY
A
569
4.602
6.029
10.110
1.00
34.79
A
O

ATOM
2440
N
LEU
A
570
2.724
4.754
10.010
1.00
37.79
A
N

ATOM
2442
CA
LEU
A
570
1.999
5.549
8.993
1.00
40.50
A
C

ATOM
2444
CB
LEU
A
570
0.514
5.665
9.387
1.00
40.83
A
C

ATOM
2447
CG
LEU
A
570
−0.463
6.442
8.489
1.00
41.93
A
C

ATOM
2449
CD1
LEU
A
570
−0.487
5.925
7.051
1.00
42.79
A
C

ATOM
2453
CD2
LEU
A
570
−1.870
6.383
9.095
1.00
42.81
A
C

ATOM
2457
C
LEU
A
570
2.572
6.949
8.737
1.00
42.14
A
C

ATOM
2458
O
LEU
A
570
2.682
7.769
9.670
1.00
43.08
A
O

ATOM
2459
N
SER
A
571
2.929
7.207
7.475
1.00
43.89
A
N

ATOM
2461
CA
SER
A
571
3.588
8.455
7.062
1.00
45.06
A
C

ATOM
2463
CB
SER
A
571
4.686
8.163
6.017
1.00
45.02
A
C

ATOM
2466
OG
SER
A
571
5.526
7.091
6.423
1.00
45.78
A
O

ATOM
2468
C
SER
A
571
2.551
9.456
6.521
1.00
46.00
A
C

ATOM
2469
O
SER
A
571
1.345
9.295
6.762
1.00
46.79
A
O

ATOM
2470
N
ARG
A
572
3.012
10.481
5.800
1.00
46.90
A
N

ATOM
2472
CA
ARG
A
572
2.146
11.585
5.348
1.00
47.52
A
C

ATOM
2474
CB
ARG
A
572
2.414
12.856
6.181
1.00
47.67
A
C

ATOM
2477
CG
ARG
A
572
3.899
13.255
6.343
1.00
48.36
A
C

ATOM
2480
CD
ARG
A
572
4.392
14.299
5.342
1.00
48.94
A
C

ATOM
2483
NE
ARG
A
572
5.846
14.476
5.371
1.00
49.60
A
N

ATOM
2485
CZ
ARG
A
572
6.548
15.158
4.461
1.00
49.93
A
C

ATOM
2486
NH1
ARG
A
572
5.942
15.748
3.432
1.00
49.93
A
N

ATOM
2489
NH2
ARG
A
572
7.869
15.255
4.580
1.00
50.04
A
N

ATOM
2492
C
ARG
A
572
2.299
11.870
3.842
1.00
47.78
A
C

ATOM
2493
O
ARG
A
572
2.330
13.032
3.413
1.00
47.93
A
O

ATOM
2494
N
TYR
A
573
2.348
10.800
3.047
1.00
47.99
A
N

ATOM
2496
CA
TYR
A
573
2.606
10.890
1.604
1.00
48.13
A
C

ATOM
2498
CB
TYR
A
573
3.839
10.038
1.264
1.00
48.32
A
C

ATOM
2501
CG
TYR
A
573
5.090
10.843
0.971
1.00
49.01
A
C

ATOM
2502
CD1
TYR
A
573
5.840
11.408
2.003
1.00
49.66
A
C

ATOM
2504
CE1
TYR
A
573
6.988
12.154
1.736
1.00
50.12
A
C

ATOM
2506
CZ
TYR
A
573
7.396
12.335
0.421
1.00
50.65
A
C

ATOM
2507
OH
TYR
A
573
8.530
13.070
0.141
1.00
51.55
A
O

ATOM
2509
CE2
TYR
A
573
6.668
11.784
−0.618
1.00
50.16
A
C

ATOM
2511
CD2
TYR
A
573
5.522
11.041
−0.340
1.00
49.75
A
C

ATOM
2513
C
TYR
A
573
1.396
10.437
0.749
1.00
47.99
A
C

ATOM
2514
O
TYR
A
573
0.637
9.549
1.157
1.00
48.18
A
O

ATOM
2515
N
ILE
A
574
1.218
11.060
−0.423
1.00
47.68
A
N

ATOM
2517
CA
ILE
A
574
0.221
10.611
−1.414
1.00
47.28
A
C

ATOM
2519
CB
ILE
A
574
−0.335
11.823
−2.263
1.00
47.36
A
C

ATOM
2521
CG1
ILE
A
574
−1.852
11.681
−2.521
1.00
47.24
A
C

ATOM
2524
CD1
ILE
A
574
−2.265
10.667
−3.589
1.00
47.19
A
C

ATOM
2528
CG2
ILE
A
574
0.468
12.038
−3.572
1.00
47.44
A
C

ATOM
2532
C
ILE
A
574
0.819
9.524
−2.312
1.00
46.58
A
C

ATOM
2533
O
ILE
A
574
0.097
8.640
−2.793
1.00
47.04
A
O

ATOM
2534
N
GLU
A
575
2.133
9.598
−2.539
1.00
45.52
A
N

ATOM
2536
CA
GLU
A
575
2.848
8.569
−3.297
1.00
44.42
A
C

ATOM
2538
CB
GLU
A
575
4.131
9.120
−3.949
1.00
44.66
A
C

ATOM
2541
CG
GLU
A
575
4.611
8.287
−5.139
1.00
45.56
A
C

ATOM
2544
CD
GLU
A
575
5.484
9.057
−6.128
1.00
47.20
A
C

ATOM
2545
OE1
GLU
A
575
6.216
9.984
−5.710
1.00
47.38
A
O

ATOM
2546
OE2
GLU
A
575
5.450
8.721
−7.335
1.00
47.58
A
O

ATOM
2547
C
GLU
A
575
3.162
7.383
−2.392
1.00
42.62
A
C

ATOM
2548
O
GLU
A
575
2.802
6.252
−2.726
1.00
43.25
A
O

ATOM
2549
N
ASP
A
576
3.840
7.644
−1.266
1.00
40.22
A
N

ATOM
2551
CA
ASP
A
576
4.075
6.649
−0.202
1.00
37.98
A
C

ATOM
2553
CB
ASP
A
576
2.750
5.995
0.225
1.00
38.18
A
C

ATOM
2556
CG
ASP
A
576
2.910
5.016
1.364
1.00
39.08
A
C

ATOM
2557
OD1
ASP
A
576
2.937
3.796
1.076
1.00
38.78
A
O

ATOM
2558
OD2
ASP
A
576
2.985
5.364
2.570
1.00
41.48
A
O

ATOM
2559
C
ASP
A
576
5.106
5.614
−0.658
1.00
35.29
A
C

ATOM
2560
O
ASP
A
576
5.117
5.222
−1.818
1.00
35.14
A
O

ATOM
2561
N
GLU
A
577
5.977
5.182
0.251
1.00
32.19
A
N

ATOM
2563
CA
GLU
A
577
7.146
4.377
−0.133
1.00
29.90
A
C

ATOM
2565
CB
GLU
A
577
8.307
4.597
0.858
1.00
29.98
A
C

ATOM
2568
CG
GLU
A
577
8.924
5.992
0.745
1.00
29.86
A
C

ATOM
2571
CD
GLU
A
577
10.252
6.149
1.479
1.00
30.30
A
C

ATOM
2572
OE1
GLU
A
577
11.230
5.443
1.141
1.00
27.60
A
O

ATOM
2573
OE2
GLU
A
577
10.322
7.008
2.384
1.00
30.64
A
O

ATOM
2574
C
GLU
A
577
6.838
2.878
−0.335
1.00
27.95
A
C

ATOM
2575
O
GLU
A
577
7.741
2.092
−0.617
1.00
26.38
A
O

ATOM
2576
N
ASP
A
578
5.568
2.488
−0.214
1.00
25.79
A
N

ATOM
2578
CA
ASP
A
578
5.152
1.130
−0.565
1.00
24.73
A
C

ATOM
2580
CB
ASP
A
578
3.756
0.802
−0.009
1.00
24.59
A
C

ATOM
2583
CG
ASP
A
578
3.755
0.507
1.479
1.00
24.22
A
C

ATOM
2584
OD1
ASP
A
578
4.758
0.759
2.173
1.00
22.79
A
O

ATOM
2585
OD2
ASP
A
578
2.761
0.021
2.040
1.00
23.67
A
O

ATOM
2586
C
ASP
A
578
5.113
0.914
−2.085
1.00
24.30
A
C

ATOM
2587
O
ASP
A
578
5.010
−0.223
−2.538
1.00
22.85
A
O

ATOM
2588
N
TYR
A
579
5.172
2.001
−2.859
1.00
24.45
A
N

ATOM
2590
CA
TYR
A
579
5.029
1.934
−4.315
1.00
25.01
A
C

ATOM
2592
CB
TYR
A
579
3.928
2.908
−4.770
1.00
25.04
A
C

ATOM
2595
CG
TYR
A
579
2.556
2.582
−4.218
1.00
24.47
A
C

ATOM
2596
CD1
TYR
A
579
2.195
2.963
−2.928
1.00
25.69
A
C

ATOM
2598
CE1
TYR
A
579
0.932
2.665
−2.409
1.00
25.75
A
C

ATOM
2600
CZ
TYR
A
579
0.022
1.977
−3.187
1.00
25.29
A
C

ATOM
2601
OH
TYR
A
579
−1.217
1.675
−2.675
1.00
25.28
A
O

ATOM
2603
CE2
TYR
A
579
0.358
1.577
−4.475
1.00
25.54
A
C

ATOM
2605
CD2
TYR
A
579
1.620
1.886
−4.984
1.00
26.01
A
C

ATOM
2607
C
TYR
A
579
6.329
2.209
−5.093
1.00
25.81
A
C

ATOM
2608
O
TYR
A
579
6.401
1.925
−6.285
1.00
26.17
A
O

ATOM
2609
N
TYR
A
580
7.349
2.751
−4.435
1.00
26.41
A
N

ATOM
2611
CA
TYR
A
580
8.617
3.046
−5.106
1.00
26.93
A
C

ATOM
2613
CB
TYR
A
580
8.598
4.475
−5.677
1.00
27.09
A
C

ATOM
2616
CG
TYR
A
580
8.584
5.554
−4.622
1.00
26.95
A
C

ATOM
2617
CD1
TYR
A
580
9.771
6.087
−4.123
1.00
27.01
A
C

ATOM
2619
CE1
TYR
A
580
9.764
7.069
−3.135
1.00
27.38
A
C

ATOM
2621
CZ
TYR
A
580
8.558
7.541
−2.647
1.00
28.47
A
C

ATOM
2622
OH
TYR
A
580
8.545
8.516
−1.674
1.00
29.60
A
O

ATOM
2624
CE2
TYR
A
580
7.363
7.032
−3.132
1.00
28.07
A
C

ATOM
2626
CD2
TYR
A
580
7.381
6.043
−4.113
1.00
27.45
A
C

ATOM
2628
C
TYR
A
580
9.823
2.867
−4.183
1.00
27.08
A
C

ATOM
2629
O
TYR
A
580
9.705
2.962
−2.949
1.00
27.01
A
O

ATOM
2630
N
LYS
A
581
10.981
2.607
−4.787
1.00
27.09
A
N

ATOM
2632
CA
LYS
A
581
12.230
2.554
−4.044
1.00
27.49
A
C

ATOM
2634
CB
LYS
A
581
13.167
1.469
−4.591
1.00
27.82
A
C

ATOM
2637
CG
LYS
A
581
12.624
0.066
−4.493
1.00
29.08
A
C

ATOM
2640
CD
LYS
A
581
12.553
−0.410
−3.054
1.00
29.95
A
C

ATOM
2643
CE
LYS
A
581
12.586
−1.923
−2.981
1.00
30.16
A
C

ATOM
2646
NZ
LYS
A
581
13.933
−2.487
−3.300
1.00
31.13
A
N

ATOM
2650
C
LYS
A
581
12.913
3.910
−4.147
1.00
27.35
A
C

ATOM
2651
O
LYS
A
581
13.313
4.327
−5.244
1.00
27.59
A
O

ATOM
2652
N
ALA
A
582
13.045
4.587
−3.008
1.00
26.87
A
N

ATOM
2654
CA
ALA
A
582
13.721
5.877
−2.940
1.00
27.05
A
C

ATOM
2656
CB
ALA
A
582
13.460
6.524
−1.587
1.00
27.03
A
C

ATOM
2660
C
ALA
A
582
15.219
5.686
−3.147
1.00
27.17
A
C

ATOM
2661
O
ALA
A
582
15.770
4.669
−2.733
1.00
26.90
A
O

ATOM
2662
N
SER
A
583
15.875
6.657
−3.789
1.00
26.98
A
N

ATOM
2664
CA
SER
A
583
17.342
6.691
−3.818
1.00
27.27
A
C

ATOM
2666
CB
SER
A
583
17.864
7.934
−4.568
1.00
27.02
A
C

ATOM
2669
OG
SER
A
583
17.666
7.842
−5.971
1.00
24.95
A
O

ATOM
2671
C
SER
A
583
17.899
6.673
−2.390
1.00
27.51
A
C

ATOM
2672
O
SER
A
583
18.853
5.960
−2.111
1.00
28.19
A
O

ATOM
2673
N
VAL
A
584
17.301
7.481
−1.511
1.00
27.95
A
N

ATOM
2675
CA
VAL
A
584
17.624
7.547
−0.081
1.00
27.95
A
C

ATOM
2677
CB
VAL
A
584
18.359
8.860
0.279
1.00
28.18
A
C

ATOM
2679
CG1
VAL
A
584
18.684
8.910
1.762
1.00
29.19
A
C

ATOM
2683
CG2
VAL
A
584
19.610
8.997
−0.529
1.00
28.53
A
C

ATOM
2687
C
VAL
A
584
16.314
7.499
0.716
1.00
27.93
A
C

ATOM
2688
O
VAL
A
584
15.532
8.445
0.693
1.00
27.03
A
O

ATOM
2689
N
THR
A
585
16.072
6.403
1.428
1.00
28.20
A
N

ATOM
2691
CA
THR
A
585
14.795
6.239
2.111
1.00
28.72
A
C

ATOM
2693
CB
THR
A
585
14.394
4.744
2.181
1.00
28.79
A
C

ATOM
2695
OG1
THR
A
585
13.033
4.623
2.621
1.00
29.29
A
O

ATOM
2697
CG2
THR
A
585
15.193
3.992
3.216
1.00
29.13
A
C

ATOM
2701
C
THR
A
585
14.779
6.882
3.494
1.00
28.58
A
C

ATOM
2702
O
THR
A
585
15.809
7.081
4.129
1.00
29.24
A
O

ATOM
2703
N
ARG
A
586
13.572
7.185
3.951
1.00
28.53
A
N

ATOM
2705
CA
ARG
A
586
13.331
7.764
5.266
1.00
27.88
A
C

ATOM
2707
CB
ARG
A
586
12.163
8.751
5.159
1.00
28.97
A
C

ATOM
2710
CG
ARG
A
586
12.163
9.613
3.892
1.00
32.87
A
C

ATOM
2713
CD
ARG
A
586
11.091
10.706
3.880
1.00
37.35
A
C

ATOM
2716
NE
ARG
A
586
11.446
11.869
4.700
1.00
40.84
A
N

ATOM
2718
CZ
ARG
A
586
12.287
12.850
4.340
1.00
42.20
A
C

ATOM
2719
NH1
ARG
A
586
12.897
12.839
3.157
1.00
42.91
A
N

ATOM
2722
NH2
ARG
A
586
12.524
13.854
5.183
1.00
42.67
A
N

ATOM
2725
C
ARG
A
586
12.978
6.639
6.271
1.00
25.82
A
C

ATOM
2726
O
ARG
A
586
12.956
6.850
7.485
1.00
25.52
A
O

ATOM
2727
N
LEU
A
587
12.724
5.449
5.742
1.00
23.19
A
N

ATOM
2729
CA
LEU
A
587
12.216
4.320
6.520
1.00
21.02
A
C

ATOM
2731
CB
LEU
A
587
11.740
3.228
5.569
1.00
21.26
A
C

ATOM
2734
CG
LEU
A
587
10.591
3.508
4.618
1.00
22.52
A
C

ATOM
2736
CD1
LEU
A
587
10.428
2.299
3.713
1.00
23.24
A
C

ATOM
2740
CD2
LEU
A
587
9.314
3.812
5.391
1.00
23.89
A
C

ATOM
2744
C
LEU
A
587
13.303
3.726
7.410
1.00
19.25
A
C

ATOM
2745
O
LEU
A
587
14.475
3.822
7.075
1.00
18.79
A
O

ATOM
2746
N
PRO
A
588
12.911
3.068
8.506
1.00
16.35
A
N

ATOM
2747
CA
PRO
A
588
13.877
2.494
9.451
1.00
14.93
A
C

ATOM
2749
CB
PRO
A
588
13.037
2.286
10.717
1.00
14.98
A
C

ATOM
2752
CG
PRO
A
588
11.683
1.973
10.177
1.00
15.18
A
C

ATOM
2755
CD
PRO
A
588
11.513
2.828
8.927
1.00
16.26
A
C

ATOM
2758
C
PRO
A
588
14.465
1.175
8.947
1.00
13.29
A
C

ATOM
2759
O
PRO
A
588
14.183
0.083
9.484
1.00
12.58
A
O

ATOM
2760
N
ILE
A
589
15.309
1.281
7.925
1.00
11.92
A
N

ATOM
2762
CA
ILE
A
589
15.866
0.118
7.230
1.00
11.54
A
C

ATOM
2764
CB
ILE
A
589
16.889
0.600
6.152
1.00
11.43
A
C

ATOM
2766
CG1
ILE
A
589
16.174
1.366
5.024
1.00
13.60
A
C

ATOM
2769
CD1
ILE
A
589
15.092
0.544
4.305
1.00
14.47
A
C

ATOM
2773
CG2
ILE
A
589
17.700
−0.581
5.601
1.00
12.99
A
C

ATOM
2777
C
ILE
A
589
16.574
−0.864
8.203
1.00
10.07
A
C

ATOM
2778
O
ILE
A
589
16.471
−2.075
8.055
1.00
9.44
A
O

ATOM
2779
N
LYS
A
590
17.300
−0.330
9.186
1.00
9.76
A
N

ATOM
2781
CA
LYS
A
590
18.065
−1.186
10.109
1.00
9.66
A
C

ATOM
2783
CB
LYS
A
590
19.111
−0.377
10.888
1.00
9.94
A
C

ATOM
2786
CG
LYS
A
590
20.252
0.122
10.016
1.00
10.30
A
C

ATOM
2789
CD
LYS
A
590
21.098
1.207
10.703
1.00
10.44
A
C

ATOM
2792
CE
LYS
A
590
22.248
1.579
9.797
1.00
12.41
A
C

ATOM
2795
NZ
LYS
A
590
23.160
2.618
10.380
1.00
12.07
A
N

ATOM
2799
C
LYS
A
590
17.174
−1.954
11.068
1.00
9.73
A
C

ATOM
2800
O
LYS
A
590
17.660
−2.830
11.790
1.00
9.50
A
O

ATOM
2801
N
TRP
A
591
15.876
−1.628
11.089
1.00
9.17
A
N

ATOM
2803
CA
TRP
A
591
14.905
−2.339
11.912
1.00
9.87
A
C

ATOM
2805
CB
TRP
A
591
14.017
−1.349
12.662
1.00
9.98
A
C

ATOM
2808
CG
TRP
A
591
14.655
−0.542
13.766
1.00
11.71
A
C

ATOM
2809
CD1
TRP
A
591
14.457
−0.709
15.103
1.00
12.20
A
C

ATOM
2811
NE1
TRP
A
591
15.141
0.252
15.803
1.00
13.37
A
N

ATOM
2813
CE2
TRP
A
591
15.793
1.065
14.924
1.00
12.15
A
C

ATOM
2814
CD2
TRP
A
591
15.490
0.607
13.627
1.00
13.10
A
C

ATOM
2815
CE3
TRP
A
591
16.031
1.299
12.533
1.00
12.17
A
C

ATOM
2817
CZ3
TRP
A
591
16.853
2.386
12.772
1.00
15.31
A
C

ATOM
2819
CH2
TRP
A
591
17.127
2.813
14.082
1.00
13.32
A
C

ATOM
2821
CZ2
TRP
A
591
16.621
2.156
15.161
1.00
12.48
A
C

ATOM
2823
C
TRP
A
591
13.997
−3.282
11.108
1.00
9.92
A
C

ATOM
2824
O
TRP
A
591
13.223
−4.039
11.706
1.00
10.09
A
O

ATOM
2825
N
MET
A
592
14.096
−3.251
9.773
1.00
9.75
A
N

ATOM
2827
CA
MET
A
592
13.094
−3.843
8.881
1.00
9.99
A
C

ATOM
2829
CB
MET
A
592
12.876
−2.908
7.667
1.00
9.83
A
C

ATOM
2832
CG
MET
A
592
12.051
−1.676
7.999
1.00
11.13
A
C

ATOM
2835
SD
MET
A
592
12.111
−0.339
6.763
1.00
14.42
A
S

ATOM
2836
CE
MET
A
592
11.786
−1.271
5.270
1.00
11.86
A
C

ATOM
2840
C
MET
A
592
13.432
−5.244
8.373
1.00
9.53
A
C

ATOM
2841
O
MET
A
592
14.602
−5.589
8.192
1.00
10.45
A
O

ATOM
2842
N
SER
A
593
12.395
−6.034
8.118
1.00
9.01
A
N

ATOM
2844
CA
SER
A
593
12.558
−7.391
7.605
1.00
9.63
A
C

ATOM
2846
CB
SER
A
593
11.241
−8.149
7.607
1.00
10.07
A
C

ATOM
2849
OG
SER
A
593
10.406
−7.605
6.617
1.00
10.36
A
O

ATOM
2851
C
SER
A
593
13.073
−7.313
6.164
1.00
9.56
A
C

ATOM
2852
O
SER
A
593
12.921
−6.287
5.511
1.00
10.05
A
O

ATOM
2853
N
PRO
A
594
13.695
−8.378
5.686
1.00
10.88
A
N

ATOM
2854
CA
PRO
A
594
14.197
−8.420
4.301
1.00
11.51
A
C

ATOM
2856
CB
PRO
A
594
14.787
−9.828
4.191
1.00
12.13
A
C

ATOM
2859
CG
PRO
A
594
15.141
−10.176
5.577
1.00
12.75
A
C

ATOM
2862
CD
PRO
A
594
14.022
−9.610
6.420
1.00
10.32
A
C

ATOM
2865
C
PRO
A
594
13.108
−8.199
3.254
1.00
11.67
A
C

ATOM
2866
O
PRO
A
594
13.366
−7.517
2.289
1.00
12.87
A
O

ATOM
2867
N
GLU
A
595
11.916
−8.754
3.455
1.00
12.18
A
N

ATOM
2869
CA
GLU
A
595
10.819
−8.588
2.509
1.00
11.54
A
C

ATOM
2871
CB
GLU
A
595
9.685
−9.578
2.796
1.00
11.95
A
C

ATOM
2874
CG
GLU
A
595
8.905
−9.349
4.080
1.00
12.54
A
C

ATOM
2877
CD
GLU
A
595
9.410
−10.169
5.261
1.00
12.35
A
C

ATOM
2878
OE1
GLU
A
595
10.587
−10.628
5.259
1.00
12.67
A
O

ATOM
2879
OE2
GLU
A
595
8.624
−10.313
6.232
1.00
11.80
A
O

ATOM
2880
C
GLU
A
595
10.325
−7.139
2.494
1.00
11.35
A
C

ATOM
2881
O
GLU
A
595
9.870
−6.621
1.462
1.00
10.36
A
O

ATOM
2882
N
SER
A
596
10.453
−6.468
3.639
1.00
11.09
A
N

ATOM
2884
CA
SER
A
596
10.129
−5.054
3.746
1.00
11.11
A
C

ATOM
2886
CB
SER
A
596
10.035
−4.639
5.215
1.00
11.61
A
C

ATOM
2889
OG
SER
A
596
9.071
−5.412
5.916
1.00
10.96
A
O

ATOM
2891
C
SER
A
596
11.154
−4.165
3.009
1.00
11.46
A
C

ATOM
2892
O
SER
A
596
10.780
−3.187
2.349
1.00
11.08
A
O

ATOM
2893
N
ILE
A
597
12.433
−4.494
3.154
1.00
11.82
A
N

ATOM
2895
CA
ILE
A
597
13.498
−3.793
2.447
1.00
12.20
A
C

ATOM
2897
CB
ILE
A
597
14.870
−4.196
3.012
1.00
12.29
A
C

ATOM
2899
CG1
ILE
A
597
15.044
−3.734
4.479
1.00
11.10
A
C

ATOM
2902
CD1
ILE
A
597
16.321
−4.267
5.140
1.00
10.75
A
C

ATOM
2906
CG2
ILE
A
597
15.980
−3.586
2.160
1.00
13.21
A
C

ATOM
2910
C
ILE
A
597
13.433
−4.051
0.923
1.00
12.61
A
C

ATOM
2911
O
ILE
A
597
13.521
−3.120
0.135
1.00
14.25
A
O

ATOM
2912
N
ASN
A
598
13.275
−5.298
0.514
1.00
12.98
A
N

ATOM
2914
CA
ASN
A
598
13.331
−5.672
−0.919
1.00
14.27
A
C

ATOM
2916
CB
ASN
A
598
13.618
−7.179
−1.052
1.00
14.04
A
C

ATOM
2919
CG
ASN
A
598
15.068
−7.523
−0.790
1.00
16.01
A
C

ATOM
2920
OD1
ASN
A
598
15.971
−6.727
−1.066
1.00
18.13
A
O

ATOM
2921
ND2
ASN
A
598
15.307
−8.734
−0.283
1.00
16.92
A
N

ATOM
2924
C
ASN
A
598
12.077
−5.337
−1.725
1.00
15.32
A
C

ATOM
2925
O
ASN
A
598
12.162
−4.886
−2.877
1.00
15.17
A
O

ATOM
2926
N
PHE
A
599
10.912
−5.552
−1.119
1.00
15.42
A
N

ATOM
2928
CA
PHE
A
599
9.636
−5.496
−1.839
1.00
15.79
A
C

ATOM
2930
CB
PHE
A
599
9.088
−6.914
−2.039
1.00
15.78
A
C

ATOM
2933
CG
PHE
A
599
10.095
−7.884
−2.566
1.00
18.17
A
C

ATOM
2934
CD1
PHE
A
599
10.746
−7.643
−3.769
1.00
20.18
A
C

ATOM
2936
CE1
PHE
A
599
11.694
−8.537
−4.245
1.00
21.90
A
C

ATOM
2938
CZ
PHE
A
599
11.975
−9.693
−3.532
1.00
20.74
A
C

ATOM
2940
CE2
PHE
A
599
11.318
−9.945
−2.336
1.00
21.69
A
C

ATOM
2942
CD2
PHE
A
599
10.391
−9.038
−1.860
1.00
19.49
A
C

ATOM
2944
C
PHE
A
599
8.574
−4.641
−1.156
1.00
15.14
A
C

ATOM
2945
O
PHE
A
599
7.427
−4.610
−1.608
1.00
15.42
A
O

ATOM
2946
N
ARG
A
600
8.951
−3.936
−0.092
1.00
15.13
A
N

ATOM
2948
CA
ARG
A
600
8.024
−3.137
0.701
1.00
15.85
A
C

ATOM
2950
CB
ARG
A
600
7.614
−1.880
−0.076
1.00
16.31
A
C

ATOM
2953
CG
ARG
A
600
8.784
−0.950
−0.377
1.00
17.77
A
C

ATOM
2956
CD
ARG
A
600
9.269
−0.173
0.835
1.00
18.17
A
C

ATOM
2959
NE
ARG
A
600
10.355
0.750
0.508
1.00
20.72
A
N

ATOM
2961
CZ
ARG
A
600
11.657
0.490
0.633
1.00
21.90
A
C

ATOM
2962
NH1
ARG
A
600
12.094
−0.680
1.078
1.00
22.93
A
N

ATOM
2965
NH2
ARG
A
600
12.543
1.419
0.299
1.00
22.61
A
N

ATOM
2968
C
ARG
A
600
6.793
−3.956
1.149
1.00
15.58
A
C

ATOM
2969
O
ARG
A
600
5.653
−3.464
1.136
1.00
15.40
A
O

ATOM
2970
N
ARG
A
601
7.046
−5.206
1.535
1.00
15.64
A
N

ATOM
2972
CA
ARG
A
601
6.022
−6.120
2.052
1.00
16.29
A
C

ATOM
2974
CB
ARG
A
601
6.363
−7.569
1.724
1.00
17.23
A
C

ATOM
2977
CG
ARG
A
601
6.233
−7.938
0.259
1.00
21.68
A
C

ATOM
2980
CD
ARG
A
601
5.955
−9.440
−0.022
1.00
25.56
A
C

ATOM
2983
NE
ARG
A
601
6.621
−9.837
−1.270
1.00
30.36
A
N

ATOM
2985
CZ
ARG
A
601
6.043
−10.295
−2.379
1.00
31.71
A
C

ATOM
2986
NH1
ARG
A
601
4.738
−10.497
−2.462
1.00
34.89
A
N

ATOM
2989
NH2
ARG
A
601
6.800
−10.599
−3.428
1.00
34.61
A
N

ATOM
2992
C
ARG
A
601
6.002
−5.963
3.571
1.00
15.73
A
C

ATOM
2993
O
ARG
A
601
7.033
−6.218
4.233
1.00
15.42
A
O

ATOM
2994
N
PHE
A
602
4.866
−5.511
4.105
1.00
14.28
A
N

ATOM
2996
CA
PHE
A
602
4.684
−5.323
5.543
1.00
14.03
A
C

ATOM
2998
CB
PHE
A
602
4.463
−3.844
5.876
1.00
13.94
A
C

ATOM
3001
CG
PHE
A
602
5.599
−2.947
5.501
1.00
15.36
A
C

ATOM
3002
CD1
PHE
A
602
6.596
−2.632
6.430
1.00
16.03
A
C

ATOM
3004
CE1
PHE
A
602
7.651
−1.772
6.090
1.00
15.79
A
C

ATOM
3006
CZ
PHE
A
602
7.690
−1.198
4.833
1.00
15.40
A
C

ATOM
3008
CE2
PHE
A
602
6.686
−1.485
3.909
1.00
15.83
A
C

ATOM
3010
CD2
PHE
A
602
5.643
−2.348
4.245
1.00
14.53
A
C

ATOM
3012
C
PHE
A
602
3.499
−6.130
6.054
1.00
13.39
A
C

ATOM
3013
O
PHE
A
602
2.353
−5.927
5.631
1.00
13.20
A
O

ATOM
3014
N
THR
A
603
3.766
−7.070
6.947
1.00
13.12
A
N

ATOM
3016
CA
THR
A
603
2.739
−7.941
7.518
1.00
12.82
A
C

ATOM
3018
CB
THR
A
603
2.851
−9.331
6.902
1.00
13.20
A
C

ATOM
3020
OG1
THR
A
603
4.143
−9.881
7.212
1.00
13.90
A
O

ATOM
3022
CG2
THR
A
603
2.771
−9.277
5.357
1.00
14.67
A
C

ATOM
3026
C
THR
A
603
2.968
−8.095
9.007
1.00
12.15
A
C

ATOM
3027
O
THR
A
603
3.936
−7.588
9.552
1.00
10.36
A
O

ATOM
3028
N
THR
A
604
2.125
−8.874
9.659
1.00
11.47
A
N

ATOM
3030
CA
THR
A
604
2.387
−9.169
11.053
1.00
11.50
A
C

ATOM
3032
CB
THR
A
604
1.228
−9.955
11.676
1.00
12.26
A
C

ATOM
3034
OG1
THR
A
604
0.043
−9.138
11.648
1.00
14.28
A
O

ATOM
3036
CG2
THR
A
604
1.493
−10.182
13.155
1.00
14.14
A
C

ATOM
3040
C
THR
A
604
3.728
−9.884
11.203
1.00
11.13
A
C

ATOM
3041
O
THR
A
604
4.391
−9.699
12.211
1.00
9.85
A
O

ATOM
3042
N
ALA
A
605
4.142
−10.679
10.206
1.00
10.23
A
N

ATOM
3044
CA
ALA
A
605
5.450
−11.338
10.258
1.00
10.32
A
C

ATOM
3046
CB
ALA
A
605
5.608
−12.374
9.156
1.00
10.78
A
C

ATOM
3050
C
ALA
A
605
6.611
−10.363
10.197
1.00
9.56
A
C

ATOM
3051
O
ALA
A
605
7.640
−10.616
10.824
1.00
8.50
A
O

ATOM
3052
N
SER
A
606
6.459
−9.272
9.445
1.00
8.64
A
N

ATOM
3054
CA
SER
A
606
7.486
−8.245
9.412
1.00
9.24
A
C

ATOM
3056
CB
SER
A
606
7.352
−7.296
8.190
1.00
9.76
A
C

ATOM
3059
OG
SER
A
606
6.179
−6.496
8.250
1.00
10.66
A
O

ATOM
3061
C
SER
A
606
7.505
−7.489
10.748
1.00
9.16
A
C

ATOM
3062
O
SER
A
606
8.572
−7.100
11.211
1.00
8.11
A
O

ATOM
3063
N
ASP
A
607
6.340
−7.307
11.379
1.00
8.37
A
N

ATOM
3065
CA
ASP
A
607
6.297
−6.717
12.720
1.00
8.68
A
C

ATOM
3067
CB
ASP
A
607
4.876
−6.507
13.225
1.00
8.94
A
C

ATOM
3070
CG
ASP
A
607
4.256
−5.197
12.785
1.00
11.42
A
C

ATOM
3071
OD1
ASP
A
607
4.925
−4.280
12.218
1.00
11.99
A
O

ATOM
3072
OD2
ASP
A
607
3.029
−5.001
13.022
1.00
12.74
A
O

ATOM
3073
C
ASP
A
607
7.034
−7.616
13.740
1.00
8.12
A
C

ATOM
3074
O
ASP
A
607
7.628
−7.111
14.678
1.00
7.11
A
O

ATOM
3075
N
VAL
A
608
6.952
−8.940
13.577
1.00
7.25
A
N

ATOM
3077
CA
VAL
A
608
7.677
−9.870
14.461
1.00
7.14
A
C

ATOM
3079
CB
VAL
A
608
7.280
−11.342
14.171
1.00
6.69
A
C

ATOM
3081
CG1
VAL
A
608
8.277
−12.331
14.822
1.00
8.13
A
C

ATOM
3085
CG2
VAL
A
608
5.840
−11.616
14.668
1.00
7.95
A
C

ATOM
3089
C
VAL
A
608
9.187
−9.687
14.332
1.00
7.61
A
C

ATOM
3090
O
VAL
A
608
9.902
−9.615
15.345
1.00
6.65
A
O

ATOM
3091
N
TRP
A
609
9.673
−9.587
13.090
1.00
7.07
A
N

ATOM
3093
CA
TRP
A
609
11.085
−9.274
12.835
1.00
7.28
A
C

ATOM
3095
CB
TRP
A
609
11.349
−9.095
11.329
1.00
7.08
A
C

ATOM
3098
CG
TRP
A
609
12.771
−8.707
10.985
1.00
7.95
A
C

ATOM
3099
CD1
TRP
A
609
13.381
−7.506
11.228
1.00
7.59
A
C

ATOM
3101
NE1
TRP
A
609
14.692
−7.555
10.821
1.00
8.83
A
N

ATOM
3103
CE2
TRP
A
609
14.958
−8.799
10.310
1.00
8.13
A
C

ATOM
3104
CD2
TRP
A
609
13.778
−9.555
10.414
1.00
6.30
A
C

ATOM
3105
CE3
TRP
A
609
13.779
−10.881
9.934
1.00
6.84
A
C

ATOM
3107
CZ3
TRP
A
609
14.944
−11.401
9.398
1.00
8.38
A
C

ATOM
3109
CH2
TRP
A
609
16.108
−10.624
9.313
1.00
7.22
A
C

ATOM
3111
CZ2
TRP
A
609
16.135
−9.313
9.749
1.00
8.92
A
C

ATOM
3113
C
TRP
A
609
11.484
−7.994
13.602
1.00
7.00
A
C

ATOM
3114
O
TRP
A
609
12.484
−7.969
14.329
1.00
7.89
A
O

ATOM
3115
N
MET
A
610
10.687
−6.954
13.449
1.00
7.31
A
N

ATOM
3117
CA
MET
A
610
11.019
−5.634
13.979
1.00
7.12
A
C

ATOM
3119
CB
MET
A
610
10.083
−4.569
13.380
1.00
7.25
A
C

ATOM
3122
CG
MET
A
610
10.433
−3.155
13.777
1.00
8.77
A
C

ATOM
3125
SD
MET
A
610
9.336
−1.944
13.037
1.00
11.18
A
S

ATOM
3126
CE
MET
A
610
10.448
−0.489
13.042
1.00
12.69
A
C

ATOM
3130
C
MET
A
610
10.945
−5.628
15.504
1.00
7.16
A
C

ATOM
3131
O
MET
A
610
11.740
−4.979
16.171
1.00
7.31
A
O

ATOM
3132
N
PHE
A
611
9.995
−6.376
16.053
1.00
7.20
A
N

ATOM
3134
CA
PHE
A
611
9.859
−6.506
17.503
1.00
6.98
A
C

ATOM
3136
CB
PHE
A
611
8.614
−7.289
17.857
1.00
7.02
A
C

ATOM
3139
CG
PHE
A
611
8.576
−7.724
19.296
1.00
8.33
A
C

ATOM
3140
CD1
PHE
A
611
8.329
−6.808
20.294
1.00
9.98
A
C

ATOM
3142
CE1
PHE
A
611
8.322
−7.188
21.610
1.00
9.82
A
C

ATOM
3144
CZ
PHE
A
611
8.587
−8.482
21.958
1.00
9.72
A
C

ATOM
3146
CE2
PHE
A
611
8.835
−9.415
20.984
1.00
11.54
A
C

ATOM
3148
CD2
PHE
A
611
8.838
−9.033
19.645
1.00
9.39
A
C

ATOM
3150
C
PHE
A
611
11.103
−7.142
18.153
1.00
6.73
A
C

ATOM
3151
O
PHE
A
611
11.557
−6.708
19.202
1.00
7.59
A
O

ATOM
3152
N
ALA
A
612
11.692
−8.119
17.491
1.00
7.27
A
N

ATOM
3154
CA
ALA
A
612
12.922
−8.703
17.973
1.00
7.36
A
C

ATOM
3156
CB
ALA
A
612
13.212
−9.987
17.272
1.00
7.52
A
C

ATOM
3160
C
ALA
A
612
14.090
−7.718
17.877
1.00
7.40
A
C

ATOM
3161
O
ALA
A
612
14.984
−7.738
18.735
1.00
7.06
A
O

ATOM
3162
N
VAL
A
613
14.094
−6.842
16.868
1.00
7.17
A
N

ATOM
3164
CA
VAL
A
613
15.098
−5.779
16.831
1.00
7.65
A
C

ATOM
3166
CB
VAL
A
613
15.096
−4.939
15.516
1.00
7.18
A
C

ATOM
3168
CG1
VAL
A
613
16.183
−3.867
15.575
1.00
8.13
A
C

ATOM
3172
CG2
VAL
A
613
15.284
−5.822
14.301
1.00
8.64
A
C

ATOM
3176
C
VAL
A
613
14.874
−4.843
18.018
1.00
7.44
A
C

ATOM
3177
O
VAL
A
613
15.816
−4.438
18.663
1.00
7.86
A
O

ATOM
3178
N
CYS
A
614
13.628
−4.521
18.312
1.00
7.31
A
N

ATOM
3180
CA
CYS
A
614
13.304
−3.712
19.482
1.00
7.38
A
C

ATOM
3182
CB
CYS
A
614
11.808
−3.409
19.500
1.00
7.62
A
C

ATOM
3185
SG
CYS
A
614
11.279
−2.363
20.856
1.00
12.24
A
S

ATOM
3186
C
CYS
A
614
13.803
−4.393
20.791
1.00
7.51
A
C

ATOM
3187
O
CYS
A
614
14.404
−3.737
21.652
1.00
8.23
A
O

ATOM
3188
N
MET
A
615
13.602
−5.700
20.939
1.00
6.99
A
N

ATOM
3190
CA
MET
A
615
14.136
−6.415
22.104
1.00
8.46
A
C

ATOM
3192
CB
MET
A
615
13.727
−7.893
22.087
1.00
8.91
A
C

ATOM
3195
CG
MET
A
615
12.273
−8.132
22.309
1.00
11.03
A
C

ATOM
3198
SD
MET
A
615
12.003
−9.900
22.802
1.00
14.28
A
S

ATOM
3199
CE
MET
A
615
12.231
−10.684
21.273
1.00
13.21
A
C

ATOM
3203
C
MET
A
615
15.657
−6.314
22.182
1.00
7.71
A
C

ATOM
3204
O
MET
A
615
16.223
−6.111
23.249
1.00
8.82
A
O

ATOM
3205
N
TRP
A
616
16.324
−6.420
21.042
1.00
7.61
A
N

ATOM
3207
CA
TRP
A
616
17.773
−6.243
20.982
1.00
7.16
A
C

ATOM
3209
CB
TRP
A
616
18.277
−6.483
19.555
1.00
7.70
A
C

ATOM
3212
CG
TRP
A
616
19.759
−6.411
19.431
1.00
6.78
A
C

ATOM
3213
CD1
TRP
A
616
20.623
−7.465
19.493
1.00
7.50
A
C

ATOM
3215
NE1
TRP
A
616
21.916
−7.021
19.337
1.00
8.34
A
N

ATOM
3217
CE2
TRP
A
616
21.913
−5.665
19.176
1.00
8.17
A
C

ATOM
3218
CD2
TRP
A
616
20.559
−5.247
19.199
1.00
5.69
A
C

ATOM
3219
CE3
TRP
A
616
20.285
−3.876
19.074
1.00
8.29
A
C

ATOM
3221
CZ3
TRP
A
616
21.327
−3.003
18.884
1.00
8.52
A
C

ATOM
3223
CH2
TRP
A
616
22.663
−3.460
18.833
1.00
7.88
A
C

ATOM
3225
CZ2
TRP
A
616
22.964
−4.786
18.940
1.00
8.12
A
C

ATOM
3227
C
TRP
A
616
18.171
−4.841
21.476
1.00
7.53
A
C

ATOM
3228
O
TRP
A
616
19.125
−4.732
22.241
1.00
8.03
A
O

ATOM
3229
N
GLU
A
617
17.425
−3.794
21.081
1.00
7.69
A
N

ATOM
3231
CA
GLU
A
617
17.671
−2.434
21.555
1.00
8.18
A
C

ATOM
3233
CB
GLU
A
617
16.718
−1.416
20.918
1.00
8.57
A
C

ATOM
3236
CG
GLU
A
617
16.871
−1.110
19.441
1.00
10.70
A
C

ATOM
3239
CD
GLU
A
617
15.817
−0.100
19.000
1.00
13.08
A
C

ATOM
3240
OE1
GLU
A
617
16.176
0.998
18.510
1.00
13.59
A
O

ATOM
3241
OE2
GLU
A
617
14.620
−0.372
19.205
1.00
14.34
A
O

ATOM
3242
C
GLU
A
617
17.496
−2.334
23.066
1.00
8.12
A
C

ATOM
3243
O
GLU
A
617
18.304
−1.700
23.749
1.00
8.06
A
O

ATOM
3244
N
ILE
A
618
16.453
−2.970
23.593
1.00
8.10
A
N

ATOM
3246
CA
ILE
A
618
16.172
−2.899
25.027
1.00
8.31
A
C

ATOM
3248
CB
ILE
A
618
14.810
−3.549
25.349
1.00
8.09
A
C

ATOM
3250
CG1
ILE
A
618
13.676
−2.696
24.783
1.00
7.50
A
C

ATOM
3253
CD1
ILE
A
618
12.296
−3.333
24.895
1.00
9.45
A
C

ATOM
3257
CG2
ILE
A
618
14.641
−3.746
26.867
1.00
9.02
A
C

ATOM
3261
C
ILE
A
618
17.314
−3.569
25.805
1.00
8.52
A
C

ATOM
3262
O
ILE
A
618
17.884
−2.983
26.731
1.00
9.07
A
O

ATOM
3263
N
LEU
A
619
17.674
−4.780
25.406
1.00
9.16
A
N

ATOM
3265
CA
LEU
A
619
18.752
−5.517
26.063
1.00
9.73
A
C

ATOM
3267
CB
LEU
A
619
18.742
−6.989
25.626
1.00
10.15
A
C

ATOM
3270
CG
LEU
A
619
17.821
−7.924
26.416
1.00
11.23
A
C

ATOM
3272
CD1
LEU
A
619
18.274
−8.131
27.852
1.00
12.73
A
C

ATOM
3276
CD2
LEU
A
619
16.384
−7.464
26.361
1.00
12.78
A
C

ATOM
3280
C
LEU
A
619
20.132
−4.906
25.858
1.00
9.41
A
C

ATOM
3281
O
LEU
A
619
21.071
−5.239
26.600
1.00
11.30
A
O

ATOM
3282
N
SER
A
620
20.249
−3.996
24.890
1.00
9.34
A
N

ATOM
3284
CA
SER
A
620
21.466
−3.226
24.656
1.00
9.57
A
C

ATOM
3286
CB
SER
A
620
21.748
−3.159
23.147
1.00
9.27
A
C

ATOM
3289
OG
SER
A
620
21.720
−4.438
22.539
1.00
9.62
A
O

ATOM
3291
C
SER
A
620
21.412
−1.788
25.217
1.00
10.03
A
C

ATOM
3292
O
SER
A
620
22.253
−0.958
24.870
1.00
10.13
A
O

ATOM
3293
N
PHE
A
621
20.438
−1.495
26.072
1.00
10.21
A
N

ATOM
3295
CA
PHE
A
621
20.281
−0.168
26.658
1.00
10.99
A
C

ATOM
3297
CB
PHE
A
621
21.380
0.092
27.686
1.00
11.57
A
C

ATOM
3300
CG
PHE
A
621
21.417
−0.916
28.786
1.00
11.76
A
C

ATOM
3301
CD1
PHE
A
621
20.585
−0.777
29.903
1.00
14.73
A
C

ATOM
3303
CE1
PHE
A
621
20.616
−1.720
30.939
1.00
13.38
A
C

ATOM
3305
CZ
PHE
A
621
21.455
−2.806
30.845
1.00
15.10
A
C

ATOM
3307
CE2
PHE
A
621
22.282
−2.966
29.728
1.00
15.45
A
C

ATOM
3309
CD2
PHE
A
621
22.257
−2.020
28.708
1.00
14.11
A
C

ATOM
3311
C
PHE
A
621
20.204
0.974
25.633
1.00
11.51
A
C

ATOM
3312
O
PHE
A
621
20.746
2.054
25.840
1.00
11.76
A
O

ATOM
3313
N
GLY
A
622
19.533
0.715
24.513
1.00
12.15
A
N

ATOM
3315
CA
GLY
A
622
19.195
1.755
23.561
1.00
12.52
A
C

ATOM
3318
C
GLY
A
622
20.125
1.958
22.389
1.00
13.31
A
C

ATOM
3319
O
GLY
A
622
19.957
2.916
21.631
1.00
13.27
A
O

ATOM
3320
N
LYS
A
623
21.117
1.086
22.224
1.00
13.94
A
N

ATOM
3322
CA
LYS
A
623
22.003
1.199
21.072
1.00
14.20
A
C

ATOM
3324
CB
LYS
A
623
23.120
0.167
21.156
1.00
15.30
A
C

ATOM
3327
CG
LYS
A
623
24.036
0.374
22.340
1.00
18.22
A
C

ATOM
3330
CD
LYS
A
623
25.359
−0.349
22.137
1.00
23.13
A
C

ATOM
3333
CE
LYS
A
623
25.198
−1.851
22.058
1.00
23.04
A
C

ATOM
3336
NZ
LYS
A
623
26.022
−2.515
23.072
1.00
22.31
A
N

ATOM
3340
C
LYS
A
623
21.223
1.016
19.765
1.00
13.35
A
C

ATOM
3341
O
LYS
A
623
20.175
0.354
19.732
1.00
12.25
A
O

ATOM
3342
N
GLN
A
624
21.720
1.631
18.694
1.00
12.33
A
N

ATOM
3344
CA
GLN
A
624
21.074
1.532
17.390
1.00
11.79
A
C

ATOM
3346
CB
GLN
A
624
21.471
2.693
16.471
1.00
12.79
A
C

ATOM
3349
CG
GLN
A
624
20.803
2.653
15.092
1.00
16.84
A
C

ATOM
3352
CD
GLN
A
624
21.480
3.512
14.033
1.00
20.72
A
C

ATOM
3353
OE1
GLN
A
624
22.510
3.139
13.484
1.00
22.00
A
O

ATOM
3354
NE2
GLN
A
624
20.863
4.642
13.706
1.00
25.56
A
N

ATOM
3357
C
GLN
A
624
21.484
0.218
16.750
1.00
10.43
A
C

ATOM
3358
O
GLN
A
624
22.674
−0.085
16.700
1.00
9.05
A
O

ATOM
3359
N
PRO
A
625
20.527
−0.543
16.226
1.00
9.21
A
N

ATOM
3360
CA
PRO
A
625
20.857
−1.773
15.510
1.00
8.85
A
C

ATOM
3362
CB
PRO
A
625
19.489
−2.336
15.099
1.00
8.81
A
C

ATOM
3365
CG
PRO
A
625
18.589
−1.182
15.135
1.00
8.12
A
C

ATOM
3368
CD
PRO
A
625
19.077
−0.284
16.226
1.00
8.87
A
C

ATOM
3371
C
PRO
A
625
21.690
−1.483
14.260
1.00
9.18
A
C

ATOM
3372
O
PRO
A
625
21.427
−0.517
13.529
1.00
8.70
A
O

ATOM
3373
N
PHE
A
626
22.699
−2.312
14.017
1.00
8.97
A
N

ATOM
3375
CA
PHE
A
626
23.530
−2.167
12.825
1.00
8.80
A
C

ATOM
3377
CB
PHE
A
626
22.755
−2.516
11.552
1.00
9.35
A
C

ATOM
3380
CG
PHE
A
626
22.317
−3.959
11.476
1.00
7.57
A
C

ATOM
3381
CD1
PHE
A
626
23.263
−4.982
11.428
1.00
8.74
A
C

ATOM
3383
CE1
PHE
A
626
22.880
−6.293
11.333
1.00
7.90
A
C

ATOM
3385
CZ
PHE
A
626
21.544
−6.621
11.266
1.00
9.02
A
C

ATOM
3387
CE2
PHE
A
626
20.584
−5.630
11.313
1.00
7.58
A
C

ATOM
3389
CD2
PHE
A
626
20.967
−4.303
11.402
1.00
7.59
A
C

ATOM
3391
C
PHE
A
626
24.153
−0.762
12.737
1.00
9.81
A
C

ATOM
3392
O
PHE
A
626
24.281
−0.193
11.669
1.00
9.56
A
O

ATOM
3393
N
PHE
A
627
24.554
−0.231
13.879
1.00
9.82
A
N

ATOM
3395
CA
PHE
A
627
25.190
1.088
13.917
1.00
11.48
A
C

ATOM
3397
CB
PHE
A
627
25.448
1.543
15.365
1.00
11.15
A
C

ATOM
3400
CG
PHE
A
627
26.395
0.662
16.150
1.00
11.35
A
C

ATOM
3401
CD1
PHE
A
627
27.774
0.810
16.042
1.00
9.33
A
C

ATOM
3403
CE1
PHE
A
627
28.637
0.017
16.772
1.00
10.69
A
C

ATOM
3405
CZ
PHE
A
627
28.131
−0.911
17.652
1.00
12.10
A
C

ATOM
3407
CE2
PHE
A
627
26.746
−1.042
17.787
1.00
10.84
A
C

ATOM
3409
CD2
PHE
A
627
25.905
−0.256
17.051
1.00
9.05
A
C

ATOM
3411
C
PHE
A
627
26.475
1.142
13.092
1.00
12.51
A
C

ATOM
3412
O
PHE
A
627
26.881
2.214
12.636
1.00
14.55
A
O

ATOM
3413
N
TRP
A
628
27.076
−0.021
12.879
1.00
12.47
A
N

ATOM
3415
CA
TRP
A
628
28.355
−0.158
12.189
1.00
13.92
A
C

ATOM
3417
CB
TRP
A
628
29.085
−1.409
12.710
1.00
13.56
A
C

ATOM
3420
CG
TRP
A
628
28.298
−2.730
12.615
1.00
13.24
A
C

ATOM
3421
CD1
TRP
A
628
28.356
−3.647
11.600
1.00
13.12
A
C

ATOM
3423
NE1
TRP
A
628
27.528
−4.710
11.871
1.00
14.92
A
N

ATOM
3425
CE2
TRP
A
628
26.894
−4.493
13.060
1.00
13.87
A
C

ATOM
3426
CD2
TRP
A
628
27.366
−3.256
13.566
1.00
12.08
A
C

ATOM
3427
CE3
TRP
A
628
26.861
−2.807
14.784
1.00
13.25
A
C

ATOM
3429
CZ3
TRP
A
628
25.928
−3.597
15.468
1.00
13.18
A
C

ATOM
3431
CH2
TRP
A
628
25.490
−4.812
14.935
1.00
12.66
A
C

ATOM
3433
CZ2
TRP
A
628
25.966
−5.276
13.739
1.00
12.17
A
C

ATOM
3435
C
TRP
A
628
28.204
−0.203
10.658
1.00
14.82
A
C

ATOM
3436
O
TRP
A
628
29.199
−0.297
9.938
1.00
16.19
A
O

ATOM
3437
N
LEU
A
629
26.963
−0.177
10.171
1.00
14.95
A
N

ATOM
3439
CA
LEU
A
629
26.653
−0.266
8.744
1.00
15.95
A
C

ATOM
3441
CB
LEU
A
629
25.711
−1.447
8.475
1.00
15.63
A
C

ATOM
3444
CG
LEU
A
629
26.128
−2.866
8.839
1.00
15.85
A
C

ATOM
3446
CD1
LEU
A
629
25.034
−3.791
8.377
1.00
17.66
A
C

ATOM
3450
CD2
LEU
A
629
27.437
−3.241
8.191
1.00
17.21
A
C

ATOM
3454
C
LEU
A
629
25.957
0.991
8.249
1.00
16.16
A
C

ATOM
3455
O
LEU
A
629
25.422
1.767
9.042
1.00
17.19
A
O

ATOM
3456
N
GLU
A
630
26.012
1.200
6.933
1.00
17.08
A
N

ATOM
3458
CA
GLU
A
630
25.159
2.176
6.244
1.00
17.66
A
C

ATOM
3460
CB
GLU
A
630
25.859
2.759
4.990
1.00
18.54
A
C

ATOM
3463
CG
GLU
A
630
27.107
3.592
5.285
1.00
22.16
A
C

ATOM
3466
CD
GLU
A
630
27.834
4.104
4.035
1.00
26.66
A
C

ATOM
3467
OE1
GLU
A
630
28.025
3.347
3.054
1.00
30.10
A
O

ATOM
3468
OE2
GLU
A
630
28.254
5.276
4.041
1.00
31.44
A
O

ATOM
3469
C
GLU
A
630
23.877
1.444
5.840
1.00
16.80
A
C

ATOM
3470
O
GLU
A
630
23.899
0.232
5.644
1.00
16.52
A
O

ATOM
3471
N
ASN
A
631
22.777
2.177
5.693
1.00
16.64
A
N

ATOM
3473
CA
ASN
A
631
21.494
1.588
5.288
1.00
16.86
A
C

ATOM
3475
CB
ASN
A
631
20.444
2.692
5.027
1.00
16.92
A
C

ATOM
3478
CG
ASN
A
631
19.758
3.184
6.315
1.00
18.23
A
C

ATOM
3479
OD1
ASN
A
631
19.981
2.645
7.395
1.00
19.71
A
O

ATOM
3480
ND2
ASN
A
631
18.935
4.230
6.196
1.00
18.99
A
N

ATOM
3483
C
ASN
A
631
21.626
0.674
4.067
1.00
16.54
A
C

ATOM
3484
O
ASN
A
631
21.011
−0.395
4.008
1.00
16.91
A
O

ATOM
3485
N
LYS
A
632
22.435
1.094
3.097
1.00
17.10
A
N

ATOM
3487
CA
LYS
A
632
22.531
0.396
1.817
1.00
17.56
A
C

ATOM
3489
CB
LYS
A
632
23.263
1.260
0.770
1.00
17.78
A
C

ATOM
3492
CG
LYS
A
632
24.756
1.461
0.990
1.00
19.40
A
C

ATOM
3495
CD
LYS
A
632
25.297
2.438
−0.081
1.00
23.92
A
C

ATOM
3498
CE
LYS
A
632
26.787
2.688
0.044
1.00
24.81
A
C

ATOM
3501
NZ
LYS
A
632
27.592
1.430
0.014
1.00
27.18
A
N

ATOM
3505
C
LYS
A
632
23.194
−0.965
1.940
1.00
17.38
A
C

ATOM
3506
O
LYS
A
632
23.086
−1.798
1.040
1.00
17.61
A
O

ATOM
3507
N
ASP
A
633
23.863
−1.195
3.064
1.00
17.62
A
N

ATOM
3509
CA
ASP
A
633
24.618
−2.423
3.287
1.00
17.79
A
C

ATOM
3511
CB
ASP
A
633
25.892
−2.111
4.070
1.00
18.50
A
C

ATOM
3514
CG
ASP
A
633
26.869
−1.242
3.289
1.00
22.13
A
C

ATOM
3515
OD1
ASP
A
633
27.019
−1.425
2.062
1.00
25.82
A
O

ATOM
3516
OD2
ASP
A
633
27.534
−0.344
3.843
1.00
29.08
A
O

ATOM
3517
C
ASP
A
633
23.830
−3.477
4.054
1.00
16.35
A
C

ATOM
3518
O
ASP
A
633
24.244
−4.631
4.106
1.00
16.00
A
O

ATOM
3519
N
VAL
A
634
22.698
−3.086
4.639
1.00
14.77
A
N

ATOM
3521
CA
VAL
A
634
21.941
−3.962
5.535
1.00
14.11
A
C

ATOM
3523
CB
VAL
A
634
20.767
−3.188
6.199
1.00
14.20
A
C

ATOM
3525
CG1
VAL
A
634
19.834
−4.110
6.957
1.00
14.96
A
C

ATOM
3529
CG2
VAL
A
634
21.298
−2.120
7.131
1.00
15.06
A
C

ATOM
3533
C
VAL
A
634
21.448
−5.224
4.823
1.00
13.43
A
C

ATOM
3534
O
VAL
A
634
21.685
−6.339
5.289
1.00
12.23
A
O

ATOM
3535
N
ILE
A
635
20.792
−5.063
3.676
1.00
13.66
A
N

ATOM
3537
CA
ILE
A
635
20.175
−6.214
3.010
1.00
13.87
A
C

ATOM
3539
CB
ILE
A
635
19.308
−5.792
1.786
1.00
14.01
A
C

ATOM
3541
CG1
ILE
A
635
18.407
−6.942
1.344
1.00
13.90
A
C

ATOM
3544
CD1
ILE
A
635
17.406
−7.408
2.394
1.00
14.48
A
C

ATOM
3548
CG2
ILE
A
635
20.169
−5.256
0.628
1.00
14.55
A
C

ATOM
3552
C
ILE
A
635
21.205
−7.287
2.666
1.00
14.30
A
C

ATOM
3553
O
ILE
A
635
20.961
−8.467
2.912
1.00
13.32
A
O

ATOM
3554
N
GLY
A
636
22.369
−6.865
2.167
1.00
14.75
A
N

ATOM
3556
CA
GLY
A
636
23.483
−7.771
1.868
1.00
14.87
A
C

ATOM
3559
C
GLY
A
636
23.898
−8.630
3.048
1.00
14.75
A
C

ATOM
3560
O
GLY
A
636
24.068
−9.846
2.937
1.00
14.77
A
O

ATOM
3561
N
VAL
A
637
24.046
−7.989
4.195
1.00
14.62
A
N

ATOM
3563
CA
VAL
A
637
24.396
−8.669
5.431
1.00
14.71
A
C

ATOM
3565
CB
VAL
A
637
24.620
−7.610
6.548
1.00
15.24
A
C

ATOM
3567
CG1
VAL
A
637
24.587
−8.215
7.928
1.00
15.93
A
C

ATOM
3571
CG2
VAL
A
637
25.932
−6.869
6.295
1.00
16.95
A
C

ATOM
3575
C
VAL
A
637
23.336
−9.700
5.841
1.00
14.05
A
C

ATOM
3576
O
VAL
A
637
23.644
−10.829
6.188
1.00
13.96
A
O

ATOM
3577
N
LEU
A
638
22.074
−9.322
5.779
1.00
13.42
A
N

ATOM
3579
CA
LEU
A
638
20.995
−10.231
6.146
1.00
13.52
A
C

ATOM
3581
CB
LEU
A
638
19.669
−9.472
6.179
1.00
13.37
A
C

ATOM
3584
CG
LEU
A
638
19.587
−8.329
7.203
1.00
12.38
A
C

ATOM
3586
CD1
LEU
A
638
18.240
−7.644
7.078
1.00
12.99
A
C

ATOM
3590
CD2
LEU
A
638
19.783
−8.855
8.587
1.00
13.05
A
C

ATOM
3594
C
LEU
A
638
20.902
−11.427
5.188
1.00
14.41
A
C

ATOM
3595
O
LEU
A
638
20.640
−12.547
5.617
1.00
13.64
A
O

ATOM
3596
N
GLU
A
639
21.119
−11.170
3.897
1.00
15.99
A
N

ATOM
3598
CA
GLU
A
639
21.032
−12.204
2.860
1.00
17.38
A
C

ATOM
3600
CB
GLU
A
639
20.974
−11.585
1.446
1.00
17.84
A
C

ATOM
3603
CG
GLU
A
639
19.567
−11.053
1.155
1.00
19.95
A
C

ATOM
3606
CD
GLU
A
639
19.349
−10.385
−0.196
1.00
24.27
A
C

ATOM
3607
OE1
GLU
A
639
20.314
−9.998
−0.890
1.00
26.43
A
O

ATOM
3608
OE2
GLU
A
639
18.156
−10.234
−0.555
1.00
28.41
A
O

ATOM
3609
C
GLU
A
639
22.171
−13.190
3.015
1.00
18.02
A
C

ATOM
3610
O
GLU
A
639
21.998
−14.362
2.755
1.00
18.32
A
O

ATOM
3611
N
LYS
A
640
23.319
−12.733
3.503
1.00
18.92
A
N

ATOM
3613
CA
LYS
A
640
24.431
−13.645
3.751
1.00
19.98
A
C

ATOM
3615
CB
LYS
A
640
25.777
−12.903
3.693
1.00
20.94
A
C

ATOM
3618
CG
LYS
A
640
26.233
−12.229
4.965
1.00
24.88
A
C

ATOM
3621
CD
LYS
A
640
27.432
−11.309
4.704
1.00
28.51
A
C

ATOM
3624
CE
LYS
A
640
28.699
−12.102
4.445
1.00
30.97
A
C

ATOM
3627
NZ
LYS
A
640
29.922
−11.339
4.842
1.00
32.88
A
N

ATOM
3631
C
LYS
A
640
24.244
−14.456
5.038
1.00
19.37
A
C

ATOM
3632
O
LYS
A
640
25.047
−15.343
5.324
1.00
20.32
A
O

ATOM
3633
N
GLY
A
641
23.172
−14.188
5.795
1.00
18.02
A
N

ATOM
3635
CA
GLY
A
641
22.864
−14.947
7.006
1.00
17.51
A
C

ATOM
3638
C
GLY
A
641
23.309
−14.328
8.324
1.00
16.94
A
C

ATOM
3639
O
GLY
A
641
23.063
−14.876
9.398
1.00
17.26
A
O

ATOM
3640
N
ASP
A
642
23.978
−13.186
8.260
1.00
15.83
A
N

ATOM
3642
CA
ASP
A
642
24.426
−12.516
9.476
1.00
15.01
A
C

ATOM
3644
CB
ASP
A
642
25.482
−11.476
9.155
1.00
15.19
A
C

ATOM
3647
CG
ASP
A
642
26.786
−12.079
8.651
1.00
18.80
A
C

ATOM
3648
OD1
ASP
A
642
27.065
−13.269
8.921
1.00
19.61
A
O

ATOM
3649
OD2
ASP
A
642
27.586
−11.400
7.975
1.00
23.88
A
O

ATOM
3650
C
ASP
A
642
23.249
−11.815
10.152
1.00
13.57
A
C

ATOM
3651
O
ASP
A
642
22.307
−11.354
9.490
1.00
12.33
A
O

ATOM
3652
N
ARG
A
643
23.362
−11.697
11.464
1.00
12.50
A
N

ATOM
3654
CA
ARG
A
643
22.331
−11.111
12.317
1.00
12.39
A
C

ATOM
3656
CB
ARG
A
643
21.489
−12.225
12.953
1.00
12.39
A
C

ATOM
3659
CG
ARG
A
643
20.694
−13.090
11.983
1.00
12.03
A
C

ATOM
3662
CD
ARG
A
643
19.623
−12.348
11.205
1.00
11.99
A
C

ATOM
3665
NE
ARG
A
643
18.815
−13.225
10.362
1.00
13.20
A
N

ATOM
3667
CZ
ARG
A
643
19.009
−13.447
9.066
1.00
12.12
A
C

ATOM
3668
NH1
ARG
A
643
20.017
−12.891
8.422
1.00
12.02
A
N

ATOM
3671
NH2
ARG
A
643
18.192
−14.246
8.407
1.00
13.42
A
N

ATOM
3674
C
ARG
A
643
22.971
−10.248
13.403
1.00
11.47
A
C

ATOM
3675
O
ARG
A
643
24.193
−10.287
13.620
1.00
12.13
A
O

ATOM
3676
N
LEU
A
644
22.153
−9.467
14.099
1.00
10.94
A
N

ATOM
3678
CA
LEU
A
644
22.594
−8.737
15.290
1.00
10.40
A
C

ATOM
3680
CB
LEU
A
644
21.419
−7.958
15.904
1.00
9.69
A
C

ATOM
3683
CG
LEU
A
644
20.852
−6.832
15.018
1.00
11.08
A
C

ATOM
3685
CD1
LEU
A
644
19.472
−6.365
15.508
1.00
9.53
A
C

ATOM
3689
CD2
LEU
A
644
21.813
−5.666
14.973
1.00
10.40
A
C

ATOM
3693
C
LEU
A
644
23.159
−9.720
16.313
1.00
10.18
A
C

ATOM
3694
O
LEU
A
644
22.586
−10.783
16.529
1.00
9.49
A
O

ATOM
3695
N
PRO
A
645
24.294
−9.404
16.929
1.00
11.40
A
N

ATOM
3696
CA
PRO
A
645
24.890
−10.317
17.908
1.00
11.04
A
C

ATOM
3698
CB
PRO
A
645
26.306
−9.773
18.072
1.00
11.53
A
C

ATOM
3701
CG
PRO
A
645
26.133
−8.323
17.893
1.00
12.78
A
C

ATOM
3704
CD
PRO
A
645
25.098
−8.180
16.770
1.00
11.64
A
C

ATOM
3707
C
PRO
A
645
24.153
−10.280
19.237
1.00
10.76
A
C

ATOM
3708
O
PRO
A
645
23.433
−9.317
19.545
1.00
10.19
A
O

ATOM
3709
N
LYS
A
646
24.334
−11.309
20.050
1.00
10.57
A
N

ATOM
3711
CA
LYS
A
646
23.713
−11.298
21.372
1.00
11.04
A
C

ATOM
3713
CB
LYS
A
646
23.920
−12.626
22.090
1.00
11.87
A
C

ATOM
3716
CG
LYS
A
646
23.106
−12.693
23.388
1.00
12.94
A
C

ATOM
3719
CD
LYS
A
646
23.208
−14.023
24.094
1.00
15.55
A
C

ATOM
3722
CE
LYS
A
646
24.549
−14.181
24.784
1.00
17.68
A
C

ATOM
3725
NZ
LYS
A
646
24.744
−13.211
25.909
1.00
17.61
A
N

ATOM
3729
C
LYS
A
646
24.245
−10.171
22.262
1.00
11.04
A
C

ATOM
3730
O
LYS
A
646
25.455
−10.098
22.512
1.00
10.00
A
O

ATOM
3731
N
PRO
A
647
23.367
−9.298
22.764
1.00
11.04
A
N

ATOM
3732
CA
PRO
A
647
23.795
−8.304
23.753
1.00
11.70
A
C

ATOM
3734
CB
PRO
A
647
22.493
−7.562
24.101
1.00
11.68
A
C

ATOM
3737
CG
PRO
A
647
21.613
−7.755
22.933
1.00
10.24
A
C

ATOM
3740
CD
PRO
A
647
21.939
−9.134
22.407
1.00
10.94
A
C

ATOM
3743
C
PRO
A
647
24.385
−9.009
24.989
1.00
12.95
A
C

ATOM
3744
O
PRO
A
647
23.903
−10.073
25.362
1.00
13.55
A
O

ATOM
3745
N
ASP
A
648
25.404
−8.419
25.596
1.00
14.13
A
N

ATOM
3747
CA
ASP
A
648
26.079
−9.025
26.746
1.00
15.83
A
C

ATOM
3749
CB
ASP
A
648
27.078
−8.037
27.343
1.00
16.30
A
C

ATOM
3752
CG
ASP
A
648
27.957
−8.685
28.387
1.00
19.77
A
C

ATOM
3753
OD1
ASP
A
648
28.581
−9.737
28.087
1.00
23.36
A
O

ATOM
3754
OD2
ASP
A
648
28.045
−8.239
29.538
1.00
22.83
A
O

ATOM
3755
C
ASP
A
648
25.132
−9.530
27.867
1.00
15.47
A
C

ATOM
3756
O
ASP
A
648
25.328
−10.620
28.405
1.00
15.60
A
O

ATOM
3757
N
LEU
A
649
24.107
−8.758
28.208
1.00
15.04
A
N

ATOM
3759
CA
LEU
A
649
23.198
−9.145
29.293
1.00
15.54
A
C

ATOM
3761
CB
LEU
A
649
22.786
−7.917
30.102
1.00
16.16
A
C

ATOM
3764
CG
LEU
A
649
23.972
−7.268
30.829
1.00
18.63
A
C

ATOM
3766
CD1
LEU
A
649
23.508
−6.172
31.752
1.00
21.84
A
C

ATOM
3770
CD2
LEU
A
649
24.819
−8.285
31.590
1.00
20.44
A
C

ATOM
3774
C
LEU
A
649
21.958
−9.928
28.864
1.00
15.26
A
C

ATOM
3775
O
LEU
A
649
21.143
−10.329
29.702
1.00
15.43
A
O

ATOM
3776
N
CYS
A
650
21.816
−10.172
27.573
1.00
14.41
A
N

ATOM
3778
CA
CYS
A
650
20.722
−10.976
27.078
1.00
14.24
A
C

ATOM
3780
CB
CYS
A
650
20.630
−10.821
25.562
1.00
14.58
A
C

ATOM
3783
SG
CYS
A
650
19.263
−11.720
24.860
1.00
14.34
A
S

ATOM
3784
C
CYS
A
650
20.886
−12.462
27.463
1.00
14.97
A
C

ATOM
3785
O
CYS
A
650
21.918
−13.062
27.147
1.00
14.59
A
O

ATOM
3786
N
PRO
A
651
19.882
−13.046
28.131
1.00
15.29
A
N

ATOM
3787
CA
PRO
A
651
19.881
−14.480
28.453
1.00
15.51
A
C

ATOM
3789
CB
PRO
A
651
18.505
−14.690
29.096
1.00
15.33
A
C

ATOM
3792
CG
PRO
A
651
18.118
−13.377
29.606
1.00
16.20
A
C

ATOM
3795
CD
PRO
A
651
18.647
−12.395
28.606
1.00
15.45
A
C

ATOM
3798
C
PRO
A
651
19.950
−15.280
27.156
1.00
15.61
A
C

ATOM
3799
O
PRO
A
651
19.232
−14.936
26.226
1.00
13.93
A
O

ATOM
3800
N
PRO
A
652
20.796
−16.304
27.069
1.00
15.46
A
N

ATOM
3801
CA
PRO
A
652
20.857
−17.144
25.865
1.00
15.22
A
C

ATOM
3803
CB
PRO
A
652
21.714
−18.328
26.322
1.00
16.43
A
C

ATOM
3806
CG
PRO
A
652
22.606
−17.704
27.397
1.00
15.77
A
C

ATOM
3809
CD
PRO
A
652
21.777
−16.707
28.093
1.00
16.56
A
C

ATOM
3812
C
PRO
A
652
19.492
−17.602
25.303
1.00
14.66
A
C

ATOM
3813
O
PRO
A
652
19.290
−17.564
24.078
1.00
13.44
A
O

ATOM
3814
N
VAL
A
653
18.583
−18.024
26.175
1.00
14.07
A
N

ATOM
3816
CA
VAL
A
653
17.232
−18.429
25.766
1.00
14.45
A
C

ATOM
3818
CB
VAL
A
653
16.422
−18.968
26.990
1.00
15.04
A
C

ATOM
3820
CG1
VAL
A
653
16.178
−17.897
28.039
1.00
16.41
A
C

ATOM
3824
CG2
VAL
A
653
15.103
−19.588
26.565
1.00
16.73
A
C

ATOM
3828
C
VAL
A
653
16.476
−17.297
25.056
1.00
13.12
A
C

ATOM
3829
O
VAL
A
653
15.724
−17.519
24.101
1.00
13.27
A
O

ATOM
3830
N
LEU
A
654
16.671
−16.075
25.525
1.00
12.25
A
N

ATOM
3832
CA
LEU
A
654
16.061
−14.930
24.859
1.00
11.55
A
C

ATOM
3834
CB
LEU
A
654
16.133
−13.699
25.762
1.00
12.25
A
C

ATOM
3837
CG
LEU
A
654
15.424
−12.465
25.211
1.00
11.73
A
C

ATOM
3839
CD1
LEU
A
654
13.992
−12.763
24.836
1.00
12.71
A
C

ATOM
3843
CD2
LEU
A
654
15.497
−11.336
26.213
1.00
15.67
A
C

ATOM
3847
C
LEU
A
654
16.705
−14.659
23.499
1.00
11.43
A
C

ATOM
3848
O
LEU
A
654
16.017
−14.299
22.532
1.00
9.70
A
O

ATOM
3849
N
TYR
A
655
18.023
−14.819
23.391
1.00
10.65
A
N

ATOM
3851
CA
TYR
A
655
18.650
−14.626
22.089
1.00
10.82
A
C

ATOM
3853
CB
TYR
A
655
20.170
−14.605
22.197
1.00
10.18
A
C

ATOM
3856
CG
TYR
A
655
20.847
−14.244
20.909
1.00
10.71
A
C

ATOM
3857
CD1
TYR
A
655
20.691
−12.978
20.344
1.00
9.23
A
C

ATOM
3859
CE1
TYR
A
655
21.328
−12.648
19.126
1.00
10.02
A
C

ATOM
3861
CZ
TYR
A
655
22.107
−13.582
18.493
1.00
10.45
A
C

ATOM
3862
OH
TYR
A
655
22.732
−13.275
17.313
1.00
11.48
A
O

ATOM
3864
CE2
TYR
A
655
22.257
−14.848
19.030
1.00
11.87
A
C

ATOM
3866
CD2
TYR
A
655
21.607
−15.175
20.222
1.00
11.48
A
C

ATOM
3868
C
TYR
A
655
18.159
−15.669
21.083
1.00
11.69
A
C

ATOM
3869
O
TYR
A
655
17.945
−15.356
19.924
1.00
13.15
A
O

ATOM
3870
N
THR
A
656
17.913
−16.896
21.538
1.00
12.50
A
N

ATOM
3872
CA
THR
A
656
17.343
−17.927
20.681
1.00
12.57
A
C

ATOM
3874
CB
THR
A
656
17.203
−19.233
21.454
1.00
12.96
A
C

ATOM
3876
OG1
THR
A
656
18.524
−19.752
21.709
1.00
13.90
A
O

ATOM
3878
CG2
THR
A
656
16.497
−20.292
20.634
1.00
13.68
A
C

ATOM
3882
C
THR
A
656
16.002
−17.478
20.123
1.00
12.60
A
C

ATOM
3883
O
THR
A
656
15.725
−17.642
18.942
1.00
12.69
A
O

ATOM
3884
N
LEU
A
657
15.196
−16.876
20.968
1.00
12.41
A
N

ATOM
3886
CA
LEU
A
657
13.896
−16.387
20.550
1.00
13.31
A
C

ATOM
3888
CB
LEU
A
657
13.159
−15.855
21.767
1.00
13.71
A
C

ATOM
3891
CG
LEU
A
657
11.651
−15.834
21.701
1.00
17.10
A
C

ATOM
3893
CD1
LEU
A
657
11.129
−17.245
21.475
1.00
17.52
A
C

ATOM
3897
CD2
LEU
A
657
11.093
−15.233
22.999
1.00
17.71
A
C

ATOM
3901
C
LEU
A
657
14.035
−15.306
19.478
1.00
12.69
A
C

ATOM
3902
O
LEU
A
657
13.318
−15.328
18.471
1.00
11.85
A
O

ATOM
3903
N
MET
A
658
14.973
−14.381
19.681
1.00
12.08
A
N

ATOM
3905
CA
MET
A
658
15.256
−13.329
18.704
1.00
12.19
A
C

ATOM
3907
CB
MET
A
658
16.394
−12.406
19.158
1.00
12.40
A
C

ATOM
3910
CG
MET
A
658
16.108
−11.534
20.375
1.00
14.24
A
C

ATOM
3913
SD
MET
A
658
17.644
−10.690
20.859
1.00
17.59
A
S

ATOM
3914
CE
MET
A
658
17.109
−9.824
22.311
1.00
17.80
A
C

ATOM
3918
C
MET
A
658
15.622
−13.928
17.361
1.00
11.84
A
C

ATOM
3919
O
MET
A
658
15.138
−13.476
16.317
1.00
11.75
A
O

ATOM
3920
N
THR
A
659
16.467
−14.964
17.370
1.00
11.94
A
N

ATOM
3922
CA
THR
A
659
16.955
−15.520
16.113
1.00
12.12
A
C

ATOM
3924
CB
THR
A
659
18.149
−16.515
16.292
1.00
12.54
A
C

ATOM
3926
OG1
THR
A
659
17.762
−17.627
17.096
1.00
16.72
A
O

ATOM
3928
CG2
THR
A
659
19.287
−15.907
17.045
1.00
12.86
A
C

ATOM
3932
C
THR
A
659
15.821
−16.169
15.321
1.00
11.44
A
C

ATOM
3933
O
THR
A
659
15.857
−16.155
14.085
1.00
11.07
A
O

ATOM
3934
N
ARG
A
660
14.828
−16.730
16.026
1.00
11.23
A
N

ATOM
3936
CA
ARG
A
660
13.648
−17.313
15.390
1.00
11.85
A
C

ATOM
3938
CB
ARG
A
660
12.801
−18.090
16.395
1.00
12.33
A
C

ATOM
3941
CG
ARG
A
660
13.442
−19.396
16.829
1.00
15.41
A
C

ATOM
3944
CD
ARG
A
660
12.668
−20.082
17.920
1.00
18.66
A
C

ATOM
3947
NE
ARG
A
660
11.342
−20.465
17.435
1.00
21.96
A
N

ATOM
3949
CZ
ARG
A
660
10.238
−20.507
18.175
1.00
24.62
A
C

ATOM
3950
NH1
ARG
A
660
10.262
−20.224
19.484
1.00
25.28
A
N

ATOM
3953
NH2
ARG
A
660
9.104
−20.872
17.604
1.00
25.04
A
N

ATOM
3956
C
ARG
A
660
12.790
−16.249
14.711
1.00
11.14
A
C

ATOM
3957
O
ARG
A
660
12.256
−16.473
13.614
1.00
11.17
A
O

ATOM
3958
N
CYS
A
661
12.695
−15.082
15.345
1.00
10.45
A
N

ATOM
3960
CA
CYS
A
661
12.009
−13.926
14.756
1.00
10.32
A
C

ATOM
3962
CB
CYS
A
661
11.839
−12.812
15.791
1.00
10.37
A
C

ATOM
3965
SG
CYS
A
661
10.842
−13.203
17.247
1.00
11.06
A
S

ATOM
3966
C
CYS
A
661
12.729
−13.350
13.538
1.00
10.43
A
C

ATOM
3967
O
CYS
A
661
12.100
−12.678
12.705
1.00
10.50
A
O

ATOM
3968
N
TRP
A
662
14.036
−13.597
13.427
1.00
9.89
A
N

ATOM
3970
CA
TRP
A
662
14.812
−13.171
12.269
1.00
9.87
A
C

ATOM
3972
CB
TRP
A
662
16.154
−12.573
12.706
1.00
9.96
A
C

ATOM
3975
CG
TRP
A
662
16.045
−11.379
13.624
1.00
7.99
A
C

ATOM
3976
CD1
TRP
A
662
15.098
−10.395
13.601
1.00
9.64
A
C

ATOM
3978
NE1
TRP
A
662
15.341
−9.479
14.599
1.00
9.65
A
N

ATOM
3980
CE2
TRP
A
662
16.458
−9.867
15.292
1.00
9.01
A
C

ATOM
3981
CD2
TRP
A
662
16.915
−11.064
14.707
1.00
8.52
A
C

ATOM
3982
CE3
TRP
A
662
18.060
−11.668
15.241
1.00
8.33
A
C

ATOM
3984
CZ3
TRP
A
662
18.678
−11.079
16.328
1.00
9.97
A
C

ATOM
3986
CH2
TRP
A
662
18.197
−9.903
16.882
1.00
9.90
A
C

ATOM
3988
CZ2
TRP
A
662
17.091
−9.285
16.390
1.00
8.65
A
C

ATOM
3990
C
TRP
A
662
15.035
−14.293
11.250
1.00
10.88
A
C

ATOM
3991
O
TRP
A
662
16.003
−14.279
10.518
1.00
11.46
A
O

ATOM
3992
N
ASP
A
663
14.117
−15.247
11.169
1.00
12.36
A
N

ATOM
3994
CA
ASP
A
663
14.145
−16.205
10.079
1.00
13.31
A
C

ATOM
3996
CB
ASP
A
663
13.079
−17.269
10.250
1.00
13.47
A
C

ATOM
3999
CG
ASP
A
663
13.383
−18.523
9.450
1.00
17.38
A
C

ATOM
4000
OD1
ASP
A
663
13.368
−18.472
8.199
1.00
19.87
A
O

ATOM
4001
OD2
ASP
A
663
13.623
−19.611
10.004
1.00
19.38
A
O

ATOM
4002
C
ASP
A
663
13.902
−15.428
8.791
1.00
13.36
A
C

ATOM
4003
O
ASP
A
663
13.021
−14.564
8.740
1.00
12.27
A
O

ATOM
4004
N
TYR
A
664
14.708
−15.693
7.772
1.00
13.88
A
N

ATOM
4006
CA
TYR
A
664
14.563
−14.999
6.493
1.00
14.75
A
C

ATOM
4008
CB
TYR
A
664
15.586
−15.465
5.445
1.00
15.39
A
C

ATOM
4011
CG
TYR
A
664
15.757
−14.437
4.351
1.00
16.86
A
C

ATOM
4012
CD1
TYR
A
664
16.650
−13.378
4.508
1.00
19.69
A
C

ATOM
4014
CE1
TYR
A
664
16.807
−12.418
3.526
1.00
21.35
A
C

ATOM
4016
CZ
TYR
A
664
16.055
−12.492
2.381
1.00
21.53
A
C

ATOM
4017
OH
TYR
A
664
16.230
−11.512
1.432
1.00
26.28
A
O

ATOM
4019
CE2
TYR
A
664
15.146
−13.520
2.189
1.00
21.81
A
C

ATOM
4021
CD2
TYR
A
664
14.992
−14.490
3.181
1.00
19.31
A
C

ATOM
4023
C
TYR
A
664
13.158
−15.162
5.918
1.00
15.14
A
C

ATOM
4024
O
TYR
A
664
12.615
−14.215
5.389
1.00
15.70
A
O

ATOM
4025
N
ASP
A
665
12.602
−16.366
6.020
1.00
15.67
A
N

ATOM
4027
CA
ASP
A
665
11.266
−16.674
5.507
1.00
16.37
A
C

ATOM
4029
CB
ASP
A
665
11.137
−18.185
5.297
1.00
16.98
A
C

ATOM
4032
CG
ASP
A
665
9.894
−18.570
4.536
1.00
20.27
A
C

ATOM
4033
OD1
ASP
A
665
8.880
−17.841
4.603
1.00
21.22
A
O

ATOM
4034
OD2
ASP
A
665
9.847
−19.600
3.828
1.00
25.29
A
O

ATOM
4035
C
ASP
A
665
10.197
−16.222
6.508
1.00
15.72
A
C

ATOM
4036
O
ASP
A
665
10.133
−16.769
7.607
1.00
14.51
A
O

ATOM
4037
N
PRO
A
666
9.382
−15.230
6.167
1.00
16.24
A
N

ATOM
4038
CA
PRO
A
666
8.375
−14.747
7.129
1.00
16.93
A
C

ATOM
4040
CB
PRO
A
666
7.583
−13.690
6.346
1.00
17.41
A
C

ATOM
4043
CG
PRO
A
666
8.026
−13.812
4.904
1.00
17.55
A
C

ATOM
4046
CD
PRO
A
666
9.371
−14.460
4.914
1.00
16.23
A
C

ATOM
4049
C
PRO
A
666
7.471
−15.869
7.673
1.00
17.49
A
C

ATOM
4050
O
PRO
A
666
7.117
−15.846
8.857
1.00
16.21
A
O

ATOM
4051
N
SER
A
667
7.161
−16.855
6.823
1.00
18.52
A
N

ATOM
4053
CA
SER
A
667
6.277
−17.980
7.182
1.00
19.22
A
C

ATOM
4055
CB
SER
A
667
6.089
−18.936
5.988
1.00
19.21
A
C

ATOM
4058
OG
SER
A
667
5.265
−18.349
5.018
1.00
22.33
A
O

ATOM
4060
C
SER
A
667
6.774
−18.786
8.355
1.00
18.58
A
C

ATOM
4061
O
SER
A
667
5.977
−19.427
9.028
1.00
19.88
A
O

ATOM
4062
N
ASP
A
668
8.083
−18.767
8.602
1.00
18.14
A
N

ATOM
4064
CA
ASP
A
668
8.691
−19.514
9.690
1.00
17.77
A
C

ATOM
4066
CB
ASP
A
668
10.041
−20.074
9.239
1.00
18.75
A
C

ATOM
4069
CG
ASP
A
668
9.875
−21.107
8.141
1.00
22.03
A
C

ATOM
4070
OD1
ASP
A
668
10.883
−21.598
7.597
1.00
27.40
A
O

ATOM
4071
OD2
ASP
A
668
8.741
−21.464
7.754
1.00
25.19
A
O

ATOM
4072
C
ASP
A
668
8.866
−18.773
10.999
1.00
16.19
A
C

ATOM
4073
O
ASP
A
668
9.285
−19.368
11.975
1.00
16.42
A
O

ATOM
4074
N
ARG
A
669
8.544
−17.484
11.041
1.00
14.15
A
N

ATOM
4076
CA
ARG
A
669
8.698
−16.742
12.294
1.00
12.17
A
C

ATOM
4078
CB
ARG
A
669
8.754
−15.241
12.032
1.00
11.55
A
C

ATOM
4081
CG
ARG
A
669
9.876
−14.823
11.139
1.00
10.93
A
C

ATOM
4084
CD
ARG
A
669
9.765
−13.404
10.667
1.00
8.98
A
C

ATOM
4087
NE
ARG
A
669
10.697
−13.209
9.551
1.00
9.01
A
N

ATOM
4089
CZ
ARG
A
669
10.533
−12.298
8.608
1.00
8.74
A
C

ATOM
4090
NH1
ARG
A
669
9.534
−11.433
8.687
1.00
9.38
A
N

ATOM
4093
NH2
ARG
A
669
11.399
−12.224
7.601
1.00
9.94
A
N

ATOM
4096
C
ARG
A
669
7.528
−17.054
13.223
1.00
11.87
A
C

ATOM
4097
O
ARG
A
669
6.428
−17.374
12.748
1.00
11.94
A
O

ATOM
4098
N
PRO
A
670
7.721
−16.936
14.531
1.00
11.24
A
N

ATOM
4099
CA
PRO
A
670
6.624
−17.164
15.492
1.00
10.97
A
C

ATOM
4101
CB
PRO
A
670
7.294
−16.965
16.857
1.00
12.04
A
C

ATOM
4104
CG
PRO
A
670
8.752
−16.960
16.597
1.00
12.70
A
C

ATOM
4107
CD
PRO
A
670
8.967
−16.549
15.200
1.00
11.74
A
C

ATOM
4110
C
PRO
A
670
5.502
−16.141
15.365
1.00
10.78
A
C

ATOM
4111
O
PRO
A
670
5.748
−15.057
14.862
1.00
10.11
A
O

ATOM
4112
N
ARG
A
671
4.306
−16.486
15.841
1.00
10.15
A
N

ATOM
4114
CA
ARG
A
671
3.225
−15.531
16.041
1.00
10.66
A
C

ATOM
4116
CB
ARG
A
671
1.913
−16.274
16.265
1.00
11.28
A
C

ATOM
4119
CG
ARG
A
671
1.425
−17.188
15.162
1.00
14.40
A
C

ATOM
4122
CD
ARG
A
671
0.097
−17.817
15.566
1.00
18.14
A
C

ATOM
4125
NE
ARG
A
671
−0.602
−18.573
14.531
1.00
19.61
A
N

ATOM
4127
CZ
ARG
A
671
−0.460
−19.884
14.309
1.00
22.54
A
C

ATOM
4128
NH1
ARG
A
671
0.379
−20.617
15.035
1.00
21.69
A
N

ATOM
4131
NH2
ARG
A
671
−1.180
−20.473
13.358
1.00
23.16
A
N

ATOM
4134
C
ARG
A
671
3.478
−14.710
17.304
1.00
9.70
A
C

ATOM
4135
O
ARG
A
671
4.179
−15.161
18.193
1.00
9.46
A
O

ATOM
4136
N
PHE
A
672
2.854
−13.549
17.425
1.00
9.68
A
N

ATOM
4138
CA
PHE
A
672
2.954
−12.793
18.661
1.00
9.83
A
C

ATOM
4140
CB
PHE
A
672
2.376
−11.377
18.529
1.00
9.02
A
C

ATOM
4143
CG
PHE
A
672
3.314
−10.400
17.874
1.00
7.29
A
C

ATOM
4144
CD1
PHE
A
672
4.499
−10.034
18.499
1.00
7.29
A
C

ATOM
4146
CE1
PHE
A
672
5.348
−9.114
17.899
1.00
6.39
A
C

ATOM
4148
CZ
PHE
A
672
5.024
−8.548
16.678
1.00
6.43
A
C

ATOM
4150
CE2
PHE
A
672
3.873
−8.906
16.040
1.00
7.92
A
C

ATOM
4152
CD2
PHE
A
672
3.008
−9.841
16.639
1.00
7.47
A
C

ATOM
4154
C
PHE
A
672
2.316
−13.516
19.857
1.00
10.52
A
C

ATOM
4155
O
PHE
A
672
2.809
−13.376
20.963
1.00
10.42
A
O

ATOM
4156
N
THR
A
673
1.245
−14.285
19.652
1.00
11.02
A
N

ATOM
4158
CA
THR
A
673
0.664
−15.049
20.764
1.00
12.24
A
C

ATOM
4160
CB
THR
A
673
−0.597
−15.834
20.351
1.00
12.82
A
C

ATOM
4162
OG1
THR
A
673
−0.322
−16.642
19.189
1.00
13.06
A
O

ATOM
4164
CG2
THR
A
673
−1.684
−14.908
19.961
1.00
14.88
A
C

ATOM
4168
C
THR
A
673
1.682
−16.025
21.330
1.00
12.24
A
C

ATOM
4169
O
THR
A
673
1.768
−16.205
22.552
1.00
13.08
A
O

ATOM
4170
N
GLU
A
674
2.448
−16.653
20.435
1.00
11.03
A
N

ATOM
4172
CA
GLU
A
674
3.482
−17.598
20.811
1.00
11.45
A
C

ATOM
4174
CB
GLU
A
674
3.971
−18.366
19.575
1.00
11.48
A
C

ATOM
4177
CG
GLU
A
674
2.851
−19.201
18.944
1.00
12.48
A
C

ATOM
4180
CD
GLU
A
674
3.143
−19.750
17.549
1.00
17.12
A
C

ATOM
4181
OE1
GLU
A
674
4.096
−19.296
16.881
1.00
15.46
A
O

ATOM
4182
OE2
GLU
A
674
2.370
−20.657
17.120
1.00
18.19
A
O

ATOM
4183
C
GLU
A
674
4.651
−16.904
21.527
1.00
11.40
A
C

ATOM
4184
O
GLU
A
674
5.194
−17.429
22.504
1.00
12.34
A
O

ATOM
4185
N
LEU
A
675
5.006
−15.714
21.070
1.00
11.03
A
N

ATOM
4187
CA
LEU
A
675
6.064
−14.951
21.712
1.00
10.62
A
C

ATOM
4189
CB
LEU
A
675
6.459
−13.750
20.855
1.00
10.87
A
C

ATOM
4192
CG
LEU
A
675
7.212
−14.093
19.574
1.00
11.12
A
C

ATOM
4194
CD1
LEU
A
675
7.279
−12.885
18.652
1.00
11.98
A
C

ATOM
4198
CD2
LEU
A
675
8.608
−14.669
19.883
1.00
12.08
A
C

ATOM
4202
C
LEU
A
675
5.674
−14.489
23.125
1.00
10.64
A
C

ATOM
4203
O
LEU
A
675
6.537
−14.412
23.997
1.00
10.13
A
O

ATOM
4204
N
VAL
A
676
4.401
−14.147
23.340
1.00
10.75
A
N

ATOM
4206
CA
VAL
A
676
3.949
−13.746
24.663
1.00
10.97
A
C

ATOM
4208
CB
VAL
A
676
2.481
−13.353
24.703
1.00
11.26
A
C

ATOM
4210
CG1
VAL
A
676
1.972
−13.247
26.176
1.00
11.67
A
C

ATOM
4214
CG2
VAL
A
676
2.265
−12.044
23.975
1.00
11.71
A
C

ATOM
4218
C
VAL
A
676
4.193
−14.922
25.623
1.00
12.06
A
C

ATOM
4219
O
VAL
A
676
4.724
−14.750
26.719
1.00
11.23
A
O

ATOM
4220
N
CYS
A
677
3.827
−16.118
25.189
1.00
12.77
A
N

ATOM
4222
CA
CYS
A
677
4.070
−17.309
26.003
1.00
13.59
A
C

ATOM
4224
CB
CYS
A
677
3.486
−18.526
25.322
1.00
14.78
A
C

ATOM
4227
SG
CYS
A
677
1.727
−18.420
25.306
1.00
23.73
A
S

ATOM
4228
C
CYS
A
677
5.544
−17.543
26.310
1.00
12.70
A
C

ATOM
4229
O
CYS
A
677
5.911
−17.813
27.472
1.00
12.44
A
O

ATOM
4230
N
SER
A
678
6.384
−17.449
25.280
1.00
10.95
A
N

ATOM
4232
CA
SER
A
678
7.809
−17.673
25.412
1.00
11.22
A
C

ATOM
4234
CB
SER
A
678
8.501
−17.631
24.052
1.00
11.49
A
C

ATOM
4237
OG
SER
A
678
8.087
−18.690
23.218
1.00
12.71
A
O

ATOM
4239
C
SER
A
678
8.463
−16.617
26.319
1.00
10.73
A
C

ATOM
4240
O
SER
A
678
9.291
−16.946
27.175
1.00
10.09
A
O

ATOM
4241
N
LEU
A
679
8.075
−15.359
26.131
1.00
10.12
A
N

ATOM
4243
CA
LEU
A
679
8.633
−14.277
26.941
1.00
10.19
A
C

ATOM
4245
CB
LEU
A
679
8.272
−12.920
26.386
1.00
10.05
A
C

ATOM
4248
CG
LEU
A
679
9.120
−12.519
25.180
1.00
10.35
A
C

ATOM
4250
CD1
LEU
A
679
8.594
−11.187
24.639
1.00
10.06
A
C

ATOM
4254
CD2
LEU
A
679
10.583
−12.406
25.546
1.00
13.61
A
C

ATOM
4258
C
LEU
A
679
8.185
−14.379
28.400
1.00
10.85
A
C

ATOM
4259
O
LEU
A
679
8.975
−14.105
29.293
1.00
10.86
A
O

ATOM
4260
N
SER
A
680
6.944
−14.812
28.632
1.00
11.33
A
N

ATOM
4262
CA
SER
A
680
6.442
−15.009
29.976
1.00
11.30
A
C

ATOM
4264
CB
SER
A
680
4.975
−15.458
29.955
1.00
11.82
A
C

ATOM
4267
OG
SER
A
680
4.160
−14.393
29.529
1.00
13.70
A
O

ATOM
4269
C
SER
A
680
7.294
−16.054
30.696
1.00
11.10
A
C

ATOM
4270
O
SER
A
680
7.569
−15.914
31.876
1.00
10.06
A
O

ATOM
4271
N
ASP
A
681
7.709
−17.079
29.965
1.00
11.27
A
N

ATOM
4273
CA
ASP
A
681
8.555
−18.151
30.489
1.00
11.79
A
C

ATOM
4275
CB
ASP
A
681
8.582
−19.302
29.480
1.00
12.73
A
C

ATOM
4278
CG
ASP
A
681
9.205
−20.567
30.017
1.00
16.09
A
C

ATOM
4279
OD1
ASP
A
681
9.063
−20.869
31.226
1.00
18.24
A
O

ATOM
4280
OD2
ASP
A
681
9.823
−21.351
29.260
1.00
19.49
A
O

ATOM
4281
C
ASP
A
681
9.962
−17.637
30.793
1.00
11.36
A
C

ATOM
4282
O
ASP
A
681
10.524
−17.962
31.832
1.00
10.57
A
O

ATOM
4283
N
VAL
A
682
10.514
−16.805
29.911
1.00
10.17
A
N

ATOM
4285
CA
VAL
A
682
11.831
−16.189
30.137
1.00
10.71
A
C

ATOM
4287
CB
VAL
A
682
12.323
−15.421
28.879
1.00
11.06
A
C

ATOM
4289
CG1
VAL
A
682
13.585
−14.610
29.186
1.00
13.37
A
C

ATOM
4293
CG2
VAL
A
682
12.586
−16.394
27.719
1.00
12.19
A
C

ATOM
4297
C
VAL
A
682
11.784
−15.270
31.371
1.00
10.10
A
C

ATOM
4298
O
VAL
A
682
12.698
−15.271
32.194
1.00
9.87
A
O

ATOM
4299
N
TYR
A
683
10.713
−14.501
31.498
1.00
9.76
A
N

ATOM
4301
CA
TYR
A
683
10.535
−13.588
32.615
1.00
10.41
A
C

ATOM
4303
CB
TYR
A
683
9.258
−12.801
32.428
1.00
10.16
A
C

ATOM
4306
CG
TYR
A
683
8.986
−11.749
33.480
1.00
11.77
A
C

ATOM
4307
CD1
TYR
A
683
9.973
−10.837
33.858
1.00
12.15
A
C

ATOM
4309
CE1
TYR
A
683
9.719
−9.862
34.816
1.00
14.98
A
C

ATOM
4311
CZ
TYR
A
683
8.480
−9.787
35.386
1.00
15.15
A
C

ATOM
4312
OH
TYR
A
683
8.225
−8.818
36.312
1.00
16.29
A
O

ATOM
4314
CE2
TYR
A
683
7.477
−10.669
35.022
1.00
16.42
A
C

ATOM
4316
CD2
TYR
A
683
7.743
−11.648
34.070
1.00
13.80
A
C

ATOM
4318
C
TYR
A
683
10.482
−14.356
33.933
1.00
10.77
A
C

ATOM
4319
O
TYR
A
683
11.155
−13.994
34.896
1.00
10.66
A
O

ATOM
4320
N
GLN
A
684
9.701
−15.438
33.952
1.00
11.00
A
N

ATOM
4322
CA
GLN
A
684
9.618
−16.300
35.132
1.00
11.22
A
C

ATOM
4324
CB
GLN
A
684
8.629
−17.444
34.930
1.00
11.31
A
C

ATOM
4327
CG
GLN
A
684
8.375
−18.269
36.236
1.00
13.65
A
C

ATOM
4330
CD
GLN
A
684
7.820
−17.402
37.374
1.00
15.94
A
C

ATOM
4331
OE1
GLN
A
684
8.477
−17.197
38.403
1.00
19.21
A
O

ATOM
4332
NE2
GLN
A
684
6.630
−16.887
37.180
1.00
16.15
A
N

ATOM
4335
C
GLN
A
684
10.971
−16.890
35.468
1.00
11.59
A
C

ATOM
4336
O
GLN
A
684
11.344
−16.943
36.636
1.00
11.70
A
O

ATOM
4337
N
MET
A
685
11.690
−17.356
34.453
1.00
12.42
A
N

ATOM
4339
CA
MET
A
685
13.022
−17.913
34.646
1.00
14.85
A
C

ATOM
4341
CB
MET
A
685
13.616
−18.457
33.334
1.00
15.51
A
C

ATOM
4344
CG
MET
A
685
15.075
−18.894
33.413
1.00
20.31
A
C

ATOM
4347
SD
MET
A
685
16.347
−17.557
33.428
1.00
30.38
A
S

ATOM
4348
CE
MET
A
685
16.971
−17.643
31.702
1.00
29.94
A
C

ATOM
4352
C
MET
A
685
13.952
−16.870
35.251
1.00
14.79
A
C

ATOM
4353
O
MET
A
685
14.707
−17.201
36.149
1.00
14.67
A
O

ATOM
4354
N
GLU
A
686
13.908
−15.623
34.767
1.00
15.09
A
N

ATOM
4356
CA
GLU
A
686
14.782
−14.564
35.321
1.00
15.60
A
C

ATOM
4358
CB
GLU
A
686
14.765
−13.293
34.457
1.00
15.66
A
C

ATOM
4361
CG
GLU
A
686
15.520
−13.394
33.143
1.00
18.58
A
C

ATOM
4364
CD
GLU
A
686
17.018
−13.650
33.305
1.00
19.75
A
C

ATOM
4365
OE1
GLU
A
686
17.692
−12.967
34.110
1.00
19.12
A
O

ATOM
4366
OE2
GLU
A
686
17.521
−14.545
32.603
1.00
25.71
A
O

ATOM
4367
C
GLU
A
686
14.431
−14.212
36.776
1.00
15.84
A
C

ATOM
4368
O
GLU
A
686
15.319
−13.886
37.568
1.00
15.94
A
O

ATOM
4369
N
LYS
A
687
13.146
−14.251
37.124
1.00
15.72
A
N

ATOM
4371
CA
LYS
A
687
12.727
−14.031
38.499
1.00
16.97
A
C

ATOM
4373
CB
LYS
A
687
11.206
−13.895
38.594
1.00
16.88
A
C

ATOM
4376
CG
LYS
A
687
10.707
−12.578
38.036
1.00
17.92
A
C

ATOM
4379
CD
LYS
A
687
9.303
−12.243
38.452
1.00
19.62
A
C

ATOM
4382
CE
LYS
A
687
8.270
−13.060
37.692
1.00
20.81
A
C

ATOM
4385
NZ
LYS
A
687
6.878
−12.646
38.085
1.00
20.18
A
N

ATOM
4389
C
LYS
A
687
13.225
−15.171
39.407
1.00
17.45
A
C

ATOM
4390
O
LYS
A
687
13.629
−14.925
40.534
1.00
18.25
A
O

ATOM
4391
N
ASP
A
688
13.214
−16.399
38.900
1.00
18.00
A
N

ATOM
4393
CA
ASP
A
688
13.607
−17.573
39.679
1.00
19.39
A
C

ATOM
4395
CB
ASP
A
688
13.129
−18.859
38.991
1.00
19.60
A
C

ATOM
4398
CG
ASP
A
688
11.616
−19.005
39.009
1.00
20.07
A
C

ATOM
4399
OD1
ASP
A
688
10.939
−18.210
39.683
1.00
18.55
A
O

ATOM
4400
OD2
ASP
A
688
11.017
−19.885
38.363
1.00
21.49
A
O

ATOM
4401
C
ASP
A
688
15.114
−17.677
39.938
1.00
20.75
A
C

ATOM
4402
O
ASP
A
688
15.519
−18.280
40.936
1.00
20.21
A
O

ATOM
4403
N
ILE
A
689
15.932
−17.094
39.064
1.00
22.34
A
N

ATOM
4405
CA
ILE
A
689
17.401
−17.136
39.206
1.00
24.85
A
C

ATOM
4407
CB
ILE
A
689
18.096
−17.337
37.831
1.00
25.22
A
C

ATOM
4409
CG1
ILE
A
689
18.027
−16.062
36.982
1.00
24.97
A
C

ATOM
4412
CD1
ILE
A
689
18.969
−16.063
35.816
1.00
26.04
A
C

ATOM
4416
CG2
ILE
A
689
17.485
−18.515
37.100
1.00
26.30
A
C

ATOM
4420
C
ILE
A
689
17.989
−15.894
39.845
1.00
26.98
A
C

ATOM
4421
O
ILE
A
689
19.220
−15.772
39.945
1.00
27.14
A
O

ATOM
4422
N
ALA
A
690
17.122
−14.964
40.247
1.00
29.52
A
N

ATOM
4424
CA
ALA
A
690
17.543
−13.708
40.840
1.00
31.03
A
C

ATOM
4426
CB
ALA
A
690
16.576
−12.605
40.460
1.00
31.13
A
C

ATOM
4430
C
ALA
A
690
17.629
−13.834
42.357
1.00
32.63
A
C

ATOM
4431
O
ALA
A
690
16.599
−13.900
43.042
1.00
32.75
A
O

ATOM
4432
N
MET
A
691
18.863
−13.859
42.864
1.00
34.71
A
N

ATOM
4434
CA
MET
A
691
19.159
−13.824
44.304
1.00
35.61
A
C

ATOM
4436
CB
MET
A
691
18.556
−12.572
44.955
1.00
36.56
A
C

ATOM
4439
CG
MET
A
691
19.081
−11.260
44.382
1.00
39.02
A
C

ATOM
4442
SD
MET
A
691
18.165
−9.844
45.010
1.00
44.70
A
S

ATOM
4443
CE
MET
A
691
16.654
−10.005
44.062
1.00
44.31
A
C

ATOM
4447
C
MET
A
691
18.685
−15.085
45.012
1.00
35.54
A
C

ATOM
4448
O
MET
A
691
18.582
−16.116
44.329
1.00
35.63
A
O

ATOM
4449
OXT
MET
A
691
18.437
−15.031
46.228
1.00
34.84
A
O

ATOM
4450
O1A
ANP
L
1
5.879
14.129
17.474
1.00
56.03
L
O

ATOM
4451
PA
ANP
L
1
5.828
13.237
18.779
1.00
54.99
L
P

ATOM
4452
O2A
ANP
L
1
4.359
12.664
18.974
1.00
55.47
L
O

ATOM
4454
O3A
ANP
L
1
6.928
12.057
18.803
1.00
58.70
L
O

ATOM
4455
PB
ANP
L
1
7.534
11.319
17.499
1.00
61.85
L
P

ATOM
4456
O1B
ANP
L
1
6.806
11.789
16.164
1.00
60.90
L
O

ATOM
4457
O2B
ANP
L
1
7.338
9.749
17.688
1.00
61.90
L
O

ATOM
4459
N3B
ANP
L
1
9.254
11.643
17.401
1.00
63.51
L
N

ATOM
4461
PG
ANP
L
1
9.852
13.230
16.957
1.00
65.53
L
P

ATOM
4462
O3G
ANP
L
1
10.884
13.100
15.748
1.00
66.11
L
O

ATOM
4464
O2G
ANP
L
1
10.586
13.911
18.193
1.00
64.86
L
O

ATOM
4466
O1G
ANP
L
1
8.643
14.135
16.458
1.00
65.59
L
O

ATOM
4467
O5*
ANP
L
1
6.277
14.111
20.050
1.00
51.13
L
O

ATOM
4468
C5*
ANP
L
1
7.549
14.739
20.107
1.00
46.73
L
C

ATOM
4471
C4*
ANP
L
1
8.168
14.467
21.461
1.00
44.62
L
C

ATOM
4473
O4*
ANP
L
1
7.254
14.809
22.510
1.00
41.60
L
O

ATOM
4474
C1*
ANP
L
1
7.281
13.799
23.515
1.00
38.50
L
C

ATOM
4476
C2*
ANP
L
1
8.155
12.643
23.037
1.00
42.11
L
C

ATOM
4478
O2*
ANP
L
1
9.304
12.486
23.860
1.00
44.90
L
O

ATOM
4480
C3*
ANP
L
1
8.524
12.998
21.614
1.00
43.96
L
C

ATOM
4482
O3*
ANP
L
1
9.901
12.797
21.351
1.00
45.53
L
O

ATOM
4484
N9
ANP
L
1
5.951
13.197
23.740
1.00
31.30
L
N

ATOM
4485
C8
ANP
L
1
5.015
12.876
22.819
1.00
28.19
L
C

ATOM
4487
N7
ANP
L
1
3.913
12.295
23.381
1.00
25.49
L
N

ATOM
4488
C5
ANP
L
1
4.161
12.228
24.694
1.00
24.63
L
C

ATOM
4489
C6
ANP
L
1
3.506
11.746
25.918
1.00
21.30
L
C

ATOM
4490
N6
ANP
L
1
2.277
11.204
25.779
1.00
18.20
L
N

ATOM
4493
C4
ANP
L
1
5.475
12.793
24.898
1.00
26.86
L
C

ATOM
4494
N3
ANP
L
1
6.067
12.897
26.207
1.00
23.82
L
N

ATOM
4495
C2
ANP
L
1
5.359
12.433
27.261
1.00
22.61
L
C

ATOM
4497
N1
ANP
L
1
4.129
11.883
27.114
1.00
19.81
L
N

ATOM
4498
O
HOH
M
1
11.906
10.877
19.048
1.00
54.80
M
O

ATOM
4501
O
HOH
W
1
19.443
−9.552
13.290
1.00
12.78
W
O

ATOM
4504
O
HOH
W
2
24.437
−5.004
22.245
1.00
16.30
W
O

ATOM
4507
O
HOH
W
3
16.956
−5.546
11.116
1.00
14.32
W
O

ATOM
4510
O
HOH
W
4
23.654
−5.882
27.256
1.00
16.76
W
O

ATOM
4513
O
HOH
W
5
19.773
−2.500
2.719
1.00
17.82
W
O

ATOM
4516
O
HOH
W
6
14.677
3.342
18.254
1.00
12.86
W
O

ATOM
4519
O
HOH
W
7
15.460
−2.754
37.319
1.00
19.09
W
O

ATOM
4522
O
HOH
W
8
0.917
−6.788
13.617
1.00
19.87
W
O

ATOM
4525
O
HOH
W
9
6.262
−4.291
9.880
1.00
17.35
W
O

ATOM
4528
O
HOH
W
10
−8.084
−9.594
20.676
1.00
19.55
W
O

ATOM
4531
O
HOH
W
11
9.378
−6.760
37.711
1.00
23.16
W
O

ATOM
4534
O
HOH
W
12
−4.324
2.362
25.030
1.00
17.21
W
O

ATOM
4537
O
HOH
W
13
2.631
−4.978
2.213
1.00
21.67
W
O

ATOM
4540
O
HOH
W
14
13.357
9.278
28.253
1.00
18.85
W
O

ATOM
4543
O
HOH
W
15
18.009
2.532
9.354
1.00
17.12
W
O

ATOM
4546
O
HOH
W
16
17.534
−9.551
37.009
1.00
20.96
W
O

ATOM
4549
O
HOH
W
17
27.129
−8.112
21.598
1.00
20.80
W
O

ATOM
4552
O
HOH
W
18
18.189
−15.606
12.347
1.00
21.79
W
O

ATOM
4555
O
HOH
W
19
13.177
0.863
35.291
1.00
23.40
W
O

ATOM
4558
O
HOH
W
20
17.054
−4.703
8.729
1.00
17.25
W
O

ATOM
4561
O
HOH
W
21
7.866
−18.942
20.500
1.00
24.06
W
O

ATOM
4564
O
HOH
W
22
14.700
7.035
22.806
1.00
16.93
W
O

ATOM
4567
O
HOH
W
23
−2.679
2.607
28.131
1.00
23.11
W
O

ATOM
4570
O
HOH
W
24
6.040
−9.803
37.824
1.00
33.92
W
O

ATOM
4573
O
HOH
W
25
10.004
−5.316
9.507
1.00
23.61
W
O

ATOM
4576
O
HOH
W
26
25.491
−5.320
24.819
1.00
23.18
W
O

ATOM
4579
O
HOH
W
27
4.534
32.921
12.514
1.00
20.02
W
O

ATOM
4582
O
HOH
W
28
21.903
−11.752
31.783
1.00
27.60
W
O

ATOM
4585
O
HOH
W
29
−2.817
−12.294
18.585
1.00
19.69
W
O

ATOM
4588
O
HOH
W
30
0.619
25.243
18.899
1.00
22.14
W
O

ATOM
4591
O
HOH
W
31
4.508
−2.772
−1.220
1.00
21.13
W
O

ATOM
4594
O
HOH
W
32
26.872
−11.629
24.125
1.00
24.32
W
O

ATOM
4597
O
HOH
W
33
26.063
−13.556
19.248
1.00
23.37
W
O

ATOM
4600
O
HOH
W
34
−4.463
26.591
28.285
1.00
28.20
W
O

ATOM
4603
O
HOH
W
35
−0.377
−9.432
8.082
1.00
25.76
W
O

ATOM
4606
O
HOH
W
36
11.357
4.915
15.323
1.00
31.17
W
O

ATOM
4609
O
HOH
W
37
0.444
−0.589
8.490
1.00
27.25
W
O

ATOM
4612
O
HOH
W
38
12.025
−12.305
3.518
1.00
20.13
W
O

ATOM
4615
O
HOH
W
39
−7.592
21.532
34.079
1.00
24.16
W
O

ATOM
4618
O
HOH
W
40
−3.034
25.675
20.623
1.00
27.86
W
O

ATOM
4621
O
HOH
W
41
19.252
−18.574
29.007
1.00
24.11
W
O

ATOM
4624
O
HOH
W
42
18.447
5.050
22.545
1.00
26.98
W
O

ATOM
4627
O
HOH
W
43
18.236
2.548
19.150
1.00
23.34
W
O

ATOM
4630
O
HOH
W
44
23.599
−4.581
0.730
1.00
23.86
W
O

ATOM
4633
O
HOH
W
45
5.670
−14.733
33.566
1.00
22.95
W
O

ATOM
4636
O
HOH
W
46
14.080
−19.737
23.406
1.00
22.24
W
O

ATOM
4639
O
HOH
W
47
22.734
4.890
34.891
1.00
26.97
W
O

ATOM
4642
O
HOH
W
48
−3.602
22.418
16.052
1.00
29.22
W
O

ATOM
4645
O
HOH
W
49
25.830
−12.392
15.030
1.00
32.70
W
O

ATOM
4648
O
HOH
W
50
−2.320
−15.117
16.246
1.00
28.09
W
O

ATOM
4651
O
HOH
W
51
2.614
−23.096
16.430
1.00
31.67
W
O

ATOM
4654
O
HOH
W
52
17.362
−18.998
43.191
1.00
26.88
W
O

ATOM
4657
O
HOH
W
53
26.474
−8.992
12.337
1.00
31.87
W
O

ATOM
4660
O
HOH
W
54
16.830
−4.474
−1.805
1.00
36.41
W
O

ATOM
4663
O
HOH
W
55
4.947
−4.071
36.311
1.00
25.83
W
O

ATOM
4666
O
HOH
W
56
1.631
1.495
10.141
1.00
25.82
W
O

ATOM
4669
O
HOH
W
57
21.157
−1.727
−0.971
1.00
32.21
W
O

ATOM
4672
O
HOH
W
58
20.249
−8.173
36.530
1.00
21.67
W
O

ATOM
4675
O
HOH
W
59
−2.610
−9.023
9.489
1.00
35.63
W
O

ATOM
4678
O
HOH
W
60
−9.404
23.395
33.556
1.00
27.23
W
O

ATOM
4681
O
HOH
W
61
11.153
3.802
−0.793
1.00
32.48
W
O

ATOM
4684
O
HOH
W
62
2.156
−13.178
30.950
1.00
32.64
W
O

ATOM
4687
O
HOH
W
63
15.393
−13.901
45.580
1.00
34.94
W
O

ATOM
4690
O
HOH
W
64
5.734
−20.060
12.705
1.00
28.43
W
O

ATOM
4693
O
HOH
W
65
−0.390
18.866
1.150
1.00
37.04
W
O

ATOM
4696
O
HOH
W
66
9.308
23.821
20.537
1.00
33.19
W
O

ATOM
4699
O
HOH
W
67
−8.657
−12.592
15.980
1.00
30.95
W
O

ATOM
4702
O
HOH
W
68
6.009
−10.288
5.499
1.00
30.71
W
O

ATOM
4705
O
HOH
W
69
5.849
−14.630
36.206
1.00
36.64
W
O

ATOM
4708
O
HOH
W
70
−0.379
−15.926
24.303
1.00
26.34
W
O

ATOM
4711
O
HOH
W
71
19.013
6.091
37.596
1.00
29.23
W
O

ATOM
4714
O
HOH
W
72
−2.437
−8.935
24.621
1.00
26.00
W
O

ATOM
4717
O
HOH
W
73
13.274
10.054
0.171
1.00
32.22
W
O

ATOM
4720
O
HOH
W
74
11.266
−4.798
37.300
1.00
27.56
W
O

ATOM
4723
O
HOH
W
75
18.634
5.650
3.509
1.00
30.22
W
O

ATOM
4726
O
HOH
W
76
17.088
−17.411
8.048
1.00
26.93
W
O

ATOM
4729
O
HOH
W
77
23.077
3.880
2.721
1.00
25.25
W
O

ATOM
4732
O
HOH
W
78
24.631
5.289
28.100
1.00
53.16
W
O

ATOM
4735
O
HOH
W
79
10.896
−4.046
−5.174
1.00
30.72
W
O

ATOM
4738
O
HOH
W
80
21.483
−18.240
22.299
1.00
31.63
W
O

ATOM
4741
O
HOH
W
81
17.664
−12.362
36.744
1.00
27.21
W
O

ATOM
4744
O
HOH
W
82
−6.800
−5.096
9.419
1.00
31.32
W
O

ATOM
4747
O
HOH
W
83
3.254
−6.214
33.543
1.00
29.36
W
O

ATOM
4750
O
HOH
W
84
−6.655
5.297
23.427
1.00
38.97
W
O

ATOM
4753
O
HOH
W
85
6.119
3.003
3.176
1.00
39.55
W
O

ATOM
4756
O
HOH
W
86
16.440
5.449
7.469
1.00
35.83
W
O

ATOM
4759
O
HOH
W
87
−6.743
15.088
41.223
1.00
33.66
W
O

ATOM
4762
O
HOH
W
88
−8.714
−10.654
12.475
1.00
45.30
W
O

ATOM
4765
O
HOH
W
89
5.455
6.147
14.560
1.00
34.25
W
O

ATOM
4768
O
HOH
W
90
7.863
−2.178
41.320
1.00
41.21
W
O

ATOM
4771
O
HOH
W
91
3.037
−8.511
31.787
1.00
43.98
W
O

ATOM
4774
O
HOH
W
92
−5.700
2.904
27.490
1.00
30.78
W
O

ATOM
4777
O
HOH
W
93
10.698
−16.094
41.240
1.00
40.42
W
O

ATOM
4780
O
HOH
W
94
8.297
−21.654
26.890
1.00
35.50
W
O

ATOM
4783
O
HOH
W
95
−7.043
26.092
27.806
1.00
33.08
W
O

ATOM
4786
O
HOH
W
96
12.953
−20.340
21.075
1.00
26.90
W
O

ATOM
4789
O
HOH
W
97
−1.020
6.390
14.791
1.00
42.20
W
O

ATOM
4792
O
HOH
W
98
9.903
−2.480
37.263
1.00
39.90
W
O

ATOM
4795
O
HOH
W
99
−14.690
5.403
20.304
1.00
43.77
W
O

ATOM
4798
O
HOH
W
100
7.497
−20.614
33.258
1.00
42.00
W
O

ATOM
4801
O
HOH
W
101
−6.310
−0.802
28.924
1.00
38.73
W
O

ATOM
4804
O
HOH
W
102
23.429
2.695
26.110
1.00
30.05
W
O

ATOM
4807
O
HOH
W
103
5.939
23.666
15.058
1.00
45.24
W
O

ATOM
4810
O
HOH
W
104
15.157
−8.657
41.812
1.00
48.42
W
O

ATOM
4813
O
HOH
W
105
22.584
5.351
6.685
1.00
32.02
W
O

ATOM
4816
O
HOH
W
106
1.947
−13.531
12.995
1.00
35.70
W
O

ATOM
4819
O
HOH
W
107
0.843
−3.343
5.954
1.00
35.00
W
O

ATOM
4822
O
HOH
W
108
10.764
8.978
−0.078
1.00
47.97
W
O

ATOM
4825
O
HOH
W
109
12.609
11.593
33.799
1.00
33.88
W
O

ATOM
4828
O
HOH
W
110
−2.559
28.085
29.916
1.00
40.24
W
O

ATOM
4831
O
HOH
W
111
−8.695
−8.532
8.837
1.00
37.60
W
O

ATOM
4834
O
HOH
W
112
1.265
18.134
33.506
1.00
37.44
W
O

ATOM
4837
O
HOH
W
113
−9.981
6.869
11.619
1.00
38.18
W
O

ATOM
4840
O
HOH
W
114
−2.744
14.784
38.949
1.00
50.37
W
O

ATOM
4843
O
HOH
W
115
20.301
−12.723
34.212
1.00
40.49
W
O

ATOM
4846
O
HOH
W
116
14.851
9.838
20.023
1.00
37.48
W
O

ATOM
4849
O
HOH
W
117
23.651
3.698
39.134
1.00
37.78
W
O

ATOM
4852
O
HOH
W
118
−18.557
13.257
30.128
1.00
41.89
W
O

ATOM
4855
O
HOH
W
119
18.487
−21.421
23.859
1.00
39.29
W
O

ATOM
4858
O
HOH
W
120
21.377
4.874
37.522
1.00
28.87
W
O

ATOM
4861
O
HOH
W
121
18.415
−7.751
−2.248
1.00
36.44
W
O

ATOM
4864
O
HOH
W
122
17.602
−7.842
12.411
1.00
16.38
W
O

ATOM
4867
O
HOH
W
123
16.678
4.872
18.751
1.00
22.46
W
O

ATOM
4870
O
HOH
W
124
14.066
−0.309
37.545
1.00
30.70
W
O

ATOM
4873
O
HOH
W
125
7.740
−4.673
37.771
1.00
27.15
W
O

ATOM
4876
O
HOH
W
126
13.728
4.405
15.630
1.00
25.76
W
O

ATOM
4879
O
HOH
W
127
27.821
−6.501
23.920
1.00
31.77
W
O

ATOM
4882
O
HOH
W
128
−3.928
27.852
25.640
1.00
29.97
W
O

ATOM
4885
O
HOH
W
129
16.702
6.462
21.069
1.00
30.52
W
O

ATOM
4888
O
HOH
W
130
26.185
−5.646
20.509
1.00
24.01
W
O

ATOM
4891
O
HOH
W
131
1.974
−3.227
0.396
1.00
29.45
W
O

ATOM
4894
O
HOH
W
132
18.503
−17.071
10.260
1.00
34.39
W
O

ATOM
4897
O
HOH
W
133
10.397
−13.616
1.651
1.00
39.32
W
O

ATOM
4900
O
HOH
W
134
−2.831
28.209
21.200
1.00
30.33
W
O

ATOM
4903
O
HOH
W
135
15.320
−22.101
24.023
1.00
25.19
W
O

ATOM
4906
O
HOH
W
136
4.007
−9.460
34.087
1.00
38.19
W
O

ATOM
4909
O
HOH
W
137
−1.239
−11.368
25.339
1.00
28.01
W
O

ATOM
4912
O
HOH
W
138
25.810
−13.282
12.651
1.00
29.26
W
O

ATOM
4915
O
HOH
W
139
−11.471
3.486
23.719
1.00
43.71
W
O

ATOM
4918
O
HOH
W
140
−14.572
6.189
16.547
1.00
32.73
W
O

ATOM
4921
O
HOH
W
141
25.455
−4.517
28.979
1.00
27.27
W
O

ATOM
4924
O
HOH
W
142
−2.265
−18.449
18.806
1.00
31.12
W
O

ATOM
4927
O
HOH
W
143
24.881
−12.339
32.109
1.00
47.48
W
O

ATOM
4930
O
HOH
W
144
3.783
−12.994
33.207
1.00
40.92
W
O

ATOM
4933
O
HOH
W
145
16.661
4.952
10.161
1.00
41.86
W
O

ATOM
4936
O
HOH
W
146
−9.286
−1.522
21.390
1.00
35.03
W
O

ATOM
4939
O
HOH
W
147
14.410
−11.209
45.987
1.00
39.95
W
O

ATOM
4942
O
HOH
W
148
−1.544
−13.594
23.703
1.00
33.58
W
O

ATOM
4945
O
HOH
W
149
4.387
7.952
19.690
1.00
35.86
W
O

ATOM
4948
O
HOH
W
150
−8.699
18.279
6.531
1.00
32.48
W
O

ATOM
4951
O
HOH
W
151
3.719
−3.684
38.401
1.00
30.50
W
O

ATOM
4954
O
HOH
W
152
3.775
−20.312
14.291
1.00
42.65
W
O

ATOM
4957
O
HOH
W
153
27.957
−13.614
22.778
1.00
37.15
W
O

ATOM
4960
O
HOH
W
154
−6.363
−9.621
22.860
1.00
31.35
W
O

ATOM
4963
O
HOH
W
155
17.426
−9.113
39.788
1.00
41.82
W
O

ATOM
4966
O
HOH
W
156
11.719
−0.755
38.894
1.00
44.37
W
O

ATOM
4969
O
HOH
W
157
−1.823
−18.279
23.964
1.00
31.03
W
O

ATOM
4972
O
HOH
W
158
1.236
19.857
5.620
1.00
33.82
W
O

ATOM
4975
O
HOH
W
159
−5.447
−2.279
8.958
1.00
43.06
W
O

ATOM
4978
O
HOH
W
160
6.495
1.870
6.024
1.00
32.59
W
O

ATOM
4981
O
HOH
W
161
−1.902
−10.079
30.428
1.00
40.56
W
O

ATOM
4984
O
HOH
W
162
12.781
−10.832
0.891
1.00
28.70
W
O

ATOM
4987
O
HOH
W
163
15.705
−18.496
12.332
1.00
42.03
W
O

ATOM
4990
O
HOH
W
164
11.477
23.027
19.258
1.00
43.18
W
O

ATOM
4993
O
HOH
W
165
11.794
−19.441
25.110
1.00
34.30
W
O

ATOM
4996
O
HOH
W
166
−9.142
6.492
24.586
1.00
37.55
W
O

ATOM
4999
O
HOH
W
167
−3.791
−17.095
17.004
1.00
40.54
W
O

ATOM
5002
O
HOH
W
168
18.861
−5.381
−3.135
1.00
38.29
W
O

ATOM
5005
O
HOH
W
169
1.506
21.043
36.589
1.00
44.96
W
O

ATOM
5008
O
HOH
W
170
12.593
−2.711
−7.043
1.00
44.98
W
O

ATOM
5011
O
HOH
W
171
15.127
−0.179
0.329
1.00
35.60
W
O

ATOM
5014
O
HOH
W
172
15.056
2.474
−0.998
1.00
37.93
W
O

ATOM
5017
O
HOH
W
173
−7.283
−6.499
7.178
1.00
49.30
W
O

ATOM
5020
O
HOH
W
174
21.316
0.314
−2.427
1.00
41.75
W
O

ATOM
5023
O
HOH
W
175
26.651
−5.640
2.963
1.00
36.35
W
O

ATOM
5026
O
HOH
W
176
29.087
−10.247
25.287
1.00
39.54
W
O

ATOM
5029
O
HOH
W
177
23.713
5.560
13.541
1.00
39.25
W
O

ATOM
5032
O
HOH
W
178
−1.768
14.984
−1.759
1.00
40.11
W
O

ATOM
5035
O
HOH
W
179
13.927
−22.767
20.107
1.00
44.51
W
O

ATOM
5038
O
HOH
W
180
−5.833
17.092
42.432
1.00
39.14
W
O

ATOM
5041
O
HOH
W
181
4.780
28.120
30.190
1.00
35.76
W
O

ATOM
5044
O
HOH
W
182
5.232
−21.397
10.130
1.00
32.74
W
O

ATOM
5047
O
HOH
W
183
−0.609
−13.905
29.169
1.00
42.77
W
O

ATOM
5050
O
HOH
W
184
−8.615
−12.423
20.365
1.00
38.88
W
O

ATOM
5053
O
HOH
W
185
−2.742
24.869
15.943
1.00
35.44
W
O

ATOM
5056
O
HOH
W
186
−6.914
23.870
13.421
1.00
38.92
W
O

ATOM
5059
O
HOH
W
187
−9.844
5.148
9.425
1.00
47.06
W
O

ATOM
5062
O
HOH
W
188
−3.377
1.908
31.500
1.00
47.62
W
O

ATOM
5065
O
HOH
W
189
8.535
−2.717
9.847
1.00
20.99
W
O

ATOM
5068
O
HOH
W
190
−2.120
23.920
11.635
1.00
33.73
W
O

ATOM
5071
O
HOH
W
191
−1.821
12.406
36.174
1.00
33.31
W
O

ATOM
5074
O
HOH
W
192
15.430
−22.456
17.980
1.00
32.67
W
O

ATOM
5077
O
HOH
W
193
26.766
−7.447
10.363
1.00
37.80
W
O

ATOM
5080
O
HOH
W
194
7.871
−12.672
1.551
1.00
33.24
W
O

ATOM
5083
O
HOH
W
195
11.658
−13.419
−1.004
1.00
38.16
W
O

ATOM
5086
O
HOH
W
196
16.826
1.526
0.614
1.00
50.30
W
O

ATOM
5089
O
HOH
W
197
15.595
6.152
14.916
1.00
40.35
W
O

ATOM
5092
O
HOH
W
198
−1.881
25.715
18.176
1.00
37.84
W
O

ATOM
5095
O
HOH
W
199
−11.651
11.014
33.297
1.00
32.46
W
O

ATOM
5098
O
HOH
W
200
18.893
−2.239
0.202
1.00
36.54
W
O

ATOM
5101
O
HOH
W
201
8.083
−15.775
41.296
1.00
35.79
W
O

ATOM
5104
O
HOH
W
202
27.247
−8.234
2.554
1.00
45.23
W
O

ATOM
5107
O
HOH
W
203
−1.222
−15.328
27.055
1.00
46.27
W
O

ATOM
5110
O
HOH
W
204
13.756
−2.002
41.227
1.00
44.19
W
O

ATOM
5113
O
HOH
W
205
18.212
11.234
28.397
1.00
46.27
W
O

ATOM
5116
O
HOH
W
206
10.446
24.528
22.495
1.00
29.18
W
O

ATOM
5119
O
HOH
W
207
9.812
7.702
16.580
1.00
47.51
W
O

ATOM
5122
O
HOH
W
208
8.614
13.189
26.746
1.00
42.96
W
O

ATOM
5125
O
HOH
W
209
26.242
4.872
13.201
1.00
34.36
W
O

ATOM
5128
O
HOH
W
210
3.417
32.021
7.569
1.00
43.78
W
O

ATOM
5131
O
HOH
W
211
13.082
12.607
−0.030
1.00
38.29
W
O

ATOM
5134
O
HOH
W
212
11.113
−16.047
1.534
1.00
48.53
W
O

ATOM
5137
O
HOH
W
213
16.799
−19.980
17.140
1.00
42.01
W
O

ATOM
5140
O
HOH
W
214
8.100
2.699
9.516
1.00
38.54
W
O

ATOM
5143
O
HOH
W
215
21.192
−10.596
35.721
1.00
42.09
W
O

ATOM
5146
O
HOH
W
216
−12.311
27.355
25.513
1.00
46.88
W
O

ATOM
5149
O
HOH
W
217
2.196
18.838
8.312
1.00
40.97
W
O

ATOM
5152
O
HOH
W
218
2.760
7.802
34.907
1.00
40.65
W
O

ATOM
5155
O
HOH
W
219
2.052
34.572
8.653
1.00
28.96
W
O

ATOM
5158
O
HOH
W
220
20.199
10.058
26.993
1.00
39.00
W
O

ATOM
5161
O
HOH
W
221
0.666
6.917
33.693
1.00
41.05
W
O

ATOM
5164
O
HOH
W
222
19.656
−20.516
17.448
1.00
49.29
W
O

ATOM
5167
O
HOH
W
223
24.529
−13.997
28.898
1.00
44.80
W
O

ATOM
5170
O
HOH
W
224
−15.502
8.924
35.463
1.00
46.22
W
O

ATOM
5173
O
HOH
W
225
6.321
6.726
39.047
1.00
40.39
W
O

ATOM
5176
O
HOH
W
226
13.346
−19.882
30.564
1.00
27.35
W
O

ATOM
5179
O
HOH
W
227
2.475
8.509
20.962
1.00
37.71
W
O

ATOM
5182
O
HOH
W
228
25.697
−17.409
7.650
1.00
40.93
W
O

ATOM
5185
O
HOH
W
229
−5.326
22.902
36.076
1.00
34.85
W
O

ATOM
5188
O
HOH
W
230
18.689
1.894
1.969
1.00
40.05
W
O

ATOM
5191
O
HOH
W
231
22.256
9.449
29.382
1.00
38.70
W
O

ATOM
5194
O
HOH
W
232
6.671
16.029
32.045
1.00
45.79
W
O

ATOM
5197
O
HOH
W
233
−12.901
11.354
24.852
1.00
42.77
W
O

ATOM
5200
O
HOH
W
234
11.146
−21.564
4.017
1.00
44.94
W
O

ATOM
5203
O
HOH
W
235
25.034
−1.313
25.290
1.00
35.63
W
O

ATOM
5206
O
HOH
W
236
−14.460
18.497
19.730
1.00
43.85
W
O

ATOM
5209
O
HOH
W
237
−12.580
11.671
30.829
1.00
49.50
W
O

ATOM
5212
O
HOH
W
238
−15.352
9.953
23.232
1.00
41.57
W
O

ATOM
5215
O
HOH
W
239
−1.668
11.121
33.395
1.00
56.23
W
O

ATOM
5218
O
HOH
W
240
8.754
−13.126
−3.263
1.00
52.79
W
O

ATOM
5221
O
HOH
W
241
−1.876
−3.651
6.368
1.00
34.87
W
O

ATOM
5224
O
HOH
W
242
19.512
−18.187
6.893
1.00
42.20
W
O

ATOM
5227
O
HOH
W
243
−8.077
30.761
18.011
1.00
33.22
W
O

ATOM
5230
O
HOH
W
244
11.861
14.174
19.992
1.00
49.09
W
O

ATOM
5233
O
HOH
W
245
0.301
11.850
−6.763
1.00
46.36
W
O

ATOM
5236
O
HOH
W
246
−2.640
12.555
0.451
1.00
48.51
W
O

ATOM
5239
O
HOH
W
247
12.588
−19.822
12.376
1.00
48.93
W
O

ATOM
5242
O
HOH
W
248
11.738
20.944
27.362
1.00
51.67
W
O

ATOM
5245
O
HOH
W
249
17.071
8.568
19.617
1.00
43.62
W
O

ATOM
5248
O
HOH
W
250
−2.350
−17.778
11.732
1.00
51.64
W
O

ATOM
5251
O
HOH
W
251
12.306
−4.700
40.223
1.00
48.28
W
O

END

[0513]

5

TABLE 6

PYK2 in pET15S

U33284

; Human protein tyrosine kinase PYK2 mRNA, complete cds

Full-length protein in pET15S: 293 aa (SEQ ID NO:2) Mass: 33872.2 pI: 6.07

PYK2 kinase domain I420-M691 (not including first 21 aa in following sequence) SEQ ID

NO:1

1
MGSSHHHHHH
SSGLVPRGSH
MIAREDVVLN
RILGEGFFGE
VYEGVYTNHK
GEKINVAVKT

61
CKKDCTLDNK
EKFMSEAVIM
KNLDHPHIVK
LIGIIEEEPT
WIIMELYPYG
ELGHYLERNK

121
NSLKVLTLVL
YSLQICKAMA
YLESINCVHR
DIAVRNILVA
SPECVKLGDF
GLSRYIEDED

181
YYKASVTRLP
IKWMSPESIN
FRRFTTASDV
WMFAVCMWEI
LSFGKQPFFW
LENKDVIGVL

241
EKGDRLPKPD
LCPPVLYTLM
TRCWDYDPSD
RPRFTELVCS
LSDVYQMEKD
IAM

SEQ ID NO:5

PYK2-C1;
5′-TCCACAG CATATG ATTGCCCGTGAAGATGTGGT-3′
33 mer

SEQ ID NO:6

PYK2-N2;
TGGAGAAGGACATTGCCATG TAG GTCGAC GAGAG (Origin)

5′-CTCTC GTCGAC CTA CATGGCAATGTCCTTCTCCA-3′
34 mer

pET15S sequence PCR product; 843 bp (SEQ ID NO: 4)

Sequence encoding PYK2 kinase domain (in small letters below) (SEQ ID NO: 3)

TCTAGAAATAATTTTGTTTAACTTTAAGAAGGAGA

TATACCATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGCAGCCATATG

attgcc
cgtgaagatg

1381
tggtcctgaa
tcgtattctt
ggggaaggct
tttttgggga
ggtctatgaa
ggtgtctaca

1441
caaatcacaa
aggggagaaa
atcaatgtag
ctgtcaagac
ctgcaagaaa
gactgcactc

1501
tggacaacaa
ggagaagttc
atgagcgagg
cagtgatcat
gaagaacctc
gaccacccgc

1561
acatcgtgaa
gctgatcggc
atcattgaag
aggagcccac
ctggatcatc
atggaattgt

1621
atccctatgg
ggagctgggc
cactacctgg
agcggaacaa
gaactccctg
aaggtgctca

1681
ccctcgtgct
gtactcactg
cagatatgca
aagccatggc
ctacctggag
agcatcaact

1741
gcgtgcacag
ggacattgct
gtccggaaca
tcctggtggc
ctcccctgag
tgtgtgaagc

1801
tgggggactt
tggtctttcc
cggtacattg
aggacgagga
ctattacaaa
gcctctgtga

1861
ctcgtctccc
catcaaatgg
atgtccccag
agtccattaa
cttccgacgc
ttcacgacag

1921
ccagtgacgt
ctggatgttc
gccgtgtgca
tgtgggagat
cctgagcttt
gggaagcagc

1981
ccttcttctg
gctggagaac
aaggatgtca
tcggggtgct
ggagaaagga
gaccggctgc

2041
ccaagcctga
tctctgtcca
ccggtccttt
ataccctcat
gacccgctgc
tgggactacg

2101
accccagtga
ccggccccgc
ttcaccgagc
tggtgtgcag
cctcagtgac
gtttatcaga

2161
tggagaagga
cattgccatg

TAGGTCGACTAGAGCCTGCAGTCTCGACCATCATCATCATCATCATTAATAAAAGGGCG

AATTCCAGCACACTGGCGGCCGTTACTAGTGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGG

[0514]

6

TABLE 7

Pyk2 Activity and the Inhibition by ATP Analogs

Pyk2
Vmax
Vmax (SE)
K
K (SE)
K (Lo 95%)
K (Up 95%)
Equation

8 ng/well
1.25e+4
9.11e+2
7.37e+0
2.79e+0
3.27e+0
1.66e+1
y = (Vmax * x)/(K + x)

Compounds
Vmax
K
K (SE)
K (Lo 95%)
K (Up 95%)
Y2
n
Equation

Adenosine
1.82e+4
2.54e+2
2.65e+2
2.47e+1
2.60e+3
7.33e+2
−5.14e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

AMP
1.82e+4
8.02e+1
3.76e+1
2.82e+1
2.28e+2
7.33e+2
−5.05e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

ADT
1.82e+4
1.49e+1
2.69e+0
9.93e+0
2.22e+1
7.33e+2
−7.69e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

AMPPCP
1.82e+4
7.69e+3
1.99e+4
2.43e+1
2.44e+6
7.33e+2
−2.03e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

AMPPNP
1.82e+4
1.81e+1
2.82e+0
1.28e+1
2.56e+1
7.33e+2
−7.18e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

ATP-g-S
1.82e+4
1.36e+1
1.49e+0
1.06e+1
1.73e+1
7.33e+2
−9.66e−1
y = ((Vmax * x{circumflex over ( )}n)/(K{circumflex over ( )}n + x{circumflex over ( )}n)) + Y2

[0515]

Number	Date	Country
60437929	Jan 2003	US
60360651	Feb 2002	US
60411398	Sep 2002	US
60412341	Sep 2002	US

Methods for the design of molecular scaffolds and ligands

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

RELATED APPLICATIONS

Provisional Applications (4)