Molecular scaffolds for kinase ligand development

BACKGROUND OF THE INVENTION

This invention relates to the field of development of ligands for protein kinases.

Examples of protein kinases are the PIM kinases, including PIM-1, PIM-2, and PIM-3. The PIM-1 proto-oncogene was originally identified as a genetic locus frequently activated by the proviral insertion of Moloney murine leukemia virus into mouse T cell lymphomas (Cuypers, H. T., Selten, G., Quint, W., Zijlstra, M., Maandag, E. R., Boelens, W., van Wezenbeek, P., Melief, C., and Berns, A. (1984) Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell 37: 141-150). The PIM-1 proto-oncogene has also been implicated in human hematopoietic malignancies with its overexpression frequently detected in human hematopoietic cell lines as well as in fresh tumor cells from patients with leukemia (Nagarajan L, Louie E, Tsujimoto Y, ar-Rushdi A, Huebner K, and Croce C M. (1986) Localization of the human PIM oncogene (PIM) to a region of chromosome 6 involved in translocations in acute leukemias. Proc. Natl. Acad. Sci. USA 83: 2556-2560; Meeker T C, Nagarajan L, ar-Rushdi A, Rovera G, Huebner K, and Croce C M. (1987) Characterization of the human PIM-1 gene: a putative proto-oncogene coding for a tissue specific member of the protein kinase family. Oncogene Res. 1: 87-101; Amson R, Sigaux F, Przedborski S, Flandrin G, Givol D, and Telerman A. (1989). The human proto-oncogene product p33PIM is expressed during fetal hematopoiesis and in diverse leukemias. Proc. Natl. Acad. Sci. USA 86: 8857-8861).

The PIM family of proto-oncogenes in human and mouse now consists of at least three members, that code for highly related serine/threonine specific protein kinases (Saris C J, Domen J, and Berns A. (1991) The PIM-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 10: 655-664; Eichmann A, Yuan L, Breant C, Alitalo K, and Koskinen P J. (2000) Developmental expression of PIM kinases suggests functions also outside of the hematopoietic system. Oncogene 19: 1215-1224). The function of these three kinases (PIM-1, PIM-2 and PIM-3) appear to complement each other in mice, as deletion of one of the PIM family protein genes did not result in any severe defects (Laird P W, van der Lugt N M, Clarke A, Domen J, Linders K, McWhir J, Berns A, Hooper M. (1993) In vivo analysis of PIM-1 deficiency. Nucl. Acids Res. 21: 4750-4755). During embryonal development PIM genes are expressed in partially overlapping fashion in cells in both immune and central nervous system as well as in epithelia (Eichmann A, Yuan L, Breant C, Alitalo K, and Koskinen P J. (2000) Developmental expression of PIM kinases suggests functions also outside of the hematopoietic system. Oncogene 19: 1215-1224). PIM-1, the prototypical member of the PIM family is located both in the cytoplasm and nucleus, but its precise role in these two locations has not been fully elucidated.

Transgenic mice with PIM-1 driven by Emu enhancer sequences demonstrated that PIM-1 function as a weak oncogene because by itself it does not lead to tumor formation but does so after a second oncogenic gene become overexpressed. In 75% of the tumors over-expressing PIM-1, the second gene found to be over-expressed is c-myc (van der Houven van Oordt C W, Schouten T G, van Krieken J H, van Dierendonck J H, van der Eb A J, Breuer M L. (1998) X-ray-induced lymphomagenesis in E mu-PIM-1 transgenic mice: an investigation of the co-operating molecular events. Carcinogenesis 19: 847-853). In fact when crosses were made between Emu-PIM transgenic mice and Emu-myc transgenic mice, the combination of genes is so oncogenic that the offsprings die in utero due to pre B cell lymphomas (Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, and Berns A. (1991) Mice bearing the Emu-myc and Emu-PIM-1 transgenes develop pre-B-cell leukemia prenatally. Mol. Cell. Biol., 11: 1176-1179).

Mice deficient for PIM-1 show normal synaptic transmission and short-term plasticity but failed to consolidate enduring LTP even though PIM-2 and PIM-3 are expressed in the hippocampus (Konietzko U, Kauselmann G, Scafidi J, Staubli U, Mikkers H, Berns A, Schweizer M, Waltereit R, and Kuhl D. (1999) PIM kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP. EMBO J. 18: 3359-3369).

Various factors are known to enhance the transcription of PIM-1 kinase in mouse and human. PIM-1 closely cooperates with another oncoprotein, c-myc, in triggering intracellular signals leading to both transformation and apoptosis and the selective inhibition of apoptotic signaling pathways leading to Bcl-2 (van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, and Berns A. (1989) Predisposition to lymphomagenesis in PIM-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell 56: 673-682; Breuer M L, Cuypers H T, Berns A. (1989). Evidence for the involvement of PIM-2, a new common proviral insertion site, in progression of lymphomas. EMBO J. 8: 743-748; Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, and Berns A. (1991) Mice bearing the E mu-myc and E mu-PIM-1 transgenes develop pre-B-cell leukemia prenatally. Mol. Cell. Biol. 11: 1176-1179; Shirogane T, Fukada T, Muller J M, Shima D T, Hibi M, and Hirano T. (1999) Synergistic roles for PIM-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity, 11: 709-719). PIM-1 kinase is induced by T cell antigen receptor cross linking by cytokines and growth factors and by mitogens including IL2, IL3, IL6, IL9, IL12, IL15, GM-CSF, G-CSF, IFNa, INFg, prolactin, ConA, PMA and anti-CD3 antibodies (Zhu N, Ramirez L M, Lee R L, Magnuson N S, Bishop G A, and Gold M R. (2002) CD40 signaling in B cells regulates the expression of the PIM-1 kinase via the NF-kappa B pathway. J. Immunol. 168: 744-754). PIM-1 expression is rapidly induced after cytokine stimulation and the proliferative response to cytokines is impaired in cells from PIM-1 deficient mice (Domen J, van der Lugt N M, Acton D, Laird P W, Linders K, Berns A. (1993) PIM-1 levels determine the size of early B lymphoid compartments in bone marrow. J. Exp. Med. 178: 1665-1673).

Recently, it has been reported that PIM family of kinases interact with Socs-1 protein, a potent inhibitor of JAK activation thereby playing a major role in signaling down stream of cytokine receptors. The phosphorylation of Socs-1 by PIM family of kinases prolongs the half-life of Socs-1 protein, thus potentiating the inhibitory effect of Socs-1 on JAK-STAT activation (Chen X P, Losman J A, Cowan S, Donahue E, Fay S, Vuong B Q, Nawijn M C, Capece D, Cohan V L, Rothman P. (2002) PIM serine/threonine kinases regulate the stability of Socs-1 protein. Proc. Natl. Acad. Sci. USA 99: 2175-2180.). PIM-1 is expressed during GI/S phase of the cell cycle suggesting that it is involved in cell cycle regulation (Liang H, Hittelman W, Nagarajan L., Ubiquitous expression and cell cycle regulation of the protein kinase PIM-1. (1996) Arch Biochem Biophys. 330: 259-265).). PIM-1 kinase activity and the protein level is increased in CD 40 mediated B cell signaling and this increase in PIM-1 level is mediated through the activation of NF-kB (Zhu et al. 2002. supra). PIM-1 can physically interact with NFATc transcription factors enhancing NFATc dependant transactivation and IL2 production in Jurkat cells (Rainio E M, Sandholm J, Koskinen P J. (2002) Cutting edge: Transcriptional activity of NFATc1 is enhanced by the PIM-1 kinase. J. Immunol. 168: 1524-1527). This indicates a novel phosphorylation dependant regulatory mechanism targeting NFATc through which PIM-1 acts as down stream effector of ras to facilitate IL2 dependant proliferation and survival of lymphoid cells (Id.).

PIM-1 is shown to interact with many other targets. Phosphorylation of Cdc25A phosphatase, a direct transcriptional target of c-myc, increase its phosphatase activity both in-vivo and in-vitro indicating that Cdc25A link PIM-1 and c-myc in cell transformation and apoptosis (Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, and Kuchino Y. (1999) Physical and functional interactions between PIM-1 kinase and Cdc25A phosphatase. Implications for the PIM-1-mediated activation of the c-Myc signaling pathway; J. Biol. Chem. 274: 18659-18666). PIM-1 also phosphorylate PTP-U2S, a tyrosine phosphatase associated with differentiation and apoptosis in myeloid cells, decreasing its phosphatase activity and hence preventing premature onset of apoptosis following PMA-induced differentiation (Wang et al. (2001) Pim-1 negatively regulates the activity of PTP-U2S phosphatase and influences terminal differentiation and apoptosis of monoblastoid leukemia cells. Arch. Biochem. Biophys. 390: 9-18). The phosphorylation of p100, a co-activator of c-myb (Weston, 1999, Reassessing the role of C-MYB in tumorigenesis. Oncogene 18: 3034-3038), by PIM-1 is involved in Ras-dependent regulation of transcription (Leverson J D, Koskinen P J, Orrico F C, Rainio E M, Jalkanen K J, Dash A B, Eisenman R N, and Ness S A. (1998) PIM-1 kinase and p100 cooperate to enhance c-Myb activity. Mol. Cell. 2: 417-425). The phosphorylation of another PIM-1 target, heterochromatin protein 1 (HP 1) has been shown to be involved in transcription repression (Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga S M. (2000) Identification of heterochromatin protein 1 (HP 1) as a phosphorylation target by PIM-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP-1 (1). FEBS Lett. 467: 17-21).

The information provided above is intended solely to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.

SUMMARY OF THE INVENTION

The present invention concerns molecular scaffolds that can be used to identify and develop ligands active on one or more kinases, for example, the PIM kinases, (e.g., PIM-1, PIM-2, and PIM-3). Compounds representing the present molecular scaffolds have been co-crystallized with PIM-1, and the co-crystal structures have been determined to confirm the orientation of the compound within the binding site. In addition, such compounds also bind to other kinases, such that the scaffolds can be used for ligand development for other kinases also. In the description herein, PIM-1 and the use of molecular scaffolds and ligands with PIM-1 are described as examples, but the invention is not limited to PIM-1.

In a first aspect, the invention provides a kinase scaffold library comprising at least one set of compounds of a chemical structure selected from the group consisting of Formula I, II, III, IV, V, VI, and VII as described herein, Formula I, II, and III as described in U.S. application Ser. No. 10/664,421 and corresponding PCT/US03/29415, and Formula I as described in U.S. application Ser. No. 10/789,818 and corresponding PCT/U.S. 2004/005904, all of which are incorporated herein by reference in their entireties. (Unless specifically indicated to the contrary, reference to any of Formulas I-VII means the Formulas I-VII described with a generic structure herein.). In certain embodiments, the scaffold library contains at least one set of compounds having chemical structures of Formula I, II, III, IV, V, VI, or VII.

Libraries with large numbers of compounds can be highly useful. In particular embodiments, a library includes at least 50, 100, 200, 300, 400, 500, 600, 800, 1000 1400, or even more different compounds of the particular chemical structure; a library can include a plurality of such sets of compounds of different chemical structures selected from the indicated Formulas; a plurality of sets of compounds of different chemical structure can include any combination of the specified chemical structures, e.g., Formulas I and II, Formulas I and III, Formulas II and III, Formulas I, II, and III (including each individual combination of the 11 Formulas listed above, taken 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 at a time); a plurality of sets is 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, or more such sets; a majority of compounds in a set or sets have been demonstrated to bind to one or more kinases; one or more kinases are selected from the kinases including PIM-1, Pyk2, c-Abl, Her2, cMet, VEGFR, EGFR, cKit, Pkcβ, p38, Cdk2, Akt, Gsk3β, or other kinase listed in Table 5; the kinase domain of the kinase has at least 30%, 35%, 40% or more sequence identity to PIM-1 kinase domain.

As used herein in connection with the present compounds, the term “scaffold library” refers to a defined set of compounds in a format suitable for testing as biochemical or biological activity modulators. For example, such compounds can be in solution or dry in wells of a plate such as a microtiter plate (or a plurality of such plates). Such a library is distinguished from conventional compound libraries and commercially available compound libraries by being selected such that at least 50, 60, 70, 80, 90, 95, 98, or 100% of the compounds in the library are derivatives of the chemical structures that have been described herein as kinase binding compounds or molecular scaffolds. Such libraries can also include compounds that are derivatives of other kinase binding compounds.

Because initial ligand identification can be carried out by fitting electronic representations of compounds in binding sites of target molecules, in another aspect the invention provides a system for fitting compounds in binding sites of one or more protein kinases. Such a system includes an electronic kinase scaffold library that includes at least one set of electronic representations of compounds of a chemical structure selected from the group consisting of Formula I, II, III, IV, V, VI, and VII as described herein, Formula I, II, and III as described in U.S. application Ser. No. 10/664,421 and corresponding PCT/US03/29415, and Formula I as described in U.S. application Ser. No. 10/789,818 and corresponding PCT/U.S. 2004/005904, where the kinase scaffold library is embedded in a computer memory device, the electronic representations of the compounds can be selectively retrieved and functionally connected with computer software adapted to fit electronic representations of compounds in an electronic representation of a binding site of a kinase. The system can also include at least one electronic representation of a kinase binding site (e.g., an electronic representation of a crystal structure of a kinase, kinase domain, or kinase binding site) embedded in computer memory such that the electronic representation of a kinase binding site can be functionally connected with the computer software. The system can include one or more electronic representations of binding sites of kinases selected from PIM-1, Pyk2, c-Abl, Her2, cMet, VEGFR, EGFR, cKit, Pkcβ, p38, Cdk2, Akt, Gsk3β, or another kinase from Table 5, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more such kinases.

In a related aspect, the invention provides a method for obtaining improved ligands binding to a kinase (e.g., PIM-1, Pyk2, c-Abl, Her2, cMet, VEGFR, EGFR, cKit, Pkcβ, p38, Cdk2, Akt, Gsk3β, or other kinase from Table 5), where the method involves determining whether a derivative of a compound of any of Formulas I, II, III, IV, V, VI, or VII that binds to the kinase, binds to the kinase with greater affinity or greater specificity or both than the parent binding compound. Binding with greater affinity or greater specificity or both than the parent compound indicates that the derivative is an improved ligand. This process can also be carried out in successive rounds of selection and derivatization and/or with multiple parent compounds to provide a compound or compounds with improved ligand characteristics. Likewise, the derivative compounds can be tested and selected to give high selectivity for the kinase, or to give cross-reactivity to a particular set of kinase targets.

In the context of the present invention, the terms “kinase” and “protein kinase” refers to an enzyme that phosphorylates other proteins. These enzymes are often grouped according to the amino acid that is phosphorylated, into tyrosine kinases, serine/threonine kinases, and histidine kinases.

The term “PIM kinase” or “PIM family kinase” means a protein kinase with greater than 45% amino acid sequence identity to PIM-1 from the same species, and includes PIM-1, PIM-2, and PIM-3. Unless clearly indicated to the contrary, use of the term “PIM kinase” constitutes a reference to any of the group of PIM kinases, specifically including individual reference to each of PIM-1, PIM-2, and PIM-3.

As used herein, the terms “ligand” and “modulator” refer to a compound that modulates the activity of a target biomolecule, e.g., an enzyme such as a kinase. Generally a ligand or modulator will be a small molecule, where “small molecule refers to a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an “improved ligand” is one that possesses better pharmacological and/or pharmacokinetic properties than a reference compound, where “better” can be defined by a person for a particular biological system or therapeutic use.

In the context of binding compounds, molecular scaffolds, and ligands, the term “derivative” or “derivative compound” refers to a compound having a chemical structure that contains a common core chemical structure as a parent or reference compound, but differs by having at least one structural difference, e.g., by having one or more substituents added and/or removed and/or substituted, and/or by having one or more atoms substituted with different atoms. Unless clearly indicated to the contrary, the term “derivative” does not mean that the derivative is synthesized using the parent compound as a starting material or as an intermediate, although in some cases, the derivative may be synthesized from the parent.

Thus, the term “parent compound” refers to a reference compound for another compound, having structural features continued in the derivative compound. Often but not always, a parent compound has a simple chemical structure than the derivative.

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.

The term “binds” in connection with the interaction between a target and a potential binding compound indicates that the potential binding compound associates with the target to a statistically significant degree as compared to association with proteins generally (i.e., non-specific binding). Thus, the term “binding compound” refers to a compound that has a statistically significant association with a target molecule. Preferably a binding compound interacts with a specified target with a dissociation constant (k_d) of 1 mM or less. A binding compound can bind with “low affinity”, “very low affinity”, “extremely low affinity”, “moderate affinity”, “moderately high affinity”, or “high affinity” as described herein.

In the context of compounds binding to a target, the term “greater affinity” indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i.e., with a lower dissociation constant. In particular embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity.

Also in the context of compounds binding to a biomolecular target, the term “greater specificity” indicates that a compound binds to a specified target to a greater extent than to another biomolecule or biomolecules that may be present under relevant binding conditions, where binding to such other biomolecules produces a different biological activity than binding to the specified target. Typically, the specificity is with reference to a limited set of other biomolecules, e.g., other kinases or even other type of enzymes. In particular embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000-fold greater specificity.

As used in connection with binding of a compound with a particular kinase, the term “interact” indicates that the distance from a bound compound to a particular amino acid residue will be 5.0 angstroms or less, or 6 angstroms or less with one water molecule coordinated between the compound and the residue, or 9 angstroms or less with two water molecules coordinated between the compound and the residue. In particular embodiments, the distance from the compound to the particular amino acid residue is 4.5 angstroms or less, 4.0 angstroms or less, or 3.5 angstroms or less. Such distances can be determined, for example, using co-crystallography, or estimated using computer fitting of a compound in the kinase active site.

Reference to particular amino acid residues in PIM-1 polypeptide residue number is defined by the numbering provided in Meeker, T. C., Nagarajan, L., ar-Rushdi, A., Rovera, G., Huebner, K., Corce, C. M.; (1987) Characterization of the human PIM-1 gene: a putative proto-oncogene coding for a tissue specific member of the protein kinase family. Oncogene Res. 1: 87-101, in accordance with the sequence provided in SEQ ID NO: 1. PIM-2 is as described in Baytel et al. (1998) The human Pim-2 proto-oncogene and its testicular expression, Biochim. Biophys. Acta 1442,274-285. PIM-3 from rat is described in Feldman, et al. (1998) KID-1, a protein kinase induced by depolarization in brain, J. Biol. Chem. 273, 16535-16543; and Kinietzko et al. (1999) Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP, EMBO J. 18, 3359-3369. (KID-1 is the same as PIM-3.) Human PIM-3 nucleic acid and amino acid sequences are provided herein.

In a related aspect, the invention provides a method for developing ligands specific for a kinase, such as a PIM kinase, e.g., PIM-1, where the method involves determining whether a derivative of a compound that binds to a plurality of kinases has greater specificity for the particular kinase than the parent compound.

As used herein in connection with binding compounds or ligands, the term specific for a kinase”, “specific for PIM-1” and terms of like import mean that a particular compound binds to the particular kinase to a statistically greater extent than to other kinases that may be present in a particular organism. Also, where biological activity other than binding is indicated, the term “specific for a kinase” indicates that a particular compound has greater biological activity associated with binding to the particular kinase than to other kinases. Preferably, the specificity is also with respect to other biomolecules (not limited to kinases) that may be present from an organism. A particular compound may also be selected that is specific for kinase sub-group (e.g., tyrosine kinases, serine/threonine kinases, histidine kinases), indicating that it binds to and/or has a greater biological activity associated with binding to a plurality of kinases in that sub-group than to other kinases.

In another aspect, the invention concerns a method for developing ligands binding to a particular kinase, e.g., PIM-1, where the method includes determining the orientation of at least one molecular scaffold of Formula I, II, III, IV, V, VI, or VII in co-crystals with the kinase; identifying chemical structures of one or more of the molecular scaffolds, that, when modified, alter the binding affinity or binding specificity or both between the molecular scaffold and the kinase; and synthesizing a ligand in which one or more of the chemical structures of the molecular scaffold is modified to provide a ligand that binds to the kinase with altered binding affinity or binding specificity or both. Due to the significant of sequence identity between various kinases, e.g., PIM-1 and the other PIM kinases, PIM-1 can also be used as a surrogate or in a homology model for orientation determination and to allow identification of chemical structures that can be modified to provide improved ligands.

By “molecular scaffold” is meant a core 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, and the target molecule can preferably be a protein or enzyme. Preferred characteristics of a scaffold can include 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 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.

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.

By “binding pocket” is meant a specific volume within a binding site. A binding pocket can often be 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, or van der Waals interactions between the molecules.

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 constituent atoms to the binding pocket and/or atoms of the target molecule at least partially defining the binding pocket.

By “co-crystals” is meant a complex of the compound, molecular scaffold, or ligand bound non-covalently to the target molecule and present in a crystal form appropriate for analysis by X-ray or protein crystallography. In preferred embodiments the target molecule-ligand complex can be a protein-ligand complex.

The phrase “alter the binding affinity or binding specificity” refers to changing the binding constant of a first compound for another, or changing the level of binding of a first compound for a second compound as compared to the level of binding of the first compound for third compounds, respectively. For example, the binding specificity of a compound for a particular protein is increased if the relative level of binding to that particular protein is increased as compared to binding of the compound to unrelated proteins.

As used herein in connection with test compounds, binding compounds, and modulators (ligands), the term “synthesizing” and like terms means chemical synthesis from one or more precursor materials.

The phrase “chemical structure of the molecular scaffold is modified” means that a derivative molecule has a chemical structure that differs from that of the molecular scaffold but still contains common core chemical structural features. The phrase does not necessarily mean that the molecular scaffold is used as a precursor in the synthesis of the derivative.

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. A compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.

Certain compounds have been identified as molecular scaffolds and binding compounds for protein kinases, as exemplified by PIM-1. Thus, in another aspect, the invention provides a method for identifying a ligand binding to specific kinase, that includes determining whether a derivative compound that includes a core structure selected from the group consisting of the core structures of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII, as described herein binds to the kinase with altered binding affinity or specificity or both as compared to a parent compound.

In reference to compounds of any of Formula I, II, III, IV, V, VI, and VII, the term “core structure” refers to the structures shown diagramatically as part of the description of compounds of each of Formulas I-VII, but excluding non-ring variable substituents. More generally, the term “core structure” refers to a characteristic chemical structure common to a set of compounds, especially a chemical structure that carries variable substituents in the compound set.

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

The invention further concerns co-crystals of a particular kinase and a kinase binding compound of Formula I, II, III, IV, V, VI, or VII. Advantageously, such co-crystals are of sufficient size and quality to allow structural determination to at least 3 Angstroms, 2.5 Angstroms, or 2.0 Angstroms. The co-crystals can, for example, be in a crystallography plate, be mounted for X-ray crystallography and/or in an X-ray beam. Such co-crystals are beneficial, for example, for obtaining structural information concerning interaction between the kinase and kinase binding compounds.

Kinase binding compounds can include compounds that interact with at least one of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186, or any 2, 3, 4, 5, 6, or 7 of those residues. Exemplary compounds that bind to PIM-1 include compounds of any of Formulas I-VII.

Likewise, in additional aspects, methods for obtaining PIM-1 co-crystals with compounds of Formula I, II, III, IV, V, VI, and VII are provided. The method involves subjecting PIM-1 protein at 5-20 mg/ml to crystallization conditions substantially equivalent to Hampton Screen 1 conditions 2, 7, 14, 17, 23, 25, 29, 36, 44, or 49, in the presence of binding compound for a time sufficient for crystal development. The binding compound may be added at various concentrations depending on the nature of the compound, e.g., final concentration of 0.5 to 1.0 mM. In many cases, the binding compound will be in an organic solvent such as dimethyl sulfoxide solution. Exemplary co-crystallization conditions include 0.4-0.9 M sodium acetate trihydrate pH 6.5, 0.1 M imidazole; or 0.2-0.7 M sodium potassium tartrate, 00.1 M MES buffer pH 6.5.

In another aspect, provision of compounds active on a variety of different kinases (e.g., PIM-1) also provides a method for modulating kinase activity by contacting the kinase with a compound of any of Formulas I, II, III, IV, V, VI, and VII that binds to the kinase. The compound is preferably provided at a level sufficient to modulate the activity of PIM-1 by at least 10%, more preferably at least 20%, 30%, 40%, or 50%. In many embodiments, the compound will be at a concentration of about 1 EM, 100 μM, or 1 mM, or in a range of 1-100 nM, 100-500 nM, 500-1000 nM, 1-100 μM, 100-500 μM, or 500-1000 μM. The compound can be one that interacts with one more of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186.

As used herein, the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as PIM-1. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme.

The term “PIM-1 activity” refers to a biochemical activity of PIM-1, particularly including kinase activity.

In the context of the use, testing, or screening of compounds that are or may be modulators, the term “contacting” means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction (e.g., modulating enzymatic action) between the compound and other specified material can occur.

In a related aspect, the invention provides a method for treating a patient suffering from or at risk of a kinase-mediated disease or condition or a disease or condition in which kinase modulation provides a therapeutic benefit, such as a disease or condition characterized by abnormal kinase activity, e.g., PIM-1 activity, where the method involves administering to the patient a compound of Formula I, II, III, IV, V, VI, or VII. The compound can, for example, be one that interacts with one or more of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186.

In certain embodiments, the disease or condition is a proliferative disease or neoplasia, such as benign or malignant tumors, psoriasis, leukemias (such as myeloblastic leukemia), lymphoma, prostate cancer, liver cancer, breast cancer, sarcoma, neuroblastoma, Wilm's tumor, bladder cancer, thyroid cancer, neoplasias of the epithelial origin such as mammacarcinoma, or a chronic inflammatory disease or condition, resulting, for example, from a persistent infection (e.g., tuberculosis, syphilis, fungal infection), from prolonged exposure to endogenous (e.g., elevated plasma lipids) or exogenous (e.g., silica, asbestos, cigarette tar, surgical sutures) toxins, and from autoimmune reactions (e.g., rheumatoid arthritis, systemic lupus erythrymatosis, multiple sclerosis, psoriasis). Thus, chronic inflammatory diseases include many common medical conditions, such as rheumatoid arthritis, restenosis, psoriasis, multiple sclerosis, surgical adhesions, tuberculosis, and chronic inflammatory lung and airway diseases, such as asthma pheumoconiosis, chronic obstructive pulmonary disease, nasal polyps, and pulmonary fibrosis. Kinase modulators may also be useful in inhibiting development of hematomous plaque and restinosis, in controlling restinosis, as anti-metastatic agents, in treating diabetic complications, as immunosuppressants, and in control of angiogenesis to the extent the kinase is involved in a particular disease or condition.

In certain embodiments, the disease or condition is one listed in Table 5; the disease or condition is one listed in Table 5. In certain embodiments, the therapeutic or prophylactic effect of the compound is due to modulation of a kinase from Table 5; the therapeutic or prophylactic effect of the compound is due to modulation of a kinase from Table 5 and the disease or condition is one that corresponds thereto in Table 5.

As used herein, the term “kinase-mediated” disease or condition and like terms refer to a disease or condition in which the biological function of a kinase affects the development and/or course of the disease or condition, and/or in which modulation of a kinase alters the development, course, and/or symptoms of the disease or condition. Similarly, the phrase “kinase modulation provides a therapeutic benefit” indicates that modulation of the level of activity of a kinase in a subject indicates that such modulation reduces the severity and/or duration of the disease, reduces the likelihood or delays the onset of the disease or condition, and/or causes an improvement in one or more symptoms of the disease or condtion. Parallel terms apply to each of the kinases indicated herein.

Because molecular scaffolds are described, a large number of different kinases can be used in connection with the described scaffolds and compounds. A list of such kinases (not intended to be comprehensive) is provided in Table 6. Exemplary kinases and a major indication for which modulation of the kinase is useful include the following:

TABLE 6IndicationTyrosine Kinasesc-ablCML (chronic myeloid leukemia)her2breast cancerc-metcancerVEGFRangiogenesisc-kitcancerSerine Kinasespkcβretinopathyp38inflammation/RAcdk2canceraktcancer/apoptosisgsk3βdiabetes

As crystals of PIM-1 and other kinases have been developed and analyzed, another aspect concerns an electronic representation of the kinase with an electronic representation of a kinase binding compound or a test compound in the binding site, where the compound has a chemical structure of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII.

Likewise, in a related aspect, the invention concerns an electronic representation of a portion of a kinase binding site, e.g., PIM-1, (which can be an active site), which includes a representation of Formula I, II, III, IV, V, VI, or VII. A binding site can be represented in various ways, e.g., as representations of atomic coordinates of residues around the binding site and/or as a binding site surface contour, and can include representations of the binding character of particular residues at the binding site, e.g., conserved residues.

In another aspect, the invention provides a method for identifying potential kinase, e.g., PIM-1 or other kinase listed herein, binding compounds by fitting at least one electronic representation of a compound of Formula I, II, III, IV, V, VI, or VII in an electronic representation of a kinase, e.g., PIM-1, binding site. The representation of the binding site may be part of an electronic representation of a larger portion(s) (e.g., kinase domain) or all of a PIM molecule or may be a representation of only the binding site. The electronic representation may be as described above or otherwise described herein.

In particular embodiments, the method involves fitting a computer representation of a compound from a computer database with a computer representation of the active site of a kinase, e.g., PIM-1; and involves removing a computer representation of a compound complexed with the kinase molecule and identifying compounds that best fit the active site based on favorable geometric fit and energetically favorable complementary interactions as potential binding compounds.

In other embodiments, the method involves modifying a computer representation of a compound complexed with a kinase molecule, e.g., PIM-1, by the deletion or addition or both of one or more chemical groups; fitting a computer representation of a compound from a computer database with a computer representation of the active site of the kinase molecule; and identifying compounds that best fit the active site based on favorable geometric fit and energetically favorable complementary interactions as potential binding compounds.

In still other embodiments, the method involves removing a computer representation of a compound complexed with a kinase, such as PIM-1, and searching a database for compounds having structural similarity to the complexed compound using a compound searching computer program or replacing portions of the complexed compound with similar chemical structures using a compound construction computer program.

Fitting a compound can include determining whether a compound will interact with one or more of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186.

In another aspect, the invention concerns a method for attaching a kinase binding compound of Formula I, II, III, IV, V, VI, or VII (e.g., a PIM-1 binding compound) to an attachment component, as well as a method for identifying attachment sites on such kinase binding compound. The method involves identifying energetically allowed sites for attachment of an attachment component; and attaching the compound or a derivative thereof to the attachment component at the energetically allowed site. In certain embodiments, the kinase is a kinase listed herein; the kinase has at least 25% amino acid sequence identity or 30% sequence similarity to wild type PIM-1, and/or includes conserved residues matching at least one of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186 (i.e., matching any one, any 2, 3, 4, 5, 6, or 7 of those residues).

Attachment components can include, for example, linkers (including traceless linkers) for attachment to a solid phase or to another molecule or other moiety. Such attachment can be formed by synthesizing the compound or derivative on the linker attached to a solid phase medium e.g., in a combinatorial synthesis in a plurality of compound. Likewise, the attachment to a solid phase medium can provide an affinity medium (e.g., for affinity chromatography).

The attachment component can also include a label, which can be a directly detectable label such as a fluorophore, or an indirectly detectable such as a member of a specific binding pair, e.g., biotin.

The ability to identify energetically allowed sites on a kinase binding compound of Formula I, II, III, IV, V, VI, and VII, e.g., a PIM-1 binding compound also, in a related aspect, provides modified binding compounds that have linkers attached, for example, compounds of Formula I-VII, preferably at an energetically allowed site for binding of the modified compound to a kinase. The linker can be attached to an attachment component as described above.

Still another aspect of the invention concerns a method for developing a ligand for a kinase that includes conserved residues matching any one, 2, 3, 4, 5, 6, or 7 of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186, by determining whether a compound of Formula I, II, III, IV, V, VI, or VII binds to the kinase. The method can also include determining whether the compound modulates the activity of the kinase. In certain embodiments, the kinase has at least 25% sequence identity or at least 30% sequence similarity to PIM-1, or PIM-1 kinase domain.

In particular embodiments, the determining includes computer fitting the compound in a binding site of the kinase and/or the method includes forming a co-crystal of the kinase and the compound. Such co-crystals can be used for determining the binding orientation of the compound with the kinase and/or provide structural information on the kinase, e.g., on the binding site and interacting amino acid residues. Such binding orientation and/or other structural information can be accomplished using X-ray crystallography.

The invention also provides compounds of Formula I, II, III, IV, V, VI, and VII that bind to and/or modulate (e.g., inhibit) kinase activity for a particular kinase, e.g., PIM-1. Accordingly, in aspects and embodiments involving kinase binding compounds, molecular scaffolds, and ligands or modulators, the compound is a weak binding compound; a moderate binding compound; a strong binding compound; a compound that binds at a level identified herein; the compound interacts with one or more of PIM-1 residues 49, 52, 65, 67, 121, 128, and 186; the compound is a small molecule; the compound binds to a plurality of different kinases (e.g., at least 5, 10, 15, 20 different kinases). In particular embodiments, the invention concerns compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII as described below.

In certain embodiments, the invention concerns compounds of Formula I:
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where, with reference to Formula I:

R¹is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyoalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂R²¹, or —S(O)₂NR¹⁶R¹⁷.

R²is hydrogen, halo, optionally substituted lower alkyl (e.g., trifluoromethyl), 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)NR¹⁶R¹⁷, —NR²²R²³, or —S(O)₂R²¹, or —S(O)₂NR¹⁶R¹⁷, with the proviso that if R²is attached to nitrogen, it is not —NR²²R²³.

R³, R⁴, R⁵and R⁶are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —C(X)R²⁰, C(X)NR¹⁶R¹⁷, S(O)₂NR¹⁶R¹⁷, —NR²²R²³, or —S(O)₂R²¹;

R¹⁶and R¹⁷are 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, or R¹⁶and R¹⁷together form a 5-7 membered carbocyclic or heterocyclic ring;

R²⁰is 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;

R²¹is optionally substituted lower alkoxy, 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;

R²²and R²³are 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, —C(X)R²⁰, C(X)NR¹⁶R¹⁷, or —S(O)₂R²¹;

w, y, and z are independently O, S, N, or CR²;

q is N or C;

X=O or S; and

n=1 or 2.

In particular embodiments of compounds of Formula I, with reference to Formula I, one or more of R¹, R², R³, R⁴, R⁵, R⁶is H; any two of R¹, R², R³, R⁴, R⁵, R⁶are H; any 3 of R¹, R², R³, R⁴, R⁵, R⁶are H; any 4 of R¹, R², R³, R⁴, R⁵, R⁶are H; any 5 of R¹, R², R³, R⁴, R⁵, R⁶are H. Specification of the preceding subgroups is intended to expressly include each possible combination of the specified substituent groups. For example, in particular embodiments, R³, R⁴, R⁵, and R⁶are H.

Likewise, in certain embodiments the invention concerns compounds of Formula II.
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Where, with reference to Formula II:

R¹is hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —C(X)R², C(X)NR³R⁴, S(O)₂NR³R⁴, —NR³R⁴, or —S(O)₂R⁵;

a, b, c, and d are independently O, S, NR³, or CR¹¹with the proviso that two of them are N (and not more than 2) and one (and not more than one) of them is either O or S, and the remaining one is CR¹¹;

R²is 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;

R³and R⁴are 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, or optionally substituted heteroaralkyl;

R⁵is 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;

R¹¹is hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —C(X)R², C(X)NR³R⁴, S(O)₂NR³R⁴, —NR³R⁴, or —S(O)₂R⁵;

In particular embodiments of compounds of Formula II, with reference to Formula II, a & b, a & c, a& d, b & c, b & d, or c & d are N. In embodiments where a & b are N, c is S or O, or d is S or O; where a & c are N, b is S or O, or d is S or O; where a & d are N, b is S or O, or c is S or O; where b & c are N, a is S or O, or d is S or O; where b & d are N, a is S or O, or c is S or O, where c &d are N, a is S or O, or b is S or O. In particular embodiments of each of the preceding designations of a, b, c, and d, R¹¹is optionally substituted hydrogen or halo; R¹¹is trifluoromethyl, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy; R¹¹is optionally substituted amine; R¹¹is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R¹¹is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R¹¹is —C(X)R², C(X)NR³R⁴, S(O)₂NR³R⁴, —NR³R⁴, or —S(O)₂R⁵.

In other embodiments, the invention concerns compounds of Formula III. Formula III
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where, with reference to Formula III:

R¹, R², and R³are independently hydrogen, halo, hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —C(X)R⁴, —C(X)NR⁵R⁶, —S(O)₂NR⁵R⁶, —NR⁵R⁶, or —S(O)₂R⁷;

R⁴is 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;

R⁵and R⁶are 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, or R⁵and R⁶together for a 5-7 membered carbocyclic or heterocyclic ring;

R⁷is 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;

X=O or S; and n=0 or 1.

In particular embodiments of compounds of Formula III, with reference to Formula III, X is O; X is S. In particular embodiments for each selection of X, R¹is H; R²is H; R³is H; R¹and R²are H; R²and R³are H. In particular embodiments for each selection of X with each selection where one of R¹, R², and R³is H, the other two of R¹, R²and R³are independently halo, trifluoromethyl; the other two of R¹, R²and R³are independently hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy; the other two of R¹, R²and R³are independently optionally substituted amine; the other two of R¹, R²and R³are independently 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; the other two of R¹, R²and R³are independently —C(X)R⁴, —C(X)NR⁵R⁶, —S(O)₂NR⁵R⁶, —NR⁵R⁶, or —S(O)₂R⁷. In particular embodiments, one of R¹, R², and R³is halo, trifluoromethyl; one of R¹, R², and R³is hydroxy, optionally substituted alkoxyl, optionally substituted thioalkoxy; one of R¹, R², and R³is optionally substituted amine; one of R¹, R², and R³is 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 one of R¹, R², and R³is C(X)R⁴, —C(X)NR⁵R⁶, —S(O)₂NR⁵R⁶, —NR⁵R⁶, or —S(O)₂R⁷.

In other embodiments, the invention concerns compounds of Formula IV.
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where, with reference to Formula IV:

R¹is 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, —NR¹⁶R¹⁷, —OR²¹, or —SR²¹;

R²and R³are 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, optionally substituted heteroaralkyl, —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —C(X)R²⁰, or —C(X)NR¹⁶R¹⁷;

R²¹is 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.

In particular embodiments of compounds of Formula IV, with reference to Formula IV, R¹is optionally substituted lower alkyl; R¹is optionally substituted lower alkenyl; R¹is optionally substituted lower alkynyl, optionally substituted cycloalkyl; R¹is optionally substituted heterocycloalkyl; R¹is optionally substituted aryl, optionally substituted aralkyl; R¹is optionally substituted heteroaryl, optionally substituted heteroaralkyl; R¹is —NR¹⁶R¹⁷, —OR²¹, —SR²¹, —C(X)R²⁰, or —C(X)NR¹⁶R¹⁷. In particular embodiments, R²or R³(but not both) is hydrogen; R²or R³(but not the other) is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl; R²or R³(but not the other) is optionally substituted heterocycloalkyl; R²or R³(but not the other) is optionally substituted aryl, optionally substituted aralkyl; R²or R³(but not the other) is optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heteroaralkyl; R²or R³(but not both) is —C(X)R²⁰, or —C(X)NR¹⁶R¹⁷. In particular embodiments, R²is H; R³is H; R²and R³are H.

The invention also concerns compounds of Formula V.
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where, with reference to Formula V:

R¹and R⁷are independently hydrogen, hydroxyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, 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, —NR¹⁶R¹⁷, —C(X)R²⁰, C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, —S(O)₂R²¹, or R¹and R⁷, when one of them is —NR¹⁶R¹⁷, hydroxyl, alkoxyl, thioalkoxyl, aralkyl or heteroaralkyl and the other one is hydrogen can combine to form ═NR¹⁶, ═O, ═S, or ═Caryl/heteroaryl, with the proviso that R¹and R⁷both cannot be hydroxyl, alkoxyl, thioalkoxyl or —NR¹⁶R¹⁷at the same time;

R²is hydrogen, halo, 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, optionally substituted heteroaralkyl, —C(X)R²⁰, or C(X)NR¹⁶R¹⁷;

R³, R⁴, R⁵, and R⁶are independently hydrogen, halo, hydroxyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —S(1)₂NR¹⁶R¹⁷, or —S(O)₂R²¹;

R²¹is 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.

In particular embodiments of compounds of Formula V, with reference to Formula V, R¹is H; R²is H; R³is H; R⁴is H; R⁵is H; R⁶is H; each combination of two of R¹, R², R³, R⁴, R, and R⁶are H and the others; each combination of three of R¹, R², R³, R⁴, R⁵, and R⁶are H; each combination of 4 of R¹, R², R³, R⁴, R⁵, and R⁶are H; each combination of 5 of R¹, R³, R⁴, R⁵, and R⁶are H.

Likewise, the invention concerns compounds of Formula VI.
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where, with reference to Formula VI:

R¹is 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, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹;

R³and R⁴are independently hydrogen, halo, hydroxyl, optionally substituted alkoxyl, optionally substituted thioalkoxy, optionally substituted amine, optionally substituted lower alkyl (e.g., trifluoromethyl), 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, —NR¹⁶R^17, —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹or R³and R⁴, when one of them is —NR¹⁶R¹⁷, hydroxyl, alkoxyl, thioalkoxyl, aralkyl or heteroaralkyl and the other one is hydrogen can combine to form ═NR¹⁶, ═O, ═S, or ═Caryl/heteroaryl, with the proviso that R¹and R⁷both cannot be hydroxyl, alkoxyl, thioalkoxyl or —NR¹⁶R¹⁷at the same time;

R²¹is 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.

In particular embodiments of compounds of Formula VI, with reference to Formula VI, R¹is H; R²is H; R³is H; R¹and R²are H; R²and R³are H; R¹is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R¹is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl; R¹is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl; R¹is —C(X)R²⁰, —C(X)NR¹⁶R⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹; R²is halo; R²is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R²is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl; R²is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or optionally substituted heteroaralkyl; R²is —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹; R³is halo; R³is trifluoromethyl; R³is optionally substituted alkoxyl, optionally substituted thioalkoxy; R³is optionally substituted amine; R³is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R³is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl; R³is optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R³is —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹.

In yet other embodiments, the invention concerns compounds of Formula VII.
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where, with reference to Formula VII:

R¹is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteralkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹;

R², R³, R⁴, R⁵, R⁶, and R⁷are independently hydrogen, halo, optionally substituted amine, optionally substituted alkoxy, optionally substituted thioether, 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, optionally substituted heteroaralkyl, —C(X)R²⁰, —C(X)NR¹⁶R¹⁷, —S(O)₂NR¹⁶R¹⁷, or —S(O)₂R²¹;

R¹⁶and R¹⁷are independently hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, or R¹⁶and R¹⁷together form a carbocyclic or heterocyclic ring;

R²⁰is hydroxyl, optionally substituted lower alkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and

R²¹is optionally substituted lower alkoxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

In particular embodiments of compounds of Formula VII, with reference to Formula VII, R¹is H; R²is H; R³is H; R⁴is H; R⁵is H; R⁶is H; R⁷is H; each combination of two of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are H; each combination of three of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are H; each combination of 4 of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are H; each combination of 5 of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are H; each combination of six of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are H (e.g., all except for R¹and R⁶).

As used in connection with the present invention, unless indicated clearly to the contrary, the description of compounds and the use of such compounds, e.g., compounds of any of Formula I-VII, includes pharmaceutically acceptable salts and solvates of such compounds.

In connection with the compounds of Formulas I-VII, the following definitions apply.

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

“Hydroxyl” refers to the group —OH.

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

“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 of 1-6, 1-4, or 1-2 carbon atoms. 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, and the like, but can also include larger ring structures such as adamantyl. 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.

“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.

“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 a straight chain alkynyl or branched alkynyl, 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.

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

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

“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.

“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.

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

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

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

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

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

“Carbocyclic” refers to a saturated, unsaturated, or aromatic group having a single ring (e.g., phenyl) or multiple condensed rings where all ring atoms are carbon atoms, which can optionally be unsubstituted or substituted with, 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.

“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.

“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.

“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.

“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.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

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

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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).

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

“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, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.

An additional aspect of this invention relates to pharmaceutical formulations or compositions, that include a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, or VII, (or a compound within a sub-group of compounds within any of those generic formulas) and at least one pharmaceutically acceptable carrier or excipient. The composition can include a plurality of different pharmacalogically active compounds.

As used herein, the term “pharmaceutical composition” refers to a preparation that includes a therapeutically significant quantity of an active agent, that is prepared in a form adapted for administration to a subject. Thus, the preparation does not include any component or components in such quantity that a reasonably prudent medical practitioner would find the preparation unsuitable for administration to a normal subject. In many cases, such a pharmaceutical composition is a sterile preparation.

In a related aspect, the invention provides kits that include a pharmaceutical composition as described herein. In particular embodiments, the pharmaceutical composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the pharmaceutical composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human; the pharmaceutical composition is approved for administration to a mammal, e.g., a human for a kinase-mediated disease or condition; the kit includes written instructions or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a kinase-mediated disease or condition; the pharmaceutical composition is packaged in unit does or single dose form, e.g., single dose pills, capsules, or the like.

In another related aspect, compounds of any of Formulas I-VII can be used in the preparation of a medicament for the treatment of a kinase-mediated disease or condition or a disease or condition in which modulation of a kinase provides a therapeutic benefit.

In the present context, the term “therapeutically effective” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.

The term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles.

“A pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise unacceptable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sodium, chloride, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, .gamma.-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

The term “pharmaceutically acceptable metabolite” refers to a pharmacologically acceptable product, which may be an active product, produced through metabolism of a specified compound (or salt thereof) in the body of a subject or patient. Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. For example, in some compounds, one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic activity and/or carboxyl groups can be esterified, e.g., glucuronidation. In some cases, there can be more than one metabolite, where an intermediate metabolite(s) is further metabolized to provide an active metabolite. For example, in some cases a derivative compound resulting from metabolic glucuronidation may be inactive or of low activity, and can be further metabolized to provide an active metabolite.

Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic representation of AMP-PNP in the binding site of PIM-1, showing conserved interacting residues.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The Tables will first be briefly described.

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:

ATOM: Refers to the relevant moiety for the table row.
Atom number: Refers to the arbitrary atom number designation within the coordinate table.
Atom Name: Identifier for the atom present at the particular coordinates.
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.
Residue Number: The amino acid residue number in the chain.
X, Y, Z: Respectively are the X, Y, and Z coordinate values.
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=o.5 indicates that the atom is present in the location 50% of the time.
B-factor: A measure of the thermal motion of the atom.
Element: Identifier for the element.

Table 2 provides an alignment of catalytic domains of several PIM kinases, including human PIM-1, PIM-2, and PIM-3 as well as PIM kinases from other species. Sequences from the following species are included in the alignment: Hs, Homo sapiens; Mm, Mus musculus; Dr, Danio rerio; Xl, Xenopus laevis; Cc, Cotumix cotumix; and Ce, Caenorhabditis elegans. Residues with >90% and >75% conservations are in red and yellow background, respectively. Phosphate binding sites are indicated by purple circles. Residues that are invariably involved in ligand binding are indicated by filled uparrows, whereas residues that can be involved in ligand binding are indicated by open uparrows. The backbone atoms of two residues (indicated by leftarrows) in the hinge region have been shown to make hydrogen bonds to ligands in many known kinase/ligand complex structures. Note that PIM family kinases all have Pro as the second residue, resulting in the loss of a hydrogen bond donor.

Table 3 provides alignments of a large set of kinases, providing identification of residues conserved between various members of the set.

Table 4 provides atomic coordinates for PIM-1 with AMP-PNP in the binding site.

Table 5 provides a list of kinases which have been correlated with diseases (or pathological condition).

I. Introduction

The present invention concerns the use of certain molecular scaffolds in the development of kinase modulators, e.g., kinase inhibitors. Such development can utilize kinase structures, for example, PIM kinase structures, structural information, and related compositions for identifying compounds that modulate kinase activity and for determining structures of other kinases. The following description utilizes PIM-1 for illustrative purposes. However, the invention is not limited to PIM-1; other protein kinases can also be utilized for modulation by the present compounds, and for developing additional modulators based on the present molecular scaffolds. The use of molecular scaffolds in connection with PIM kinases and Pyk2 is described in U.S. application Ser. No. 10/664,421 and corresponding PCT/US03/29415, and Formula I as described in U.S. application Ser. No. 10/789,818 and corresponding PCT/U.S. 2004/005904 respectively. Both of those applications are incorporated herein by reference in their entireties, including drawings.

Kinases, e.g., PIM-1, are involved in a variety of disease conditions, and a number have been utilized as therapeutic targets.

Exemplary Diseases Associated with Kinases

As indicated above, the present invention is exemplified in connection with PIM-1. As indicated in the Background above, PIM-1 functions as a weak oncogene. In transgenic mice with PIM-1 driven by Emu enhancer sequences, overexpression of PIM-1 by itself it does not lead to tumor formation, but does so in conjunction with overexpression of a second oncogenic gene. In 75% of tumors over-expressing PIM-1, the second gene found to be overexpressed was c-myc (van der Houven van Oordt C W, Schouten T G, van Krieken J H, van Dierendonck J H, van der Eb A J, Breuer M L. (1998) X-ray-induced lymphomagenesis in E mu-PIM-1 transgenic mice: an investigation of the co-operating molecular events. Carcinogenesis 19: 847-853). Other PIM kinases are also involved, as the functions of the various PIM kinases appears to be at least partially complementary.

Since PIM-1 is a protooncogene and it closely cooperates with other protooncogenes like c-myc in triggering intracellular signals leading to cell transformation, PIM-1 inhibitors have therapeutic applications in the treatment of various cancers, as wells as other disease states. Some examples are described below.

Prostate Cancer

A significant inter-relationship between PIM-1 and a disease state was reported in prostate cancer (Dhanasekaran et al. (2001) Delineation of prognostic biomarkers in prostate cancer. Nature 412: 822-826.) Using microarrays of complementary DNA, the gene expression profiles of approximately 10,000 genes from more than 50 normal and neoplastic prostate cancer specimens and three common prostate cancer cell lines were examined. Two of these genes, hepsin, a transmembrane serine protease, and PIM-1, a serine/threonine kinase are upregulated to several-fold. The PIM-1 kinase is strongly expressed in the cytoplasm of prostate cancer tissues while the normal tissues showed no or weak staining with anti-PIM-1 antibody (Id.) indicating PIM-1 is an appropriate target for drug development.

Leukemia

PIM-1 has been mapped to the 6p21 chromosomal region in humans. Nagarajan et al. (Nagarajan et al. (1986) Localization of the human pim oncogene (PIM) to a region of chromosome 6 involved in translocations in acute leukemias. Proc. Natl. Acad. Sci. USA 83: 2556-2560) reported increased expression of PIM-1 in K562 erythroleukemia cell lines which contain cytogenetically demonstrable rearrangement in the 6p21 region. A characteristic chromosome anomaly, a reciprocal translocation t(6;9)(p21;q33), has been described in myeloid leukemias that may be due to involvement of PIM-1. Amson et al. (1989) also observed overexpression in 30% of myeloid and lymphoid acute leukemia. These studies also indicate a role for PIM-1 protooncogene during development and in deregulation in various leukemias.

Kaposi Sarcoma

Analysis of gene expression profiles by microarrays in human hematopoietic cells after in vitro infection with human Herpes virus (HHV 8), also known as Kaposi Sarcoma associated virus (KSHV), resulted in differential expression of 400 genes out of about 10,000 analyzed. Of these four hundred genes, PIM-2 is upregulated more than 3.5 fold indicating PIM-2 as a potential target for therapeutic intervention. Thus, inhibitors selective to PIM-2 are of great therapeutic value in treating disease states mediated by HHV8 (Mikovits et al. (2001) Potential cellular signatures of viral infections in human hematopoietic cells. Dis. Markers 17: 173-178.)

Asthma and Allergy.

The increase in eosinophils at the site of antigen challenge has been used as evidence that eosinophils play a role in pathophysiology of asthma. Aberrant production of several different cytokines has been shown to result in eosinophilia. The cytokine IL-5 for example influences the development and maturation of eosinophils in a number of ways. Using microarray techniques, a role for PIM-1 in IL-5 signaling pathway in eosinophils was indicated. (Temple et al. (2001) Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes. Am. J. Respir. Cell Mol. Biol. 25: 425-433.) Thus, inhibitors of PIM-1 can have therapeutic value in treatment of asthma and allergies.

Inflammation

PIM-1 and/or the compounds described herein can also be useful for treatment of inflammation, either chronic or acute. Chronic inflammation is regarded as prolonged inflammation (weeks or months), involving simultaneous active inflammation, tissue destruction, and attempts at healing. (R. S. Cotran, V. Kumar, and S. L. Robbins, Saunders Co., (1989) Robbins Pathological Basis of Disease, p. 75.) Although chronic inflammation can follow an acute inflammatory episode, it can also begin as a process that progresses over time, e.g., as a result of a chronic infection such as tuberculosis, syphilis, fungal infection which causes a delayed hypersensitivity reaction, prolonged exposure to endogenous or exogenous toxins, or autoimmune reactions (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis). Chronic inflammatory disease thus include many common medical conditions such as autoimmune disorders such as those listed above, chronic infections, surgical adhesions, chronic inflammatory lung and airway diseases (e.g., asthma, pneumoconiosis, chronic obstructive pulmonary disease, nasal polyps, and pulmonary fibrosis). For skin and airway inflammatory disease, topical or inhaled forms of drug administration can be used respectively.

While kinase-related diseases and conditions are exemplified in connection with PIM-1, numerous other kinases have been correlated with particular disease and conditions, and are identified as target in a number of current treatments. Compounds derived from the present scaffolds can be developed to target such additional kinases for treating associated diseases and conditions.

II. Crystalline Kinases

In development of kinase modulators based on molecular scaffolds, crystalline kinases (e.g., human PIM-1) include native crystals, derivative crystals and co-crystals are useful. Native crystals generally comprise substantially pure polypeptides corresponding to the kinase in crystalline form. Crystal structures for a number of different kinases (or kinase domains) have been determined and are available for use in the present methods.

It is to be understood that the crystalline kinases are not limited to naturally occurring or native kinase. Indeed, the crystals of the invention include crystals of mutants of native kinases. Mutants of native kinases are obtained by replacing at least one amino acid residue in a native kinase with a different amino acid residue, or by adding or deleting amino acid residues within the native polypeptide or at the N- or C-terminus of the native polypeptide, and have substantially the same three-dimensional structure as the native kinase from which the mutant is derived.

By having substantially the same three-dimensional structure is meant having a set of atomic structure coordinates that have a root-mean-square deviation of less than or equal to about 2 Å when superimposed with the atomic structure coordinates of the native kinase from which the mutant is derived when at least about 50% to 100% of the Ca atoms of the native kinase domain are included in the superposition.

Amino acid substitutions, deletions and additions which do not significantly interfere with the three-dimensional structure of the kinase will depend, in part, on the region of the kinase where the substitution, addition or deletion occurs. In highly variable regions of the molecule, non-conservative substitutions as well as conservative substitutions may be tolerated without significantly disrupting the three-dimensional, structure of the molecule. In highly conserved regions, or regions containing significant secondary structure, conservative amino acid substitutions are preferred. Such conserved and variable regions can be identified by sequence alignment of a particular kinase (e.g., PIM-1) with other kinases). Such alignment of some kinases is provided in Table 3.

Conservative amino acid substitutions are well known in the art, and include substitutions made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the amino acid residues involved. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; amino acids with uncharged polar head groups having similar hydrophilicity values include the following: leucine, isoleucine, valine; glycine, alanine; asparagine, glutamine; serine, threonine; phenylalanine, tyrosine. Other conservative amino acid substitutions are well known in the art.

For kinases obtained in whole or in part by chemical synthesis, the selection of amino acids available for substitution or addition is not limited to the genetically encoded amino acids. Indeed, the mutants described herein may contain non-genetically encoded amino acids. Conservative amino acid substitutions for many of the commonly known non-genetically encoded amino acids are well known in the art. Conservative substitutions for other amino acids can be determined based on their physical properties as compared to the properties of the genetically encoded amino acids.

In some instances, it may be particularly advantageous or convenient to substitute, delete and/or add amino acid residues to a native kinase in order to provide convenient cloning sites in cDNA encoding the polypeptide, to aid in purification of the polypeptide, and for crystallization of the polypeptide. Such substitutions, deletions and/or additions which do not substantially alter the three dimensional structure of the native kinase domain will be apparent to those of ordinary skill in the art.

It should be noted that the mutants contemplated herein need not all exhibit kinase activity. Indeed, amino acid substitutions, additions or deletions that interfere with the kinase activity but which do not significantly alter the three-dimensional structure of the domain are specifically contemplated by the invention. Such crystalline polypeptides, or the atomic structure coordinates obtained therefrom, can be used to identify compounds that bind to the native domain. These compounds can affect the activity of the native domain.

The derivative crystals of the invention can comprise a crystalline kinase polypeptide in covalent association with one or more heavy metal atoms. The polypeptide may correspond to a native or a mutated kinase. Heavy metal atoms useful for providing derivative crystals include, by way of example and not limitation, gold, mercury, selenium, etc.

The co-crystals of the invention generally comprise a crystalline kinase domain polypeptide in association with one or more compounds. The association may be covalent or non-covalent. Such compounds include, but are not limited to, cofactors, substrates, substrate analogues, inhibitors, allosteric effectors, etc.

Exemplary mutations for PIM family kinases include the substitution or of the proline at the site corresponding to residue 123 in human PIM-1. One useful substitution is a proline to methionine substitution at residue 123 (P123M). Such substitution is useful, for example, to assist in using PIM family kinases to model other kinases that do not have proline at that site. Additional exemplary mutations include substitution or deletion of one or more of PIM-1 residues 124-128 or a residue from another PIM aligning with PIM-1 residues 124-128. For example, a PIM residue aligning with PIM-1 residue 128 can be deleted. Mutations at other sites can likewise be carried out, e.g., to make a mutated PIM family kinase more similar to another kinase for structure modeling and/or compound fitting purposes.

III. Three Dimensional Structure Determination Using X-Ray Crystallography

X-ray crystallography is a method of solving the three dimensional structures of molecules. The structure of a molecule is calculated from X-ray diffraction patterns using a crystal as a diffraction grating. Three dimensional structures of protein molecules arise from crystals grown from a concentrated aqueous solution of that protein. The process of X-ray crystallography can include the following steps:

- (a) synthesizing and isolating (or otherwise obtaining) a polypeptide;
- (b) growing a crystal from an aqueous solution comprising the polypeptide with or without a modulator; and
- (c) collecting X-ray diffraction patterns from the crystals, determining unit cell dimensions and symmetry, determining electron density, fitting the amino acid sequence of the polypeptide to the electron density, and refining the structure.

Production of Polypeptides

The native and mutated kinase polypeptides described herein may be chemically synthesized in whole or part using techniques that are well-known in the art (see, e.g., Creighton (1983) Biopolymers 22(1): 49-58).

Alternatively, methods which are well known to those skilled in the art can be used to construct expression vectors containing the native or mutated kinase polypeptide coding sequence and appropriate transcriptional/translational control signals. These methods include in vitro recombinant DNA techniques, synthetic techniques and in vivo recombination/genetic recombination. See, for example, the techniques described in Maniatis, T (1989). Molecular cloning: A laboratory Manual. Cold Spring Harbor Laboratory, New York. Cold Spring Harbor Laboratory Press; and Ausubel, F. M. et al. (1994) Current Protocols in Molecular Biology. John Wiley & Sons, Secaucus, N.J.

A variety of host-expression vector systems may be utilized to express the kinase coding sequence. These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing the kinase domain coding sequence; yeast transformed with recombinant yeast expression vectors containing the kinase domain coding sequence; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing the kinase domain coding sequence; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing the kinase domain coding sequence; or animal cell systems. The expression elements of these systems vary in their strength and specificities.

Depending on the host/vector system utilized, any of a number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used in the expression vector. For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage λ, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used; when cloning in insect cell systems, promoters such as the baculovirus polyhedrin promoter may be used; when cloning in plant cell systems, promoters derived from the genome of plant cells (e.g., heat shock promoters; the promoter for the small subunit of RUBISCO; the promoter for the chlorophyll a/b binding protein) or from plant viruses (e.g., the ³⁵S RNA promoter of CaMV; the coat protein promoter of TMV) may be used; when cloning in mammalian cell systems, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter) may be used; when generating cell lines that contain multiple copies of the kinase domain DNA, SV4O-, BPV- and EBV-based vectors may be used with an appropriate selectable marker.

Exemplary methods describing methods of DNA manipulation, vectors, various types of cells used, methods of incorporating the vectors into the cells, expression techniques, protein purification and isolation methods, and protein concentration methods are disclosed in detail in PCT publication WO 96/18738. This publication is incorporated herein by reference in its entirety, including any drawings. Those skilled in the art will appreciate that such descriptions are applicable to the present invention and can be easily adapted to it.

Crystal Growth

Crystals are grown from an aqueous solution containing the purified and concentrated polypeptide by a variety of techniques. These techniques include batch, liquid, bridge, dialysis, vapor diffusion, and hanging drop methods. McPherson (1982) John Wiley, New York; McPherson (1990) Eur. J. Biochem. 189: 1-23; Webber (1991) Adv. Protein Chem. 41: 1-36, incorporated by reference herein in their entireties, including all figures, tables, and drawings.

The native crystals of the invention are, in general, grown by adding precipitants to the concentrated solution of the polypeptide. The precipitants are added at a concentration just below that necessary to precipitate the protein. Water is removed by controlled evaporation to produce precipitating conditions, which are maintained until crystal growth ceases.

For crystals of the invention, exemplary crystallization conditions are described in the Examples. Those of ordinary skill in the art will recognize that the exemplary crystallization conditions can be varied. Such variations may be used alone or in combination. In addition, other crystallizations may be found, e.g., by using crystallization screening plates to identify such other conditions.

Derivative crystals of the invention can be obtained by soaking native crystals in mother liquor containing salts of heavy metal atoms. It has been found that soaking a native crystal in a solution containing about 0.1 mM to about 5 mM thimerosal, 4-chloromeruribenzoic acid or KAu(CN)₂for about 2 hr to about 72 hr provides derivative crystals suitable for use as isomorphous replacements in determining the X-ray crystal structure of PIM-1.

Co-crystals of the invention can be obtained by soaking a native crystal in mother liquor containing compound that binds the kinase, or can be obtained by co-crystallizing the kinase polypeptide in the presence of a binding compound.

Generally, co-crystallization of kinase and binding compound can be accomplished using conditions identified for crystallizing the corresponding kinase without binding compound. It is advantageous if a plurality of different crystallization conditions have been identified for the kinase, and these can be tested to determine which condition gives the best co-crystals. It may also be beneficial to optimize the conditions for co-crystallization. Exemplary co-crystallization conditions are provided in the Examples.

Determining Unit Cell Dimensions and the Three Dimensional Structure of a Polypeptide or Polypeptide Complex

Once the crystal is grown, it can be placed in a glass capillary tube or other mounting device and mounted onto a holding device connected to an X-ray generator and an X-ray detection device. Collection of X-ray diffraction patterns are well documented by those in the art. See, e.g., Ducruix and Geige, (1992), IRL Press, Oxford, England, and references cited therein. A beam of X-rays enters the crystal and then diffracts from the crystal. An X-ray detection device can be utilized to record the diffraction patterns emanating from the crystal. Although the X-ray detection device on older models of these instruments is a piece of film, modern instruments digitally record X-ray diffraction scattering. X-ray sources can be of various types, but advantageously, a high intensity source is used, e.g., a synchrotron beam source.

Methods for obtaining the three dimensional structure of the crystalline form of a peptide molecule or molecule complex are well known in the art. See, e.g., Ducruix and Geige, (1992), IRL Press, Oxford, England, and references cited therein. The following are steps in the process of determining the three dimensional structure of a molecule or complex from X-ray diffraction data.

After the X-ray diffraction patterns are collected from the crystal, the unit cell dimensions and orientation in the crystal can be determined. They can be determined from the spacing between the diffraction emissions as well as the patterns made from these emissions. The unit cell dimensions are characterized in three dimensions in units of Angstroms (one Å=10¹⁰meters) and by angles at each vertices. The symmetry of the unit cell in the crystals is also characterized at this stage. The symmetry of the unit cell in the crystal simplifies the complexity of the collected data by identifying repeating patterns. Application of the symmetry and dimensions of the unit cell is described below.

Each diffraction pattern emission is characterized as a vector and the data collected at this stage of the method determines the amplitude of each vector. The phases of the vectors can be determined using multiple techniques. In one method, heavy atoms can be soaked into a crystal, a method called isomorphous replacement, and the phases of the vectors can be determined by using these heavy atoms as reference points in the X-ray analysis. (Otwinowski, (1991), Daresbury, United Kingdom, 80-86). The isomorphous replacement method usually utilizes more than one heavy atom derivative. In another method, the amplitudes and phases of vectors from a crystalline polypeptide with an already determined structure can be applied to the amplitudes of the vectors from a crystalline polypeptide of unknown structure and consequently determine the phases of these vectors. This second method is known as molecular replacement and the protein structure which is used as a reference must have a closely related structure to the protein of interest. (Naraza (1994) Proteins 11: 281-296). Thus, the vector information from a kinase of known structure, such as those reported herein, are useful for the molecular replacement analysis of another kinase with unknown structure.

Once the phases of the vectors describing the unit cell of a crystal are determined, the vector amplitudes and phases, unit cell dimensions, and unit cell symmetry can be used as terms in a Fourier transform function. The Fourier transform function calculates the electron density in the unit cell from these measurements. The electron density that describes one of the molecules or one of the molecule complexes in the unit cell can be referred to as an electron density map. The amino acid structures of the sequence or the molecular structures of compounds complexed with the crystalline polypeptide may then be fitted to the electron density using a variety of computer programs. This step of the process is sometimes referred to as model building and can be accomplished by using computer programs such as Turbo/FRODO or “O”. (Jones (1985) Methods in Enzymology 115: 157-171).

A theoretical electron density map can then be calculated from the amino acid structures fit to the experimentally determined electron density. The theoretical and experimental electron density maps can be compared to one another and the agreement between these two maps can be described by a parameter called an R-factor. A low value for an R-factor describes a high degree of overlapping electron density between a theoretical and experimental electron density map.

The R-factor is then minimized by using computer programs that refine the theoretical electron density map. A computer program such as X-PLOR can be used for model refinement by those skilled in the art. Bringer (1992) Nature 355: 472-475. Refinement may be achieved in an iterative process. A first step can entail altering the conformation of atoms defined in an electron density map. The conformations of the atoms can be altered by simulating a rise in temperature, which will increase the vibrational frequency of the bonds and modify positions of atoms in the structure. At a particular point in the atomic perturbation process, a force field, which typically defines interactions between atoms in terms of allowed bond angles and bond lengths, Van der Waals interactions, hydrogen bonds, ionic interactions, and hydrophobic interactions, can be applied to the system of atoms. Favorable interactions may be described in terms of free energy and the atoms can be moved over many iterations until a free energy minimum is achieved. The refinement process can be iterated until the R-factor reaches a minimum value.

The three dimensional structure of the molecule or molecule complex is described by atoms that fit the theoretical electron density characterized by a minimum R-value. A file can then be created for the three dimensional structure that defines each atom by coordinates in three dimensions. An example of such a structural coordinate file is shown in Table 1.

IV. Structures of an Exemplary Kinase Domain: Human PIM-1

As an example of kinase structure, high-resolution three-dimensional structures and atomic structure coordinates of crystalline PIM-1 and PIM-1 co-complexed with exemplary binding compounds as determined by X-ray crystallography are provided. The specific methods used to obtain the structure coordinates are provided in the examples. The atomic structure coordinates of crystalline PIM-1 are listed in Table 1, and atomic coordinates for PIM-1 co-crystallized with AMP-PMP are provided in Table 4. Co-crystal coordinates can be used in the same way, e.g., in the various aspects described herein, as coordinates for the protein by itself.

Those having skill in the art will recognize that atomic structure coordinates as determined by X-ray crystallography are not without error. Thus, it is to be understood that any set of structure coordinates obtained for crystals of PIM-1, whether native crystals, derivative crystals or co-crystals, that have a root mean square deviation (“r.m.s.d.”) of less than or equal to about 1.5 Å when superimposed, using backbone atoms (N, C_α, C and 0), on the structure coordinates listed in Table 1 (or Table 4) are considered to be identical with the structure coordinates listed in the Table 1 (or Table 4) when at least about 50% to 100% of the backbone atoms of PIM-1 are included in the superposition.

In addition to the PIM-1 structures provided herein, additional protein kinase structures are available and can be used, for example, publicly available structures deposited in the Protein Data Bank (PDB) (available for example, over the Internet). Higher quality structures are preferred (e.g., at least 2.5, 2.2, 2.0, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, or 1.2 Å resolution, as they provide more or more precise information for compound fitting and selection or design of derivatives.

V. Uses of the Crystals and Atomic Structure Coordinates

Kinase crystals, and particularly the atomic structure coordinates obtained therefrom, have a wide variety of uses. For example, the kinase crystals such as those described herein can be used as a starting point in any of the methods of use for kinases known in the art or later developed. Such methods of use include, for example, identifying molecules that bind to the native or mutated catalytic domain of kinases. The crystals and structure coordinates are particularly useful for identifying ligands that modulate kinase activity as an approach towards developing new therapeutic agents. In particular, the crystals and structural information are useful in methods for ligand development utilizing molecular scaffolds.

The structure coordinates described herein can be used as phasing models for determining the crystal structures of additional kinases, as well as the structures of co-crystals of such kinases with ligands such as inhibitors, agonists, antagonists, and other molecules. The structure coordinates, as well as models of the three-dimensional structures obtained therefrom, can also be used to aid the elucidation of solution-based structures of native or mutated kinases, such as those obtained via NMR.

VI. Electronic Representations of Kinase Structures

Structural information of kinases or portions of kinases (e.g., kinase active sites) can be represented in many different ways. Particularly useful are electronic representations, as such representations allow rapid and convenient data manipulations and structural modifications. Electronic representations can be embedded in many different storage or memory media, frequently computer readable media. Examples include without limitations, computer random access memory (RAM), floppy disk, magnetic hard drive, magnetic tape (analog or digital), compact disk (CD), optical disk, CD-ROM, memory card, digital video disk (DVD), and others. The storage medium can be separate or part of a computer system. Such a computer system may be a dedicated, special purpose, or embedded system, such as a computer system that forms part of an X-ray crystallography system, or may be a general purpose computer (which may have data connection with other equipment such as a sensor device in an X-ray crystallographic system. In many cases, the information provided by such electronic representations can also be represented physically or visually in two or three dimensions, e.g., on paper, as a visual display (e.g., on a computer monitor as a two dimensional or pseudo-three dimensional image) or as a three dimensional physical model. Such physical representations can also be used, alone or in connection with electronic representations. Exemplary useful representations include, but are not limited to, the following:

Atomic Coordinate Representation

One type of representation is a list or table of atomic coordinates representing positions of particular atoms in a molecular structure, portions of a structure, or complex (e.g., a co-crystal). Such a representation may also include additional information, for example, information about occupancy of particular coordinates.

Energy Surface or Surface of Interaction Representation

Another representation is an energy surface representation, e.g., of an active site or other binding site, representing an energy surface for electronic and steric interactions. Such a representation may also include other features. An example is the inclusion of representation of a particular amino acid residue(s) or group(s) on a particular amino acid residue(s), e.g., a residue or group that can participate in H-bonding or ionic interaction.

Structural Representation

Still another representation is a structural representation, i.e., a physical representation or an electronic representation of such a physical representation. Such a structural representation includes representations of relative positions of particular features of a molecule or complex, often with linkage between structural features. For example, a structure can be represented in which all atoms are linked; atoms other than hydrogen are linked; backbone atoms, with or without representation of side chain atoms that could participate in significant electronic interaction, are linked; among others. However, not all features need to be linked. For example, for structural representations of portions of a molecule or complex, structural features significant for that feature may be represented (e.g., atoms of amino acid residues that can have significant binding interaction with a ligand at a binding site. Those amino acid residues may not be linked with each other.

A structural representation can also be a schematic representation. For example, a schematic representation can represent secondary and/or tertiary structure in a schematic manner. Within such a schematic representation of a polypeptide, a particular amino acid residue(s) or group(s) on a residue(s) can be included, e.g., conserved residues in a binding site, and/or residue(s) or group(s) that may interact with binding compounds.

VII. Structure Determination for Kinases with Unknown Structure Using Structural Coordinates

Structural coordinates, such as those set forth in Table 1, can be used to determine the three dimensional structures of kinases with unknown structure. The methods described below can apply structural coordinates of a polypeptide with known structure to another data set, such as an amino acid sequence, X-ray crystallographic diffraction data, or nuclear magnetic resonance (NMR) data. Preferred embodiments of the invention relate to determining the three dimensional structures of other PIM kinases, other serine/threonine kinases, and related polypeptides.

Structures Using Amino Acid Homology

Homology modeling is a method of applying structural coordinates of a polypeptide of known structure to the amino acid sequence of a polypeptide of unknown structure. This method is accomplished using a computer representation of the three dimensional structure of a polypeptide or polypeptide complex, the computer representation of amino acid sequences of the polypeptides with known and unknown structures, and standard computer representations of the structures of amino acids. Homology modeling generally involves (a) aligning the amino acid sequences of the polypeptides with and without known structure; (b) transferring the coordinates of the conserved amino acids in the known structure to the corresponding amino acids of the polypeptide of unknown structure; refining the subsequent three dimensional structure; and (d) constructing structures of the rest of the polypeptide. One skilled in the art recognizes that conserved amino acids between two proteins can be determined from the sequence alignment step in step (a).

The above method is well known to those skilled in the art. (Greer (1985) Science 228: 1055; Blundell et al. A (1988) Eur. J. Biochemi. 172: 513. An exemplary computer program that can be utilized for homology modeling by those skilled in the art is the Homology module in the Insight II modeling package distributed by Accelerys Inc.

Alignment of the amino acid sequence is accomplished by first placing the computer representation of the amino acid sequence of a polypeptide with known structure above the amino acid sequence of the polypeptide of unknown structure. Amino acids in the sequences are then compared and groups of amino acids that are homologous (e.g., amino acid side chains that are similar in chemical nature—aliphatic, aromatic, polar, or charged) are grouped together. This method will detect conserved regions of the polypeptides and account for amino acid insertions or deletions.

Once the amino acid sequences of the polypeptides with known and unknown structures are aligned, the structures of the conserved amino acids in the computer representation of the polypeptide with known structure are transferred to the corresponding amino acids of the polypeptide whose structure is unknown. For example, a tyrosine in the amino acid sequence of known structure may be replaced by a phenylalanine, the corresponding homologous amino acid in the amino acid sequence of unknown structure.

The structures of amino acids located in non-conserved regions are to be assigned manually by either using standard peptide geometries or molecular simulation techniques, such as molecular dynamics. The final step in the process is accomplished by refining the entire structure using molecular dynamics and/or energy minimization. The homology modeling method is well known to those skilled in the art and has been practiced using different protein molecules. For example, the three dimensional structure of the polypeptide corresponding to the catalytic domain of a serine/threonine protein kinase, myosin light chain protein kinase, was homology modeled from the cAMP-dependent protein kinase catalytic subunit. (Knighton et al. (1992) Science 258: 130-135.)

Structures Using Molecular Replacement

Molecular replacement is a method of applying the X-ray diffraction data of a polypeptide of known structure to the X-ray diffraction data of a polypeptide of unknown sequence. This method can be utilized to define the phases describing the X-ray diffraction data of a polypeptide of unknown structure when only the amplitudes are known. X-PLOR is a commonly utilized computer software package used for molecular replacement. Brunger (1992) Nature 355: 472-475. AMORE is another program used for molecular replacement. Navaza (1994) Acta Crystallogr. A50: 157-163. Preferably, the resulting structure does not exhibit a root-mean-square deviation of more than 3 Å.

A goal of molecular replacement is to align the positions of atoms in the unit cell by matching electron diffraction data from two crystals. A program such as X-PLOR can involve four steps. A first step can be to determine the number of molecules in the unit cell and define the angles between them. A second step can involve rotating the diffraction data to define the orientation of the molecules in the unit cell. A third step can be to translate the electron density in three dimensions to correctly position the molecules in the unit cell. Once the amplitudes and phases of the X-ray diffraction data is determined, an R-factor can be calculated by comparing electron diffraction maps calculated experimentally from the reference data set and calculated from the new data set. An R-factor between 30-50% indicates that the orientations of the atoms in the unit cell are reasonably determined by this method. A fourth step in the process can be to decrease the R-factor to roughly 20% by refining the new electron density map using iterative refinement techniques described herein and known to those or ordinary skill in the art.

Structures Using NMR Data

Structural coordinates of a polypeptide or polypeptide complex derived from X-ray crystallographic techniques can be applied towards the elucidation of three dimensional structures of polypeptides from nuclear magnetic resonance (NMR) data. This method is used by those skilled in the art. (Wuthrich, (1986), John Wiley and Sons, New York: 176-199; Pflugrath et al. (1986) J. Mol. Biol. 189: 383-386; Kline et al. (1986) J. Mol. Biol. 189: 377-382). While the secondary structure of a polypeptide is often readily determined by utilizing two-dimensional NMR data, the spatial connections between individual pieces of secondary structure are not as readily determinable. The coordinates defining a three-dimensional structure of a polypeptide derived from X-ray crystallographic techniques can guide the NMR spectroscopist to an understanding of these spatial interactions between secondary structural elements in a polypeptide of related structure.

The knowledge of spatial interactions between secondary structural elements can greatly simplify Nuclear Overhauser Effect (NOE) data from two-dimensional NMR experiments. Additionally, applying the crystallographic coordinates after the determination of secondary structure by NMR techniques only simplifies the assignment of NOEs relating to particular amino acids in the polypeptide sequence and does not greatly bias the NMR analysis of polypeptide structure. Conversely, using the crystallographic coordinates to simplify NOE data while determining secondary structure of the polypeptide would bias the NMR analysis of protein structure.

VIII. Structure-Based Design of Modulators of Kinase Function Utilizing Structural Coordinates

Structure-based modulator design and identification methods are powerful techniques that can involve searches of computer databases containing a wide variety of potential modulators and chemical functional groups. The computerized design and identification of modulators is useful as the computer databases contain more compounds than the chemical libraries, often by an order of magnitude. For reviews of structure-based drug design and identification (see Kuntz et al. (1994), Acc. Chem. Res. 27: 117; Guida (1994) Current Opinion in Struc. Biol. 4: 777; Colman (1994) Current Opinion in Struc. Biol. 4: 868).

The three dimensional structure of a polypeptide defined by structural coordinates can be utilized by these design methods, for example, the structural coordinates of Table 1. In addition, the three dimensional structures of kinases determined by the homology, molecular replacement, and NMR techniques described herein can also be applied to modulator design and identification methods.

For identifying modulators, structural information for a native kinase, in particular, structural information for the active site of the kinase, can be used. However, it may be advantageous to utilize structural information from one or more co-crystals of the kinase with one or more binding compounds. It can also be advantageous if the binding compound has a structural core in common with test compounds.

Design by Searching Molecular Data Bases

One method of rational design searches for modulators by docking the computer representations of compounds from a database of molecules. Publicly available databases include, for example:

- a) ACD from Molecular Designs Limited
- b) NCI from National Cancer Institute
- c) CCDC from Cambridge Crystallographic Data Center
- d) CAST from Chemical Abstract Service
- e) Derwent from Derwent Information Limited
- f) Maybridge from Maybridge Chemical Company LTD
- g) Aldrich from Aldrich Chemical Company
- h) Directory of Natural Products from Chapman & Hall

One such data base (ACD distributed by Molecular Designs Limited Information Systems) contains compounds that are synthetically derived or are natural products. Methods available to those skilled in the art can convert a data set represented in two dimensions to one represented in three dimensions. These methods are enabled by such computer programs as CONCORD from Tripos Associates or DE-Converter from Molecular Simulations Limited.

Multiple methods of structure-based modulator design are known to those in the art. (Kuntz et al., (1982), J. Mol. Biol. 162: 269; Kuntz et al., (1994), Acc. Chem. Res. 27: 117; Meng et al., (1992), J Compt. Chem. 13: 505; Bohm, (1994), J. Comp. Aided Molec. Design 8: 623).

A computer program widely utilized by those skilled in the art of rational modulator design is DOCK from the University of California in San Francisco. The general methods utilized by this computer program and programs like it are described in three applications below. More detailed information regarding some of these techniques can be found in the Accelerys User Guide, 1995. A typical computer program used for this purpose can comprise the following steps:

- (a) remove the existing compound from the protein;
- (b) dock the structure of another compound into the active-site using the computer program (such as DOCK) or by interactively moving the compound into the active-site;
- (c) characterize the space between the compound and the active-site atoms;
- (d) search libraries for molecular fragments which (i) can fit into the empty space between the compound and the active-site, and (ii) can be linked to the compound; and
- (e) link the fragments found above to the compound and evaluate the new modified compound.

Part (c) refers to characterizing the geometry and the complementary interactions formed between the atoms of the active site and the compounds. A favorable geometric fit is attained when a significant surface area is shared between the compound and active-site atoms without forming unfavorable steric interactions. One skilled in the art would note that the method can be performed by skipping parts (d) and (e) and screening a database of many compounds.

Structure-based design and identification of modulators of kinase function can be used in conjunction with assay screening. As large computer databases of compounds (around 10,000 compounds) can be searched in a matter of hours, the computer-based method can narrow the compounds tested as potential modulators of kinase function in biochemical or cellular assays.

The above descriptions of structure-based modulator design are not all encompassing and other methods are reported in the literature:

(1) CAVEAT: Bartlett et al., (1989), in Chemical and Biological Problems in Molecular Recognition, Roberts, S. M.; Ley, S. V.; Campbell, M. M. eds.; Royal Society of Chemistry: Cambridge, pp 182-196.
(2) FLOG: Miller et al., (1994), J. Comp. Aided Molec. Design 8: 153.
(3) PRO Modulator: Clark et al., (1995), J. Comp. Aided Molec. Design 9: 13.
(4) MCSS: Miranker and Karplus, (1991), Proteins: Structure, Function, and Genetics 11: 29.
(5) AUTODOCK: Goodsell and Olson, (1990), Proteins. Structure, Function, and Genetics 80.195.
(6) GRID: Goodford, (1985), J. Med. Chem. 28: 849.

Design by Modifying Compounds in Complex with a Kinase

Another way of identifying compounds as potential modulators is to modify an existing modulator in the polypeptide active site. For example, the computer representation of modulators can be modified within the computer representation of a PIM-1 or other PIM kinase active site. Detailed instructions for this technique can be found in the Accelerys User Manual, 1995 in LUDI. The computer representation of the modulator is typically modified by the deletion of a chemical group or groups or by the addition of a chemical group or groups.

Upon each modification to the compound, the atoms of the modified compound and active site can be shifted in conformation and the distance between the modulator and the active-site atoms may be scored along with any complementary interactions formed between the two molecules. Scoring can be complete when a favorable geometric fit and favorable complementary interactions are attained. Compounds that have favorable scores are potential modulators.

Design by Modifying the Structure of Compounds that Bind a Kinase

A third method of structure-based modulator design is to screen compounds designed by a modulator building or modulator searching computer program. Examples of these types of programs can be found in the Molecular Simulations Package, Catalyst. Descriptions for using this program are documented in the Molecular Simulations User Guide (1995). Other computer programs used in this application are ISIS/HOST, ISIS/BASE, ISIS/DRAW) from Molecular Designs Limited and UNITY from Tripos Associates.

These programs can be operated on the structure of a compound that has been removed from the active site of the three dimensional structure of a compound-kinase complex. Operating the program on such a compound is preferable since it is in a biologically active conformation.

A modulator construction computer program is a computer program that may be used to replace computer representations of chemical groups in a compound complexed with a kinase or other biomolecule with groups from a computer database. A modulator searching computer program is a computer program that may be used to search computer representations of compounds from a computer data base that have similar three dimensional structures and similar chemical groups as compound bound to a particular biomolecule.

A typical program can operate by using the following general steps:

- (a) map the compounds by chemical features such as by hydrogen bond donors or acceptors, hydrophobic/lipophilic sites, positively ionizable sites, or negatively ionizable sites;
- (b) add geometric constraints to the mapped features; and
- (c) search databases with the model generated in (b).

Those skilled in the art also recognize that not all of the possible chemical features of the compound need be present in the model of (b). One can use any subset of the model to generate different models for data base searches.

Modulator Design Using Molecular Scaffolds

The present invention can also advantageously utilize methods for designing compounds, designated as molecular scaffolds, that can act broadly across families of molecules and for using the molecular scaffold to design ligands that target individual or multiple members of those families. In preferred embodiments, the molecules can be proteins and a set of chemical compounds can be assembled that have properties such that they are 1) chemically designed to act on certain protein families and/or 2) behave more like molecular scaffolds, meaning that they have chemical substructures that make them specific for binding to one or more proteins in a family of interest. Alternatively, molecular scaffolds can be designed that are preferentially active on an individual target molecule.

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 50 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.

By “clog P” is meant the calculated log P of a compound, “P” referring to the partition coefficient between octanol and water.

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.

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.

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.

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 preferentially target individual members of a molecular family based on the same molecular scaffold, and act on them in a specific manner.

Binding Assays

The methods of the present invention can 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 described herein 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.

By binding with “low affinity” is meant binding to the target molecule with a dissociation constant (k_d) of greater than 1 μM under standard conditions. By binding with “very low affinity” is meant binding with a k_dof above about 100 μM under standard conditions. By binding with “extremely low affinity” is meant binding at a k_dof above about 1 mM under standard conditions. By “moderate affinity” is meant binding with a k_dof from about 200 nM to about 1 μM under standard conditions. By “moderately high affinity” is meant binding at a k_dof from about 1 nM to about 200 nM. By binding at “high affinity” is meant binding at a k_dof 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 ug/well, 37° C. for one hour.

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 IC₅₀or EC₅₀of above 100 μM under standard conditions. By “extremely low activity” is meant an IC₅₀or EC₅₀of above 1 mM under standard conditions. By “moderate activity” is meant an IC₅₀or EC₅₀of 200 nM to 1 μM under standard conditions. By “moderately high activity” is meant an IC₅₀or EC₅₀of 1 μM to 200 nM. By “high activity” is meant an IC₅₀or EC₅₀of 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.

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.

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

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.

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 general, 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.

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.

Surface Plasmon Resonance

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., (2000) BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121: 313-21; Liparoto et al., (1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12: 316-21; Lipschultz et al., (2000) Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. 20(3): 310-8; Malmqvist., (1999) BIACORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27: 335-40; Alfthan, (1998) Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics. 13: 653-63; Fivash et al., (1998) BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9: 97-101; Price et al.; (1998) Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumour Biology 19 Suppl 1: 1-20; Malmqvist et al, (1997) Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. 1: 378-83; O'Shannessy et al., (1996) Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236: 275-83; Malmborg et al., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods. 183: 7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83: 143-51; and O'Shannessy, (1994) 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.

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.

High Throughput Screening (HTS) Assays

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.

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.

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.

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 sphingolipid target are sought, known ligands of the target can be present in control/calibration assay wells.

Measuring Enzymatic and Binding Reactions During Screening Assays

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.

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., (1972) The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, N.Y., Page 437.

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., (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd.; and Bell, (1981) Spectroscopy In Biochemistr, Vol. I, pp. 155-194, CRC Press.

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.

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.

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., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17: 27.

FP is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., (1995) Nature 375: 254-256; Dandliker, W. B., et al., (1981) Methods in Enzymology 74: 3-28) 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., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays, J Biomol Screen 5: 77-88.

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 fluorophores. 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.

Exemplary normal-and-polarized fluorescence readers include the POLARION® fluorescence polarization system (Tecan A G, 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).

Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Heim et al., (1996) Curr. Biol. 6: 178-182; Mitra et al., (1996) Gene 173: 13-17; and Selvin et al., (1995) Meth. Enzymol. 246: 300-345. 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.).

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., (1997) J. Lipid Res. 38: 2365-2373; Kahl et al., (1996) Anal. Biochem. 243: 282-283; Undenfriend et al., (1987) Anal. Biochem. 161: 494-500). 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.).

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.

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.

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., (1998) Anal. Biochem. 257: 112-119).

Assay Compounds and Molecular Scaffolds

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 5. Guidance that can be useful in identifying criteria for a particular application can be found in Lipinski et al., (1997) Advanced Drug Delivery Reviews 23 3-25, which is hereby incorporated by reference in its entirety.

A scaffold may 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.

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.

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. Examples of libraries are provided above.

Libraries of the present invention can contain at least one compound than 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.

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.

Compound libraries of 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., (1990) Biochemistry, 87, 6378-6382; Houghten et al., (1991) Nature, 354, 84-86; Lam et al., (1991) Nature, 354, 82-84; Brenner et al., (1992) Proc. Natl. Acad. Sci. USA, 89, 5381-5383; R. A. Houghten, (1993) Trends Genet., 9, 235-239; E. R. Felder, (1994) Chimia, 48, 512-541; Gallop et al., (1994) J. Med. Chem., 37, 1233-1251; Gordon et al., (1994) J. Med Chem., 37, 1385-1401; Carell et al., (1995) Chem. Biol., 3, 171-183; Madden et al., Perspectives in Drug Discovery and Design 2, 269-282; Lebl et al., (1995) Biopolymers, 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, fingi, bacteria, and plants.

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 C M., (1999) Recent advances in liquid-phase combinatorial chemistry, Combinatorial Chemistry & High Throughput Screening. 2: 299-318).

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, (2000) Annu Rev Pharmacol Toxicol 40: 273-82, Parallel array and mixture-based synthetic combinatorial chemistry; solution-phase combinatorial chemistry (Merritt, (1998) Comb Chem High Throughput Screen 1(2): 57-72, Solution phase combinatorial chemistry, Coe et al., (1998-99) Mol Divers; 4(1): 31-8, Solution-phase combinatorial chemistry, Sun, (1999) Comb Chem High Throughput Screen 2(6): 299-318, Recent advances in liquid-phase combinatorial chemistry); synthesis on soluble polymer (Gravert et al., (1997) Curr Opin Chem Biol 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., (1999) J Comb Chem 1(4): 235-82, Comprehensive survey of combinatorial library synthesis: 1998. Freidinger R M., (1999) Nonpeptidic ligands for peptide and protein receptors, Current Opinion in Chemical Biology; and Kundu et al., Prog Drug Res; 53: 89-156, Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries). Compounds may be clinically tagged for ease of identification (Chabala, (1995) Curr Opin Biotechnol 6(6): 633-9, Solid-phase combinatorial chemistry and novel tagging methods for identifying leads).

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

Libraries of nucleic acids are prepared by various techniques, including by way of non-limiting example the ones described herein, for the isolation of aptamers. Libraries that include oligonucleotides and polyaminooligonucleotides (Markiewicz et al., (2000) Synthetic oligonucleotide combinatorial libraries and their applications, Farmaco. 55: 174-7) 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, (2000) Mass spectrometry in combinatorial chemistry, Mass Spectrometry Reviews. 19: 139-61) 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).

Peptidomimetics are identified using combinatorial chemistry and solid phase synthesis (Kim H O. Kahn M., (2000) 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; al-Obeidi, (1998) Mol Biotechnol 9(3): 205-23, Peptide and peptidomimetic libraries. Molecular diversity and drug design). The synthesis may be entirely random or based in part on a known polypeptide.

Polypeptide libraries can be prepared according to various techniques. In brief, phage display techniques can be used to produce polypeptide ligands (Gram H., (1999) Phage display in proteolysis and signal transduction, Combinatorial Chemistry & High Throughput Screening. 2: 19-28) 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.

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., (2000) 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; Poul M A. Becerril B. Nielsen U B. Morisson P. Marks J D., (2000) Selection of tumor-specific internalizing human antibodies from phage libraries. Source Journal of Molecular Biology. 301: 1149-61; Amersdorfer P. Marks J D., (2001) Phage libraries for generation of anti-botulinum scFv antibodies, Methods in Molecular Biology. 145: 219-40; Hughes-Jones N C. Bye J M. Gorick B D. Marks J D. Ouwehand W H., (1999) Synthesis of Rh Fv phage-antibodies using VH and VL germline genes, British Journal of Haematology. 105: 811-6; McCall A M. Amoroso A R. Sautes C. Marks J D. Weiner L M., (1998) Characterization of anti-mouse Fc gamma RII single-chain Fv fragments derived from human phage display libraries, Immunotechnology. 4: 71-87; 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., (1998) 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 Acad Sci USA 95: 6157-62).

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., (1999) Combinatorial chemistry: polymer supported synthesis of peptide and non-peptide libraries, Progress in Drug Research 53: 89-156) 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., (1999) Computational approaches to structure-based ligand design, Pharmacology & Therapeutics 84: 179-91; Kirkpatrick D L. Watson S. Ulhaq S., (1999) Structure-based drug design: combinatorial chemistry and molecular modeling, Combinatorial Chemistry & High Throughput Screening. 2: 211-21; Eliseev A V. Lehn J M., (1999) Dynamic combinatorial chemistry: evolutionary formation and screening of molecular libraries, Current Topics in Microbiology & Immunology 243: 159-72; Bolger et al., (1991) Methods Enz. 203: 21-45; Martin, (1991) Methods Enz. 203: 587-613; Neidle et al., (1991) Methods Enz. 203: 433-458; U.S. Pat. No. 6,178,384).

Crystallography

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. 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., 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.

The co-crystallography analysis can be performed by co-complexing each scaffold with its target at concentrations of the scaffold that showed activity in the screening assay. This co-complexing can 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. Each scaffold complexed to the target molecule can then be screened with a suitable number of crystallization screening conditions at 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.

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 might 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. This process allows 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.

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.

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

Virtual Assays

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., QUANTA®, Accelerys, San Diego, Calif.). 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.

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, 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 Free Energy Perturbations (FEP), to account for other energetic effects such as desolvation penalties. 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.

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. 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.

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.

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.

The crystallization experiment can be set-up by placing small aliquots of the concentrated protein-compound complex (1 μl) in a 96 well format and sampling under 96 crystallization conditions. (Other screening formats can also be used, e.g., plates with greater than 96 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.

Ligand Design and Preparation

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.

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.

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.

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.

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, carboxamide, nitro, and ester moieties; an amine of formula —NX₂X₃, where X₂and X₃are 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 X₄is 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 X₇and 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 X₈and X₉are 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 X₁₀is 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, NX₁₁X₁₂, where X₁₁and X₁₂are 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, carboxamide, nitro, and ester moieties; an aldehyde of formula —CHO; a sulfone of formula —SO₂X₁₃, where X₁₃is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring moieties; and a nitro of formula —NO₂.

Identification of Attachment Sites on Molecular Scaffolds and Ligands

In addition to the identification and development of ligands for kinases and other enzymes, 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 kinase 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.

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.

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.

The binding energy of a compound and the effects on binding energy for attaching the molecule to another component can be calculated approximately using any of a variety of available software or by manual calculation. An example is the following:

Calculations were performed to estimate binding energies of different organic molecules to two Kinases: Pim-1 and CDK2. The organic molecules considered included Staurosporine, identified compounds that bind to PIM-1, and several linkers.

Calculated binding energies between protein-ligand complexes were obtained using the FlexX score (an implementation of the Bohm scoring function) within the Tripos software suite. The form for that equation is shown in Eqn. 1 below:

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

- where: ΔGtr is a constant term that accounts for the overall loss of rotational and translational entropy of the ligand, 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.

This method estimates the free energy 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 free energy penalty incurred by attaching linkers to molecules being screened and the binding energy that a lead compound should have in order to overcome the free energy penalty of the linker. The method does not account for solvation and the entropic penalty is likely overestimated for cases where the linker is bound to a solid phase through another binding complex, such as a biotin:streptavidin complex.

Co-crystals were aligned by superimposing residues of PIM-1 with corresponding residues in CDK2. The PIM-1 structure used for these calculations was a co-crystal of PIM-1 with a binding compound. The CDK2: Staurosporine co-crystal used was from the Brookhaven database file 1aq1. Hydrogen atoms were added to the proteins and atomic charges were assigned using the AMBER95 parameters within Sybyl. Modifications to the compounds described were made within the Sybyl modeling suite from Tripos.

These calculations indicate that the calculated binding energy for compounds that bind strongly to a given target (such as Staurosporine:CDK2) can be lower than −25 kcal/mol, while the calculated binding affinity for a good scaffold or an unoptimized binding compound can be in the range of −15 to −20. The free energy penalty for attachment to a linker such as the ethylene glycol or hexatriene is estimated as typically being in the range of +5 to +15 kcal/mol.

Linkers

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.

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; (1998) Tetrahedron organic chemistry series Vol. 17; Pergamon; p 85).

Labels

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).

Solid Phase Media

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.

Identification of Biological Agents

The possession of structural information about a protein also provides for the identification of useful biological agents, such as epitopes for development of antibodies, identification of mutation sites expected to affect activity, and identification of attachment sites allowing attachment of the protein to materials such as labels, linkers, peptides, and solid phase media.

Antibodies (Abs) finds multiple applications in a variety of areas including biotechnology, medicine and diagnosis, and indeed they are one of the most powerful tools for life science research. Abs directed against protein antigens can recognize either linear or native three-dimensional (3D) epitopes. The obtention of Abs that recognize 3D epitopes require the use of whole native protein (or of a portion that assumes a native conformation) as immunogens. Unfortunately, this not always a choice due to various technical reasons: for example the native protein is just not available, the protein is toxic, or its is desirable to utilize a high density antigen presentation. In such cases, immunization with peptides is the alternative. Of course, Abs generated in this manner will recognize linear epitopes, and they might or might not recognize the source native protein, but yet they will be useful for standard laboratory applications such as western blots. The selection of peptides to use as immunogens can be accomplished by following particular selection rules and/or use of epitope prediction software.

Though methods to predict antigenic peptides are not infallible, there are several rules that can be followed to determine what peptide fragments from a protein are likely to be antigenic. These rules are also dictated to increase the likelihood that an Ab to a particular peptide will recognize the native protein.

- 1. Antigenic peptides should be located in solvent accessible regions and contain both hydrophobic and hydrophilic residues.
  - For proteins of known 3D structure, solvent accessibility can be determined using a variety of programs such as DSSP, NACESS, or WHATIF, among others.
  - If the 3D structure is not known, use any of the following web servers to predict accessibilities: PHD, JPRED, PredAcc (c) ACCpro
- 2. Preferably select peptides lying in long loops connecting Secondary Structure (SS) motifs, avoiding peptides located in helical regions. This will increase the odds that the Ab recognizes the native protein. Such peptides can, for example, be identified from a crystal structure or crystal structure-based homology model.
  - For protein with known 3D coordinates, SS can be obtained from the sequence link of the relevant entry at the Brookhaven data bank. The PDBsum server also offer SS analysis of pdb records.
  - When no structure is available secondary structure predictions can be obtained from any of the following servers: PHD, JPRED, PSI-PRED, NNSP, etc
- 3. When possible, choose peptides that are in the N- and C-terminal region of the protein. Because the N- and C-terminal regions of proteins are usually solvent accessible and unstructured, Abs against those regions are also likely to recognize the native protein.
- 4. For cell surface glycoproteins, eliminate from initial peptides those containing consensus sites for N-glycosilation.
  - N-glycosilation sites can be detected using Scanprosite, or NetNGlyc

In addition, several methods based on various physio-chemical properties of experimental determined epitopes (flexibility, hydrophibility, accessibility) have been published for the prediction of antigenic determinants and can be used. The antizenic index and Preditop are example.

Perhaps the simplest method for the prediction of antigenic determinants is that of Kolaskar and Tongaonkar, which is based on the occurrence of amino acid residues in experimentally determined epitopes. (Kolaskar and Tongaonkar (1990) A semi-empirical method for prediction of antigenic determinants on protein antigens. FEBBS Lett. 276(1-2): 172-174.) The prediction algorithm works as follows:

- 1. Calculate the average propensity for each overlapping 7-mer and assign the result to the central residue (i+3) of the 7-mer.
- 2. Calculate the average for the whole protein.
- 3. (a) If the average for the whole protein is above 1.0 then all residues having average propensity above 1.0 are potentially antigenic.
- 3. (b) If the average for the whole protein is below 1.0 then all residues having above the average for the whole protein are potentially antigenic.
- 4. Find 8-mers where all residues are selected by step 3 above (6-mers in the original paper)

The Kolaskar and Tongaonkar method is also available from the GCG package, and it runs using the command egcg.

Crystal structures also allow identification of residues at which mutation is likely to alter the activity of the protein. Such residues include, for example, residues that interact with substrate, conserved active site residues, and residues that are in a region of ordered secondary structure of involved in tertiary interactions. The mutations that are likely to affect activity will vary for different molecular contexts. Mutations in an active site that will affect activity are typically substitutions or deletions that eliminate a charge-charge or hydrogen bonding interaction, or introduce a steric interference. Mutations in secondary structure regions or molecular interaction regions that are likely to affect activity include, for example, substitutions that alter the hydrophobicity/hydrophilicity of a region, or that introduce a sufficient strain in a region near or including the active site so that critical residue(s) in the active site are displaced. Such substitutions and/or deletions and/or insertions are recognized, and the predicted structural and/or energetic effects of mutations can be calculated using conventional software.

IX. Kinase Activity Assays

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.

An assay for kinase activity that can be used for 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: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.

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-EL/well in kinase buffer. Add compounds at 1 EL/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).

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

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.

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.

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 luminescent proximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.

X. Organic Synthetic Techniques

The versatility of computer-based modulator design and identification lies in the diversity of structures screened by the computer programs. The computer programs can search databases that contain very large numbers of molecules and can modify modulators already complexed with the enzyme with a wide variety of chemical functional groups. A consequence of this chemical diversity is that a potential modulator of kinase function may take a chemical form that is not predictable. A wide array of organic synthetic techniques exist in the art to meet the challenge of constructing these potential modulators. Many of these organic synthetic methods are described in detail in standard reference sources utilized by those skilled in the art. One example of such a reference is March, 1994, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, New York, McGraw Hill. Thus, the techniques useful to synthesize a potential modulator of kinase function identified by computer-based methods are readily available to those skilled in the art of organic chemical synthesis.

XI. Isomers, Prodrugs, and Active Metabolites

The present compounds are described herein with generic formulas and specific compounds. In addition, the present compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. These include, for example, tautomers, enantiomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g., carboxylic acid esters), solvated forms, different crystal forms or polymorphs, and active metabolites.

A. Tautomers, Stereoisomers, Regioisomers, and Solvated Forms

It is understood that certain compounds may exhibit tautomerism. In such cases, the formula drawings within this specification expressly depict only one of the possible tautomeric forms. It is therefore to be understood that within the invention the formulas are intended to represent any tautomeric form of the depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the formula drawings.

Likewise, some of the present compounds may contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms. Thus, such compounds may be present as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms are included within the formulas provided herein.

In certain embodiments, a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70% e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understood by those skilled in the art, an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. In certain embodiments, the compound is present in optically pure form.

For compounds is which synthesis involves addition of a single group at a double bond, particularly a carbon-carbon double bond, the addition may occur at either of the double bond-linked atoms. For such compounds, the present invention includes both such regioisomers.

Additionally, the formulas are intended to cover solvated as well as unsolvated forms of the identified structures. For example, the indicated structures include both both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

B. Prodrugs and Metabolites

In addition to the present formulas and compounds described herein, the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts.

In this context, prodrugs are compounds that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such a compound. A common example is an alkyl ester of a carboxylic acid.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the follow types:

Oxidative reactions, such as oxidation of alcohol, carbonyl, and acid functions, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-delakylation, oxidative Q- and S-delakylation, oxidative deamination, as well as other oxidative reactions.

Reductive reactions, such as reduction of carbonyl groups, reduction of alcoholic groups and carbon-carbon double bonds, reduction of nitrogen-containing functions groups, and other reduction reactions.

Reactions without change in the state of oxidation, such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improves uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety in intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. (See, e.g., Cheng et al., U.S. Patent publ. 20040077595, application Ser. No. 10/656,838, incorporated herein by reference.) Such carrier prodrugs are often advantageous for orally administered drugs. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols. Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Ed. Wermuth, Academic Press, San Diego, Calif., 2001.

Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive.

Metabolites, e.g., active metabolites overlap with prodrugs as described above, e.g., bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject or patient. Of these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, the prodrug compounds is generally inactive or of lower activity than the metabolic product. For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug.

Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, Drug Dev Res 34: 220-230; Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Academic Press, San Diego, Calif., 2001.

C. Pharmaceutically Acceptable Salts

Compounds can be formulated as or be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19^thed., Mack Publishing Co., Easton, Pa., Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound is dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol in solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt is prepared by reacting the free base and acid in an organic solvent.

Thus, for example, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes.

Unless specified to the contrary, specification of a compound herein includes pharmaceutically acceptable salts of such compound.

D. Polymorphic Forms

In the case of agents that are solids, it is understood by those skilled in the art that the compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

XII. Administration

The methods and compounds will typically be used in therapy for human patients. However, they may also be used to treat similar or identical diseases in other vertebrates such as other primates, sports animals, and pets such as horses, dogs and cats.

Suitable dosage forms, in part, depend upon the use or the route of administration, for example, oral, transdermal, transmucosal, or by injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, 18^thed., Mack Publishing Co., Easton, Pa., 1990 (hereby incorporated by reference herein).

Carriers or excipients can be used to produce pharmaceutical compositions. The carriers or excipients can be chosen to facilitate administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. Examples of physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose.

The compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, or transdermal. Oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.

Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. For injection, the compounds of the invention are formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal).

The amounts of various compound to be administered can be determined by standard procedures taking into account factors such as the compound IC₅₀, the biological half-life of the compound, the age, size, and weight of the patient, and the disorder associated with the patient. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be between about 0.01 and 50 mg/kg, preferably 0.1 and 20 mg/kg of the patient being treated. Multiple doses may be used.

XIII. Manipulation of Kinase Coding Sequences

Through the availability of the coding sequences for many different kinases, any of a variety of different molecular techniques can be performed as desired, e.g., cloning, construction of recombinant sequences, production and purification of recombinant protein, introduction of particular kinase sequences into other organisms, and the like.

Techniques for the manipulation of nucleic acids, such as, e.g., subcloning, labeling probes (e.g., random-primer labeling using Klenow polymerase, nick translation, amplification), sequencing, hybridization and the like are well disclosed in the scientific and patent literature, see, e.g., Sambrook, ed., Molecular Cloning: a Laboratory Manual (2nd ed.), Vols. 1-3, Cold Spring Harbor Laboratory, (1989); Current Protocols in Molecular Biology, Ausubel, ed. John Wiley & Sons, Inc., New York (1997); Laboratory Techniques in Biochemistry and Molecular Biology: Hybridization With Nucleic Acid Probes, Part I. Theory and Nucleic Acid Preparation, Tijssen, ed. Elsevier, N.Y. (1993). Nucleic acid sequences can be amplified as necessary for further use using amplification methods, such as PCR, isothermal methods, rolling circle methods, etc., are well known to the skilled artisan. See, e.g., Saiki, “Amplification of Genomic DNA” in PCR Protocols, Innis et al., Eds., Academic Press, San Diego, Calif. 1990, pp 13-20; Wharam et al., Nucleic Acids Res. 2001 Jun. 1; 29(11): E54-E54; Hafner et al., Biotechniques 2001 April; 30(4): 852-6, 858, 860 passim; Zhong et al., Biotechniques 2001 April; 30(4): 852-6, 858, 860 passim.

Nucleic acids, vectors, capsids, polypeptides, and the like can be analyzed and quantified by any of a number of general means well known to those of skill in the art. These include, e.g., analytical biochemical methods such as NMR, spectrophotometry, radiography, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and hyperdiffusion chromatography, various immunological methods, e.g. fluid or gel precipitin reactions, immunodiffusion, immuno-electrophoresis, radioimmunoassays (RIAs), enzyme-linked immunosorbent assays (ELISAs), immuno-fluorescent assays, Southern analysis, Northern analysis, dot-blot analysis, gel electrophoresis (e.g., SDS-PAGE), nucleic acid or target or signal amplification methods, radiolabeling, scintillation counting, and affinity chromatography.

Obtaining and manipulating nucleic acids used to practice the methods of the invention can be performed by cloning from genomic samples, and, if desired, screening and re-cloning inserts isolated or amplified from, e.g., genomic clones or cDNA clones. Sources of nucleic acid used in the methods of the invention include genomic or cDNA libraries contained in, e.g., mammalian artificial chromosomes (MACs), see, e.g., U.S. Pat. Nos. 5,721,118; 6,025,155; human artificial chromosomes, see, e.g., Rosenfeld (1997) Nat. Genet. 15: 333-335; yeast artificial chromosomes (YAC); bacterial artificial chromosomes (BAC); P1 artificial chromosomes, see, e.g., Woon (1998) Genomics 50: 306-316; P1-derived vectors (PACs), see, e.g., Kern (1997) Biotechniques 23: 120-124; cosmids, recombinant viruses, phages or plasmids.

The nucleic acids of the invention can be operatively linked to a promoter. A promoter can be one motif or an array of nucleic acid control sequences which direct transcription of a nucleic acid. A promoter can include necessary nucleic acid sequences near the start site of transcription, such as, in the case of a polymerase II type promoter, a TATA element. A promoter also optionally includes distal enhancer or repressor elements which can be located as much as several thousand base pairs from the start site of transcription. A “constitutive” promoter is a promoter which is active under most environmental and developmental conditions. An “inducible” promoter is a promoter which is under environmental or developmental regulation. A “tissue specific” promoter is active in certain tissue types of an organism, but not in other tissue types from the same organism. The term “operably linked” refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter, or array of transcription factor binding sites) and a second nucleic acid sequence, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence.

The nucleic acids of the invention can also be provided in expression vectors and cloning vehicles, e.g., sequences encoding the polypeptides of the invention. Expression vectors and cloning vehicles of the invention can comprise viral particles, baculovirus, phage, plasmids, phagemids, cosmids, fosmids, bacterial artificial chromosomes, viral DNA (e.g., vaccinia, adenovirus, foul pox virus, pseudorabies and derivatives of SV40), P1-based artificial chromosomes, yeast plasmids, yeast artificial chromosomes, and any other vectors specific for specific hosts of interest (such as bacillus, Aspergillus and yeast). Vectors of the invention can include chromosomal, non-chromosomal and synthetic DNA sequences. Large numbers of suitable vectors are known to those of skill in the art, and are commercially available.

The nucleic acids of the invention can be cloned, if desired, into any of a variety of vectors using routine molecular biological methods; methods for cloning in vitro amplified nucleic acids are disclosed, e.g., U.S. Pat. No. 5,426,039. To facilitate cloning of amplified sequences, restriction enzyme sites can be “built into” a PCR primer pair. Vectors may be introduced into a genome or into the cytoplasm or a nucleus of a cell and expressed by a variety of conventional techniques, well described in the scientific and patent literature. See, e.g., Roberts (1987) Nature 328: 731; Schneider (1995) Protein Expr. Purif 6435: 10; Sambrook, Tijssen or Ausubel. The vectors can be isolated from natural sources, obtained from such sources as ATCC or GenBank libraries, or prepared by synthetic or recombinant methods. For example, the nucleic acids of the invention can be expressed in expression cassettes, vectors or viruses which are stably or transiently expressed in cells (e.g., episomal expression systems). Selection markers can be incorporated into expression cassettes and vectors to confer a selectable phenotype on transformed cells and sequences. For example, selection markers can code for episomal maintenance and replication such that integration into the host genome is not required.

In one aspect, the nucleic acids of the invention are administered in vivo for in situ expression of the peptides or polypeptides of the invention. The nucleic acids can be administered as “naked DNA” (see, e.g., U.S. Pat. No. 5,580,859) or in the form of an expression vector, e.g., a recombinant virus. The nucleic acids can be administered by any route, including peri- or intra-tumorally, as described below. Vectors administered in vivo can be derived from viral genomes, including recombinantly modified enveloped or non-enveloped DNA and RNA viruses, preferably selected from baculoviridiae, parvoviridiae, picornoviridiae, herpesveridiae, poxyiridae, adenoviridiae, or picornnaviridiae. Chimeric vectors may also be employed which exploit advantageous merits of each of the parent vector properties (See e.g., Feng (1997) Nature Biotechnology 15: 866-870). Such viral genomes may be modified by recombinant DNA techniques to include the nucleic acids of the invention; and may be further engineered to be replication deficient, conditionally replicating or replication competent. In alternative aspects, vectors are derived from the adenoviral (e.g., replication incompetent vectors derived from the human adenovirus genome, see, e.g., U.S. Pat. Nos. 6,096,718; 6,110,458; 6,113,913; 5,631,236); adeno-associated viral and retroviral genomes. Retroviral vectors can include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof; see, e.g., U.S. Pat. Nos. 6,117,681; 6,107,478; 5,658,775; 5,449,614; Buchscher (1992) J. Virol. 66: 2731-2739; Johann (1992) J. Virol. 66: 1635-1640). Adeno-associated virus (AAV)-based vectors can be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and in in vivo and ex vivo gene therapy procedures; see, e.g., U.S. Pat. Nos. 6,110,456; 5,474,935; Okada (1996) Gene Ther. 3: 957-964.

The present invention also relates to fusion proteins, and nucleic acids encoding them. A polypeptide of the invention can be fused to a heterologous peptide or polypeptide, such as N-terminal identification peptides which impart desired characteristics, such as increased stability or simplified purification. Peptides and polypeptides of the invention can also be synthesized and expressed as fusion proteins with one or more additional domains linked thereto for, e.g., producing a more immunogenic peptide, to more readily isolate a recombinantly synthesized peptide, to identify and isolate antibodies and antibody-expressing B cells, and the like. Detection and purification facilitating domains include, e.g., metal chelating peptides such as polyhistidine tracts and histidine-tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized immunoglobulin, and the domain utilized in the FLAGS extension/affinity purification system (Immunex Corp, Seattle Wash.). The inclusion of a cleavable linker sequences such as Factor Xa or enterokinase (Invitrogen, San Diego Calif.) between a purification domain and the motif-comprising peptide or polypeptide to facilitate purification. For example, an expression vector can include an epitope-encoding nucleic acid sequence linked to six histidine residues followed by a thioredoxin and an enterokinase cleavage site (see e.g., Williams (1995) Biochemistry 34: 1787-1797; Dobeli (1998) Protein Expr. Purif 12: 404-414). The histidine residues facilitate detection and purification while the enterokinase cleavage site provides a means for purifying the epitope from the remainder of the fusion protein. In one aspect, a nucleic acid encoding a polypeptide of the invention is assembled in appropriate phase with a leader sequence capable of directing secretion of the translated polypeptide or fragment thereof. Technology pertaining to vectors encoding fusion proteins and application of fusion proteins are well disclosed in the scientific and patent literature, see e.g., Kroll (1993) DNA Cell. Biol. 12: 441-53.

The nucleic acids and polypeptides of the invention can be bound to a solid support, e.g., for use in screening and diagnostic methods. Solid supports can include, e.g., membranes (e.g., nitrocellulose or nylon), a microtiter dish (e.g., PVC, polypropylene, or polystyrene), a test tube (glass or plastic), a dip stick (e.g., glass, PVC, polypropylene, polystyrene, latex and the like), a microfuge tube, or a glass, silica, plastic, metallic or polymer bead or other substrate such as paper. One solid support uses a metal (e.g., cobalt or nickel)-comprising column which binds with specificity to a histidine tag engineered onto a peptide.

Adhesion of molecules to a solid support can be direct (i.e., the molecule contacts the solid support) or indirect (a “linker” is bound to the support and the molecule of interest binds to this linker). Molecules can be immobilized either covalently (e.g., utilizing single reactive thiol groups of cysteine residues (see, e.g., Colliuod (1993) Bioconjugate Chem. 4: 528-536) or non-covalently but specifically (e.g., via immobilized antibodies (see, e.g., Schuhmann (1991) Adv. Mater. 3: 388-391; Lu (1995) Anal. Chem. 67: 83-87; the biotin/strepavidin system (see, e.g., Iwane (1997) Biophys. Biochem. Res. Comm. 230: 76-80); metal chelating, e.g., Langmuir-Blodgett films (see, e.g., Ng (1995) Langmuir 11: 4048-55); metal-chelating self-assembled monolayers (see, e.g., Sigal (1996) Anal. Chem. 68: 490-497) for binding of polyhistidine fusions.

Indirect binding can be achieved using a variety of linkers which are commercially available. The reactive ends can be any of a variety of functionalities including, but not limited to: amino reacting ends such as N-hydroxysuccinimide (NHS) active esters, imidoesters, aldehydes, epoxides, sulfonyl halides, isocyanate, isothiocyanate, and nitroaryl halides; and thiol reacting ends such as pyridyl disulfides, maleimides, thiophthalimides, and active halogens. The heterobifunctional crosslinking reagents have two different reactive ends, e.g., an amino-reactive end and a thiol-reactive end, while homobifunctional reagents have two similar reactive ends, e.g., bismaleimidohexane (BMH) which permits the cross-linking of sulfhydryl-containing compounds. The spacer can be of varying length and be aliphatic or aromatic. Examples of commercially available homobifunctional cross-linking reagents include, but are not limited to, the imidoesters such as dimethyl adipimidate dihydrochloride (DMA); dimethyl pimelimidate dihydrochloride (DMP); and dimethyl suberimidate dihydrochloride (DMS). Heterobifunctional reagents include commercially available active halogen-NHS active esters coupling agents such as N-succinimidyl bromoacetate and N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB) and the sulfosuccinimidyl derivatives such as sulfosuccinimidyl(4-iodoacetyl)aminobenzoate (sulfo-SIAB) (Pierce). Another group of coupling agents is the heterobifunctional and thiol cleavable agents such as N-succinimidyl 3-(2-pyridyidithio)propionate (SPDP) (Pierce Chemicals, Rockford, Ill.).

Antibodies can also be used for binding polypeptides and peptides of the invention to a solid support. This can be done directly by binding peptide-specific antibodies to the column or it can be done by creating fusion protein chimeras comprising motif-containing peptides linked to, e.g., a known epitope (e.g., a tag (e.g., FLAG, myc) or an appropriate immunoglobulin constant domain sequence (an “immunoadhesin,” see, e.g., Capon (1989) Nature 377: 525-531 (1989).

Nucleic acids or polypeptides of the invention can be immobilized to or applied to an array. Arrays can be used to screen for or monitor libraries of compositions (e.g., small molecules, antibodies, nucleic acids, etc.) for their ability to bind to or modulate the activity of a nucleic acid or a polypeptide of the invention. For example, in one aspect of the invention, a monitored parameter is transcript expression of a gene comprising a nucleic acid of the invention. One or more, or, all the transcripts of a cell can be measured by hybridization of a sample comprising transcripts of the cell, or, nucleic acids representative of or complementary to transcripts of a cell, by hybridization to immobilized nucleic acids on an array, or “biochip.” By using an “array” of nucleic acids on a microchip, some or all of the transcripts of a cell can be simultaneously quantified. Alternatively, arrays comprising genomic nucleic acid can also be used to determine the genotype of a newly engineered strain made by the methods of the invention. Polypeptide arrays” can also be used to simultaneously quantify a plurality of proteins.

The terms “array” or “microarray” or “biochip” or “chip” as used herein is a plurality of target elements, each target element comprising a defined amount of one or more polypeptides (including antibodies) or nucleic acids immobilized onto a defined area of a substrate surface. In practicing the methods of the invention, any known array and/or method of making and using arrays can be incorporated in whole or in part, or variations thereof, as disclosed, for example, in U.S. Pat. Nos. 6,277,628; 6,277,489; 6,261,776; 6,258,606; 6,054,270; 6,048,695; 6,045,996; 6,022,963; 6,013,440; 5,965,452; 5,959,098; 5,856,174; 5,830,645; 5,770,456; 5,632,957; 5,556,752; 5,143,854; 5,807,522; 5,800,992; 5,744,305; 5,700,637; 5,556,752; 5,434,049; see also, e.g., WO 99/51773; WO 99/09217; WO 97/46313; WO 96/17958; see also, e.g., Johnston (1998) Curr. Biol. 8: R171-R174; Schummer (1997) Biotechniques 23: 1087-1092; Kern (1997) Biotechniques 23: 120-124; Solinas-Toldo (1997) Genes, Chromosomes & Cancer 20: 399-407; Bowtell (1999) Nature Genetics Supp. 21: 25-32. See also published U.S. patent applications Nos. 20010018642; 20010019827; 20010016322; 20010014449; 20010014448; 20010012537; 20010008765.

Host Cells and Transformed Cells Comprising Kinase Sequences

As indicated above, availability of kinase coding sequences also allows provision of a transformed cell comprising a kinase nucleic acid sequence, e.g., a sequence encoding a kinase polypeptide, or a vector. The host cell may be any of the host cells familiar to those skilled in the art, including prokaryotic cells, eukaryotic cells, such as bacterial cells, fungal cells, yeast cells, mammalian cells, insect cells, or plant cells. Exemplary bacterial cells include E. coli, Streptomyces, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus. Exemplary insect cells include Drosophila S2 and Spodoptera Sf9. Exemplary animal cells include CHO, COS or Bowes melanoma or any mouse or human cell line. The selection of an appropriate host is within the abilities of those skilled in the art.

Vectors may be introduced into the host cells using any of a variety of techniques, including transformation, transfection, transduction, viral infection, gene guns, or Ti-mediated gene transfer. Particular methods include calcium phosphate transfection, DEAE-Dextran mediated transfection, lipofection, or electroporation.

Engineered host cells can be cultured in conventional nutrient media modified as appropriate for activating promoters, selecting transformants or amplifying the genes of the invention. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter may be induced by appropriate means (e.g., temperature shift or chemical induction) and the cells may be cultured for an additional period to allow them to produce the desired polypeptide or fragment thereof.

Cells can be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract is retained for further purification. Microbial cells employed for expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents. Such methods are well known to those skilled in the art. The expressed polypeptide or fragment can be recovered and purified from recombinant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Protein refolding steps can be used, as necessary, in completing configuration of the polypeptide. If desired, high performance liquid chromatography (HPLC) can be employed for final purification steps.

Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts and other cell lines capable of expressing proteins from a compatible vector, such as the C127, 3T3, CHO, HeLa and BHK cell lines.

The constructs in host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. Depending upon the host employed in a recombinant production procedure, the polypeptides produced by host cells containing the vector may be glycosylated or may be non-glycosylated. Polypeptides of the invention may or may not also include an initial methionine amino acid residue.

Cell-free translation systems can also be employed to produce a polypeptide of the invention. Cell-free translation systems can use mRNAs transcribed from a DNA construct comprising a promoter operably linked to a nucleic acid encoding the polypeptide or fragment thereof. In some aspects, the DNA construct may be linearized prior to conducting an in vitro transcription reaction. The transcribed mRNA is then incubated with an appropriate cell-free translation extract, such as a rabbit reticulocyte extract, to produce the desired polypeptide or fragment thereof.

The expression vectors can contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in E. coli.

For transient expression in mammalian cells, cDNA encoding a polypeptide of interest may be incorporated into a mammalian expression vector, e.g. pcDNA1, which is available commercially from Invitrogen Corporation (San Diego, Calif., U.S.A.; catalogue number V490-20). This is a multifunctional 4.2 kb plasmid vector designed for cDNA expression in eukaryotic systems, and cDNA analysis in prokaryotes, incorporated on the vector are the CMV promoter and enhancer, splice segment and polyadenylation signal, an SV40 and Polyoma virus origin of replication, and M13 origin to rescue single strand DNA for sequencing and mutagenesis, Sp6 and T7 RNA promoters for the production of sense and anti-sense RNA transcripts and a Col E1-like high copy plasmid origin. A polylinker is located appropriately downstream of the CMV promoter (and 3′ of the T7 promoter).

The cDNA insert may be first released from the above phagemid incorporated at appropriate restriction sites in the pcDNAI polylinker. Sequencing across the junctions may be performed to confirm proper insert orientation in pcDNAI. The resulting plasmid may then be introduced for transient expression into a selected mammalian cell host, for example, the monkey-derived, fibroblast like cells of the COS-1 lineage (available from the American Type Culture Collection, Rockville, Md. as ATCC CRL 1650).

For transient expression of the protein-encoding DNA, for example, COS-1 cells may be transfected with approximately 8 μg DNA per 10⁶COS cells, by DEAE-mediated DNA transfection and treated with chloroquine according to the procedures described by Sambrook et al, Molecular Cloning: A Laboratory Manual, 1989, Cold Spring Harbor Laboratory Press, Cold Spring Harbor N.Y, pp. 16.30-16.37. An exemplary method is as follows. Briefly, COS-1 cells are plated at a density of 5×10⁶cells/dish and then grown for 24 hours in FBS-supplemented DMEM/F12 medium. Medium is then removed and cells are washed in PBS and then in medium. A transfection solution containing DEAE dextran (0.4 mg/ml), 100 μM chloroquine, 10% NuSerum, DNA (0.4 mg/ml) in DMEM/F 12 medium is then applied on the cells 10 ml volume. After incubation for 3 hours at 37° C., cells are washed in PBS and medium as just described and then shocked for 1 minute with 10% DMSO in DMEM/F12 medium. Cells are allowed to grow for 2-3 days in 10% FBS-supplemented medium, and at the end of incubation dishes are placed on ice, washed with ice cold PBS and then removed by scraping. Cells are then harvested by centrifugation at 1000 rpm for 10 minutes and the cellular pellet is frozen in liquid nitrogen, for subsequent use in protein expression. Northern blot analysis of a thawed aliquot of frozen cells may be used to confirm expression of receptor-encoding cDNA in cells under storage.

In a like manner, stably transfected cell lines can also prepared, for example, using two different cell types as host: CHO K1 and CHO Pro5. To construct these cell lines, cDNA coding for the relevant protein may be incorporated into the mammalian expression vector pRC/CMV (Invitrogen), which enables stable expression. Insertion at this site places the cDNA under the expression control of the cytomegalovirus promoter and upstream of the polyadenylation site and terminator of the bovine growth hormone gene, and into a vector background comprising the neomycin resistance gene (driven by the SV40 early promoter) as selectable marker.

An exemplary protocol to introduce plasmids constructed as described above is as follows. The host CHO cells are first seeded at a density of 5×10⁵in 10% FBS-supplemented MEM medium. After growth for 24 hours, fresh medium is added to the plates and three hours later, the cells are transfected using the calcium phosphate-DNA co-precipitation procedure (Sambrook et al, supra). Briefly, 3 μg of DNA is mixed and incubated with buffered calcium solution for 10 minutes at room temperature. An equal volume of buffered phosphate solution is added and the suspension is incubated for 15 minutes at room temperature. Next, the incubated suspension is applied to the cells for 4 hours, removed and cells were shocked with medium containing 15% glycerol. Three minutes later, cells are washed with medium and incubated for 24 hours at normal growth conditions. Cells resistant to neomycin are selected in 10% FBS-supplemented alpha-MEM medium containing G418 (1 mg/ml). Individual colonies of G418-resistant cells are isolated about 2-3 weeks later, clonally selected and then propagated for assay purposes.

EXAMPLES
Example 1
Cloning of PIM-1

The PIM-1 DNA encoding amino acids 1-313 and 29-313 were 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 2
Purification of PIM-1

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 Byroad 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.

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 3
Variants and Derivatives of PIM-1

In mouse, PIM-1 is expressed as two forms of 44 kDa and 33 kDa. The p44 kDa PIM-1 is encoded by the same gene as p33 kDa PIM-1 but the translation is initiated at an upstream CUG codon (Saris C J, Domen J, and Berns A. (1991) The PIM-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 10: 655-664.) This results in expression of p44 PIM-1 having a unique 11 kDa N terminal extension that is followed by the p33 PIM-1 sequence. The p33 kDa PIM-1 contains almost the entire kinase domain and both p33 and p44 kDa have comparable kinase activity and both can prevent apoptosis (Lilly M, Sandholm J, Cooper J J, Koskinen P J, and Kraft A. (1999) The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway. Oncogene., 18: 4022-4031). CD40 engagement caused significant increase in the levels of both 33 and 44 kDa forms of PIM1 in cytoplasmic extracts of WEHI-231 cells (Zhu N, Ramirez L M, Lee R L, Magnuson N S, Bishop G A, and Gold M R. (2002) CD40 signaling in B cells regulates the expression of the PIM-1 kinase via the NF-kappa B pathway. J. Immunol. 168: 744-754). Recently it has been shown that the p33 kDa form was more strongly associated with Socs-1 than the p44 kDa form (Chen X P, Losman J A, Cowan S, Donahue E, Fay S, Vuong B Q, Nawijn M C, Capece D, Cohan V L, Rothman P. (2002) PIM serine/threonine kinases regulate the stability of Socs-1 protein. Proc Natl Acad Sci USA., 99: 2175-2180).

There are no reports of PIM-1 existing in more than one form in human. Analysis of PIM-1 gene sequence reveals that the presence of in-frame stop codons block synthesis of proteins with N terminal extensions. However, the human PIM-2 gene contains no in-frame stop codon, based on the reported DNA sequence. Therefore, alternate initiation at an upstream start codon is possible. We have expressed the PIM-2 kinase domain in E. coli and purified the protein by the same methods as described for PIM-1 kinase.

Example 4
Crystallization of PIM-1

PIM-1 Protein Crystal Growth:

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 (HS1 and HS2) and yielded successful crystals growing in at least 10 conditions from HS1 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.

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.

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

- 1) HS1 # 17 was optimized to 0.2 M LiCl, 0.1 M Tris pH 8.5 and 5%-15% Polyethylene glycol 4000;
- 2) HS1 # 25 was optimized to 0.4 M-0.9 M Sodium Acetate trihydrate pH 6.5 and 0.1 M Imidazole;
- 3) HS1 # 29 was optimized to 0.2M-0.7 M Sodium Potassium tartrate and 0.1 M MES buffer pH 6.5;
- 4) HS1 # 44 was optimized to 0.25 M Magnesium formate.

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.

Seleno Methionine Labeled PIM-1 Protein Crystal Growth.

Se-Met labeled PIM 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.

PIM-1 protein/Molecular Scaffolds Co-Crystal Growth:

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.

PIM-1/Compound Co-Crystal Screening in HS1:

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. Interestingly, some crystals that were grown in the presence of colored compounds were also colored the same way.

Example 5
Diffraction Analysis of PIM-1

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.

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.

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

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.

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.

PIM-1 Structure Determination and Refinement

Data Set: Native, Resolution: 2.13

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

- EPMR (Public domain)
- AmoRe (from CCP4))
- And a homology model of PIM-1 based on the protein Phosphorylase Kinase (PDB ID: 1PHK—Owen et al., 1995, Structure 3: 467)

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

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

- Model Building in 0 (from DatOno AB)
- Annealing in CNX (from Accelerys)
- SigmaA weighting and Solvent Flattening the resultant map with DM (from CCP4)

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

Data Set: SeMet (2 Wavelengths), Resolution: 3.3

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

Data Set: SeMet (1 Wavelength), Resolution: 2.6

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.

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

Data Set: Native, Resolution: 2.1

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

Example 6
Co-Crystal Structures

Exemplary co-crystal structures have been determined for 7 compounds with PIM-1, using methods as generally described above. Those co-crystals are the following (the number indicates the compound id and the compound source is provided in parentheses):

- PIM1_—5321980 (Chembridge)
- PIM1_RB00137 (Maybridge)
- PIM1_—5264241 (Chembridge)
- PIM1_RJF00907 (Maybridge)
- PIM1_—5140994 (Chembridge)
- PIM1_—5108305 (Chembridge)
- PIM1_BTB02713 (Maybridge)

Example 7
PIM Binding Assays

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 ATPγ[³⁵S] (˜10 nCi). As compound is added, the signal decreases, since less ATPγ[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).

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.

Determination of IC50 for compounds by competitive binding assays. (Note that K_Iis the dissociation constant for inhibitor binding; K_Dis 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:
$When using radiolabeled substrate K_{I} = \frac{IC50}{1 + [L^{*}] / K_{D}} .$

the IC50˜K_Iwhen there is a small amount of labeled substrate.

Example 8
PIM Activity Assays

Inhibitory or exhitory activity of compounds binding to PIM-1 was determined using the kinase activity assay described in the detailed description.

Exemplary compounds within Formula I, Formula II, and Formula III 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.

Example 9
Synthesis of the Compounds of Formula I

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The 2-arylbenzimidazoles derivatives, represented by Formula I, can be prepared as shown in Scheme 1.

Step 1 Preparation of Formula (3)

Compound of formula (3) was prepared by a reaction of a compound of formula (1) with an alkyl halide of formula (2)(e.g. X=Br) in an inert solvent (e.g. DMF), in the presence of a base (e.g. NaH) and heated near 100° C. for 24-36 h. Compound of formula (3) was purified by column chromatography.

Step 2 Preparation of Formula (4)

Compound of formula (4) was prepared by a reaction of a compound of formula (3) with a reducing agent (e.g. SnCl₂) in a polar solvent (e.g. EtOH) and heated near 100° C. for 5-12 h. When the reaction is completed, the product of formula (4) is isolated by conventional means (e.g. aqueous base workup).

Step 3 Preparation of Formula I

Compound of formula I was prepared by the reaction of the compound of formula (4) with an imidate of formula (5) in a polar solvent (e.g. EtOH) and heated near 80° C. for 12-18 h. Compound of formula I was purified by column chromatography.
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Step 1 Preparation of Formula I

Compound of formula I was prepared by the reaction of the compound of formula (4) with an aldehyde of formula (6) in a polar solvent (e.g. EtOH) and heated near 80° C. for 12-22 h. Compound of formula I was purified by column chromatography.
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Step 1 Preparation of Formula I

Compound of formula I was prepared by the reaction of the compound of formula (4) with an aldehyde of formula (7) in an inorganic acid (e.g. polyphosphoric acid) and heating near 190-220° C. for 5-12 h. Compound of formula I was purified by column chromatography.

Example 10
Synthesis of the Compounds of Formula II

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Synthesis schemes for exemplary groups of compounds within Formula II are provided below. Persons skilled in chemical synthesis will readily understand how to synthesize additional compounds within Formula II.
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The thiadiazole derivative, represented by formula Ia, can be prepared as shown in Scheme 4.

Step-1 Preparation of Formula (10)

Compound of formula (10) was prepared by reaction of a compound of formula (8) (e.g. m-toluic hydrazide) with an isothiocyanate of formula (9), in a basic solvent (e.g. pyridine), typically heated near 65° C. for 2-6 hours.

Step-2 Preparation of Formula IIa

Compound of formula IIa was prepared by dissolving a compound of formula (10) in POCl₃and heated near 80° C. for 2-4 hours. When the reaction is substantially complete, the product of formula Ia is isolated by conventional means (e.g. reverse phase HPLC).
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The oxadiazole derivatives, represented by formula IIb, can be prepared as shown in Scheme 5.

Step-1 Preparation of Formula (10)

Compound of formula (10) was prepared by reaction of a compound of formula (8), e.g. m-toluic hydrazide, with an isothiocyanate of formula (9), in a basic solvent (e.g. pyridine), typically heated near 65° C. for 2-6 hours.

Step-2 Preparation of Formula IIb

Compound of formula IIb was prepared by dissolving a compound of formula (10) in SOCl₂and heated near 80° C. for 2-4 hours. When the reaction is substantially complete, the product of formula II was isolated by conventional means (e.g. reverse phase HPLC).

Example 11
Synthesis of the Compounds of Formula IIIa, where n=0

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where the squiggly lines indicate a mixture of stereoisomers.

The Pyridazinone derivatives, represented by formula IIIa, can be prepared as shown in Scheme 6.

Step-1 Preparation of Formula (12)

The compound of formula (12) was prepared by reaction of a 4-oxo-butyric acid derivative of formula (11) with hydrazine, in a basic solvent (e.g. pyridine), typically heated near 65° C. for 2-6 hours.

Step-2 Preparation of Formula IIIaa

The compound of formula IIIaa was prepared by dissolving a compound of formula (12) in an inert solvent and adding an oxidizing agent (e.g. Br₂, chloranil, or Pd(C) under an air atmosphere. When the reaction is substantially complete, the product of formula IIIaa is isolated by conventional means (e.g. reverse phase HPLC).

Step-3 Preparation of Formula IIIab

Compounds of Formula IIIaa (X=0) can be converted into compounds where X=S, by treatment with Lawesson's reagent or P₂S₅stirred in an inert solvent at ambient temperature for 2-6 hours. When the reaction is substantially complete, the product of formula IIIb is isolated by conventional means (e.g. reverse phase HPLC).

Synthesis of the compounds of Formula IIIb, where n=1:
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The Pyridazinone derivatives, represented by formula IIIba, can be prepared as shown in Scheme 7.

Step-1 Preparation of Formula IIIba

The compound of formula IIIba was prepared by reaction of an acyl-acrylic acid of formula (13) with hydrazine, in a basic solvent (e.g. aqueous NaOH), typically stirred at ambient temperature for 2-6 hours. When the reaction is substantially complete, the product of formula IIIa (X=0) is isolated by conventional means (e.g. reverse phase HPLC).

Step-2 Preparation of Formula IIIbb

Compounds of Formula IIIba (X=0) can be converted into compounds where X S, by treatment with Lawesson's reagent or P₂S₅stirred in an inert solvent at ambient temperature for 2-6 hours. When the reaction is substantially complete, the product of formula IIIbb is isolated by conventional means (e.g. reverse phase HPLC).

Example 12
Synthesis of the Compounds of Formula IV

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The 4-hydroxypyrimidine derivatives, represented by formula IVa, can be prepared as shown in Scheme 8.

Step-1 Preparation of Formula (15)

Compound (15) was prepared by reaction of compound (14) with benzyl bromide in an inert solvent (e.g. DMF), in the presence of a base (e.g. Et₃N), at room temperature for 4 hours. Product (15) is purified by a conventional way (e.g. recrystallization).

Step-2 Preparation of Formula (16)

Compound (16) was prepared by reaction of compound (15) with N-iodosuccinimide in chloroform under reflux for several hours. Product (16) was purified by a conventional way (e.g. recrystallization).

Step-3 Preparation of Formula (17)

Compound (17) was prepared by reaction of compound (16) with benzyl bromide in an inert solvent (e.g. DMF), in the presence of a base (e.g. NaH) at room temperature for several hours.

Step 4 Preparation of Formula (18)

The compound of formula (18) was prepared by reaction of compound (17), with a suitable reagent for coupling reaction (e.g. phenylboronic acid) in a suitable mixture of solvent (e.g. dimethoxyethane and water), in the presence of a base (e.g. K₂CO₃), typically heated to 100° C. for several hours. The product was isolated by a conventional way (e.g. flash chromatography).

Step 5 Preparation of Formula (19)

The compound of formula (19) was prepared by reaction of a compound of formula (18), with an oxidizing reagent (e.g. MCPBA) in a suitable solvent (e.g. CH₂Cl₂), typically at room temperature for a few hours.

Step 6 Preparation of Formula (20)

The compound of formula (20) was prepared by reaction of a compound of formula (19) with a nucleophilic reagent (e.g. piperazine), in the presence of a base (e.g. Cs₂CO₃) in a suitable solvent (e.g. dioxane) reflux for several hours. The product is purified in a conventional way (e.g. flash chromatography).

Step 7 Preparation of Formula IV

The compound of formula IVa was prepared conventionally by hydrogenation of a compound of formula (20) in the presence of a catalyst (e.g. Pd(OH)₂/C), under hydrogen in a suitable solvent (e.g. methanol) at room temperature for several hours.
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The 4-hydroxypyrimidine derivatives, represented by formula IV, can be prepared as shown in Scheme 9.

Step 1 Preparation of Formula IVb

The compound of formula IVb was prepared by reaction of a compound of formula (21) with an electrophilic reagent (phenyl isocyanate), in the presence of a base (e.g. Et₃N) in a suitable solvent (e.g. CH₂Cl₂) at room temperature for several hours. When the reaction is substantially complete, the product of formula IVb was isolated by conventional means (e.g. flash chromatography).
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The 4-hydroxypyrimidine derivatives, represented by formula IVc, were prepared as shown in Scheme 10.

Step-1 Preparation of Formula (23)

The compound of formula (23) was prepared by reaction of a compound of formula (22), with an alkyl halide reagent (e.g. methyl iodide) 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.

Step-2 Preparation of Formula IVc

The compound of formula (25) was prepared y by reaction of a compound of formula (23) with an alkylisothiourea (e.g. S-methylisothiourea, H₂NCNHSCH₃), while heating in a suitable solvent (e.g. ethanol) at 75° C. for several hours. When the reaction is substantially complete, the product of formula IVc was isolated by conventional means; for example, recrystallization.

4. Alternate Synthesis of the Compounds of Formula IV—Scheme 11
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Step-1 Preparation of Formula (28)

Compound of formula (28) was prepared conventionally by reaction of a compound of formula (26), with thiourea of formula (27), in a polar solvent (e.g. ethanol), and typically heated near 80° C. for 12-36 hours and isolating the product by column chromatography.

Step-2 Preparation of Formula (29)

Compound of formula (29) was prepared by reaction of a compound of formula (28) with an alkylating agent (e.g. ethylbromoacetate), in the presence of a base (e.g. K₂CO₃) in a suitable solvent (e.g. acetonitrile) at room temperature or reflux for several hours. When the reaction is substantially complete, the product of formula IVc was isolated by conventional means.

Example 13
Synthesis of the Compounds of Formula V

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1. Synthesis of the Compounds of Formula Va, where R¹, R², R³, and R⁶are Methyl; R⁴and R⁵are Hydrogen—Scheme 12
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The isoindole derivatives, represented by formula Va, can be prepared as shown in Scheme 12.

Step-1 Preparation of Formula Va

The compound of formula (30) can be reacted with diketone compounds of formula (31), in aqueous acetic acid and typically heated near 100° C. for 12-36 hours. The compound can be isolated by conventional methods (e.g. recrystallization).

2. Synthesis of the Compounds of Formula Vb, where R³, R⁶, R⁴and R⁵are Hydrogen; R⁷is hydroxy—Scheme 13
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Step-1 Preparation of Formula Vb

The compound of Formula Vb is prepared conventionally by reaction of a compound of formula (32) with a Grignard reagent (e.g. Phenyl magnesium bromide), in a suitable solvent (e.g. benzene) and refluxed for 1 hour. When the reaction is substantially complete, the product of is isolated by conventional means (e.g., column chromatography).

3. Synthesis of the Compounds of Formula Vc, where where R¹, R², R³, R⁴, R⁵, R⁶, and R⁷are Hydrogen—Scheme 14
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Step-1 Preparation of Vc

The compound (34) and the ammonium tetrathiomolybdate of formula (35) are reacted at room temperature with aqueous CH₃CN as the solvent. When the reaction is substantially complete (typically 1 hour), the solvent is removes by evaporation at reduced pressure. The product Vc is isolated by conventional means (e.g. ether extraction). (Ramesha, et. al., J. Org. Chem., 1995, 60, 7682-7683; and references therein).

Example 14
Synthesis of the Compounds of Formula VI

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1. Synthesis of the Compounds of Formula VIa, where R⁴=H—Scheme 15
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Pyrazolidinone derivatives, represented by formula VI, can be prepared as shown in Scheme-15.

Step-1 Preparation of Formula (37)

The compound of formula (37) is prepared conventionally by reaction of a compound of formula (36), with an alkyl halide reagent (e.g. methyl iodide) 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.

Step-2 Preparation of Formula VIa

Compound of formula (37) is reacted with hydrazine of formula (38) along with a catalytic amount of concentrated acid (e.g. hydrochloric acid) at 120° C. The liberation of alcohol and water results in the formation of the product of formula VIa, can be isolated through conventional means, for example column chromatography.

2. Alternate Synthesis of the Compounds of Formula VI, where R⁴═H:—Scheme 16
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Step-1 Preparation of Formula VIb

Compound of formula (36) is reacted with hydrazine of formula (38) along with a catalytic amount of concentrated acid (e.g. hydrochloric acid) at 120° C. The liberation of alcohol and water results in the formation of the product of formula VIb, can be isolated through conventional means, for example column chromatography.

Step-2 Preparation of Formula VIa:

The compound of formula VI is prepared conventionally by reaction of a compound of formula (42) with an alkylating agent of formula (43) (e.g. ethylbromoacetate), in the presence of a base (e.g. K₂CO₃) in a suitable solvent (e.g. acetonitrile) at room temperature or reflux for several hours. When the reaction is substantially complete, the product of Formula VI is isolated by conventional means; for example, recrystallization.

Example 15
Synthesis of the Compounds of Formula VII

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1. Synthesis of the Compounds of Formula VII—Scheme 17
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The 8-aminoquinoline derivatives, represented by formula VII, can be prepared as shown in Scheme-17. In this particular scheme, R⁵, R⁶, and R⁷are hydrogen.

Step-1 Preparation of Formula (41)

The compound of formula (41) can be prepared via a Skraup reaction by reaction of a compound of formula (39) (e.g. 2-nitroaniline), with glycerol (40), in the presence of sulfuric acid in an inert solvent (e.g. dioxane) and typically heated to >100° C. for 2-24 hours. The addition of nitrobenzene or arsenic oxide can aid the reaction (Claus and Schoeller, J. Prakt. Chem. 1893, 48, 140. Mosher, H. S. et. al., Org. Syn. CV 3, 568).

Step-2 Preparation of Formula (42)

The compound of formula (42) can be prepared conventionally by reaction of a compound of formula (41) with a reducing agent (e.g. hydrogen gas, 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 (41) can be isolated by conventional means, (e.g. filtration through Celite).

Step-3 Preparation of Formula VII

The compound of formula (42) can be reacted with a compound of formula (43) where X is a leaving group (e.g. bromide, chloride) or an electrophilic substituent (e.g. isocyanate, isothiocyanate), in the presence of base (e.g. K₂CO₃), in an inert solvent (e.g. DMF). Representaive examples of compounds of formula (43) include benzoyl chloride, benzenesulfonyl chloride, 3-bromo-2-methylpropane, benzyl bromide, phenyl isocyanate, and phenyl isothiocyanate. When the reaction is substantially complete, the product of formula VII can be isolated by conventional means (e.g. silica gel chromatography).

2. Alternative Exemplary Synthesis of Compounds of Formula VII—Scheme 18
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The 8-aminoquinoline derivatives, represented by formula VII, can be prepared as shown in Scheme-18.

Step-1 Preparation of Formula (41)

The compound of formula (41) can be prepared via a Friedländer synthesis by reaction of a compound of formula (44) (e.g. 2-amino-3-nitro-acetophenone), with a compound of formula (45) (e.g. acetone), in the presence of base (e.g. potassium hydroxide, piperidine) in an inert solvent (e.g. ethanol) and possible with heating for 2-24 hours (Eckert, K. Angew. Chem. Int. Ed. 1981, 20, 208).

Step-2 Preparation of Formula (42)

The compound of formula (42) can be prepared conventionally by reaction of a compound of formula (41) with a reducing agent (e.g. hydrogen gas, 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 (42) can be isolated by conventional means, (e.g. filtration through Celite).

Step-3 Preparation of Formula VII

The compound of formula (42) can be reacted with a compound of formula (48) where X is a leaving group (e.g. bromide, chloride) or an electrophilic substituent (e.g. isocyanate, isothiocyanate), in the presence of base (e.g. K₂CO₃), in an inert solvent (e.g. DMF). Representaive examples of compounds of formula (43) include benzoyl chloride, benzenesulfonyl chloride, 3-bromo-2-methylpropane, benzyl bromide, phenyl isocyanate, and phenyl isothiocyanate. When the reaction is substantially complete, the product of formula VII can be isolated by conventional means (e.g. silica gel chromatography).

Example 16
Site-Directed Mutagenesis of Kinases

Mutagenesis of kinases, e.g. PIM kinases, such as the P123M mutation of PIM-1 can be carried out according to the following procedure (or other procedures available persons performing molecular biological techniques) as described in Molecular Biology: Current Innovations and Future Trends. Eds. A. M. Griffin and H. G. Griffin. (1995) ISBN 1-898486-01-8, Horizon Scientific Press, PO Box 1, Wymondham, Norfolk, U.K., among others.

In vitro site-directed mutagenesis is an invaluable technique for studying protein structure-function relationships, gene expression and vector modification. Several methods have appeared in the literature, but many of these methods require single-stranded DNA as the template. The reason for this, historically, has been the need for separating the complementary strands to prevent reannealing. Use of PCR in site-directed mutagenesis accomplishes strand separation by using a denaturing step to separate the complementing strands and allowing efficient polymerization of the PCR primers. PCR site-directed methods thus allow site-specific mutations to be incorporated in virtually any double-stranded plasmid; eliminating the need for M13-based vectors or single-stranded rescue.

It is often desirable to reduce the number of cycles during PCR when performing PCR-based site-directed mutagenesis to prevent clonal expansion of any (undesired) second-site mutations. Limited cycling which would result in reduced product yield, is offset by increasing the starting template concentration. A selection is used to reduce the number of parental molecules coming through the reaction. Also, in order to use a single PCR primer set, it is desirable to optimize the long PCR method. Further, because of the extendase activity of some thermostable polymerases it is often necessary to incorporate an end-polishing step into the procedure prior to end-to-end ligation of the PCR-generated product containing the incorporated mutations in one or both PCR primers.

The following protocol provids as a facile method for site-directed mutagenesis and accomplishes the above desired features by the incorporation of the following steps:

- (i) increasing template concentration approximately 1000-fold over conventional PCR conditions; (ii) reducing the number of cycles from 25-30 to 5-10; (iii) adding the restriction endonuclease DpnI (recognition target sequence: 5-Gm6ATC-3, where the A residue is methylated) to select against parental DNA (note: DNA isolated from almost all common strains of E. coli is Dam-methylated at the sequence 5-GATC-3); (iv) using Taq Extender in the PCR mix for increased reliability for PCR to 10 kb; (v) using Pfu DNA polymerase to polish the ends of the PCR product, and (vi) efficient intramolecular ligation in the presence of T4 DNA ligase.

Plasmid template DNA (approximately 0.5 pmole) is added to a PCR cocktail containing, in 25 ul of 1× mutagenesis buffer: (20 mM Tris HCl, pH 7.5; 8 mM MgCl2; 40 ug/ml BSA); 12-20 pmole of each primer (one of which must contain a 5-prime phosphate), 250 uM each dNTP, 2.5 U Taq DNA polymerase, 2.5 U of Taq Extender (Stratagene).

The PCR cycling parameters are 1 cycle of: 4 min at 94 C, 2 min at 50 C and 2 min at 72 C; followed by 5-10 cycles of 1 min at 94 C, 2 min at 54 C and 1 min at 72 C (step 1).

The parental template DNA and the linear, mutagenesis-primer incorporating newly synthesized DNA are treated with DpnI (10 U) and Pfu DNA polymerase (2.5U). This results in the DpnI digestion of the in vivo methylated parental template and hybrid DNA and the removal, by Pfu DNA polymerase, of the Taq DNA polymerase-extended base(s) on the linear PCR product.

The reaction is incubated at 37 C for 30 min and then transferred to 72 C for an additional 30 min (step 2).

Mutagenesis buffer (lx, 115 ul, containing 0.5 mM ATP) is added to the DpnI-digested, Pfu DNA polymerase-polished PCR products.

The solution is mixed and 10 ul is removed to a new microfuge tube and T4 DNA ligase (2-4 U) added.

The ligation is incubated for greater than 60 min at 37 C (step 3).

The treated solution is transformed into competent E. coli (step 4).

In addition to the PCT-based site-directed mutagenesis described above, other methods are available. Examples include those described in Kunkel (1985) Proc. Natl. Acad. Sci. 82: 488-492; Eckstein et al. (1985) Nucl. Acids Res. 13: 8764-8785; and using the GeneEditor™ Site-Directed Mutageneis Sytem from Promega.

All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.

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.

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, variations can be made to crystallization or co-crystallization conditions for PIM proteins. Thus, such additional embodiments are within the scope of the present invention and the following claims.

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.

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.

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.

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

TABLE 1HEADER---- XX-XXX-XX xxxxCOMPND---REMARK3REMARK3REFINEMENT.REMARK3PROGRAM: REFMAC 5.1.19REMARK3AUTHORS: MURSHUDOV, VAGIN, DODSONREMARK3REMARK3REFINEMENT TARGET: MAXIMUM LIKELIHOODREMARK3REMARK3DATA USED IN REFINEMENT.REMARK3RESOLUTION RANGE HIGH (ANGSTROMS): 2.00REMARK3RESOLUTION RANGE LOW (ANGSTROMS): 84.52REMARK3DATA CUTOFF (SIGMA(F)): NONEREMARK3COMPLETENESS FOR RANGE (%): 99.27REMARK3NUMBER OF REFLECTIONS: 28693REMARK3REMARK3FIT TO DATA USED IN REFINEMENT.REMARK3CROSS-VALIDATION METHOD: THROUGHOUTREMARK3FREE R VALUE TEST SET SELECTION: RANDOMREMARK3R VALUE (WORKING + TEST SET): 0.22119REMARK3R VALUE (WORKING SET): 0.22012REMARK3FREE R VALUE: 0.24194REMARK3FREE R VALUE TEST SET SIZE (%): 5.0REMARK3FREE R VALUE TEST SET COUNT: 1498REMARK3REMARK3FIT IN THE HIGHEST RESOLUTION BIN.REMARK3TOTAL NUMBER OF BINS USED: 20REMARK3BIN RESOLUTION RANGE HIGH: 2.000REMARK3BIN RESOLUTION RANGE LOW: 2.052REMARK3REFLECTION IN BIN (WORKING SET): 2096REMARK3BIN R VALUE (WORKING SET): 0.344REMARK3BIN FREE R VALUE SET COUNT: 102REMARK3BIN FREE R VALUE: 0.359REMARK3REMARK3NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.REMARK3ALL ATOMS: 2382REMARK3REMARK3B VALUES.REMARK3FROM WILSON PLOT (A**2): NULLREMARK3MEAN B VALUE (OVERALL, A**2): 49.236REMARK3OVERALL 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.REMARK3ESU BASED ON R VALUE (A): 0.158REMARK3ESU BASED ON FREE R VALUE (A): 0.142REMARK3ESU BASED ON MAXIMUM LIKELIHOOD (A): 0.127REMARK3ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2): 4.758REMARK3REMARK3CORRELATION COEFFICIENTS.REMARK3CORRELATION COEFFICIENT FO-FC: 0.954REMARK3CORRELATION COEFFICIENT FO-FC FREE: 0.947REMARK3REMARK3RMS DEVIATIONS FROM IDEAL VALUESCOUNTRMSWEIGHTREMARK3BOND LENGTHS REFINED ATOMS (A):2296;0.011;0.021REMARK3BOND ANGLES REFINED ATOMS (DEGREES):3114;1.088;1.945REMARK3TORSION ANGLES, PERIOD 1 (DEGREES): 273;3.838;5.000REMARK3CHIRAL-CENTER RESTRAINTS (A**3): 332;0.081;0.200REMARK3GENERAL PLANES REFINED ATOMS (A):1784;0.004;0.020REMARK3NON-BONDED CONTACTS REFINED ATOMS (A):1094;0.215;0.200REMARK3H-BOND (X...Y) REFINED ATOMS (A): 138;0.121;0.200REMARK3SYMMETRY VDW REFINED ATOMS (A): 60;0.282;0.200REMARK3SYMMETRY H-BOND REFINED ATOMS (A): 19;0.247;0.200REMARK3REMARK3ISOTROPIC THERMAL FACTOR RESTRAINTS.COUNTRMSWEIGHTREMARK3MAIN-CHAIN BOND REFINED ATOMS (A**2):1365;1.058;1.500REMARK3MAIN-CHAIN ANGLE REFINED ATOMS (A**2):2212;2.010;2.000REMARK3SIDE-CHAIN BOND REFINED ATOMS (A**2): 931;2.240;3.000REMARK3SIDE-CHAIN ANGLE REFINED ATOMS (A**2): 902;3.766;4.500REMARK3REMARK3NCS RESTRAINTS STATISTICSREMARK3NUMBER OF NCS GROUPS: NULLREMARK3REMARK3REMARK3TLS DETAILSREMARK3NUMBER OF TLS GROUPS: NULLREMARK3REMARK3REMARK3BULK SOLVENT MODELLING.REMARK3METHOD USED: BABINET MODEL WITH MASKREMARK3PARAMETERS FOR MASK CALCULATIONREMARK3VDW PROBE RADIUS: 1.40REMARK3ION PROBE RADIUS: 0.80REMARK3SHRINKAGE RADIUS: 0.80REMARK3REMARK3OTHER REFINEMENT REMARKS: NULLREMARK3CISPEP1GLU 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 0.00000ATOM1NPROA339.285100.137−4.4931.0093.84NATOM2CAPROA338.92299.154−3.4301.0093.59CATOM3CBPROA339.62497.864−3.8961.0093.79CATOM4CGPROA3310.73298.328−4.8331.0093.76CATOM5CDPROA3310.20199.562−5.4991.0093.83CATOM6CPROA339.41399.588−2.0381.0093.22CATOM7OPROA338.647100.212−1.2881.0093.33OATOM8NLEUA3410.66799.251−1.7161.0092.55NATOM9CALEUA3411.32599.616−0.4571.0091.82CATOM10CBLEUA3411.402101.150−0.3031.0092.11CATOM11CGLEUA3412.362101.7090.7561.0092.47CATOM12CD1LEUA3413.829101.5130.3491.0092.34CATOM13CD2LEUA3412.044103.1831.0241.0093.01CATOM14CLEUA3410.75898.9410.8081.0090.98CATOM15OLEUA3411.16497.8281.1571.0091.10OATOM16NGLUA359.83799.6141.4981.0089.80NATOM17CAGLUA359.34699.1142.7801.0088.50CATOM18CBGLUA3510.29799.5263.9011.0088.76CATOM19CGGLUA3510.444101.0394.0471.0089.07CATOM20CDGLUA3511.208101.4365.2921.0089.82CATOM21OE1GLUA3510.603101.4036.4001.0090.45OATOM22OE2GLUA3512.411101.7805.1621.0089.60OATOM23CGLUA357.96399.6723.0601.0087.48CATOM24OGLUA357.22099.1143.8751.0087.62OATOM25NSERA367.640100.7812.3821.0085.74NATOM26CASERA366.316101.4272.4241.0083.76CATOM27CBSERA366.258102.5761.4021.0084.10CATOM28OGSERA367.465103.3321.3991.0084.47OATOM29CSERA365.170100.4442.1501.0081.91CATOM30OSERA363.997100.7552.3891.0081.51OATOM31NGLNA375.53599.2621.6511.0079.60NATOM32CAGLNA374.60098.1791.3631.0077.25CATOM33CBGLNA375.31697.0580.6141.0077.48CATOM34CGGLNA376.19597.509−0.5541.0077.20CATOM35CDGLNA376.64596.330−1.4141.0077.20CATOM36OE1GLNA375.82795.483−1.7991.0077.03OATOM37NE2GLNA377.94296.268−1.7091.0076.81NATOM38CGLNA373.97097.6042.6231.0075.49CATOM39OGLNA372.87997.0432.5671.0075.51OATOM40NTYRA384.65597.7473.7561.0073.43NATOM41CATYRA384.20897.1295.0041.0071.44CATOM42CBTYRA385.10095.9315.3731.0070.49CATOM43CGTYRA385.22794.9194.2551.0067.67CATOM44CD1TYRA384.25893.9294.0671.0065.14CATOM45CE1TYRA384.36193.0193.0321.0063.31CATOM46CZTYRA385.44693.0872.1771.0062.94CATOM47OHTYRA385.56892.1911.1511.0064.24OATOM48CE2TYRA386.41794.0542.3391.0063.82CATOM49CD2TYRA386.30494.9673.3711.0065.13CATOM50CTYRA384.12598.0996.1691.0071.00CATOM51OTYRA385.02198.9146.3851.0070.68OATOM52NGLNA393.02697.9866.9131.0070.43NATOM53CAGLNA392.79798.7568.1241.0069.86CATOM54CBGLNA391.29899.0218.2791.0070.46CATOM55CGGLNA390.934100.0079.3851.0073.80CATOM56CDGLNA390.37899.31910.6351.0077.97CATOM57OE1GLNA39−0.75098.79410.6251.0079.52OATOM58NE2GLNA391.16199.33011.7171.0078.94NATOM59CGLNA393.33397.9679.3221.0068.49CATOM60OGLNA392.70497.0039.7771.0068.58OATOM61NVALA404.49198.3909.8341.0066.87NATOM62CAVALA405.14197.68810.9401.0065.53CATOM63CBVALA406.60098.13711.1381.0065.20CATOM64CG1VALA407.31097.20112.1001.0064.63CATOM65CG2VALA407.33698.1749.8041.0065.16CATOM66CVALA404.37697.83712.2551.0064.96CATOM67OVALA403.83398.89312.5471.0065.27OATOM68NGLYA414.33996.76613.0421.0064.02NATOM69CAGLYA413.64096.76414.3101.0062.22CATOM70CGLYA414.54596.34115.4511.0061.31CATOM71OGLYA415.74796.57215.4061.0060.92OATOM72NPROA423.96695.72516.4781.0060.62NATOM73CAPROA424.72395.31317.6661.0060.91CATOM74CBPROA423.63694.75518.6021.0060.81CATOM75CGPROA422.34795.33218.0891.0060.97CATOM76CDPROA422.52995.40116.5991.0060.64CATOM77CPROA425.75994.23517.3851.0060.96CATOM78OPROA425.62693.47816.4241.0060.93OATOM79NLEUA436.78394.18018.2261.0061.11NATOM80CALEUA437.73793.08418.2001.0061.79CATOM81CBLEUA438.92493.41119.1101.0061.59CATOM82CGLEUA4310.16292.51119.1071.0062.19CATOM83CD1LEUA4311.00092.70417.8481.0061.21CATOM84CD2LEUA4311.00392.78220.3441.0062.67CATOM85CLEUA437.02791.79518.6431.0062.48CATOM86OLEUA436.14391.82419.5111.0062.19OATOM87NLEUA447.39690.67118.0301.0063.26NATOM88CALEUA446.81189.37818.3871.0063.89CATOM89CBLEUA446.25788.66317.1541.0063.70CATOM90CGLEUA445.13589.36216.3791.0063.05CATOM91CD1LEUA444.80188.56215.1311.0062.30CATOM92CD2LEUA443.89489.53917.2411.0062.27CATOM93CLEUA447.79188.47419.1101.0064.82CATOM94OLEUA447.38687.66919.9511.0065.08OATOM95NGLYA459.07188.60218.7841.0066.08NATOM96CAGLYA4510.08887.73419.3571.0068.09CATOM97CGLYA4511.51788.12219.0271.0069.52CATOM98OGLYA4511.76388.93718.1241.0069.05OATOM99NSERA4612.44887.51719.7741.0071.08NATOM100CASERA4613.89187.76419.6621.0072.58CATOM101CBSERA4614.31188.92220.5881.0072.92CATOM102OGSERA4615.65589.32720.3641.0074.04OATOM103CSERA4614.68886.51320.0271.0073.06CATOM104OSERA4614.26585.72020.8751.0073.26OATOM105NGLYA4715.84986.34919.3941.0073.67NATOM106CAGLYA4716.73385.23419.7071.0074.04CATOM107CGLYA4717.73984.96518.6081.0074.12CATOM108OGLYA4718.13385.88917.8831.0074.48OATOM109NGLYA4818.15083.69818.4901.0073.84NATOM110CAGLYA4819.10983.25717.4781.0073.16CATOM111CGLYA4818.60283.39216.0481.0072.45CATOM112OGLYA4819.39183.37415.0931.0072.37OATOM113NPHEA4917.28283.53115.9111.0071.52NATOM114CAPHEA4916.64783.75514.6121.0070.43CATOM115CBPHEA4915.21583.18714.5901.0070.83CATOM116CGPHEA4914.30183.75215.6611.0073.19CATOM117CD1PHEA4913.58484.93315.4391.0074.32CATOM118CE1PHEA4912.73885.45316.4191.0075.71CATOM119CZPHEA4912.58784.78717.6381.0075.96CATOM120CE2PHEA4913.29083.60517.8741.0075.42CATOM121CD2PHEA4914.13983.09016.8831.0074.82CATOM122CPHEA4916.69685.23114.1571.0068.55CATOM123OPHEA4916.78585.50912.9631.0069.15OATOM124NGLYA5016.66386.16415.1061.0066.20NATOM125CAGLYA5016.62587.58814.7951.0062.55CATOM126CGLYA5015.56288.35115.5781.0059.75CATOM127OGLYA5015.31688.05616.7541.0059.86OATOM128NSERA5114.94589.33214.9161.0056.20NATOM129CASERA5113.86690.14815.4801.0051.75CATOM130CBSERA5114.30091.61415.5871.0051.18CATOM131OGSERA5115.45491.75016.4011.0048.30OATOM132CSERA5112.69990.07614.5371.0049.79CATOM133OSERA5112.84890.34113.3441.0048.22OATOM134NVALA5211.53889.72415.0641.0047.77NATOM135CAVALA5210.34589.55114.2431.0046.96CATOM136CBVALA529.79588.09114.3121.0046.48CATOM137CG1VALA528.57087.92413.3971.0045.18CATOM138CG2VALA5210.87387.08213.9551.0045.83CATOM139CVALA529.26590.51514.7011.0047.44CATOM140OVALA528.87490.49315.8691.0048.09OATOM141NTYRA538.78491.34613.7791.0047.68NATOM142CATYRA537.72392.31514.0551.0048.21CATOM143CBTYRA538.10293.71113.5321.0047.13CATOM144CGTYRA539.29094.33514.2231.0046.28CATOM145CD1TYRA5310.59393.94913.8971.0043.98CATOM146CE1TYRA5311.68994.49514.5321.0042.59CATOM147CZTYRA5311.49895.47515.5211.0043.72CATOM148OHTYRA5312.59896.01216.1591.0043.55OATOM149CE2TYRA5310.22695.88415.8641.0044.06CATOM150CD2TYRA539.11795.30515.2211.0045.68CATOM151CTYRA536.43691.88613.3631.0049.25CATOM152OTYRA536.46691.33512.2581.0048.07OATOM153NSERA545.30692.16214.0081.0050.84NATOM154CASERA543.99691.95913.3981.0053.09CATOM155CBSERA542.88992.09214.4451.0053.24CATOM156OGSERA541.60991.93913.8541.0055.73OATOM157CSERA543.82693.01912.3421.0054.41CATOM158OSERA544.30394.12912.5101.0055.46OATOM159NGLYA553.15192.69111.2481.0056.17NATOM160CAGLYA553.04393.62510.1431.0058.09CATOM161CGLYA551.80093.3919.3271.0060.22CATOM162OGLYA551.16492.3439.4331.0060.35OATOM163NILEA561.45794.3818.5131.0062.12NATOM164CAILEA560.30794.3057.6351.0064.34CATOM165CBILEA56−0.84795.1888.1691.0064.42CATOM166CG1ILEA56−1.39194.6399.5001.0065.47CATOM167CD1ILEA56−2.24095.67010.2811.0066.61CATOM168CG2ILEA56−1.96995.2737.1491.0065.46CATOM169CILEA560.75994.7806.2671.0065.56CATOM170OILEA561.42295.8056.1551.0065.96OATOM171NARGA570.41994.0175.2331.0067.26NATOM172CAARGA570.73194.3863.8581.0068.96CATOM173CBARGA570.62893.1612.9461.0068.74CATOM174CGARGA571.13993.3611.5201.0068.49CATOM175CDARGA570.43392.4240.5321.0068.56CATOM176NEARGA571.26691.2720.1791.0068.20NATOM177CZARGA570.77790.086−0.2081.0068.80CATOM178NH1ARGA57−0.55189.870−0.2911.0069.12NATOM179NH2ARGA571.61689.106−0.5171.0069.04NATOM180CARGA57−0.25995.4483.4221.0070.41CATOM181OARGA57−1.43095.1463.1711.0070.64OATOM182NVALA580.21896.6913.3451.0072.30NATOM183CAVALA58−0.62697.8442.9981.0073.91CATOM184CBVALA580.19399.1772.9691.0073.84CATOM185CG1VALA58−0.704100.3732.6701.0073.85CATOM186CG2VALA580.92499.3944.2971.0073.45CATOM187CVALA58−1.34897.6021.6661.0074.98CATOM188OVALA58−2.46898.0811.4651.0075.68OATOM189NSERA59−0.71096.8220.7881.0075.93NATOM190CASERA59−1.26896.456−0.5211.0076.51CATOM191CBSERA59−0.25595.617−1.3201.0076.86CATOM192OGSERA591.10396.061−1.0491.0078.49OATOM193CSERA59−2.61795.721−0.4601.0076.40CATOM194OSERA59−3.38295.775−1.4221.0076.81OATOM195NASPA60−2.90295.0260.6451.0075.89NATOM196CAASPA60−4.17494.2990.7901.0075.35CATOM197CBASPA60−4.23093.077−0.1481.0075.67CATOM198CGASPA60−3.12492.0640.1261.0076.95CATOM199OD1ASPA60−2.83591.7881.3071.0078.19OATOM200OD2ASPA60−2.48891.483−0.7881.0077.92OATOM201CASPA60−4.54393.8722.2171.0074.33CATOM202OASPA60−5.33992.9472.3981.0074.34OATOM203NASNA61−3.96594.5413.2151.0072.99NATOM204CAASNA61−4.19494.2194.6331.0071.45CATOM205CBASNA61−5.59994.6515.0741.0072.10CATOM206CGASNA61−5.79096.1585.0261.0073.42CATOM207OD1ASNA61−5.33396.8855.9261.0074.58OATOM208ND2ASNA61−6.47196.6363.9751.0074.28NATOM209CASNA61−3.92892.7595.0351.0069.65CATOM210OASNA61−4.53592.2425.9751.0069.76OATOM211NLEUA62−3.02092.0984.3231.0067.18NATOM212CALEUA62−2.62390.7384.6801.0064.33CATOM213CBLEUA62−1.90190.0573.5181.0064.74CATOM214CGLEUA62−1.29188.6853.8211.0065.22CATOM215CD1LEUA62−2.38387.6354.0091.0065.88CATOM216CD2LEUA62−0.32588.2642.7251.0065.33CATOM217CLEUA62−1.69890.7665.8831.0061.89CATOM218OLEUA62−0.68291.4535.8631.0061.51OATOM219NPROA63−2.04490.0106.9201.0059.57NATOM220CAPROA63−1.16489.8408.0831.0057.75CATOM221CBPROA63−1.96388.8888.9831.0057.73CATOM222CGPROA63−3.37689.1068.5731.0058.58CATOM223CDPROA63−3.30389.2617.0801.0059.38CATOM224CPROA630.18089.2217.6941.0055.60CATOM225OPROA630.21188.1637.0751.0055.56OATOM226NVALA641.27489.9028.0251.0053.21NATOM227CAVALA642.60989.3757.7731.0050.67CATOM228CBVALA643.30690.0976.5901.0050.93CATOM229CG1VALA642.44190.0405.3261.0050.56CATOM230CG2VALA643.64191.5376.9431.0049.88CATOM231CVALA643.49289.4459.0251.0049.15CATOM232OVALA643.17590.1509.9811.0049.44OATOM233NALAA654.58788.6929.0151.0046.68NATOM234CAALAA655.60488.77410.0461.0044.84CATOM235CBALAA655.88187.38410.6541.0045.04CATOM236CALAA656.83489.3159.3561.0043.92CATOM237OALAA657.12388.9128.2181.0043.40OATOM238NILEA667.54790.23310.0121.0042.88NATOM239CAILEA668.71690.8839.4051.0042.53CATOM240CBILEA668.49492.4109.2521.0043.51CATOM241CG1ILEA667.26092.6798.3831.0044.11CATOM242CD1ILEA666.68594.1128.5011.0047.03CATOM243CG2ILEA669.70493.0678.6361.0042.39CATOM244CILEA669.95890.57210.2141.0042.61CATOM245OILEA6610.11991.05711.3421.0041.89OATOM246NLYSA6710.82089.7319.6411.0041.21NATOM247CALYSA6711.97189.19310.3531.0041.66CATOM248CBLYSA6712.05287.66410.1641.0041.05CATOM249CGLYSA6713.28887.01310.7611.0042.61CATOM250CDLYSA6713.16585.49510.6661.0044.83CATOM251CELYSA6714.21384.78011.4881.0046.29CATOM252NZLYSA6714.16583.30911.2281.0046.83NATOM253CLYSA6713.24389.8339.8671.0041.57CATOM254OLYSA6713.54889.7738.6711.0040.97OATOM255NHISA6813.98890.41510.8071.0041.97NATOM256CAHISA6815.25491.08710.5531.0043.17CATOM257CBHISA6815.34392.41911.3181.0042.46CATOM258CGHISA6814.35293.44010.8581.0040.77CATOM259ND1HISA6813.01893.38411.2031.0043.58NATOM260CE1HISA6812.37694.39310.6401.0041.67CATOM261NE2HISA6813.24795.1009.9421.0041.02NATOM262CD2HISA6814.48994.52210.0621.0037.93CATOM263CHISA6816.40890.21710.9601.0045.01CATOM264OHISA6816.46689.74412.0891.0044.97OATOM265NVALA6917.34090.02710.0301.0046.61NATOM266CAVALA6918.51689.22510.2721.0049.40CATOM267CBVALA6918.53887.9699.3591.0049.48CATOM268CG1VALA6919.73887.0939.6751.0050.89CATOM269CG2VALA6917.26687.1469.5291.0049.70CATOM270CVALA6919.74690.10310.0381.0051.36CATOM271OVALA6919.87990.7218.9831.0050.89OATOM272NGLUA7020.63490.16211.0261.0053.97NATOM273CAGLUA7021.87090.92410.8961.0057.27CATOM274CBGLUA7022.48091.21912.2721.0057.98CATOM275CGGLUA7021.67492.20513.1051.0061.81CATOM276CDGLUA7022.52493.24013.8391.0066.09CATOM277OE1GLUA7021.98293.92814.7441.0067.00OATOM278OE2GLUA7023.72993.37713.5181.0068.05OATOM279CGLUA7022.86190.14810.0571.0058.15CATOM280OGLUA7023.11588.97710.3321.0057.86OATOM281NLYSA7123.42090.8079.0411.0060.40NATOM282CALYSA7124.43390.1938.1741.0062.67CATOM283CBLYSA7124.98291.2077.1661.0062.59CATOM284CGLYSA7123.99991.5446.0561.0063.22CATOM285CDLYSA7124.63492.3874.9731.0064.60CATOM286CELYSA7123.64492.6353.8481.0065.13CATOM287NZLYSA7124.15993.5862.8311.0066.01NATOM288CLYSA7125.56789.5898.9871.0064.37CATOM289OLYSA7125.99088.4628.7371.0064.24OATOM290NASPA7226.02990.3369.9861.0067.27NATOM291CAASPA7227.15389.92810.8201.0070.03CATOM292CBASPA7227.48391.03711.8141.0070.83CATOM293CGASPA7228.29492.16211.1771.0073.07CATOM294OD1ASPA7227.82892.76410.1741.0075.44OATOM295OD2ASPA7229.41292.51111.6111.0074.89OATOM296CASPA7226.92388.61411.5511.0071.40CATOM297OASPA7227.87587.89511.8511.0071.59OATOM298NARGA7325.65888.28711.8051.0073.23NATOM299CAARGA7325.30487.06812.5401.0074.86CATOM300CBARGA7324.24187.38013.6021.0075.53CATOM301CGARGA7324.74188.29314.7181.0079.03CATOM302CDARGA7323.95988.15116.0431.0084.58CATOM303NEARGA7323.69286.75216.3941.0088.34NATOM304CZARGA7324.59885.90116.8781.0089.85CATOM305NH1ARGA7325.85786.29317.0831.0090.48NATOM306NH2ARGA7324.23984.65017.1611.0090.61NATOM307CARGA7324.83985.92911.6301.0075.02CATOM308OARGA7324.06785.06712.0541.0075.13OATOM309NILEA7425.32185.92610.3861.0075.26NATOM310CAILEA7424.96984.8859.4201.0075.36CATOM311CBILEA7424.35985.5038.1271.0075.17CATOM312CG1ILEA7423.18886.4258.4651.0074.84CATOM313CD1ILEA7422.66087.2047.2801.0075.37CATOM314CG2ILEA7423.89384.4087.1661.0074.86CATOM315CILEA7426.18984.0229.0881.0075.92CATOM316OILEA7427.20184.5198.5781.0076.08OATOM317NSERA7526.09082.7309.3861.0076.26NATOM318CASERA7527.15581.7849.0721.0076.63CATOM319CBSERA7527.18480.64110.0941.0077.05CATOM320OGSERA7526.00779.83910.0091.0078.24OATOM321CSERA7526.99081.2267.6601.0076.35CATOM322OSERA7527.91881.2856.8551.0076.40OATOM323NASPA7625.79880.7037.3721.0075.95NATOM324CAASPA7625.51280.0256.1091.0075.64CATOM325CBASPA7624.52878.8756.3321.0076.36CATOM326CGASPA7625.11277.7567.1571.0078.38CATOM327OD1ASPA7625.82876.9066.5791.0080.43OATOM328OD2ASPA7624.90077.6428.3911.0081.66OATOM329CASPA7624.94880.9525.0431.0074.58CATOM330OASPA7623.94681.6355.2621.0074.37OATOM331NTRPA7725.59280.9453.8791.0073.73NATOM332CATRPA7725.14881.7282.7301.0072.88CATOM333CBTRPA7726.15982.8262.3981.0072.08CATOM334CGTRPA7726.34583.8543.4551.0068.72CATOM335CD1TRPA7727.10583.7484.5821.0067.14CATOM336NE1TRPA7727.03884.9115.3131.0066.79NATOM337CE2TRPA7726.22885.8004.6571.0066.47CATOM338CD2TRPA7725.77685.1633.4781.0066.40CATOM339CE3TRPA7724.92685.8702.6201.0065.70CATOM340CZ3TRPA7724.55787.1692.9581.0065.66CATOM341CH2TRPA7725.02387.7704.1391.0065.79CATOM342CZ2TRPA7725.85887.1045.0001.0065.98CATOM343CTRPA7725.02080.8081.5291.0073.58CATOM344OTRPA7725.72779.8021.4341.0073.41OATOM345NGLYA7824.12781.1590.6101.0074.27NATOM346CAGLYA7823.95980.407−0.6231.0075.77CATOM347CGLYA7823.49181.313−1.7401.0077.06CATOM348OGLYA7823.42682.534−1.5671.0077.12OATOM349NGLUA7923.15780.725−2.8871.0078.52NATOM350CAGLUA7922.68581.517−4.0221.0080.32CATOM351CBGLUA7923.71081.532−5.1701.0080.86CATOM352CGGLUA7924.08380.152−5.7231.0083.43CATOM353CDGLUA7924.71380.234−7.1081.0085.86CATOM354OE1GLUA7925.81380.822−7.2351.0086.43OATOM355OE2GLUA7924.10779.708−8.0711.0086.75OATOM356CGLUA7921.31181.091−4.5181.0080.80CATOM357OGLUA7920.94879.917−4.4531.0080.46OATOM358NLEUA8020.55882.069−5.0121.0081.81NATOM359CALEUA8019.23381.837−5.5821.0082.81CATOM360CBLEUA8018.44183.152−5.5961.0082.78CATOM361CGLEUA8018.28983.870−4.2541.0083.30CATOM362CD1LEUA8017.54585.189−4.4321.0083.40CATOM363CD2LEUA8017.58882.965−3.2381.0083.57CATOM364CLEUA8019.34381.256−6.9981.0083.29CATOM365OLEUA8020.44081.256−7.5701.0083.54OATOM366NPROA8118.23580.753−7.5671.0083.78NATOM367CAPROA8118.22180.340−8.9861.0083.97CATOM368CBPROA8116.75879.937−9.2181.0083.94CATOM369CGPROA8116.26779.535−7.8711.0084.00CATOM370CDPROA8116.92780.513−6.9231.0083.86CATOM371CPROA8118.62381.488−9.9261.0084.09CATOM372OPROA8118.91081.267−11.1021.0084.07OATOM373NASNA8218.64482.700−9.3761.0084.20NATOM374CAASNA8219.07083.916−10.0641.0083.96CATOM375CBASNA8218.27685.106−9.4921.0084.25CATOM376CGASNA8218.73886.449−10.0261.0085.14CATOM377OD1ASNA8218.86986.643−11.2411.0085.89OATOM378ND2ASNA8218.97987.393−9.1151.0084.89NATOM379CASNA8220.58684.137−9.9351.0083.40CATOM380OASNA8221.19084.889−10.7091.0083.24OATOM381NGLYA8321.19183.461−8.9581.0082.90NATOM382CAGLYA8322.59783.634−8.6261.0082.10CATOM383CGLYA8322.84584.924−7.8631.0081.49CATOM384OGLYA8323.38285.883−8.4301.0081.74OATOM385NTHRA8422.43784.944−6.5901.0080.61NATOM386CATHRA8422.60986.097−5.6871.0079.41CATOM387CBTHRA8421.29086.893−5.5431.0079.60CATOM388OG1THRA8420.71887.127−6.8361.0080.05OATOM389CG2THRA8421.56188.322−5.0071.0079.91CATOM390CTHRA8423.08185.643−4.3021.0078.07CATOM391OTHRA8422.72884.557−3.8411.0078.47OATOM392NARGA8523.86686.489−3.6431.0075.99NATOM393CAARGA8524.44386.177−2.3381.0073.77CATOM394CBARGA8525.76886.943−2.1841.0074.21CATOM395CGARGA8526.45386.829−0.8331.0075.15CATOM396CDARGA8527.40485.638−0.7251.0075.91CATOM397NEARGA8528.21385.7310.4871.0076.30NATOM398CZARGA8528.95784.7390.9721.0077.02CATOM399NH1ARGA8529.00583.5600.3521.0076.24NATOM400NH2ARGA8529.65584.9292.0861.0077.19NATOM401CARGA8523.45786.502−1.1991.0071.72CATOM402OARGA8523.41587.632−0.6961.0071.91OATOM403NVALA8622.65385.514−0.8091.0068.61NATOM404CAVALA8621.66085.6930.2621.0065.46CATOM405CBVALA8620.19185.642−0.2651.0065.32CATOM406CG1VALA8619.97786.633−1.3941.0064.79CATOM407CG2VALA8619.82284.250−0.7091.0065.00CATOM408CVALA8621.86684.6561.3721.0063.06CATOM409OVALA8622.54383.6491.1441.0063.20OATOM410NPROA8721.30184.8872.5631.0060.50NATOM411CAPROA8721.39983.9073.6491.0058.23CATOM412CBPROA8720.57084.5444.7741.0058.22CATOM413CGPROA8720.59085.9994.4781.0059.47CATOM414CDPROA8720.53586.0822.9861.0060.10CATOM415CPROA8720.79782.5643.2371.0056.09CATOM416OPROA8719.80282.5242.5131.0055.24OATOM417NMETA8821.41681.4793.6811.0054.23NATOM418CAMETA8820.86680.1423.4581.0053.19CATOM419CBMETA8821.63879.1114.2951.0054.18CATOM420CGMETA8821.27377.6454.0251.0057.50CATOM421SDMETA8821.34177.2132.2471.0065.32SATOM422CEMETA8823.11377.1482.0021.0062.88CATOM423CMETA8819.36380.1033.7751.0050.99CATOM424OMETA8818.56579.5942.9791.0049.59OATOM425NGLUA8918.98280.6884.9181.0048.97NATOM426CAGLUA8917.57580.7545.3171.0046.86CATOM427CBGLUA8917.39281.6866.5221.0045.85CATOM428CGGLUA8915.94481.8036.9911.0045.51CATOM429CDGLUA8915.80382.5418.3031.0044.03CATOM430OE1GLUA8916.81983.0088.8561.0047.34OATOM431OE2GLUA8914.67182.6388.7901.0044.02OATOM432CGLUA8916.65381.1684.1711.0046.50CATOM433OGLUA8915.61280.5483.9621.0046.41OATOM434NVALA9017.03182.2153.4291.0046.05NATOM435CAVALA9016.24382.6692.2751.0045.86CATOM436CBVALA9016.75984.0181.7251.0046.25CATOM437CG1VALA9015.96684.4310.4911.0045.50CATOM438CG2VALA9016.66385.1022.8001.0046.57CATOM439CVALA9016.23481.6391.1371.0045.66CATOM440OVALA9015.21081.3990.5251.0045.75OATOM441NVALA9117.38981.0530.8511.0045.99NATOM442CAVALA9117.49080.034−0.1971.0046.17CATOM443CBVALA9118.91379.465−0.2791.0046.54CATOM444CG1VALA9118.97578.292−1.2841.0047.68CATOM445CG2VALA9119.89280.556−0.6741.0048.34CATOM446CVALA9116.49678.9090.0941.0044.94CATOM447OVALA9115.63178.603−0.7291.0045.36OATOM448NLEUA9216.59178.3521.3021.0043.94NATOM449CALEUA9215.70477.2601.7491.0042.33CATOM450CBLEUA9216.10676.7723.1371.0040.99CATOM451CGLEUA9217.57776.4173.3161.0040.75CATOM452CD1LEUA9217.79875.8674.7111.0037.63CATOM453CD2LEUA9218.06175.4102.2471.0040.38CATOM454CLEUA9214.24577.6411.7421.0042.09CATOM455OLEUA9213.40176.8881.2431.0041.96OATOM456NLEUA9313.93678.8122.2891.0042.17NATOM457CALEUA9312.55679.2802.3281.0043.42CATOM458CBLEUA9312.46180.6323.0511.0042.52CATOM459CGLEUA9312.41680.6454.5891.0042.30CATOM460CD1LEUA9312.57682.0745.0951.0039.64CATOM461CD2LEUA9311.11780.0695.1071.0039.20CATOM462CLEUA9311.94779.3820.9211.0044.51CATOM463OLEUA9310.82378.9400.6911.0044.42OATOM464NLYSA9412.69079.981−0.0121.0046.08NATOM465CALYSA9412.22280.098−1.3911.0047.69CATOM466CBLYSA9413.26680.807−2.2541.0048.80CATOM467CGLYSA9413.14682.329−2.1951.0052.89CATOM468CDLYSA9414.13383.009−3.1261.0057.20CATOM469CELYSA9413.76182.810−4.5981.0058.87CATOM470NZLYSA9412.41183.360−4.9191.0060.23NATOM471CLYSA9411.90378.730−1.9811.0047.52CATOM472OLYSA9410.87078.564−2.6331.0048.02OATOM473NLYSA9512.79277.766−1.7331.0047.55NATOM474CALYSA9512.61576.380−2.1851.0048.35CATOM475CBLYSA9513.83675.536−1.8291.0048.23CATOM476CGLYSA9515.02375.801−2.7471.0048.74CATOM477CDLYSA9516.29375.188−2.2121.0050.92CATOM478CELYSA9516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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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5.69259.5235.2731.0042.45CATOM1510NE2HISA21925.98259.0106.4551.0043.76NATOM1511CD2HISA21924.93559.2467.3171.0041.90CATOM1512CHISA21921.40462.5217.8431.0039.33CATOM1513OHISA21920.77962.3708.8891.0038.64OATOM1514NGLYA22020.96563.2706.8361.0038.11NATOM1515CAGLYA22019.78464.1036.9501.0037.81CATOM1516CGLYA22018.52763.3947.4051.0038.27CATOM1517OGLYA22017.93163.7458.4291.0037.53OATOM1518NARGA22118.12262.3866.6471.0038.11NATOM1519CAARGA22116.85561.7176.8951.0038.50CATOM1520CBARGA22116.54260.7295.7671.0040.47CATOM1521CGARGA22116.58561.4014.3881.0045.37CATOM1522CDARGA22116.57560.4483.1851.0051.09CATOM1523NEARGA22116.58461.2001.9191.0053.82NATOM1524CZARGA22117.69061.4951.2221.0055.73CATOM1525NH1ARGA22118.89461.0991.6461.0056.00NATOM1526NH2ARGA22117.59462.1640.0751.0055.14NATOM1527CARGA22116.82461.0508.2561.0037.41CATOM1528OARGA22115.87361.2549.0131.0037.16OATOM1529NSERA22217.85860.2908.5971.0036.13NATOM1530CASERA22217.83659.5639.8631.0035.73CATOM1531CBSERA22218.90058.4489.8901.0034.73CATOM1532OGSERA22220.21558.9689.7721.0036.77OATOM1533CSERA22217.94160.51911.0691.0035.26CATOM1534OSERA22217.36560.25012.1371.0035.32OATOM1535NALAA22318.64761.63310.8991.0034.89NATOM1536CAALAA22318.74362.64311.9581.0034.34CATOM1537CBALAA22319.84763.66011.6661.0032.42CATOM1538CALAA22317.39963.35012.1011.0034.25CATOM1539OALAA22316.99263.72613.2141.0033.94OATOM1540NALAA22416.69963.52310.9831.0033.64NATOM1541CAALAA22415.38464.15211.0331.0032.93CATOM1542CBALAA22414.86264.4569.6511.0033.29CATOM1543CALAA22414.41063.26911.8121.0033.44CATOM1544OALAA22413.64563.77012.6511.0033.58OATOM1545NVALA22514.45561.96211.5621.0032.40NATOM1546CAVALA22513.56961.00312.2281.0031.69CATOM1547CBVALA22513.72459.57411.6221.0032.53CATOM1548CG1VALA22513.08358.50412.5071.0030.93CATOM1549CG2VALA22513.12359.54410.2191.0032.75CATOM1550CVALA22513.85660.98813.7401.0032.12CATOM1551OVALA22512.94360.87614.5521.0031.44OATOM1552NTRPA22615.12561.11714.1101.0031.95NATOM1553CATRPA22615.47661.17315.5301.0032.47CATOM1554CBTRPA22616.99061.27915.7211.0033.06CATOM1555CGTRPA22617.32261.49417.1831.0032.56CATOM1556CD1TRPA22617.33462.68217.8511.0032.49CATOM1557NE1TRPA22617.66062.47919.1731.0032.64NATOM1558CE2TRPA22617.83461.13419.3831.0031.73CATOM1559CD2TRPA22617.63160.48518.1481.0031.24CATOM1560CE3TRPA22617.75759.08918.0941.0032.89CATOM1561CZ3TRPA22618.09658.39119.2611.0032.32CATOM1562CH2TRPA22618.28659.08020.4781.0033.34CATOM1563CZ2TRPA22618.15760.44420.5521.0032.43CATOM1564CTRPA22614.75462.37216.1781.0032.00CATOM1565OTRPA22614.07162.22417.1921.0031.94OATOM1566NSERA22714.87263.54615.5581.0031.65NATOM1567CASERA22714.21764.75216.0731.0031.57CATOM1568CBSERA22714.61165.98215.2591.0031.61CATOM1569OGSERA22713.91666.04814.0161.0033.45OATOM1570CSERA22712.69564.59916.1611.0031.31CATOM1571OSERA22712.05265.15117.0721.0030.56OATOM1572NLEUA22812.12463.84115.2291.0030.36NATOM1573CALEUA22810.70163.54515.2171.0030.48CATOM1574CBLEUA22810.30062.86513.9011.0030.69CATOM1575CGLEUA22810.32563.76712.6611.0031.45CATOM1576CD1LEUA22810.06962.94711.3891.0030.81CATOM1577CD2LEUA2289.32164.91712.7841.0030.15CATOM1578CLEUA22810.31562.66116.3941.0029.84CATOM1579OLEUA2289.22762.81516.9581.0030.50OATOM1580NGLYA22911.20661.75116.7651.0029.67NATOM1581CAGLYA22911.00860.89517.9201.0029.67CATOM1582CGLYA22910.99461.72319.2081.0030.52CATOM1583OGLYA22910.16961.48620.1051.0028.98OATOM1584NILEA23011.92062.67019.3071.0030.54NATOM1585CAILEA23011.98663.58720.4591.0031.11CATOM1586CBILEA23013.19964.56420.3341.0031.68CATOM1587CG1ILEA23014.52663.79220.2811.0030.92CATOM1588CD1ILEA23014.82462.99221.5461.0030.66CATOM1589CG2ILEA23013.22965.55321.5331.0030.61CATOM1590CILEA23010.69364.39720.5321.0031.56CATOM1591OILEA23010.05064.48821.5961.0031.09OATOM1592NLEUA23110.28964.92819.3731.0030.97NATOM1593CALEUA2319.05065.71119.2571.0030.14CATOM1594CBLEUA2318.89466.23917.8281.0030.10CATOM1595CGLEUA2317.62767.04317.5561.0032.25CATOM1596CD1LEUA2317.73368.37218.3101.0030.47CATOM1597CD2LEUA2317.41967.24616.0651.0030.92CATOM1598CLEUA2317.79864.95019.6891.0030.59CATOM1599OLEUA2316.94965.48420.4391.0030.81OATOM1600NLEUA2327.65563.72119.2101.0029.58NATOM1601CALEUA2326.49962.91619.5521.0030.41CATOM1602CBLEUA2326.47061.60918.7451.0030.17CATOM1603CGLEUA2325.30160.64219.0331.0030.99CATOM1604CD1LEUA2323.94761.34618.9191.0033.55CATOM1605CD2LEUA2325.35959.46518.0731.0031.95CATOM1606CLEUA2326.43962.63021.0621.0030.78CATOM1607OLEUA2325.37162.72121.6671.0031.42OATOM1608NTYRA2337.57162.27221.6501.0030.02NATOM1609CATYRA2337.64662.04223.1031.0030.55CATOM1610CBTYRA2339.06861.66223.5261.0030.26CATOM1611CGTYRA2339.20961.37325.0081.0028.93CATOM1612CD1TYRA2339.25562.41625.9301.0029.15CATOM1613CE1TYRA2339.35362.17127.3111.0028.65CATOM1614CZTYRA2339.40760.88227.7691.0031.81CATOM1615OHTYRA2339.50560.68129.1321.0036.02OATOM1616CE2TYRA2339.36559.80126.8781.0030.59CATOM1617CD2TYRA2339.26760.05825.4861.0028.47CATOM1618CTYRA2337.21663.30623.8341.0031.37CATOM1619OTYRA2336.41663.25024.7691.0032.79OATOM1620NASPA2347.76264.43423.4071.0031.52NATOM1621CAASPA2347.41165.75023.9341.0033.52CATOM1622CBASPA2348.15666.83323.1621.0034.26CATOM1623CGASPA2347.95168.22423.7451.0037.82CATOM1624OD1ASPA2348.20668.45024.9561.0039.31OATOM1625OD2ASPA2347.53169.15623.0301.0039.97OATOM1626CASPA2345.92366.02323.9231.0034.29CATOM1627OASPA2345.36866.52424.9311.0035.28OATOM1628NMETA2355.25865.69522.8101.0033.03NATOM1629CAMETA2353.81965.90422.7131.0033.96CATOM1630CBMETA2353.29365.62521.3051.0033.12CATOM1631CGMETA2353.64166.70820.2861.0036.42CATOM1632SDMETA2352.96566.24618.6921.0039.55SATOM1633CEMETA2354.17465.26018.1471.0043.23CATOM1634CMETA2353.02065.07823.7031.0033.96CATOM1635OMETA2352.13365.60724.3371.0035.00OATOM1636NVALA2363.32263.78723.8161.0034.07NATOM1637CAVALA2362.51862.89324.6601.0035.02CATOM1638CBVALA2362.40561.47624.0551.0035.33CATOM1639CG1VALA2361.75761.56222.6731.0034.30CATOM1640CG2VALA2363.76360.80523.9371.0033.11CATOM1641CVALA2362.95562.84326.1291.0035.63CATOM1642OVALA2362.22562.32626.9701.0035.58OATOM1643NCYSA2374.13163.38926.4321.0036.11NATOM1644CACYSA2374.64263.38327.8141.0036.98CATOM1645CBCYSA2375.97262.63027.9091.0036.35CATOM1646SGCYSA2375.79660.84427.7571.0038.34SATOM1647CCYSA2374.79064.77828.4161.0037.40CATOM1648OCYSA2374.98364.90729.6281.0038.17OATOM1649NGLYA2384.72265.81227.5761.0036.49NATOM1650CAGLYA2384.79167.18328.0451.0036.34CATOM1651CGLYA2386.18667.71728.2591.0037.64CATOM1652OGLYA2386.35368.84228.7191.0037.75OATOM1653NASPA2397.19866.91627.9391.0038.11NATOM1654CAASPA2398.58067.36928.0091.0039.21CATOM1655CBASPA2399.05667.33929.4581.0040.74CATOM1656CGASPA23910.21468.30229.7351.0045.40CATOM1657OD1ASPA23910.58669.13528.8671.0049.01OATOM1658OD2ASPA23910.82268.27430.8281.0050.33OATOM1659CASPA2399.41866.43427.1421.0039.28CATOM1660OASPA2398.95765.35426.7691.0039.18OATOM1661NILEA24010.63066.85626.8091.0039.54NATOM1662CAILEA24011.52966.06625.9831.0039.95CATOM1663CBILEA24012.64166.96425.4401.0040.83CATOM1664CG1ILEA24013.30667.74026.5781.0041.83CATOM1665CD1ILEA24014.45568.62726.1251.0044.95CATOM1666CG2ILEA24012.09267.91124.3441.0039.77CATOM1667CILEA24012.10664.91626.8271.0040.26CATOM1668OILEA24012.18765.04628.0491.0040.89OATOM1669NPROA24112.47063.79126.2101.0040.14NATOM1670CAPROA24112.94162.62026.9711.0041.03CATOM1671CBPROA24112.87961.49425.9321.0040.79CATOM1672CGPROA24113.15062.18724.6221.0039.44CATOM1673CDPROA24112.44463.51824.7571.0039.54CATOM1674CPROA24114.36162.73727.5481.0042.89CATOM1675OPROA24114.63962.10928.5711.0042.98OATOM1676NPHEA24215.24363.50826.9121.0044.80NATOM1677CAPHEA24216.64463.55527.3401.0046.51CATOM1678CBPHEA24217.58962.94426.2851.0045.41CATOM1679CGPHEA24217.14561.61725.7351.0043.12CATOM1680CD1PHEA24216.88560.54526.5781.0042.42CATOM1681CE1PHEA24216.49659.31326.0681.0041.08CATOM1682CZPHEA24216.36759.14824.6761.0043.10CATOM1683CE2PHEA24216.61860.22223.8241.0040.87CATOM1684CD2PHEA24217.01261.43824.3501.0042.39CATOM1685CPHEA24217.10464.97327.6391.0048.94CATOM1686OPHEA24216.78365.91326.9031.0048.57OATOM1687NGLUA24317.88465.11228.7141.0052.57NATOM1688CAGLUA24318.51466.39129.0461.0055.94CATOM1689CBGLUA24318.20466.79330.4961.0057.25CATOM1690CGGLUA24316.93067.63430.6641.0062.51CATOM1691CDGLUA24316.91168.91229.8141.0068.14CATOM1692OE1GLUA24317.90169.69729.8541.0069.83OATOM1693OE2GLUA24315.89469.14029.1041.0069.55OATOM1694CGLUA24320.02266.36428.8131.0056.70CATOM1695OGLUA24320.59667.32928.2911.0057.61OATOM1696NHISA24420.65465.25029.1691.0057.00NATOM1697CAHISA24422.11165.14529.1281.0057.57CATOM1698CBHISA24422.63464.65330.4841.0057.93CATOM1699CGHISA24422.17765.49131.6411.0060.15CATOM1700ND1HISA24421.24365.04032.5631.0061.46NATOM1701CE1HISA24421.02165.98633.4591.0061.53CATOM1702NE2HISA24421.77267.04033.1451.0061.93NATOM1703CD2HISA24422.50166.76132.0081.0060.89CATOM1704CHISA24422.63264.25127.9991.0057.12CATOM1705OHISA24421.94663.32127.5641.0056.42OATOM1706NASPA24523.85064.55027.5421.0056.65NATOM1707CAASPA24524.53663.77826.5081.0056.51CATOM1708CBASPA24525.98264.25426.3641.0056.84CATOM1709CGASPA24526.09365.55125.6021.0058.28CATOM1710OD1ASPA24525.10966.32225.5551.0060.57OATOM1711OD2ASPA24527.13265.88925.0031.0061.68OATOM1712CASPA24524.52062.28926.7921.0055.85CATOM1713OASPA24524.24061.48725.9021.0055.84OATOM1714NGLUA24624.80761.92628.0381.0055.12NATOM1715CAGLUA24624.81460.52828.4731.0054.57CATOM1716CBGLUA24625.22760.41429.9481.0055.49CATOM1717CGGLUA24626.24761.43930.4191.0059.92CATOM1718CDGLUA24625.60162.74530.8531.0064.57CATOM1719OE1GLUA24624.86462.73231.8731.0066.43OATOM1720OE2GLUA24625.82463.77930.1651.0066.00OATOM1721CGLUA24623.46459.83828.2841.0052.76CATOM1722OGLUA24623.40558.63727.9981.0051.94OATOM1723NGLUA24722.38160.58328.4911.0051.08NATOM1724CAGLUA24721.03760.03128.2891.0050.00CATOM1725CBGLUA24719.98260.94928.8881.0050.91CATOM1726CGGLUA24720.04861.06930.3981.0054.76CATOM1727CDGLUA24719.07062.08930.9191.0059.14CATOM1728OE1GLUA24719.18963.28130.5681.0061.88OATOM1729OE2GLUA24718.17261.69331.6721.0063.68OATOM1730CGLUA24720.73459.78526.8101.0047.56CATOM1731OGLUA24720.17758.75726.4631.0046.72OATOM1732NILEA24821.10260.73825.9571.0046.28NATOM1733CAILEA24820.96460.59824.4981.0046.12CATOM1734CBILEA24821.44661.87623.7541.0045.90CATOM1735CG1ILEA24820.59963.09224.1411.0044.91CATOM1736CD1ILEA24821.11064.41923.5881.0044.29CATOM1737CG2ILEA24821.44461.65822.2331.0045.48CATOM1738CILEA24821.74159.39023.9881.0046.47CATOM1739OILEA24821.22158.61323.1991.0046.50OATOM1740NILEA24922.97759.22324.4621.0046.70NATOM1741CAILEA24923.84558.11924.0211.0047.73CATOM1742CBILEA24925.31558.34224.5161.0048.27CATOM1743CG1ILEA24925.88259.63423.9291.0050.01CATOM1744CD1ILEA24927.16260.11424.6381.0054.07CATOM1745CG2ILEA24926.20857.16724.1271.0049.80CATOM1746CILEA24923.34456.75224.4631.0047.21CATOM1747OILEA24923.47355.75423.7351.0047.14OATOM1748NARGA25022.79856.69725.6711.0046.59NATOM1749CAARGA25022.25955.45426.1971.0046.70CATOM1750CBARGA25022.05255.57327.7121.0046.73CATOM1751CGARGA25021.61254.29728.4151.0047.47CATOM1752CDARGA25021.70254.41529.9421.0049.11CATOM1753NEARGA25021.29053.19130.6311.0050.87NATOM1754CZARGA25020.21753.07631.4291.0050.66CATOM1755NH1ARGA25019.41254.11731.6561.0046.65NATOM1756NH2ARGA25019.95551.90932.0061.0050.26NATOM1757CARGA25020.94955.09725.4831.0046.42CATOM1758OARGA25020.61753.92225.3521.0047.00OATOM1759NGLYA25120.22456.11325.0181.0046.84NATOM1760CAGLYA25118.98255.93624.2691.0047.26CATOM1761CGLYA25117.85555.18024.9681.0047.36CATOM1762OGLYA25116.93654.70224.3181.0047.71OATOM1763NGLNA25217.92155.06726.2901.0046.77NATOM1764CAGLNA25216.87254.40027.0581.0046.61CATOM1765CBGLNA25217.43853.96528.4101.0047.77CATOM1766CGGLNA25216.74552.79729.0341.0053.27CATOM1767CDGLNA25217.36251.49528.5931.0058.82CATOM1768OE1GLNA25216.92250.90227.5871.0062.58OATOM1769NE2GLNA25218.38151.04029.3281.0059.71NATOM1770CGLNA25215.72055.38827.2641.0044.36CATOM1771OGLNA25215.91456.45827.8421.0043.90OATOM1772NVALA25314.53455.03626.7891.0042.26NATOM1773CAVALA25313.36655.91726.8871.0041.30CATOM1774CBVALA25312.51555.90025.5741.0040.85CATOM1775CG1VALA25311.39856.91725.6571.0041.13CATOM1776CG2VALA25313.38656.18424.3301.0041.05CATOM1777CVALA25312.45255.55828.0801.0040.21CATOM1778OVALA25311.87054.47528.1281.0039.18OATOM1779NPHEA25412.31256.49429.0041.0040.53NATOM1780CAPHEA25411.41556.34030.1471.0041.30CATOM1781CBPHEA25412.12556.74931.4461.0042.46CATOM1782CGPHEA25411.18156.97932.5971.0045.89CATOM1783CD1PHEA25410.69855.89033.3541.0048.15CATOM1784CE1PHEA2549.79456.08734.4531.0046.65CATOM1785CZPHEA2549.36857.39134.7621.0047.61CATOM1786CE2PHEA2549.84058.49933.9901.0048.28CATOM1787CD2PHEA25410.74258.28732.9221.0047.87CATOM1788CPHEA25410.19257.21629.9601.0040.77CATOM1789OPHEA25410.32458.38829.6301.0040.62OATOM1790NPHEA2559.01156.65630.2021.0039.76NATOM1791CAPHEA2557.77257.37730.0411.0040.05CATOM1792CBPHEA2556.74456.51229.2931.0038.87CATOM1793CGPHEA2557.04756.40827.8441.0038.12CATOM1794CD1PHEA2556.52057.33226.9451.0037.51CATOM1795CE1PHEA2556.83457.26725.5881.0037.08CATOM1796CZPHEA2557.71556.27725.1261.0038.31CATOM1797CE2PHEA2558.25155.35326.0341.0037.42CATOM1798CD2PHEA2557.91755.42927.3791.0036.49CATOM1799CPHEA2557.23357.90131.3551.0040.75CATOM1800OPHEA2556.97457.13932.2801.0041.63OATOM1801NARGA2567.07859.21431.4141.0042.10NATOM1802CAARGA2566.61359.91132.6141.0043.68CATOM1803CBARGA2567.28461.29132.7221.0044.33CATOM1804CGARGA2567.05062.23331.5491.0046.48CATOM1805CDARGA2567.91563.50831.6061.0049.15CATOM1806NEARGA2569.24863.27731.0341.0053.26NATOM1807CZARGA25610.33464.01831.2931.0054.62CATOM1808NH1ARGA25610.26065.06032.1331.0055.57NATOM1809NH2ARGA25611.50263.72030.7161.0052.61NATOM1810CARGA2565.09660.05132.6581.0043.59CATOM1811OARGA2564.52560.25133.7241.0044.72OATOM1812NGLNA2574.45459.93031.4981.0042.63NATOM1813CAGLNA2573.00159.94931.4031.0041.06CATOM1814CBGLNA2572.53861.06130.4451.0042.46CATOM1815CGGLNA2572.89062.45130.9011.0046.35CATOM1816CDGLNA2571.90862.98431.9161.0051.18CATOM1817OE1GLNA2570.69362.91731.7111.0052.75OATOM1818NE2GLNA2572.42863.50433.0201.0055.05NATOM1819CGLNA2572.51058.61830.8721.0038.68CATOM1820OGLNA2573.26757.84930.3001.0038.45OATOM1821NARGA2581.22658.35331.0471.0036.14NATOM1822CAARGA2580.61457.17730.4791.0036.06CATOM1823CBARGA258−0.82057.04830.9971.0034.77CATOM1824CGARGA258−1.40255.65930.8471.0039.04CATOM1825CDARGA258−1.62455.23029.4421.0040.99CATOM1826NEARGA258−1.79953.78929.3001.0040.39NATOM1827CZARGA258−2.32753.21928.2151.0043.89CATOM1828NH1ARGA258−2.73053.96627.1581.0045.06NATOM1829NH2ARGA258−2.44451.89928.1621.0040.81NATOM1830CARGA2580.59957.34528.9501.0035.62CATOM1831OARGA2580.07158.32528.4631.0035.32OATOM1832NVALA2591.15956.38528.2211.0034.94NATOM1833CAVALA2591.22356.44026.7551.0034.87CATOM1834CBVALA2592.62956.92626.2771.0035.54CATOM1835CG1VALA2592.78256.82424.7471.0034.21CATOM1836CG2VALA2592.90258.36526.7521.0033.65CATOM1837CVALA2590.96755.03326.2351.0035.77CATOM1838OVALA2591.57954.06226.7281.0035.74OATOM1839NSERA2600.05554.90125.2671.0035.24NATOM1840CASERA260−0.26953.60124.6981.0036.49CATOM1841CBSERA260−1.24753.74923.5251.0036.47CATOM1842OGSERA260−0.60854.28522.3771.0037.04OATOM1843CSERA2600.97352.85524.2261.0037.15CATOM1844OSERA2601.98153.46523.8741.0037.30OATOM1845NSERA2610.87651.53324.1781.0037.42NATOM1846CASERA2612.00050.70123.7671.0037.73CATOM1847CBSERA2611.65949.22523.9411.0038.27CATOM1848OGSERA2611.47548.93925.3161.0042.42OATOM1849CSERA2612.39950.96522.3251.0037.68CATOM1850OSERA2613.57850.91421.9971.0036.60OATOM1851NGLUA2621.41351.26021.4781.0037.69NATOM1852CAGLUA2621.66251.57820.0801.0038.33CATOM1853CBGLUA2620.34351.65519.3071.0040.07CATOM1854CGGLUA262−0.52250.40119.4441.0047.46CATOM1855CDGLUA262−1.13849.95418.1251.0055.14CATOM1856OE1GLUA262−1.71650.81117.4071.0058.98OATOM1857OE2GLUA262−1.05848.74017.7991.0059.70OATOM1858CGLUA2622.46952.87819.9451.0036.65CATOM1859OGLUA2623.44252.91119.2271.0036.27OATOM1860NCYSA2632.07353.93120.6511.0035.34NATOM1861CACYSA2632.82255.18820.6211.0034.46CATOM1862CBCYSA2632.05156.27221.3631.0034.30CATOM1863SGCYSA2632.72857.93121.2071.0034.38SATOM1864CCYSA2634.25055.02121.1811.0034.46CATOM1865OCYSA2635.22155.47720.5561.0032.45OATOM1866NGLNA2644.38554.32522.3211.0033.42NATOM1867CAGLNA2645.71554.00822.8591.0033.11CATOM1868CBGLNA2645.62953.11024.0971.0033.38CATOM1869CGGLNA2645.02253.78125.3641.0035.44CATOM1870CDGLNA2645.29652.96826.6471.0037.59CATOM1871OE1GLNA2646.16252.09826.6551.0039.41OATOM1872NE2GLNA2644.56653.26227.7171.0033.63NATOM1873CGLNA2646.57853.31421.7951.0033.15CATOM1874OGLNA2647.75353.68921.6061.0032.43OATOM1875NHISA2656.00152.32221.1101.0032.53NATOM1876CAHISA2656.71051.57520.0681.0034.99CATOM1877CBHISA2655.83650.45519.4691.0036.23CATOM1878CGHISA2656.51549.68718.3691.0039.71CATOM1879ND1HISA2656.48150.08617.0501.0040.80NATOM1880CE1HISA2657.18949.24416.3141.0042.05CATOM1881NE2HISA2657.68748.31217.1101.0042.46NATOM1882CD2HISA2657.28648.57018.4021.0042.81CATOM1883CHISA2657.22652.50818.9681.0034.14CATOM1884OHISA2658.41052.46318.6131.0034.55OATOM1885NLEUA2666.35553.37218.4451.0032.99NATOM1886CALEUA2666.77854.30617.3941.0032.41CATOM1887CBLEUA2665.58755.14716.8961.0032.45CATOM1888CGLEUA2665.86356.20915.8181.0033.18CATOM1889CD1LEUA2666.58455.61914.6051.0030.32CATOM1890CD2LEUA2664.51156.82015.3671.0030.03CATOM1891CLEUA2667.88555.21117.9041.0031.79CATOM1892OLEUA2668.90755.41717.2311.0031.14OATOM1893NILEA2677.70655.75019.1121.0031.36NATOM1894CAILEA2678.70256.66119.6661.0030.41CATOM1895CBILEA2678.27357.18421.0521.0029.95CATOM1896CG1ILEA2677.13458.21020.9241.0030.35CATOM1897CD1ILEA2676.41058.51322.2711.0030.22CATOM1898CG2ILEA2679.47257.84921.7511.0028.77CATOM1899CILEA26710.05255.95619.7821.0031.85CATOM1900OILEA26711.09356.48519.3401.0032.22OATOM1901NARGA26810.03454.77420.3881.0032.17NATOM1902CAARGA26811.24853.98820.5941.0034.65CATOM1903CBARGA26810.92752.71321.3691.0035.11CATOM1904CGARGA26810.70752.93122.8641.0039.57CATOM1905CDARGA26810.39851.63723.6001.0045.10CATOM1906NEARGA2689.72551.86624.8901.0048.08NATOM1907CZARGA26810.37052.33825.9351.0049.97CATOM1908NH1ARGA26811.66352.60925.8061.0053.48NATOM1909NH2ARGA2689.75352.55127.0931.0048.54NATOM1910CARGA26811.92153.62219.2781.0034.22CATOM1911OARGA26813.14053.49119.2231.0034.73OATOM1912NTRPA26911.12453.46418.2251.0034.43NATOM1913CATRPA26911.64953.13516.8891.0034.10CATOM1914CBTRPA26910.50352.65715.9921.0034.69CATOM1915CGTRPA26910.92152.00814.7161.0036.80CATOM1916CD1TRPA26912.19151.63214.3521.0039.30CATOM1917NE1TRPA26912.18251.08113.0901.0038.76NATOM1918CE2TRPA26910.89551.07112.6181.0037.50CATOM1919CD2TRPA26910.07451.66913.6091.0036.90CATOM1920CE3TRPA2698.70351.78713.3591.0035.95CATOM1921CZ3TRPA2698.19751.33212.1361.0037.55CATOM1922CH2TRPA2699.04750.76511.1721.0036.64CATOM1923CZ2TRPA26910.39250.61811.4011.0036.32CATOM1924CTRPA26912.34654.35116.2791.0034.12CATOM1925OTRPA26913.46154.24815.7661.0034.65OATOM1926NCYSA27011.70455.51416.3471.0033.89NATOM1927CACYSA27012.31556.76215.8811.0033.18CATOM1928CBCYSA27011.36457.95816.0301.0032.73CATOM1929SGCYSA2709.89457.93314.9801.0034.78SATOM1930CCYSA27013.59357.08516.6271.0033.31CATOM1931OCYSA27014.47157.75916.0851.0033.37OATOM1932NLEUA27113.68656.63517.8791.0032.81NATOM1933CALEUA27114.83556.93418.7111.0033.61CATOM1934CBLEUA27114.40557.34220.1431.0033.79CATOM1935CGLEUA27113.57358.64920.2231.0033.39CATOM1936CD1LEUA27113.17858.97121.6681.0032.58CATOM1937CD2LEUA27114.33059.82019.6021.0029.30CATOM1938CLEUA27115.80555.76618.7611.0034.83CATOM1939OLEUA27116.53655.61319.7271.0034.16OATOM1940NALAA27215.83654.95817.7051.0035.68NATOM1941CAALAA27216.79653.85317.6581.0037.00CATOM1942CBALAA27216.56352.99416.4291.0037.89CATOM1943CALAA27218.19154.46017.6581.0037.13CATOM1944OALAA27218.43655.46616.9961.0036.83OATOM1945NLEUA27319.08753.88618.4471.0038.00NATOM1946CALEUA27320.46454.37818.5371.0039.46CATOM1947CBLEUA27321.26653.53119.5321.0039.79CATOM1948CGLEUA27320.99053.79521.0111.0040.61CATOM1949CD1LEUA27321.92352.96621.9141.0040.75CATOM1950CD2LEUA27321.17455.27721.3041.0039.54CATOM1951CLEUA27321.14654.35017.1681.0040.47CATOM1952OLEUA27321.74255.33116.7471.0040.46OATOM1953NARGA27421.05153.22516.4701.0041.49NATOM1954CAARGA27421.67053.13815.1511.0043.63CATOM1955CBARGA27421.92951.68314.7531.0044.96CATOM1956CGARGA27422.91750.94315.6651.0051.46CATOM1957CDARGA27423.14549.47015.2751.0060.47CATOM1958NEARGA27423.42649.35413.8421.0066.38NATOM1959CZARGA27423.51148.21213.1721.0069.93CATOM1960NH1ARGA27423.34447.04813.7921.0071.16NATOM1961NH2ARGA27423.77548.23911.8681.0072.00NATOM1962CARGA27420.78453.82614.1171.0042.18CATOM1963OARGA27419.63253.46913.9591.0042.54OATOM1964NPROA27521.32554.80713.4091.0041.48NATOM1965CAPROA27520.56655.52912.3831.0041.53CATOM1966CBPROA27521.65556.30211.6481.0041.70CATOM1967CGPROA27522.61856.62912.7451.0041.06CATOM1968CDPROA27522.69355.34013.5461.0041.06CATOM1969CPROA27519.78454.62411.4291.0041.71CATOM1970OPROA27518.63354.93211.1321.0039.61OATOM1971NSERA27620.39353.51610.9931.0041.90NATOM1972CASERA27619.77452.58710.0401.0042.57CATOM1973CBSERA27620.83151.6249.4461.0043.08CATOM1974OGSERA27621.29050.68310.4191.0045.84OATOM1975CSERA27618.59751.79910.6131.0041.74CATOM1976OSERA27617.78651.2879.8451.0042.39OATOM1977NASPA27718.49751.69611.9421.0040.48NATOM1978CAASPA27717.34451.03812.5751.0039.45CATOM1979CBASPA27717.67650.52013.9811.0040.14CATOM1980CGASPA27718.67149.37413.9741.0041.45CATOM1981OD1ASPA27718.69748.57713.0101.0043.47OATOM1982OD2ASPA27719.47149.22114.9151.0043.49OATOM1983CASPA27716.10251.94612.6761.0038.59CATOM1984OASPA27715.01051.48613.0141.0037.61OATOM1985NARGA27816.26953.22712.3641.0037.09NATOM1986CAARGA27815.14554.15912.4481.0035.81CATOM1987CBARGA27815.65755.59812.5451.0034.54CATOM1988CGARGA27816.40755.83613.8361.0034.40CATOM1989CDARGA27817.01757.22513.9571.0035.33CATOM1990NEARGA27818.11957.18614.9131.0035.31NATOM1991CZARGA27819.16357.99614.9131.0036.13CATOM1992NH1ARGA27819.28658.97114.0101.0034.75NATOM1993NH2ARGA27820.10357.81515.8291.0036.28NATOM1994CARGA27814.22353.98311.2431.0036.08CATOM1995OARGA27814.68753.61010.1561.0036.69OATOM1996NPROA27912.93654.27511.4211.0035.45NATOM1997CAPROA27911.98454.19310.3141.0035.56CATOM1998CBPROA27910.62754.30311.0041.0035.57CATOM1999CGPROA27910.91555.14712.2241.0035.53CATOM2000CDPROA27912.28454.71012.6771.0035.37CATOM2001CPROA27912.17455.3229.3111.0035.53CATOM2002OPROA27912.78456.3549.6261.0035.63OATOM2003NTHRA28011.66155.1078.1011.0034.84NATOM2004CATHRA28011.61856.1457.0791.0034.43CATOM2005CBTHRA28011.50955.5135.6831.0034.63CATOM2006OG1THRA28010.34454.6905.6551.0034.43OATOM2007CG2THRA28012.71254.5555.3791.0035.88CATOM2008CTHRA28010.33456.9007.3371.0034.28CATOM2009OTHRA2809.50156.4588.1201.0033.22OATOM2010NPHEA28110.12958.0126.6371.0035.30NATOM2011CAPHEA2818.89358.7716.7971.0035.82CATOM2012CBPHEA2818.89260.0205.9071.0036.90CATOM2013CGPHEA2819.98461.0096.2231.0038.29CATOM2014CD1PHEA28110.33261.3007.5361.0039.19CATOM2015CE1PHEA28111.32062.2347.8231.0039.73CATOM2016CZPHEA28111.96862.8746.8101.0041.57CATOM2017CE2PHEA28111.62162.6085.4831.0043.04CATOM2018CD2PHEA28110.63361.6815.2001.0041.16CATOM2019CPHEA2817.69057.8946.4771.0036.17CATOM2020OPHEA2816.67157.9247.1791.0035.36OATOM2021NGLUA2827.81557.1015.4141.0035.33NATOM2022CAGLUA2826.74156.1944.9921.0035.04CATOM2023CBGLUA2827.15455.4613.7001.0035.95CATOM2024CGGLUA2826.09254.5303.1411.0038.88CATOM2025CDGLUA2826.50453.8721.8191.0042.76CATOM2026OE1GLUA2827.65454.0561.3621.0043.67OATOM2027OE2GLUA2825.65453.1821.2331.0043.19OATOM2028CGLUA2826.38555.1996.0841.0034.27CATOM2029OGLUA2825.20954.9866.3781.0034.51OATOM2030NGLUA2837.39754.5946.6931.0034.18NATOM2031CAGLUA2837.19453.6407.7951.0034.58CATOM2032CBGLUA2838.51253.0128.2081.0035.26CATOM2033CGGLUA2839.07752.0967.1311.0038.60CATOM2034CDGLUA28310.40651.5017.5021.0040.02CATOM2035OE1GLUA28311.34052.2577.8321.0041.52OATOM2036OE2GLUA28310.51750.2667.4351.0044.14OATOM2037CGLUA2836.52454.2599.0141.0033.96CATOM2038OGLUA2835.70053.6149.6741.0033.93OATOM2039NILEA2846.85955.5179.2981.0033.26NATOM2040CAILEA2846.20456.23310.4011.0031.63CATOM2041CBILEA2846.88957.59010.6501.0031.52CATOM2042CG1ILEA2848.28257.37311.2521.0029.17CATOM2043CD1ILEA2849.19558.58511.1901.0032.09CATOM2044CG2ILEA2846.00258.48911.6021.0029.23CATOM2045CILEA2844.73256.43010.0891.0031.80CATOM2046OILEA2843.85656.16510.9171.0031.97OATOM2047NGLNA2854.45156.9178.8861.0032.64NATOM2048CAGLNA2853.07057.2048.5151.0032.77CATOM2049CBGLNA2853.02258.0997.2801.0032.86CATOM2050CGGLNA2853.37359.5667.6131.0032.93CATOM2051CDGLNA2853.05660.5076.4851.0035.30CATOM2052OE1GLNA2853.63760.4015.3951.0034.32OATOM2053NE2GLNA2852.12261.4236.7251.0033.69NATOM2054CGLNA2852.23955.9488.3341.0033.74CATOM2055OGLNA2851.02155.9968.4541.0034.52OATOM2056NASNA2862.88954.8168.0841.0034.59NATOM2057CAASNA2862.16553.5338.0161.0036.22CATOM2058CBASNA2862.77052.6076.9661.0035.90CATOM2059CGASNA2862.45053.0425.5531.0037.57CATOM2060OD1ASNA2861.39753.6115.2831.0037.74OATOM2061ND2ASNA2863.37352.7854.6421.0039.91NATOM2062CASNA2862.07952.8059.3601.0036.58CATOM2063OASNA2861.43251.7679.4661.0037.11OATOM2064NHISA2872.72353.35610.3841.0036.48NATOM2065CAHISA2872.67752.77111.7171.0036.00CATOM2066CBHISA2873.52553.59612.6971.0035.69CATOM2067CGHISA2873.70352.93814.0291.0033.97CATOM2068ND1HISA2874.82652.21114.3591.0035.79NATOM2069CE1HISA2874.70651.74915.5921.0034.10CATOM2070NE2HISA2873.53752.13816.0661.0036.32NATOM2071CD2HISA2872.88852.87515.1031.0033.02CATOM2072CHISA2871.23852.72412.2231.0036.98CATOM2073OHISA2870.47553.66311.9851.0036.67OATOM2074NPROA2880.87051.63812.9091.0037.63NATOM2075CAPROA288−0.46551.48013.4681.0038.40CATOM2076CBPROA288−0.31850.20314.3151.0039.46CATOM2077CGPROA2880.68449.42013.5761.0040.31CATOM2078CDPROA2881.69950.44713.1741.0038.01CATOM2079CPROA288−0.93652.65214.3251.0037.78CATOM2080OPROA288−2.09653.02414.2271.0038.92OATOM2081NTRPA289−0.06253.23115.1431.0037.99NATOM2082CATRPA289−0.45954.38715.9511.0036.84CATOM2083CBTRPA2890.64254.77916.9321.0037.43CATOM2084CGTRPA2890.19755.89217.8621.0036.44CATOM2085CD1TRPA289−0.60155.77618.9691.0036.79CATOM2086NE1TRPA289−0.80057.01419.5421.0035.91NATOM2087CE2TRPA289−0.13657.95618.7951.0035.04CATOM2088CD2TRPA2890.50057.28117.7301.0035.44CATOM2089CE3TRPA2891.27558.03416.8221.0034.75CATOM2090CZ3TRPA2891.36559.41217.0001.0033.10CATOM2091CH2TRPA2890.71960.04618.0721.0032.65CATOM2092CZ2TRPA289−0.02459.33718.9801.0035.41CATOM2093CTRPA289−0.88655.59815.1021.0037.02CATOM2094OTRPA289−1.70356.40215.5511.0036.85OATOM2095NMETA290−0.37555.70413.8751.0037.67NATOM2096CAMETA290−0.68156.85713.0021.0039.50CATOM2097CBMETA2900.47557.11912.0381.0038.69CATOM2098CGMETA2901.77057.55212.7371.0039.97CATOM2099SDMETA2902.02659.34012.6601.0043.39SATOM2100CEMETA2900.82659.82613.6091.0036.57CATOM2101CMETA290−1.97356.78712.1861.0041.20CATOM2102OMETA290−2.26957.70311.3971.0040.58OATOM2103NGLNA291−2.73555.70912.3381.0043.28NATOM2104CAGLNA291−3.92855.51611.5041.0045.49CATOM2105CBGLNA291−4.29454.03111.4201.0046.70CATOM2106CGGLNA291−3.16953.16310.8631.0052.12CATOM2107CDGLNA291−2.98953.2579.3301.0058.53CATOM2108OE1GLNA291−3.10754.3398.7231.0059.20OATOM2109NE2GLNA291−2.67452.1138.7081.0062.36NATOM2110CGLNA291−5.11256.32912.0011.0045.68CATOM2111OGLNA291−5.16556.70813.1771.0045.87OATOM2112NASPA292−6.06456.59011.1001.0046.07NATOM2113CAASPA292−7.30557.33111.4101.0046.57CATOM2114CBASPA292−8.19556.55612.3911.0047.72CATOM2115CGASPA292−8.32455.09912.0181.0052.03CATOM2116OD1ASPA292−8.71454.83610.8581.0054.96OATOM2117OD2ASPA292−8.03154.16412.8051.0056.19OATOM2118CASPA292−7.07158.73911.9611.0045.48CATOM2119OASPA292−7.77959.18112.8801.0044.34OATOM2120NVALA293−6.06759.43311.4241.0044.87NATOM2121CAVALA293−5.75060.78711.8821.0044.61CATOM2122CBVALA293−4.49561.33811.1811.0044.85CATOM2123CG1VALA293−4.79161.6629.7351.0044.77CATOM2124CG2VALA293−3.98962.56811.8961.0043.11CATOM2125CVALA293−6.93561.70911.6401.0044.94CATOM2126OVALA293−7.65861.53210.6531.0045.74OATOM2127NLEUA294−7.14962.66812.5381.0044.60NATOM2128CALEUA294−8.20963.65012.3541.0044.83CATOM2129CBLEUA294−8.48964.41613.6411.0043.88CATOM2130CGLEUA294−9.00963.72114.8861.0044.35CATOM2131CD1LEUA294−9.11864.76015.9721.0042.61CATOM2132CD2LEUA294−10.33763.03614.6321.0045.06CATOM2133CLEUA294−7.76364.65511.3121.0045.35CATOM2134OLEUA294−6.57064.88811.1421.0045.48OATOM2135NLEUA295−8.72865.26610.6291.0046.10NATOM2136CALEUA295−8.44466.3589.7121.0046.34CATOM2137CBLEUA295−9.64566.5868.7901.0047.42CATOM2138CGLEUA295−9.55265.9687.3801.0050.24CATOM2139CD1LEUA295−9.35264.4607.4151.0051.66CATOM2140CD2LEUA295−10.81266.2886.5951.0054.37CATOM2141CLEUA295−8.12367.61210.5271.0046.02CATOM2142OLEUA295−8.53167.72311.6931.0044.80OATOM2143NPROA296−7.36668.5449.9551.0046.46NATOM2144CAPROA296−7.04869.79010.6581.0047.09CATOM2145CBPROA296−6.40570.6339.5611.0046.93CATOM2146CGPROA296−5.69869.6098.7411.0045.84CATOM2147CDPROA296−6.70868.4968.6381.0046.93CATOM2148CPROA296−8.28270.46511.2661.0048.28CATOM2149OPROA296−8.28070.73912.4741.0047.68OATOM2150NGLNA297−9.33570.68410.4801.0050.01NATOM2151CAGLNA297−10.53771.32811.0221.0051.78CATOM2152CBGLNA297−11.57271.6369.9331.0052.87CATOM2153CGGLNA297−12.55272.78110.2981.0055.96CATOM2154CDGLNA297−11.85874.12210.6321.0060.05CATOM2155OE1GLNA297−11.22174.7399.7651.0062.29OATOM2156NE2GLNA297−11.99274.57011.8841.0060.16NATOM2157CGLNA297−11.17570.55012.1811.0051.71CATOM2158OGLNA297−11.53671.14013.2011.0052.21OATOM2159NGLUA298−11.29269.23412.0341.0051.63NATOM2160CAGLUA298−11.81968.39113.1081.0051.67CATOM2161CBGLUA298−11.71466.92212.7361.0052.61CATOM2162CGGLUA298−12.71666.40611.7321.0056.45CATOM2163CDGLUA298−12.56864.90811.5521.0060.37CATOM2164OE1GLUA298−11.60664.48010.8741.0061.21OATOM2165OE2GLUA298−13.40364.16012.1121.0063.66OATOM2166CGLUA298−10.99168.58614.3721.0050.78CATOM2167OGLUA298−11.52368.66615.4901.0050.03OATOM2168NTHRA299−9.67668.62414.1861.0049.28NATOM2169CATHRA299−8.75668.81215.2911.0048.32CATOM2170CBTHRA299−7.31068.85514.7811.0048.02CATOM2171OG1THRA299−7.00767.63614.0961.0045.02OATOM2172CG2THRA299−6.32468.91015.9511.0047.18CATOM2173CTHRA299−9.07270.09516.0401.0048.76CATOM2174OTHRA299−9.13570.10117.2681.0047.62OATOM2175NALAA300−9.25271.18115.2931.0049.46NATOM2176CAALAA300−9.54072.46815.8871.0050.94CATOM2177CBALAA300−9.54173.55614.8201.0050.83CATOM2178CALAA300−10.87572.43816.6641.0051.99CATOM2179OALAA300−10.96172.94017.7931.0051.96OATOM2180NGLUA301−11.89671.83216.0641.0053.05NATOM2181CAGLUA301−13.21871.75716.6891.0054.49CATOM2182CBGLUA301−14.22071.09415.7541.0055.03CATOM2183CGGLUA301−14.92672.07314.8311.0058.47CATOM2184CDGLUA301−15.12971.51813.4291.0061.94CATOM2185OE1GLUA301−15.41870.30313.2871.0062.49OATOM2186OE2GLUA301−15.00672.30612.4591.0064.87OATOM2187CGLUA301−13.17771.01818.0261.0054.40CATOM2188OGLUA301−13.65271.53619.0481.0054.62OATOM2189NILEA302−12.58169.82618.0111.0054.14NATOM2190CAILEA302−12.48768.97019.1961.0053.52CATOM2191CBILEA302−12.12467.52918.7911.0053.66CATOM2192CG1ILEA302−13.15066.98117.7951.0053.26CATOM2193CD1ILEA302−12.81365.60917.2541.0052.59CATOM2194CG2ILEA302−12.04766.62420.0261.0053.65CATOM2195CILEA302−11.49669.46220.2461.0053.50CATOM2196OILEA302−11.80069.42221.4401.0053.33OATOM2197NHISA303−10.32269.93719.8221.0053.16NATOM2198CAHISA303−9.25870.22020.7931.0053.02CATOM2199CBHISA303−8.01869.39020.4591.0051.63CATOM2200CGHISA303−8.21267.92620.6801.0047.34CATOM2201ND1HISA303−8.39667.04319.6401.0045.24NATOM2202CE1HISA303−8.54065.82220.1191.0042.60CATOM2203NE2HISA303−8.45665.88321.4371.0042.67NATOM2204CD2HISA303−8.25167.18821.8151.0043.90CATOM2205CHISA303−8.86171.67120.9601.0054.55CATOM2206OHISA303−8.26572.03621.9791.0054.31OATOM2207NLEUA304−9.16872.50019.9661.0056.55NATOM2208CALEUA304−8.69673.87619.9991.0059.36CATOM2209CBLEUA304−7.96774.21118.7011.0058.46CATOM2210CGLEUA304−6.47973.87018.5491.0058.16CATOM2211CD1LEUA304−6.02672.66919.3901.0055.35CATOM2212CD2LEUA304−6.16073.65317.0611.0056.12CATOM2213CLEUA304−9.83274.87320.2731.0062.12CATOM2214OLEUA304−9.58676.06720.4311.0062.18OATOM2215NHISA305−11.06174.36120.3401.0065.89NATOM2216CAHISA305−12.27875.15020.5711.0069.84CATOM2217CBHISA305−12.20175.96321.8841.0070.73CATOM2218CGHISA305−11.78075.13823.0691.0074.80CATOM2219ND1HISA305−12.61174.20623.6641.0077.77NATOM2220CE1HISA305−11.97673.62924.6741.0078.93CATOM2221NE2HISA305−10.76074.14924.7531.0079.02NATOM2222CD2HISA305−10.61175.09323.7601.0077.72CATOM2223CHISA305−12.59176.04719.3821.0071.35CATOM2224OHISA305−12.45877.27219.4631.0072.07OATOM2225NSERA306−12.99875.42618.2751.0073.04NATOM2226CASERA306−13.37276.16117.0661.0074.54CATOM2227CBSERA306−12.56375.68515.8501.0074.28CATOM2228OGSERA306−11.27076.30915.8431.0074.68OATOM2229CSERA306−14.87876.06116.8041.0075.41CATOM2230OSERA306−15.58877.08016.8581.0076.03OATOM2231OXTSERA306−15.39774.96616.5421.0075.98OATOM2232N3IMDI18.12871.29826.4391.0062.13NATOM2233C4IMDI18.44171.42827.7551.0062.64CATOM2234C5IMDI17.73172.51328.2671.0061.10CATOM2235C2IMDI17.24572.27626.1251.0061.77CATOM2236N1IMDI17.00173.01627.2421.0061.00NATOM2237OHOHW1−0.73254.5289.7281.0045.36OATOM2238OHOHW219.63058.7166.5761.0043.01OATOM2239OHOHW30.31061.2642.8491.0032.73OATOM2240OHOHW418.44064.20621.5271.0032.96OATOM2241OHOHW512.98880.6688.4241.0039.01OATOM2242OHOHW6−1.36851.61730.4891.0040.35OATOM2243OHOHW716.48875.63310.8961.0039.22OATOM2244OHOHW822.71562.6954.2861.0041.65OATOM2245OHOHW915.54667.9759.9691.0034.80OATOM2246OHOHW109.87357.7333.2001.0034.66OATOM2247OHOHW1122.04177.1978.2231.0059.58OATOM2248OHOHW1213.92168.2957.8011.0043.48OATOM2249OHOHW13−2.00149.45429.3351.0040.96OATOM2250OHOHW1422.26159.91410.8821.0037.32OATOM2251OHOHW1519.41950.73416.9661.0040.82OATOM2252OHOHW1615.33857.1599.0221.0039.03OATOM2253OHOHW1717.96166.5499.8821.0039.50OATOM2254OHOHW184.81876.3410.5451.0044.94OATOM2255OHOHW198.85579.1967.5181.0039.17OATOM2256OHOHW2017.07254.13021.8441.0043.20OATOM2257OHOHW211.32569.5877.1101.0036.36OATOM2258OHOHW228.15061.6561.2201.0040.26OATOM2259OHOHW23−4.43566.66610.9791.0043.16OATOM2260OHOHW2410.51380.7139.1171.0042.28OATOM2261OHOHW2515.49765.16424.5571.0034.79OATOM2262OHOHW269.90052.8313.5891.0042.40OATOM2263OHOHW27−0.20071.7198.3871.0041.34OATOM2264OHOHW28−7.39859.98215.5511.0040.20OATOM2265OHOHW293.49281.32221.0131.0047.98OATOM2266OHOHW30−4.71467.42525.0261.0043.45OATOM2267OHOHW3115.25168.12212.6731.0036.68OATOM2268OHOHW32−5.70962.26015.1191.0039.90OATOM2269OHOHW334.55383.95511.4461.0045.99OATOM2270OHOHW3418.79157.16928.0571.0043.68OATOM2271OHOHW3518.23165.46414.8721.0037.87OATOM2272OHOHW368.97153.78930.8601.0043.70OATOM2273OHOHW375.18050.9839.9001.0039.96OATOM2274OHOHW38−4.08160.21125.4791.0043.04OATOM2275OHOHW39−1.65050.29824.9531.0050.05OATOM2276OHOHW40−0.32379.6862.1811.0064.08OATOM2277OHOHW41−4.01458.3329.2321.0045.77OATOM2278OHOHW4210.27350.30618.8991.0043.91OATOM2279OHOHW4316.89054.8838.9551.0043.73OATOM2280OHOHW443.73065.9932.0971.0044.04OATOM2281OHOHW4523.97270.5632.2751.0040.95OATOM2282OHOHW4624.63358.60210.0521.0042.68OATOM2283OHOHW4719.82861.6184.3581.0051.38OATOM2284OHOHW4822.51790.82315.9521.0070.96OATOM2285OHOHW4929.35460.9213.1671.0057.58OATOM2286OHOHW5011.46882.36912.2891.0050.02OATOM2287OHOHW5124.77262.519−4.1211.0045.22OATOM2288OHOHW523.21168.55431.5821.0069.57OATOM2289OHOHW537.93650.00223.1241.0047.40OATOM2290OHOHW5415.58771.21217.0461.0052.35OATOM2291OHOHW5515.88479.008−3.5801.0056.72OATOM2292OHOHW5625.27956.11010.2301.0044.21OATOM2293OHOHW5712.51458.7674.8371.0052.23OATOM2294OHOHW581.68878.2344.5431.0043.74OATOM2295OHOHW599.01882.80311.1681.0050.76OATOM2296OHOHW60−0.21785.7426.0961.0053.93OATOM2297OHOHW61−2.93082.30921.7721.0058.06OATOM2298OHOHW625.50451.2255.1301.0048.90OATOM2299OHOHW6320.07654.4697.3501.0061.18OATOM2300OHOHW645.72268.809−1.9341.0059.42OATOM2301OHOHW6527.88266.292−1.5121.0065.79OATOM2302OHOHW6619.67672.15323.2291.0061.17OATOM2303OHOHW67−5.50171.4145.3011.0061.16OATOM2304OHOHW6815.01658.0566.4731.0049.90OATOM2305OHOHW69−2.01255.7306.1301.0056.99OATOM2306OHOHW70−9.44770.1887.6821.0057.22OATOM2307OHOHW712.48455.120−0.0381.0049.25OATOM2308OHOHW72−7.90859.2378.4791.0065.73OATOM2309OHOHW7322.35373.25511.7641.0060.74OATOM2310OHOHW7419.47767.32411.8571.0050.67OATOM2311OHOHW7514.50647.97013.2801.0062.36OATOM2312OHOHW7616.86247.8078.7681.0052.55OATOM2313OHOHW7713.31353.08332.0981.0054.43OATOM2314OHOHW7817.50350.79819.0411.0055.72OATOM2315OHOHW79−12.73662.09418.1891.0053.56OATOM2316OHOHW8033.90862.97910.7121.0063.79OATOM2317OHOHW81−6.87060.60522.6281.0049.67OATOM2318OHOHW829.98747.58214.0461.0066.52OATOM2319OHOHW8323.18373.2872.5101.0052.15OATOM2320OHOHW8427.57855.7709.0601.0063.00OATOM2321OHOHW855.57682.970−1.7481.0062.58OATOM2322OHOHW86−0.50984.3303.8571.0059.32OATOM2323OHOHW8713.66591.473−3.5521.0061.08OATOM2324OHOHW88−2.86175.397−2.0381.0063.22OATOM2325OHOHW8910.20473.97929.7901.0066.32OATOM2326OHOHW9020.07078.9836.9711.0067.67OATOM2327OHOHW9117.16977.34721.9101.0065.17OATOM2328OHOHW92−2.87053.04518.1631.0059.47OATOM2329OHOHW9311.62771.62823.4401.0063.19OATOM2330OHOHW948.31074.960−2.6781.0055.47OATOM2331OHOHW95−12.00278.8514.3041.0058.94OATOM2332OHOHW965.56649.15722.7961.0051.78OATOM2333OHOHW9731.35861.4780.5971.0066.61OATOM2334OHOHW9824.03564.093−2.0911.0047.25OATOM2335OHOHW9911.29469.11134.2951.0070.13OATOM2336OHOHW10018.99964.123−2.1681.0062.14OATOM2337OHOHW101−9.73961.4937.6981.0082.68OATOM2338OHOHW10222.43552.02525.4391.0054.62OATOM2339OHOHW1035.04549.27612.1141.0055.83OATOM2340OHOHW104−3.96550.52412.2241.0062.13OATOM2341OHOHW10513.47275.94526.2501.0061.94OATOM2342OHOHW10615.56072.15626.2971.0058.39OATOM2343OHOHW107−0.19596.03419.6351.0069.60OATOM2344OHOHW1081.24388.090−4.0311.0062.22OATOM2345OHOHW10919.97383.75920.5851.0071.41OATOM2346OHOHW110−8.15273.4868.2881.0053.47OATOM2347OHOHW11123.42081.7229.2331.0071.36OATOM2348OHOHW1121.59682.691−0.0961.0071.76OATOM2349OHOHW1135.65756.059−1.3361.0064.94OATOM2350OHOHW11413.96751.5758.3741.0051.56OATOM2351OHOHW11512.41678.38925.2001.0066.19OATOM2352OHOHW11617.23583.39211.4471.0052.25OATOM2353OHOHW11714.76752.85221.3141.0047.79OATOM2354OHOHW11819.07560.231−4.0281.0064.68OATOM2355OHOHW11925.47666.80028.8231.0055.96OATOM2356OHOHW1204.47370.02130.0201.0056.80OATOM2357OHOHW1218.40080.05118.5801.0047.86OATOM2358OHOHW122−0.27481.3746.4671.0070.59OATOM2359OHOHW1238.01651.0833.8261.0050.11OATOM2360OHOHW124−5.76255.3238.6031.0059.77OATOM2361OHOHW12524.80194.210−1.1151.0067.33OATOM2362OHOHW1269.71048.66926.3281.0063.06OATOM2363OHOHW1278.68499.06314.1671.0063.47OATOM2364OHOHW12819.45183.6488.5111.0051.41OATOM2365OHOHW129−10.88961.95510.2151.0055.28OATOM2366OHOHW130−4.25361.86627.6521.0061.67OATOM2367OHOHW13127.03090.3403.8481.0080.85OATOM2368OHOHW13210.97787.13122.6231.0065.06OATOM2369OHOHW13314.63465.394−2.5211.0056.18OATOM2370OHOHW134−3.40552.80820.6921.0057.93OATOM2371OHOHW135−5.42055.45115.5251.0051.90OATOM2372OHOHW1368.05679.67122.6751.0059.54OATOM2373OHOHW13728.39257.7864.7551.0078.57OATOM2374OHOHW13818.31299.6899.7671.0061.28OATOM2375OHOHW13933.44663.25317.7231.0059.53OATOM2376OHOHW14024.28356.20617.4741.0054.00OATOM2377OHOHW14116.80850.39232.5001.0057.59OATOM2378OHOHW14215.74683.812−7.4611.0064.85OATOM2379OHOHW143−7.08294.424−2.1691.0067.76OATOM2380OHOHW14413.63149.31210.7491.0054.19OATOM2381OHOHW14530.24761.19323.4401.0071.27OATOM2382OHOHW14613.01080.075−6.5281.0068.99O

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TABLE 4

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
CD1
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
GLN
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
111
63.764
42.908
4.700
1.00
25.91
C

ATOM
1159
CD1
LEU
A
111
64.830
43.473
5.621
1.00
26.41
C

ATOM
1160
CD2
LEU
A
111
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

TABLE 5

DISEASES ASSOCIATED WITH GENETIC DEFECTS IN KINASES

Serine/Threonine Protein Kinases

CYCLIN-DEPENDENT KINASE 7; CDK7

DYSTROPHIA MYOTONICA; DM

MINIBRAIN (DROSOPHILA) HOMOLOG; MNBH

RAC SERINE/THREONINE PROTEIN KINASE

SERINE-THREONINE PROTEIN KINASE N; PKN

SERINE/THREONINE PROTEIN KINASE 2; STK2

PROTEIN KINASE, DNA-ACTIVATED, CATALYTIC SUBUNIT; PRKDC

ZIPPER PROTEIN KINASE; ZPK

PROTEIN-TYROSINE KINASE STY

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

MKN28 KINASE

PROTEIN KINASE, X-LINKED; PRKX

ELK-RELATED TYROSINE KINASE; ERK

RIBOSOMAL PROTEIN S6 KINASE, 90 KD, POLYPEPTIDE 3; RPS6KA3

GLYCOGEN STORAGE DISEASE VIII

DEATH-ASSOCIATED PROTEIN KINASE 1; DAPK1

PCTAIRE PROTEIN KINASE 1; PCTK1

PROTEIN KINASE, INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA; PRKR

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 1; ACVRLK1

PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA

PROTEIN KINASE, Y-LINKED; PRKY

G PROTEIN-COUPLED RECEPTOR KINASE 2 (DROSOPHILA)-LIKE; GPRK2L

PROTEIN KINASE C, THETA FORM; PRKCQ

LIM DOMAIN KINASE 1; LIMK1

PHOSPHOGLYCERATE KINASE 1; PGK1

LIM DOMAIN KINASE 2; LIMK2

C-JUN KINASE

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 2; ACVRLK2

JANUS KINASE 1; JAK1

ELKL MOTIF KINASE; EMK1

MALE GERM CELL-ASSOCIATED KINASE; MAK

CASEIN KINASE 2, ALPHA-PRIME SUBUNIT; CSNK2A2

CASEIN KINASE 2, BETA POLYPEPTIDE; CSNK2B

CASEIN KINASE 2, ALPHA 1 POLYPEPTIDE; CSNK2A1

LEUKEMIA, CHRONIC MYELOID; CML

RET PROTO-ONCOGENE; RET

HEMATOPOIETIC PROGENITOR KINASE 1

CONSERVED HELIX-LOOP-HELIX UBIQUITOUS KINASE; CHUK

CASEIN KINASE 1, DELTA; CSNK1D

CASEIN KINASE 1, EPSILON; CSNK1E

DEATH-ASSOCIATED PROTEIN; DAP

V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; AKT1

TUMOR PROTEIN p53; TP53

PROTEIN PHOSPHATASE 1, REGULATORY (INHIBITOR) SUBUNIT 2; PPP1R2

SEVERE COMBINED IMMUNODEFICIENCY DISEASE-1; SCID1

HYPERLIPOPROTEINEMIA, TYPE I

COLLAGEN, TYPE I, ALPHA-1 CHAIN; COL1A1

UBIQUITIN-BINDING PROTEIN P62

TAY-SACHS DISEASE; TSD

CYSTIC FIBROSIS; CF

p160-ROCK

BCL2-ASSOCIATED ATHANOGENE 1; BAG1

HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1; HPRT1

ONCOGENE PIM-1; PIM1; PIM

CARTILAGE-DERIVED MORPHOGENETIC PROTEIN 1

GALACTOSEMIA

GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL CYTOCHROME-b-POSITIVE FORM I

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2

RHODOPSIN; RHO

MOTHERS AGAINST DECAPENTAPLEGIC (DROSOPHILA) HOMOLOG 2; MADH2

TRIPLE FUNCTIONAL DOMAIN; TRIO

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1

GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 1; GTF2H1

ANTI-MULLERIAN HORMONE TYPE II RECEPTOR; AMHR2

V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF

BONE MORPHOGENETIC RECEPTOR TYPE II; BMPR2

GLYCOGEN STORAGE DISEASE V

COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT III

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 1; ARAF1

GAUCHER DISEASE, TYPE I; GD I

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 2; ARAF2

CYCLIN A; CCNA

ANEMIA, HYPOCHROMIC; ANH1

GRANULOMATOUS DISEASE, CHRONIC; CGD

ACTIVIN A RECEPTOR, TYPE I; ACVR1

Serine Protein Kinases

CYCLIN-DEPENDENT KINASE 7; CDK7

DYSTROPHIA MYOTONICA; DM

MINIBRAIN (DROSOPHILA) HOMOLOG; MNBH

RAC SERINE/THREONINE PROTEIN KINASE

SERINE-THREONINE PROTEIN KINASE N; PKN

PROTEIN KINASE, SERINE/ARGININE-SPECIFIC

PROTEIN SERINE KINASE H1; PSKH1

SERINE/THREONINE PROTEIN KINASE 2; STK2

PROTEIN KINASE, DNA-ACTIVATED, CATALYTIC SUBUNIT; PRKDC

ZIPPER PROTEIN KINASE; ZPK

PROTEIN-TYROSINE KINASE STY

SYK-RELATED TYROSINE KINASE; SRK

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

MKN28 KINASE

NON-METASTATIC CELLS 1, PROTEIN EXPRESSED IN; NME1

ELK-RELATED TYROSINE KINASE; ERK

PROTEIN KINASE, X-LINKED; PRKX

FIBROBLAST GROWTH FACTOR RECEPTOR-2; FGFR2

RIBOSOMAL PROTEIN S6 KINASE, 90 KD, POLYPEPTIDE 3; RPS6KA3

PCTAIRE PROTEIN KINASE 1; PCTK1

DEATH-ASSOCIATED PROTEIN KINASE 1; DAPK1

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 1; ACVRLK1

GLYCOGEN STORAGE DISEASE VIII

PROTEIN KINASE, INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA; PRKR

PROTEIN KINASE, Y-LINKED; PRKY

G PROTEIN-COUPLED RECEPTOR KINASE 2 (DROSOPHILA)-LIKE; GPRK2L

LIM DOMAIN KINASE 1; LIMK1

PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA

PROTEIN KINASE C, THETA FORM; PRKCQ

C-JUN KINASE

PHOSPHOGLYCERATE KINASE 1; PGK1

LIM DOMAIN KINASE 2; LIMK2

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 2; ACVRLK2

JANUS KINASE 1; JAK1

INSULIN RECEPTOR; INSR

CASEIN KINASE 2, ALPHA 1 POLYPEPTIDE; CSNK2A1

CASEIN KINASE 2, BETA POLYPEPTIDE; CSNK2B

CASEIN KINASE 2, ALPHA-PRIME SUBUNIT; CSNK2A2

ATAXIA-TELANGIECTASIA; AT

MALE GERM CELL-ASSOCIATED KINASE; MAK

ELKL MOTIF KINASE; EMK1

LEUKEMIA, CHRONIC MYELOID; CML

HEMATOPOIETIC PROGENITOR KINASE 1

RET PROTO-ONCOGENE; RET

CASEIN KINASE 1, DELTA; CSNK1D

CASEIN KINASE 1, EPSILON; CSNK1E

CONSERVED HELIX-LOOP-HELIX UBIQUITOUS KINASE; CHUK

HYPERCHOLESTEROLEMIA, FAMILIAL; FHC

TUMOR PROTEIN p53; TP53

TAY-SACHS DISEASE; TSD

DEATH-ASSOCIATED PROTEIN; DAP

V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; AKT1

COLLAGEN, TYPE I, ALPHA-1 CHAIN; COL1A1

SEVERE COMBINED IMMUNODEFICIENCY DISEASE-1; SCID1

ADENOMATOUS POLYPOSIS OF THE COLON; APC

PROTEIN PHOSPHATASE 1, REGULATORY (INHIBITOR) SUBUNIT 2; PPP1R2

UBIQUITIN-BINDING PROTEIN P62

MUSCULAR DYSTROPHY, TARDIVE, DREIFUSS-EMERY TYPE, WITH CONTRACTURES

CAVEOLIN, CAVEOLAE PROTEIN, 22-KD; CAV

FIBROBLAST GROWTH FACTOR RECEPTOR-3; FGFR3

CYSTIC FIBROSIS; CF

HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1; HPRT1

GROWTH FACTOR RECEPTOR-BOUND PROTEIN-10; GRB10

HYPERLIPOPROTEINEMIA, TYPE I

CREB-BINDING PROTEIN; CREBBP

THYROID AUTOANTIGEN 70 KD; G22P1

ONCOGENE PIM-1; PIM1; PIM

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3

CYCLIC-AMP-RESPONSE-ELEMENT-BINDING PROTEIN-1; CREB1

BCL2-ASSOCIATED ATHANOGENE 1; BAG1

P32 SPLICING FACTOR SF2 ASSOCIATED PROTEIN

CARTILAGE-DERIVED MORPHOGENETIC PROTEIN 1

p160-ROCK

GROWTH FACTOR RECEPTOR-BOUND PROTEIN-14; GRB14

THROMBASTHENIA OF GLANZMANN AND NAEGELI

INSULIN RECEPTOR SUBSTRATE 1; IRS1

GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL CYTOCHROME-b-POSITIVE FORM I

GUANYLATE CYCLASE 2D, MEMBRANE; GUC2D

GALACTOSEMIA

RHODOPSIN; RHO

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2

ICHTHYOSIS, X-LINKED

TRIPLE FUNCTIONAL DOMAIN; TRIO

MOTHERS AGAINST DECAPENTAPLEGIC (DROSOPHILA) HOMOLOG 2; MADH2

MCF.2 CELL LINE DERIVED TRANSFORMING SEQUENCE; MCF2

ESTROGEN RECEPTOR; ESR

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 1; ARAF1

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 2; ARAF2

BONE MORPHOGENETIC RECEPTOR TYPE II; BMPR2

GAUCHER DISEASE, TYPE I; GD I

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1

GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 1; GTF2H1

CHYMOTRYPSIN-LIKE PROTEASE; CTRL

GLYCOGEN STORAGE DISEASE V

CYCLIN A; CCNA

LETHAL GIANT LARVAE (DROSOPHILA) HOMOLOG 1; LLGL1

GRANULOMATOUS DISEASE, CHRONIC; CGD

CASEIN, BETA; CSN2

DENTIN MATRIX ACIDIC PHOSPHOPROTEIN 1; DMP1

TREACHER COLLINS-FRANCESCHETTI SYNDROME 1; TCOF1

COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT III

DIABETES MELLITUS, AUTOSOMAL DOMINANT

V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF

ANEMIA, HYPOCHROMIC; ANH1

ANTI-MULLERIAN HORMONE TYPE II RECEPTOR; AMHR2

PLASMINOGEN ACTIVATOR INHIBITOR, TYPE 2; PAI2

ACTIVIN A RECEPTOR, TYPE I; ACVR1

Threonine Protein Kinases

CYCLIN-DEPENDENT KINASE 7; CDK7

DYSTROPHIA MYOTONICA; DM

MINIBRAIN (DROSOPHILA) HOMOLOG; MNBH

RAC SERINE/THREONINE PROTEIN KINASE

SERINE-THREONINE PROTEIN KINASE N; PKN

SERINE/THREONINE PROTEIN KINASE 2; STK2

PROTEIN KINASE, DNA-ACTIVATED, CATALYTIC SUBUNIT; PRKDC

ZIPPER PROTEIN KINASE; ZPK

PROTEIN-TYROSINE KINASE STY

PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 1; PRKMK1

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

MKN28 KINASE

PROTEIN KINASE, X-LINKED; PRKX

ELK-RELATED TYROSINE KINASE; ERK

GLYCOGEN STORAGE DISEASE VIII

PYRUVATE KINASE DEFICIENCY OF ERYTHROCYTE

RIBOSOMAL PROTEIN S6 KINASE, 90 KD, POLYPEPTIDE 3; RPS6KA3

DEATH-ASSOCIATED PROTEIN KINASE 1; DAPK1

PCTAIRE PROTEIN KINASE 1; PCTK1

PROTEIN KINASE, INTERFERON-INDUCIBLE DOUBLE-STRANDED RNA; PRKR

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 1; ACVRLK1

PROTEIN KINASE, Y-LINKED; PRKY

G PROTEIN-COUPLED RECEPTOR KINASE 2 (DROSOPHILA)-LIKE; GPRK2L

PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA

PROTEIN KINASE C, THETA FORM; PRKCQ

MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE AND BECKER

TYPES; DMD

LIM DOMAIN KINASE 1; LIMK1

PHOSPHOGLYCERATE KINASE 1; PGK1

LIM DOMAIN KINASE 2; LIMK2

C-JUN KINASE

ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 2; ACVRLK2

JANUS KINASE 1; JAK1

CASEIN KINASE 2, ALPHA 1 POLYPEPTIDE; CSNK2A1

CASEIN KINASE 2, BETA POLYPEPTIDE; CSNK2B

MALE GERM CELL-ASSOCIATED KINASE; MAK

MEVALONICACIDURIA

ELKL MOTIF KINASE; EMK1

CASEIN KINASE 2, ALPHA-PRIME SUBUNIT; CSNK2A2

MAP KINASE KINASE 6

CASEIN KINASE 1, EPSILON; CSNK1E

CASEIN KINASE 1, DELTA; CSNK1D

LEUKEMIA, CHRONIC MYELOID; CML

CONSERVED HELIX-LOOP-HELIX UBIQUITOUS KINASE; CHUK

HEMATOPOIETIC PROGENITOR KINASE 1

RET PROTO-ONCOGENE; RET

PROTEIN PHOSPHATASE 1, REGULATORY (INHIBITOR) SUBUNIT 2; PPP1R2

DUAL SPECIFICITY PHOSPHATASE 1; DUSP1

V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; AKT1

DEATH-ASSOCIATED PROTEIN; DAP

TUMOR PROTEIN p53; TP53

GLYCOGEN STORAGE DISEASE II

SEVERE COMBINED IMMUNODEFICIENCY DISEASE-1; SCID1

UBIQUITIN-BINDING PROTEIN P62

HYPERLIPOPROTEINEMIA, TYPE I

BCL2-ASSOCIATED ATHANOGENE 1; BAG1

ONCOGENE PIM-1; PIM1; PIM

HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1; HPRT1

p160-ROCK

CARTILAGE-DERIVED MORPHOGENETIC PROTEIN 1

CYSTIC FIBROSIS; CF

TAY-SACHS DISEASE; TSD

COLLAGEN, TYPE I, ALPHA-1 CHAIN; COL1A1

GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL CYTOCHROME-b-POSITIVE FORM I

NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2

GALACTOSEMIA

MOTHERS AGAINST DECAPENTAPLEGIC (DROSOPHILA) HOMOLOG 2; MADH2

TRIPLE FUNCTIONAL DOMAIN; TRIO

ANTI-MULLERIAN HORMONE TYPE II RECEPTOR; AMHR2

BONE MORPHOGENETIC RECEPTOR TYPE II; BMPR2

V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF

CYCLIN A; CCNA

COMPLEX IV, CYTOCHROME c OXIDASE SUBUNIT III

RHODOPSIN; RHO

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 1; ARAF1

GRANULOMATOUS DISEASE, CHRONIC; CGD

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1

ANEMIA, HYPOCHROMIC; ANH1

GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 1; GTF2H1

GLYCOGEN STORAGE DISEASE V

GAUCHER DISEASE, TYPE I; GD I

ADENINE PHOSPHORIBOSYLTRANSFERASE; APRT

V-RAF MURINE SARCOMA 3611 VIRAL ONCOGENE HOMOLOG 2; ARAF2

ACTIVIN A RECEPTOR, TYPE I; ACVR1

Tyrosine Protein Kinases

NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1

PROTEIN-TYROSINE KINASE, CYTOPLASMIC; PTK2

SYK-RELATED TYROSINE KINASE; SRK

PROTEIN TYROSINE KINASE CTK; CTK

TYRO3 PROTEIN TYROSINE KINASE; TYRO3

BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK

LEUKOCYTE TYROSINE KINASE; LTK

PROTEIN-TYROSINE KINASE SYK; SYK

PROTEIN-TYROSINE KINASE STY

TEK TYROSINE KINASE, ENDOTHELIAL; TEK

ELK-RELATED TYROSINE KINASE; ERK

TYROSINE KINASE WITH IMMUNOGLOBULIN AND EGF FACTOR HOMOLOGY DOMAINS; TIE

PROTEIN TYROSINE KINASE TKF

NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 3; NTRK3

MIXED-LINEAGE PROTEIN KINASE-3; MLK3

PROTEIN KINASE, MITOGEN-ACTIVATED 4; PRKM4

PROTEIN KINASE, MITOGEN-ACTIVATED 1; PRKM1

PROTEIN TYROSINE KINASE PTK7; PTK7

PROTEIN TYROSINE KINASE EEK

MINIBRAIN (DROSOPHILA) HOMOLOG; MNBH

BONE MARROW KINASE, X-LINKED; BMX

EPH-LIKE TYROSINE KINASE 1; ETK1

MACROPHAGE STIMULATING 1 RECEPTOR; MST1R

BTK-ASSOCIATED PROTEIN, 135 KD

LYMPHOCYTE-SPECIFIC PROTEIN TYROSINE KINASE; LCK

FIBROBLAST GROWTH FACTOR RECEPTOR-2; FGFR2

PROTEIN TYROSINE KINASE-3; TYK3; FER

PROTEIN TYROSINE KINASE TXK; TXK

TEC PROTEIN TYROSINE KINASE; TEC

PROTEIN TYROSINE KINASE-2; TYK2

EPH-RELATED RECEPTOR TYROSINE KINASE LIGAND 1; EPLG1

T-CELL TYROSINE KINASE EMT; EMT

EPH TYROSINE KINASE 1; EPHT1

ZONA PELLUCIDA RECEPTOR TYROSINE KINASE, 95 KD; ZRK

PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 1; PRKMK1

EPH TYROSINE KINASE 3; EPHT3

GROWTH ARREST-SPECIFIC GENE-6; GAS6

KINASE INSERT DOMAIN RECEPTOR; KDR

AXL RECEPTOR TYROSINE KINASE; AXL

FIBROBLAST GROWTH FACTOR RECEPTOR-1; FGFR1

V-ERB-B2 AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOG 2; ERBB2

FMS-LIKE TYROSINE KINASE-3; FLT3

NEUROEPITHELIAL TYROSINE KINASE; NEP

NEUROTROPHIC TYROSINE KINASE RECEPTOR-RELATED 3; NTRKR3

EPH-RELATED RECEPTOR TYROSINE KINASE LIGAND 5; EPLG5

NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 2; NTRK2

RYK RECEPTOR-LIKE TYROSINE KINASE

TYROSINE KINASE, B-LYMPHOCYTE SPECIFIC; BLK

EPH TYROSINE KINASE 2; EPHT2

EPH-RELATED RECEPTOR TYROSINE KINASE LIGAND 2; EPLG2

GLYCOGEN STORAGE DISEASE VIII

EPH-RELATED RECEPTOR TYROSINE KINASE LIGAND 7; EPLG7

JANUS KINASE 1; JAK1

FMS-RELATED TYROSINE KINASE-1; FLT1

PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE I, ALPHA; PRKAR1A

WEE-1 TYROSINE KINASE; WEE1

EPH-LIKE TYROSINE KINASE 2; ETK2

RECEPTOR TYROSINE KINASE MuSK

INSULIN RECEPTOR; INSR

JANUS KINASE 3 JAK3

FMS-RELATED TYROSINE KINASE-3 LIGAND

PROTEIN KINASE C, BETA 1; PRKCB1

TYROSINE KINASE-TYPE CELL SURFACE RECEPTOR HER3; HER3

JANUS KINASE 2; JAK2

LIM DOMAIN KINASE 1; LIMK1

DUAL SPECIFICITY PHOSPHATASE 1; DUSP1

MUSCULAR DYSTROPHY, PSEUDOHYPERTROPHIC PROGRESSIVE, DUCHENNE AND BECKER

TYPES; DMD

HEMOPOIETIC CELL KINASE; HCK

TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,

ETA POLYPEPTIDE; YWHAH

RET PROTO-ONCOGENE; RET

TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,

ZETA POLYPEPTIDE; YWHAZ

TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN,

BETA POLYPEPTIDE; YWHAB

HEPATOMA TRANSMEMBRANE KINASE; HTK

MAP KINASE KINASE 6

PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, ALPHA POLYPEPTIDE; PIK3CA

CYCLIN-DEPENDENT KINASE INHIBITOR 3; CDKN3

DIACYLGLYCEROL KINASE, DELTA, 130 KD

PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR TYPE, 13; PTPN13

ABELSON MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1; ABL1

DIACYLGLYCEROL KINASE, ALPHA; DAGK1

FOCAL ADHESION KINASE 2

EPITHELIAL DISCOIDIN DOMAIN RECEPTOR 1; EDDR1

ANAPLASTIC LYMPHOMA KINASE; ALK

PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, GAMMA POLYPEPTIDE; PIK3CG

PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT; PIK3R1

EPH HOMOLOGY KINASE-1; EHK1

V-KIT HARDY-ZUCKERMAN 4 FELINE SARCOMA VIRAL ONCOGENE HOMOLOG; KIT

FIBROBLAST GROWTH FACTOR RECEPTOR-3; FGFR3

VASCULAR ENDOTHELIAL GROWTH FACTOR C; VEGFC

MACROPHAGE STIMULATING 1; MST1

HYPERCHOLESTEROLEMIA, FAMILIAL; FHC

EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR

S100 CALCIUM-BINDING PROTEIN A10; S100A10

NEUROFIBROMATOSIS, TYPE I; NF1

ONCOGENE TRK

LEUKEMIA, CHRONIC MYELOID; CML

GROWTH FACTOR RECEPTOR-BOUND PROTEIN-7; GRB7

S100 CALCIUM-BINDING PROTEIN A4; S100A4

RAS p21 PROTEIN ACTIVATOR; RASA2

ADENOMATOUS POLYPOSIS OF THE COLON; APC

MET PROTO-ONCOGENE; MET

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3

smg GDS-ASSOCIATED PROTEIN

UBIQUITIN-BINDING PROTEIN P62

LYMPHOCYTE CYTOSOLIC PROTEIN 2; LCP2

EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE-15; EPS15

GROWTH FACTOR RECEPTOR-BOUND PROTEIN-10; GRB10

GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR RECEPTOR-ALPHA; GDNFRA

SHC TRANSFORMING PROTEIN; SHC1

CYSTIC FIBROSIS; CF

TROPOMYOSIN 3; TPM3

CELL DIVISION CYCLE 2, G1 TO S AND G2 TO M; CDC2

MUSCULAR DYSTROPHY, LIMB GIRDLE, TYPE 2C; LGMD2C

ASH PROTEIN

TAY-SACHS DISEASE; TSD

AGRIN; AGRN

S100 CALCIUM-BINDING PROTEIN A6; S100A6

AGRANULOCYTOSIS, INFANTILE GENETIC

TRIPLE FUNCTIONAL DOMAIN; TRIO

HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1; HPRT1

CYTOVILLIN

GOLGI APPARATUS PROTEIN 1; GLG1

GROWTH FACTOR RECEPTOR-BOUND PROTEIN-14; GRB14

V-FES FELINE SARCOMA VIRAL/V-FPS FUJINAMI AVIAN SARCOMA VIRAL ONCOGENE

HOMOLOG; FES

TRANSLOCATED PROMOTER REGION

P32 SPLICING FACTOR SF2 ASSOCIATED PROTEIN

CARTILAGE-DERIVED MORPHOGENETIC PROTEIN 1

PAIRED BOX HOMEOTIC GENE 5; PAX5

INSULIN RECEPTOR SUBSTRATE 1; IRS1

SON OF SEVENLESS (DROSOPHILA) HOMOLOG 2; SOS2

PHOSPHATIDYLINOSITOL GLYCAN CLASS A; PIGA

ICHTHYOSIS, X-LINKED

RHODOPSIN; RHO

SEVERE COMBINED IMMUNODEFICIENCY DISEASE, AUTOSOMAL RECESSIVE, T-

NEGATIVE/B-POSITIVE TYPE

CAS-BR-M (MURINE) ECOTROPIC RETROVIRAL TRANSFORMING SEQUENCE; CBL

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2

COLONY-STIMULATING FACTOR-1 RECEPTOR; CSF1R

PHOSPHODIESTERASE I/NUCLEOTIDE PYROPHOSPHATASE 1; PDNP1

NUCLEOPHOSMIN; NPM1

ADDUCIN 1; ADD1

NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS

HYALURONAN-MEDIATED MOTILITY RECEPTOR; HMMR

ESTROGEN RECEPTOR; ESR

SRC-LIKE ADAPTER; SLA

BECKWITH-WIEDEMANN SYNDROME; BWS

TYLOSIS WITH ESOPHAGEAL CANCER; TOC

PLACENTAL GROWTH FACTOR; PGF

ETS VARIANT GENE 6; ETV6

MEMBRANE COMPONENT, CHROMOSOME 6, POLYPEPTIDE 2; M6P2

INTERLEUKIN-4; IL4

GARDNER-RASHEED FELINE SARCOMA VIRAL (V-FGR) ONCOGENE; FGR

FIBROBLAST GROWTH FACTOR-8; FGF8

SORTING NEXIN-1; SNX1

TRANSCRIPTION FACTOR 1, HEPATIC; TCF1

HEPATOCYTE GROWTH FACTOR; HGF

INTERLEUKIN-6 RECEPTOR; IL6R

V-YES-1 YAMAGUCHI SARCOMA VIRAL ONCOGENE; YES1

ENDOGLIN; ENG

THANATOPHORIC DYSPLASIA WITH KLEEBLATTSCHAEDEL

HEMATOPOIETIC CELL-SPECIFIC LYN SUBSTRATE 1; HCLS1

GENERAL TRANSCRIPTION FACTOR IIH, POLYPEPTIDE 1; GTF2H1

V-SIS PLATELET-DERIVED GROWTH FACTOR BETA POLYPEPTIDE; PDGFB

DIABETES MELLITUS, AUTOSOMAL DOMINANT

PROGRAMMED CELL DEATH 1; PDCD1

TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE I; TGFBR1

EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE-8; EPS8

VASCULAR ENDOTHELIAL GROWTH FACTOR; VEGF

CELL ADHESION REGULATOR; CAR

ANEMIA, CONGENITAL HYPOPLASTIC, OF BLACKFAN AND DIAMOND

GAUCHER DISEASE, TYPE I; GD I

MAPLE SYRUP URINE DISEASE; MSUD

MCF.2 CELL LINE DERIVED TRANSFORMING SEQUENCE; MCF2

GRANULOMATOUS DISEASE, CHRONIC; CGD

ANGIOPOIETIN 2; ANGPT2

HYPOGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED

GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR RECEPTOR-BETA

H4 GENE

Molecular scaffolds for kinase ligand development

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