Crystal structure of beta site APP cleaving enzyme (BACE) and methods of use thereof

FIELD OF THE INVENTION

[0003] The present invention relates to the mutant BACE proteins, recombinant BACE proteins, processes for crystallizing BACE and in particular to its crystal structure and to the uses of this structure in drug discovery.

BACKGROUND TO THE INVENTION

[0004] Alzheimer's Disease

[0005] Alzheimer's disease (AD) is estimated to afflict more than 20 million people worldwide and is believed to be the most common form of dementia. Alzheimer's disease is a progressive dementia in which massive deposits of aggregated protein breakdown products—amyloid plaques and neurofibrillary tangles accumulate in the brain. The amyloid plaques are thought to be responsible for the mental decline seen in Alzheimer's patients.

[0006] Aβ or amyloid-β-protein is the major constituent of the plaques which are characteristic of Alzheimer's disease (De Strooper et al, 1999). Aβ is a 39-42 residue peptide formed by the specific cleavage of a class I transmembrane protein called APP, or amyloid precursor protein. A β-secretase activity cleaves this protein between residues Met671 and Asp672 (numbering of 770aa isoform of APP) to form the N-terminus of Aβ. A second cleavage of the peptide is associated with β-secretase to form the C-terminus of the Aβ peptide.

[0007] Beta Site APP Cleaving Enzyme (BACE) and Alzheimer's Disease

[0008] Several groups have identified and isolated aspartate proteases that have β-secretase activity (Hussain et al., 1999; Lin et. al, 2000; Yan et. al, 1999; Sinha et. al., 1999 and Vassar et. al., 1999). β-secretase is also known in the literature as Asp2 (Yan et. al, 1999), Beta site APP Cleaving Enzyme (BACE or BACE1 ) (Vassar et. al., 1999) or memapsin-2 (Lin et al., 2000). BACE was identified using a number of experimental approaches such as EST database analysis (Hussain et al. 1999); expression cloning (Vassar et al. 1999); identification of human homologs from public databases of predicted C. elegans proteins (Yan et al. 1999) and finally utilizing an inhibitor to purify the protein from human brain (Sinha et al. 1999). Thus, five groups employing three different experimental approaches led to the identification of the same enzyme, making a strong case that BACE is a β-secretase. Mention is also made of the patent literature: WO96/40885, EP871720, U.S. Pat. Nos. 5,942,400 and 5,744,346, EP855444, U.S. Pat. No. 6,319,689, WO99/64587, WO99/31236, EP1037977, WO00/17369, WO01/23533, WO0047618, WO00/58479, WO00/69262, WO01/00663, WO01/00665, U.S. Pat. No. 6,313,268.

[0009] BACE is a membrane bound type 1 protein that is synthesized as a partially active proenzyme, and is abundantly expressed in brain tissue. It is thought to represent the major β-secretase activity, and is considered to be the rate-limiting step in the production of Aβ. It is thus of special interest in the pathology of Alzheimer's disease, and in the development of drugs as a treatment for Alzheimer's disease.

[0010] BACE was found to be a pepsin-like aspartyl proteinase, the mature enzyme consisting of the N-terminal catalytic domain, a transmembrane domain, and a small cytoplasmic domain. BACE has an optimum activity at pH 4.0-5.0 (Vassar et al, 1999) and is inhibited weakly by standard pepsin inhibitors such as pepstatin. It has been shown that the catalytic domain minus the transmembrane and cytoplasmic domain has activity against substrate peptides (Lin et al, 2000). Consequently, this soluble catalytic domain is suitable for crystallization studies and a crystal structure of this will give a representative structure of the BACE active site for the design of inhibitor molecules.

[0011] The likelihood of developing Alzheimer's disease increases with age, and as the aging, population of the developed world increases, this disease becomes a greater and greater problem. In addition to this, there is a familial link to Alzheimer's disease and consequently any individuals possessing the double mutation of APP known as the Swedish mutation (in which the mutated APP forms a considerably improved substrate for BACE) have a much greater chance of developing AD, and also of developing it at an early age (see also U.S. Pat. Nos. 6,245,964 and 5,877,399 pertaining to transgenic rodents comprising APP-Swedish). Consequently there is a strong case for developing a compound that can be used in a prophylactic fashion for these individuals.

[0012] Hence, drugs that reduce or block BACE activity would reduce Aβ levels and levels of fragments of Aβ in the brain or elsewhere where Aβ or fragments thereof deposit and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Aβ or fragments thereof (Yankner, 1996; De Strooper and Konig, 1999). BACE is therefore an important candidate for the development of drugs as a treatment against Alzheimer's disease and/or against such other maladies.

[0013] The therapeutic potential of inhibiting the deposition of Aβ has motivated many groups to isolate and characterize secretase enzymes and to identify their potential inhibitors (see, e.g., WO01/23533 A2, EP0855444, WO00/17369, WO00/58479, WO00/47618, WO00/77030, WO01/00665, WO01/00663, WO01/29563, WO002/25276, U.S. Pat No. 5,942,400, U.S. Pat. No. 6,245,884, U.S. Pat. No. 6,221,667, U.S. Pat. No. 6,211,235, WO02/02505, WO02/02506, WO02/02512, WO02/02518, WO02/02520, WO02/14264).

[0014] The gene encoding APP is found on chromosome 21, which is also the chromosome found as an extra copy in Downs syndrome. Downs syndrome patients tend to acquire Alzheimers disease at an early age, with almost all those over 40 years of age showing Alzheimers-type pathology (Oyama et al., 1994). This is thought to be due to the extra copy of the APP gene found in these patients, which leads to overexpression of APP and therefore to increased levels of APPβ causing the high prevalence of Alzheimers disease seen in this population. Thus inhibitors of BACE could be useful in reducing Alzheimers-type pathology in Down's syndrome patients.

[0015] It would therefore be useful to inhibit the deposition of Aβ and portions thereof by inhibiting BACE through inhibitors designed from the BACE structure as provided herein. The determination of the three-dimensional structure of BACE provides a basis for the design of new and specific ligands for BACE. For example, knowing the three-dimensional structure of BACE, computer modelling programs may be used to design different molecules expected to interact with possible or confirmed binding cavities or other to structural or functional features of BACE or structure-based design approaches may used such as those described in Blundell et al (Nature Reviews, Drug Discovery, Vol 1, pg 45-54, 2002).

[0016] Ideally it would be desirable to have an abundant supply of this enzyme in homogenous form. It would also be preferable to solve the structure of a form of BACE with an unoccupied active site. This could be used to soak in small molecule inhibitors of the enzyme and to investigate their binding modes. We describe here the high yielding production of BACE from bacterial cells in homogenous form, and the generation of protein suitable for crystallisation and structure determination of BACE in Apo form

[0017] Protein Crystallisation

[0018] It is well known in the art of protein chemistry that crystallising a protein is an uncertain and difficult process without any clear expectation of success. It is now evident that protein crystallization is the main hurdle in protein structure determination. For this reason, protein crystallization has become a research subject in and of itself, and is not simply an extension of the protein crystallographer's laboratory. There are many references, which describe the difficulties associated with growing protein crystals (Kierzek A M. and Zielenkiewicz P. (2001) Biophysical Chemistry 91 1-20 Models of protein crystal growth, Wiencek J M (1999) Annu Rev Biomed Eng 1 505-534 New Strategies for crystal growth).

[0019] The reasons why it is commonly held that crystallization of protein molecules from solution is the major obstacle in the process of determining protein structures are many; proteins are complex molecules, and the delicate balance involving specific and non-specific interactions with other protein molecules and small molecules in solution, is difficult to predict.

[0020] Each protein crystallizes under a unique set of conditions, which cannot be predicted in advance. Simply supersaturating the protein to bring it out of solution will not work, the result would, in most cases, be an amorphous precipitate. Many precipitating agents are used, common ones are different salts, and polyethylene glycols, but others are known. In addition, additives such as metals and detergents can be added to modulate the behaviour of the protein in solution. Many kits are available (e.g., from Hampton Research), which attempt to cover as many parameters in crystallization space as possible, but in many cases these are just a starting point to optimize crystalline precipitates and crystals which are unsuitable for diffraction analysis. Successful crystallization is aided by knowledge of the proteins behaviour in terms of solubility, dependence on metal ions for correct folding or activity, interactions with other molecules and any other information that is available. Even so, crystallization of proteins is often regarded as a time-consuming process, whereby subsequent experiments build on observations of past trials.

[0021] In cases where protein crystals are obtained, these are not necessarily always suitable for diffraction analysis; they may be limited in resolution, and it may subsequently be difficult to improve them to the point at which they will diffract to the resolution required for analysis. Limited resolution in a crystal can be due to several things. It may be due to intrinsic mobility of the protein within the crystal; this can be difficult to overcome, even with other crystal forms. It may be due to high solvent content within the crystal, which consequently results in weak scattering. Alternatively, it could be due to defects within the crystal lattice, which means that the diffracted x-rays will not be completely in phase from unit to unit within the lattice. Any one of these or a combination of these could mean that the crystals are not suitable for structure determination.

[0022] Some proteins never crystallize, and after a reasonable attempt it is necessary to examine the protein itself and consider whether it is possible to make individual domains, different N or C-terminal truncations, or point mutations. It is often hard to predict how a protein could be re-engineered in such a manner as to improve crystallisability. Sometimes the inclusion of a ligand in the crystallisation mixture is essential for the production suitable crystals. Our understanding of crystallisation mechanisms is still incomplete and the factors of protein structure, which are involved in crystallisation, are not well known.

[0023] BACE Production for Crystallisation

[0024] Beta secretase (BACE) is an integral membrane protein containing a signal sequence, a pro-peptide, a catalytic aspartyl protease domain, a transmembrane region and a C-terminal cytoplasmic region. During transit through the endoplasmic reticulum, Golgi apparatus and trans Golgi network the pro-peptide is cleaved by a furin-like protease (Bennett et al 2000, Creemers et al 2001) and N-glycosylation is added and matured (Haniu et al 2000). The protein contains 4 potential N-linked glycosylation sites, all of which are used (Bennett et al, 2000).

[0025] Certain active recombinant BACEs—different from those of the herein invention—have been produced using heterologous expression systems for mammalian cells (Vassar et al, 1999, Hussain et al, 1999), insect cells (Mallender et al, 2000) and bacterial cells (Lin et al 2000). Preferred constructs for crystallisation would be soluble and lack glycosylation: the former can be achieved by C-terminal truncation of the protein to remove the transmembrane and cytoplasmic regions; while glycosylation could be removed either by use of a deglycosylating agent such as PNGase F, by expression of the protein in bacteria or by mutation of the glycosylation sites.

[0026] The protein used for BACE crystallisation by Hong et al (2000) was produced in bacteria and was truncated at the C-terminus. Their protein was produced as insoluble inclusion bodies and required refolding to give soluble, active protein. Refolding of BACE is made more complex by the presence of 3 disulphide bonds in the native protease domain, which require careful control of redox conditions to form during in-vitro refolding. The protein produced by Hong et al was a mixture of products and was crystallised with inhibitor bound (see WO 01/00663, WO 01/00665, and U.S. Pat. No. 6,545,127).

[0027] Mention is also made of WO 02/25276, which describes the crystallisation of BACE produced in mammalian cells. The protein produced also was a mixture of protein species and was also crystallized with an inhibitor bound.

[0028] Mention is also made of WO03/012089, which describes the crystallisation of BACE produced from insect cells. The co-ordinates of BACE with an inhibitor bound are provided.

SUMMARY OF THE INVENTION

[0029] In general aspects, the present invention is concerned with the provision of a new, high resolution, apo, crystal form of BACE and the use of this structure in identifying or obtaining agent compounds (especially inhibitors of BACE) for modulating BACE activity, and in preferred embodiments identifying or obtaining actual agent compounds/inhibitors. Crystal structure information presented herein is useful in designing potential inhibitors and modelling them or their potential interaction with the BACE binding cavity. Potential inhibitors may be brought into contact with BACE to test for ability to interact with the BACE binding cavity. Actual inhibitors may be identified from among potential inhibitors synthesized following design and model work performed in silico. An inhibitor identified using the present invention may be formulated into a composition, for instance a composition comprising a pharmaceutically acceptable excipient, and may be used in the manufacture of a medicament for use in a method of treatment.

[0030] Thus, according to a first aspect of the present invention there is provided a mutant BACE protein, which protein lacks one or more proteolytic cleavage sites recognized by clostripain (or another protease which recognizes the same cleavage site as clostripain). In particular, the protein is a BACE protein, which comprises the sequence set out in residues 45 to 455 of SEQ ID NO:2 (43 to 453 SwissProt P56817), or a fragment thereof comprising residues corresponding to 58 to 398 of SEQ ID NO:2, modified by the following changes: (a) substitution or deletion of at least one residue which is a proteolytic cleavage site recognised by clostripain; and (b) optionally the replacement of from 1 to 30 other amino 25 acids by an equivalent or fewer number of amino acids. It will be understood that when the BACE protein comprises a fragment as defined above, the fragment will comprise at least feature (a) and optionally feature (b).

[0031] The modification is such that the BACE protein preferably retains at least one proteolytic cleavage site recognised by clostripain so that it may be cleaved to provide homogeneous location at which cleavage occurs.

[0032] According to a second aspect of the present invention there is provided a mutant BACE protein which is truncated at the N-terminal up to and including R42, R45, G55, R56 or R57. In a preferred aspect, when the protein is truncated up and including R56 the residue at position 57 is not arginine. It may for example be lysine.

[0033] In a third aspect the invention provides a mutant BACE protein selected from: (a) SEQ ID 6; (b) SEQ ID 8; (c) SEQ ID 10; (d) SEQ ID 12; (e) SEQ ID 14; (f) SEQ ID 16; (g) SEQ ID 18; (h) SEQ ID 19; (i) SEQ ID 20; (j) SEQ ID 21.

[0034] In another aspect, the invention contemplates a nucleic acid (e.g. DNA or RNA) sequence encoding the BACE protein of the invention, as well as the complementary nucleic acid sequence counterpart.

[0035] The nucleic acids of the invention may be isolated, or may be present in the context of a vector or host cell. Thus, in another aspect, the invention contemplates a vector comprising the nucleic acid of the invention.

[0036] The nature of the vector of the invention is not critical to the invention. Any suitable vector may be used, including expression vectors, plasmid, virus, bacteriophage, transposon, minichromosome, liposome or mechanical carrier.

[0037] The expression vectors of the invention are DNA constructs suitable for expressing DNA which encodes the desired peptide and which may include: (a) a regulatory element (e.g. a promoter, operator, activator, repressor and/or enhancer), (b) a structural or coding sequence which is transcribed into mRNA and (c) appropriate transcription, translation, initiation and termination sequences. They may also contain sequence encoding any of various tags (e.g. to facilitate subsequent purification of the expressed protein, such as affinity (e.g. His tags).

[0038] Particularly preferred are vectors which comprise an expression element or elements operably linked to the DNA of the invention to provide for expression thereof at suitable levels. Any of a wide variety of expression elements may be used, and the expression element or elements may for example be selected from promoters, enhancers, ribosome binding sites, operators and activating sequences. Such expression elements may comprise an enhancer, and for example may be regulatable, for example being inducible (via the addition of an inducer).

[0039] The vector may further comprise a positive selectable marker and/or a negative selectable marker. The use of a positive selectable marker facilitates the selection and/or identification of cells containing the vector.

[0040] In another aspect, the invention contemplates a host cell comprising the vector of the invention. The nucleic acid of the invention may be intrdoduced into the host cell by any of a large number of convenient methods, including calcium phosphate transfection, DEAE-Dextran mediated transfection, electroporation or any other method known in the art.

[0041] Any suitable host cell may be used, including prokaryotic host cells (such as Escherichia, coli, Streptomyces spp. and Bacillus subtilis) and eukaryotic host cells. Suitable eukaryotic host cells include insect cells (e.g. using the baculovirus expression system), mammalian cells, fungal (e.g. yeast) cells and plant cells. Preferred mammalian cells are animal cells such as CHO, COS, C 127, 3T3, HeLa, HEK 293, NIH 3T3, BHK and Bowes melanoma (particularly preferred being CHO-K1, COS7, Y1 adrenal and carcinoma cells).

[0042] Cell-free translation systems can also be used to produce the peptides of the invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989).

[0043] Prokaryotic host cells are preferred in circumstances where the BACE protein is required in an unglycosylated state.

[0044] According to another aspect of the invention there is provided a process for producing the BACE protein of the invention comprising the steps of: (a) culturing the host cell of the invention under conditions suitable for expression of the BACE protein; and optionally (b) isolating the expressed recombinant BACE protein.

[0045] In a further aspect the invention provides a method of making BACE protein which comprises protedlytically cleaving a BACE protein which lacks one of more proteolytic cleavage sites as described above, the cleavage desirably occurring at (and including) one of position 42, 45, 55, 56 or 57, preferably 42, 56 or 57. Clostripain, or another protease which recognises the same cleavage site as clostripain, may be used.

[0046] Thus the resulting BACE protein of this aspect of invention will be a protein whose N-terminal corresponds to 45, 48, 58, 59 or 60 of SEQ ID NO:2, and whose C-terminal region extends to and includes at least 398 of SEQ ID NO:2. Preferably the C-terminal region terminates at a residue between a point corresponding to and including 398 up to and including 455. This BACE protein may additionally comprise a C-terminal tag, such as a tag comprising from 5 to 15 residues, such as a his tag or the like.

[0047] In another aspect of the invention there is provided a process for producing refolded recombinant BACE protein comprising the steps of: (a) solubilising the recombinant BACE; (b) diluting the solubilised BACE into an aqueous buffer containing sulfobetaine (for example at a concentration of 10 to 50 mM, for example 10 mM); and (c) maintaining the diluted solution at low temperature (for example, 3 to 6° C.) and at high pH (e.g. 9 to 10.5) for at least 2 weeks (typically 3 weeks, more typically 4 weeks).

[0048] In another aspect the invention provides a process for producing a crystal of BACE comprising the step of growing the crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME (for example, 20-24% PEG 5000 MME, e.g. 20-22.5% PEG 5000 MME), 180-220 mM (e.g. 200 mM) ammonium iodide and 180-22-mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In a further aspect the reservoir buffer may additionally comprise from 0 to 5% (v/v) glycerol, for example 2.5% v/v.

[0049] In another aspect the invention provides various BACE crystals, including a crystal of BACE having a hexagonal space group P622 (and optionally having unit cell dimensions of a=b=103.2 Å, c=169.1 Å,α=β=60°, γ=120 °, and a unit cell variability of 5% in all dimensions); a crystal of BACE having a resolution better than 3 Å (for example, better than 2.5 Å, e.g. better than 1.8 Å), and a crystal of BACE comprising a structure defined by all or a portion of the co-ordinates of Table 1.

[0050] In another aspect the invention provides a three-dimensional representation of BACE or of a portion of BACE, which representation comprises all or a portion of the coordinates of Table 1. The representation is preferably a BACE model.

[0051] The invention also contemplates a three-dimensional representation of a compound which fits the BACE model of the invention.

[0052] The invention also contemplates a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing a BACE model; (b) providing a molecular structure to be fitted to said BACE model; and (c) fitting the molecular structure to the BACE model to produce a compound model.

[0053] In another aspect the invention provides a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE as defined by the coordinates of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0054] In another aspect the invention provides a computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to the selected coordinates; and (c) fitting the structure to the selected coordinates of the BACE structure.

[0055] In another aspect the invention provides a computer-based method of rational drug design comprising comprising: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0056] In another aspect the invention provides a method for identifying a candidate modulator (e.g. candidate inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0057] In another aspect the invention provides a method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one (e.g. a plurality of) BACE binding site(s); (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0058] In another aspect the invention provides a method of assessing the ability of a candidate modulator to interact with BACE which comprises the steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a crystallized complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0059] In another aspect the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) mixing BACE with the compound to form a BACE-compound complex; (b) crystallizing the BACE-compound complex; and (c) determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0060] In another aspect the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE; (b) soaking the crystal with one or more compound(s) to form a complex; and (c) determining the structure of the complex by employing the data of Table 1.

[0061] In another aspect the invention provides a method of determining the three dimensional structure of a BACE homologue or analogue of unknown structure, the method comprising the steps of: (a) aligning a representation of an amino acid sequence of the BACE homologue or analogue with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation for the BACE homologue or analogue which substantially preserves the structure of said matched homologous regions.

[0062] In another aspect the invention provides a method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising: (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0063] In another aspect the invention provides a computer system containing one or more of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof; (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0064] In another aspect the invention provides a computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the Cα or backbone atoms (nitrogen-carbonα-carbon) of Table 1 of less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the residue backbone atoms.

[0065] In another aspect the invention provides a computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0066] In another aspect the invention provides a computer readable medium with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0067] In another aspect the invention provides a method for determining the structure of a protein, which method comprises; providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0068] In another aspect the invention contemplates BACE modulator molecules, medicaments, pharmaceutical compositions and drugs obtainable by, or obtained by, the processes and methods of the invention, and to methods of therapy (e.g. the treatment of Alzheimer's disease) using such products.

[0069] It is to be understood that, except where explicitly stated otherwise, references herein to “BACE protein” or “BACE peptide”, “mutant BACE protein” or “mutant BACE peptide” and to “BACE protein” or “BACE peptide”, as well as references to any of the foregoing which are further defined inter alia by reference to one or more specific amino acid sequences, are intended to cover BACE homologues, allelic forms, species variants, derivatives and muteins thereof (as defined below).

[0070] Thus, references to mutant BACE proteins having particular amino acid sequences may optionally be interpreted to cover the corresponding homologues, allelic forms, species variants, derivatives and muteins (as defined below) of that particular BACE amino acid sequence.

DEFINITIONS

[0071] Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

[0072] The term “isolated” is used herein to indicate that the isolated moiety (e.g. peptide or nucleic acid) exists in a physical milieu distinct from that in which it occurs in nature. For example, the isolated peptide may be substantially isolated with respect to the complex cellular milieu in which it naturally occurs. The absolute level of purity is not critical, and those skilled in the art can readily determine appropriate levels of purity according to the use to which the peptide is to be put. The term “isolating” when used a step in a process is to be interpreted accordingly.

[0073] In many circumstances, the isolated moiety will form part of a composition (for example a more or less crude extract containing many other molecules and substances), buffer system, matrix or excipient, which may for example contain other components (including proteins, such as albumin).

[0074] In other circumstances, the isolated moiety may be purified to essential homogeneity, for example as determined by PAGE or column chromatography (for example HPLC or mass spectrometry). In preferred embodiments, the isolated peptide or nucleic acid of the invention is essentially the sole peptide or nucleic acid in a given composition.

[0075] The proteins and nucleic acids of the invention need not be isolated in the sense defined above, however. For example, more or less crude culture supernatants (e.g. “spent” medium) may contain sufficient concentrations of the proteins or nucleic acids of the invention for use in several applications. Preferably, such supernatants are fractionated and/or extracted, but in many circumstances they may be used without pretreatment. They are preferably derived from spent media used to culture the host cells of the invention (for example, the bacterial sources described infra). The supernatants are preferably sterile. They may be treated in various ways, for example by concentration, filtration, centrifugation, spray drying, dialysis and/or lyophilisation. Conveniently, the culture supernatants are simply centrifuged to remove cells/cell debris and filtered.

[0076] The term “pharmaceutical composition” is used herein to define a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.

[0077] The term “recombinant” as applied to the proteins of the invention is used herein to define a protein that has been produced by that body of techniques collectively known as “recombinant DNA technology” (for example, using the nucleic acid, vectors and or host cells described herein).

[0078] The term “synthetic” as applied to the peptides of the invention is used herein to define a peptide that has been chemically synthesised in vitro (for example by any of the commercially available solid-phase peptide-synthesis systems).

[0079] As used herein in relation to the vectors of the invention, the term “operably linked” refers to a condition in which portions of a linear nucleic acid sequence are capable of influencing the activity of other portions of the same linear nucleic acid sequence. For example, DNA for a signal peptide (secretory leader) is operably linked to DNA for a polypeptide if it is expressed as a precursor which participates in the secretion of the polypeptide; a promoter is operably linked to a coding sequence if it controls the transcription of the sequence; a ribosome binding site is operably linked to a coding sequence if it is positioned in the correct reading-frame so as to permit translation.

[0080] By “apo-structure” we mean the three-dimensional structure of the protein that contains no ligand, e.g. substrate or product or cofactor or inhibitor i.e. the active site of the protein is empty.

[0081] In the following by “binding site” or “binding cavity” we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a BACE binding cavity, which may bind to an agent compound such as a candidate inhibitor. Depending on the particular molecule in the cavity, sites may exhibit attractive or repulsive binding interactions, brought about by charge, steric considerations and the like.

[0082] Binding sites are sites within a macromolecule, or on its surface, at which ligands can bind. Examples are the catalytic or active site of an enzyme (the site on an enzyme at which the amino acid residues involved in catalysing the enzymatic reaction are located), allosteric binding sites (ligand binding sites distinct from the catalytic site, but which can modulate enzymatic activity upon ligand binding), cofactor binding sites (sites involved in binding/co-ordinating cofactors e.g. metal ions), or substrate binding sites (the ligand binding sites on a protein at which the substrates for the enzymatic reaction bind). There are also sites of protein-protein interaction.

[0083] In the following by “active site” we mean a site (such as an atom, a functional group of an amino acid residue or a plurality of such atoms and/or groups) in a BACE binding cavity, which is involved in catalysis.

[0084] By “fitting”, is meant determining by automatic, or semi-automatic means, interactions between one or more atoms of a candidate molecule and at least one atom of a BACE structure of the invention, and calculating the extent to which such interactions are stable. Interactions include attraction and repulsion, brought about by charge, steric considerations and the like. Various computer-based methods for fitting are described further herein.

[0085] By “root mean square deviation” we mean the square root of the arithmetic mean of the squares of the deviations from the mean.

[0086] By a “computer system” we mean the hardware means, software means and data storage means used to analyse atomic coordinate data. The minimum hardware means of the computer-based systems of the present invention typically comprises a central processing unit (CPU), input means, output means and data storage means. Desirably a monitor is provided to visualise structure data. The data storage means may be RAM or means for accessing computer readable media of the invention. Examples of such systems are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running Unix based, Windows NT or IBM OS/2 operating systems.

[0087] By “computer readable media” we mean any medium or media, which can be read and accessed directly by a computer e.g. so that the media is suitable for use in the above-mentioned computer system. Such media include, but are not limited to: magnetic storage media such as floppy discs, hard disc storage medium and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.

[0088] The term “homologue” is used herein in two distinct senses. It is used sensu stricto to define proteins that share a common ancestor. In this sense it covers orthologues (species variants which have diverged in different organisms following a speciation event) and paralogues (variants which have diverged within the same organism after a gene duplication event). Thus, there is a direct evolutionary relationship between such homologues and this may be reflected in structural and/or functional similarities. For example, orthologues may perform the same role in each organism in which they are found, while paralogues may perform functionally related (but distinct) roles within the same organism.

[0089] The term is also used herein sensu lato to define proteins which are to some extent structurally similar (i.e. not necessarily evolutionary related and/or structurally and functionally equivalent). In this sense, homology is recognised on the basis of purely structural criteria by the presence of amino acid sequence identities and/or conservative amino acid changes and/or similar secondary, tertiary or quaternary structures.

[0090] The term “analogue” is used herein to define proteins with similar functions and/or structures and which are not necessarily evolutionary related. Protein analogues which share function but which have no or little structural similarities are likely to have arisen by convergent evolution. Conversely, protein analogues which share structural similarities but which exhibit few or no functional similarities are likely to have arisen by divergent evolution. Protein analogues may be identified, for example, by screening a library of proteins to detect those with similar function(s) but different physical properties, or by screening for proteins which share structural features but not necessarily any functions (e.g. by immunological screening).

[0091] The term “equivalent” is used herein to define those protein analogues which exhibit substantially the same function(s) and which share at least some structural features (e.g. functional domains), but which have not evolved from a common ancestor. Such equivalents are typically synthetic proteins (see below) and may be generated, for example, by identifying sequences of functional importance (e.g. by identifying conserved or canonical sequences, functional domains or by mutagenesis followed by functional assay), selecting an amino acid sequence on that basis and then synthesising a peptide based on the selected amino acid sequence. Such synthesis can be achieved by any of many different methods known in the art, including solid phase peptide synthesis (to generate synthetic peptides) and the assembly (and subsequent cloning) of oligonucleotides. Some synthetic protein analogues may be chimaeras (see below), and such equivalents can be designed and assembled for example by concatenation of two or more different structural and/or functional peptide domains from different proteins using recombinant DNA techniques (see below).

[0092] The BACE protein homologues of the invention therefore include proteins and peptides having at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity with the reference protein, and include truncated forms of the BACE proteins of the invention. Such truncates are preferably at least 25%, 35%, 50% or 75% of the length of the corresponding specifically exemplified proteins and may have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity) with that specifically exemplified protein.

[0093] Particularly preferred homologues are truncates that contain a segment preferably comprising at least 8, 15, 20 or 30 contiguous amino acids that share at least 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% sequence identity with that specifically exemplified protein.

[0094] A “conservative amino acid change” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g. lysine, arginine and histidine), acidic side chains (e.g. aspartic acid and glutamic acid), non-charged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine and cysteine), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan), beta-branched side chains (e.g. threonine, valine and isoleucine), and aromatic side chains (e.g. tyrosine, phenylalanine, tryptophan and histidine).

[0095] Thus, references herein to proteins and peptides that are to some defined extent “identical” (or which share a defined extent of “identity”) with a reference protein or peptide may also optionally be interpreted to include proteins and peptides in which conservative amino acid changes are disregarded so that the original amino acid and its changed counterpart are regarded as identical for the purposes of sequence comparisons.

[0096] The term “allelic form” is used herein to define a naturally-occurring alternative forms of the sequence present in the BACE protein which reflect naturally-occurring differences in the BACE gene pool. Preferably, allelic variants of the proteins of the invention have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90% or 95% sequence identity) with the corresponding specifically exemplified BACE protein, where sequence identity is determined by comparing the nucleotide sequences of the polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.

[0097] The term “species variant” (or orthologue) is used herein to define the corresponding protein from a different organism. Thus, species variants share a direct evolutionary relationship.

[0098] The term “derivative” as applied herein to the BACE proteins of the invention is used to define proteins which are modified versions of the specifically exemplified proteins of the invention. Such derivatives may include fusion proteins, in which the proteins of the invention have been fused to one or more different proteins, peptides or amino acid tags (for example an antibody or a protein domain conferring a biochemical activity, to act as a label, or to facilitate purification). Particularly preferred are derivatives in which the peptides are modified by a polyHis (6×His) tag to facilitate purification of the peptide derivative on Ni2+ agarose beads.

[0099] The derivatives may also be products of synthetic processes that use a peptide of the invention as a starting material or reactant.

[0100] The term “mutein” is used herein to define proteins that are mutant forms of the BACE proteins of the invention, i.e. proteins in which one or more amino acids have been added, altered, deleted, replaced, inserted or substituted. Thus, the terms “BACE mutein” and “mutant BACE protein” are used interchangeably herein. The muteins/mutant BACE proteins of the invention therefore include fragments, truncates and fusion proteins and peptides (e.g. comprising fused immunoglobulin, receptor, tag, label or enzyme moieties).

[0101] The muteins of the invention therefore include truncated forms of the BACE proteins of the invention. Such truncates are preferably least 25%, 35%, 50% or 75% of the length of the corresponding specifically exemplified BACE protein and may have at least 60% sequence identity (more preferably, at least 75%, 80%, 85%, 90% or 95% sequence identity) with that specifically exemplified protein.

[0102] Particularly preferred are truncates that contain a segment preferably comprising at least 8, 15, 20 or 30 contiguous amino acids that share at least 75%, 80%, 85%, 90% or 95% sequence identity with that specifically exemplified protein.

[0103] For the purposes of the present invention, sequence identity is determined by comparing the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps. In particular, sequence identity may be determined using any of a number of mathematical algorithms. A nonlimiting example of a mathematical algorithm used for comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87: 2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5877.

[0104] Another example of a mathematical algorithm used for comparison of sequences is the algorithm of Myers and Miller (1988) CABIOS 4: 11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444-2448.

[0105] Preferred for use according to the present invention is the WU-BLAST (Washington University BLAST) version 2.0 software. WU-BLAST version 2.0 executable programs for several UNIX platforms can be downloaded from ftp://blast.wustl.edu/blast/executables. This program is based on WU-BLAST version 1.4, which in turn is based on the public domain NCBI-BLAST version 1.4 (Altschul and Gish, 1996, Local alignment statistics, Doolittle ed., Methods in Enzymology 266: 460-480; Altschul et al., 1990, Basic local alignment search tool, Journal of Molecular Biology 215: 403-410; Gish and States, 1993, Identification of protein coding regions by database similarity search, Nature Genetics 3: 266-272; Karlin and Altschul, 1993, Applications and statistics for multiple high-scoring segments in molecular sequences, Proc. Natl. Acad. Sci. USA 90: 5873-5877; all of which are incorporated by reference herein).

[0106] In all search programs in the suite the gapped alignment routines are integral to the database search itself. Gapping can be turned off if desired. The default penalty (Q) for a gap of length one is Q=9 for proteins and BLASTP, and Q=10 for BLASTN, but may be changed to any integer. The default per-residue penalty for extending a gap (R) is R=2 for proteins and BLASTP, and R=10 for BLASTN, but may be changed to any integer. Any combination of values for Q and R can be used in order to align sequences so as to maximize overlap and identity while minimizing sequence gaps. The default amino acid comparison matrix is BLOSUM62, but other amino acid comparison matrices such as PAM can be utilized.

[0107] The muteins of the invention also include peptides in which mutations have been introduced which effectively promote or impair one or more activities of the protein, for example mutations which promote or impair the function of a receptor, a recognition sequence or an effector binding site.

[0108] Muteins may be produced by any convenient method. Conveniently, site-directed mutagenesis with mutagenic oligonucleotides may be employed using a double stranded template (pBluescript KS II construct containing nucleic acid encoding the BACE protein), (e.g. Chameleon™ or QuikChange™-Stratagene™) or cassette mutagenesis methods my be employed. After verifying each mutant derivative by sequencing, the mutated gene is excised and inserted into a suitable vector so that the modified protein can be over-expressed and purified.

BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Table 1, provides the coordinates of the BACE structure. The numbering of the residues used in this Table (see Section (D) below) correspond to the numbering of used by Hong et al, ibid. Elsewhere—unless indicated to the contrary—in the specification the numbering of the SwissProt database entry P56817 is used. Residue 1 of Table 1 corresponds to 62 of SwissProt P56817, and residue 385 corresponds to 446 of SwissProt P56817. In the sequence listing below, the SwissProt P56817 residues 14-453 are shown as 16-455 of SEQ ID NO:2.

[0110]
FIG. 1 represents the packing arrangements of the BACE monomers within the P61,22 crystal lattice.

[0111]
FIG. 2 shows the superposition of BACE in complex with OM99-2 (1FKN), in black, with BACE, of the invention, in the absence of ligand (grey). The position of OM99-2 is defined by a stick representation of the inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

[0112] A. Construct Design

[0113] BACE protease is expressed, at high levels, as insoluble inclusion bodies in bacterial cells. To prepare functional protein appropriate for enzyme assay and structural studies these inclusion bodies are solubilised using denaturants and the slow removal of these denaturants results in the formation of the correct tertiary structure. In addition BACE is expressed as a pro-sequence and requires activation by a protease before it is fully functional.

[0114] One of the problems of the techniques described in the art (Tang et al) for isolation of BACE from inclusion bodies is the generation of a mixture of products from the uncontrolled cleavage process. Choppa et al describe the isolation of BACE from mammalian cells and the subsequent cleavage with protease, which also gives a mixture of protein species. Thus there is a need in the art for a method of generating active BACE as a homogenous species.

[0115] A further problem with the prior art techniques is the low yield of crystallisable material obtained. The inventors surprisingly found that the present invention results in a high yield from bacterial cells, in particular E. coli.

[0116] The inventors utilized clostripain as an activating protease to perform this cleavage in a controlled manner but this produced multiple species of BACE, as determined by mass spectrometry. In order to obtain a uniform homogenous protein after activation, a number of different constructs were produced. These constructs focused on the mutation of two of the clostripain cleavage sites (R56 and R57).

[0117] The sequences of the invention were designed to achieve a single cleavage point upon activation by clostripain, as activation of wild type sequence in this way resulted in a non-crystallisable protein with heterogeneous N termini.

[0118] The BACE constructs of the invention contain successful modifications of the BACE sequence to allow generation of homogeneous protein product from the use of clostripain. The sequence of the invention contains substitution for another amino acid residue or deletion of the arginine 56 and/or arginine 57 (numbering based on wild type full length sequence, SWISS_PROT P56817). In a preferred aspect of the invention this is a conserved substitution. 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, positively charged amino acids include lysine and arginine and histidine. In a preferred aspect the mutation introduced is substitution of arginine to lysine at position 56 and/or 57, more preferably 56 and 57. This results in, as oppose to the wild type, the production of a single species of activated protein upon limited digest with clostripain. Clostripain cleavage occurs at a single site and is thus specific and generates a single species in minutes.

[0119] The advantage of these mutations is that they allow the controlled cleavage at arginine residue 42 and hence provides a single N-terminus.

[0120] This controlled cleavage thus provides a means to produce a substantially homogeneous composition of a BACE protein of the invention. By substantially homogeneous, it is meant that at least 95%, preferably at least 98% and more preferably at least 99% of the BACE protein in the composition has the same N-terminus. The N-terminus may be selected from residues 43 (i.e. by cleavage at 42), 46, 56, 57 or 58, preferably from 43, 56, 57 or 58, more preferably 43, 56 or 57.

[0121] These mutations can be introduced onto any sequence of BACE by site-directed mutagenesis techniques, to facilitate the generation of homogeneous material for structural or activity studies. Thus proteins of the invention are BACE proteins with residues 56 and/or 57 either mutated or deleted. Proteins of the invention also include BACE mutants described below in section (C).

[0122] The invention is exemplified by several constructs (SEQ ID 5-18). These were built based 15 on the wild type sequence (BACE WT, SEQ ID 2) where R56 and/or R57 were mutated to K or deleted. These were BACE WT R56KR57K (SEQ ID 6), BACE WT R57K (SEQ ID 8), BACE WT R57del (SEQ ID 10). This was also performed on the BACE construct BACE N->Q to give BACE N->Q R56KR57K (SEQ ID 12), BACE N->Q R57K (SEQ ID 16), BACE N->Q R57del (SEQ ID 18). The BACE N->Q construct contains 4 additional mutations of asparagines to glutamine and a C-terminal His tag as well as the arginine mutations. BACE N->Q without the His tag was mutated at 56 and 57 to give BACE N->Q R56K R57K no His (SEQ ID 14).

[0123] SEQ ID 19 is the activated from of SEQ ID 6, SEQ ID 21 the activated form of SEQ ID 12 and SEQ ID 20 the activated form of SEQ ID 14, i.e. the form in which the protein is crystallized:

[0124] The three BACE constructs BACE WT R56KR57K, BACE N->Q R56KR57K, and BACE N->Q R56KR57K no His gave higher expression levels.

[0125] Thus the invention concerns any BACE proteins with one or more of: a mutation at 56, and mutation at 57, or a deletion at 56 or a deletion at 57, but preferably 56 and 57 mutated, and crystals thereof i.e. any BACE protein comprising residues 56-396 of BACE (based on numbering of SwissProt P56817) and containing these mutations.

[0126] B. Refolding Protocol

[0127] The protein was expressed in E. coli as inclusion bodies, as outlined above. In an improvement of existing techniques BACE isolated from inclusion bodies was refolded by the use of high pH, a sulfobetaine refolding agent, and a longer duration at high pH. This refolding protocol increased the yield of refolded protein obtained and also gave high and reproducible yields of refolded BACE suitable for crystallisation.

[0128] The use of high pH in refolding (Burton et el, 1989) and of sulfobetaines as solubilising molecules in folding experiments (Goldberg et al, 1996) has previously been described. Here we describe the use of a combination of these technologies to give an unprecedented high yield of BACE. In addition to this combination of high pH and sulfobetaine, in another deviation from existing protocols for refolding BACE, the pH is maintained at high pH for at least 2 weeks. This is in comparison to the method of Tang et al, where BACE is solubilised at high pH and then the pH lowered before protein recovery at least 2-3 weeks later, preferably 3-4 weeks later.

[0129] Another aspect of the invention therefore concerns a novel method of producing soluble BACE proteins of the invention, utilizing a refolding protocol comprising the combined techniques of high pH buffer and the use of sulfobetaine, and also maintaining this high pH over at least two weeks.

[0130] More specifically, a method for producing refolded recombinant BACE comprising refolding the BACE under conditions which denature and then slowly renature the enzyme into a soluble form wherein: (a) the BACE is solubilised using a chaotrope such as urea or guanidine at 8-10M (typically 8 M urea solution) including one or more reducing agents at a pH of greater than 8.0 e.g. pH 9.0-10.5; (b) the BACE is then diluted into an aqueous buffer, like 20 mM-Tris, pH 9.0, containing sulfobetaine, preferably 10 mM sulfobetaine, where the sulfobetaine is preferably NDSB256 (3-(benzyldimethylammonio) propanesulfonate); (c) the solution is maintained at low temperature, e.g. 3-6° C. typically 4° C., and at high pH, typically approximately pH 9.0, for at least 2 weeks (typically 3 weeks, more typically 4 weeks) before proceeding with purification.

[0131] C. Protein Crystals.

[0132] Described herein is a crystal of BACE having a hexagonal space group P6122, and unit cell dimensions a=b=103.2 Å, c=169.1 Å, α=β=60°, γ=120°. Unit cell variability of 5% may be observed in all dimensions. Such crystals contain one copy of BACE in the asymmetric unit.

[0133] Such a crystal may be obtained using the methods described in the accompanying examples.

[0134] The crystal may be of the BACE protein of SEQ ID 19 although as explained earlier any homologue, allelic form, species variant, derivative or mutein (as hereinbefore defined) may be used. Thus, it will be understood by those of skill in the art that some variation to the primary amino acid sequence may be made without significant alteration to the resulting crystal structure. Such minor variations include the replacement of one or more amino acids, for example from 1 to 30, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids by an equivalent or fewer number of amino acids.

[0135] The methodology used to provide a BACE crystal illustrated herein may be used generally to provide a human BACE apo crystal resolvable at a resolution of at least 3 Å.

[0136] The invention thus further provides an apo BACE crystal having a resolution better than, i.e. numerically lower than, 2.5 Å.

[0137] The invention also provides a BACE crystal having a resolution better than, i.e. numerically lower than, 1.8 Å.

[0138] The invention also provides apo crystals of BACE resolvable to at least 2.5 Å capable of being soaked with compound(s) to form co-complex structures.

[0139] The proteins may be wild-type proteins or variants thereof, which are modified to promote crystal formation, for example by N-terminal truncations and/or deletion of loop regions, which prevent crystal formation.

[0140] The methods described herein may be used to make a BACE protein crystal, particularly of a BACE protein of SEQ ID 19-21, which method comprises growing a crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME, preferably 20-24% PEG 5000 MME, more preferably 20-22.5% PEG 5000 MME, with 180-220 mM (e.g. 200 mM) ammonium iodide and 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In a preferred embodiment, this reservoir buffer may also contain from 0 to 5% glycerol, e.g. about 2.5% glycerol. The growing of the crystal is by vapour diffusion and is performed by placing an aliquot of the protein solution on a cover slip as a hanging drop above a well containing the reservoir buffer. The concentration of the protein solution used was approximately 7 mg/ml.

[0141] Other crystals of the invention include crystals which have selected coordinates of the binding pocket, wherein the amino acid residues associated with those selected coordinates are located in a protein framework which holds these amino acids in a relative spatial configuration corresponding to the spatial configuration of those amino acids in Table 1. By “corresponding to”, it is meant within an rm.s.d. of less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å from the Cα or backbone atoms of Table 1, preferably the Cα atoms.

[0142] Crystals of the invention also include crystals of BACE mutants (muteins). In addition, BACE mutants may be crystallized in co-complex with known BACE substrates or inhibitors or novel compounds.

[0143] As explained herein, a mutant BACE (or BACE mutein) is a BACE protein characterized by the replacement or deletion of at least one amino acid from the wild type BACE. Such a mutant may be prepared for example by site-specific mutagenesis, or incorporation of natural or unnatural amino acids.

[0144] As explained herein, the present invention therefore contemplates BACE mutants (or muteins) as hereinbefore defined.

[0145] For example, the BACE mutants may define a polypeptide which is obtained by replacing at least one amino acid residue in a native or synthetic BACE with a different amino acid residue and/or by adding and/or deleting amino acid residues within the native polypeptide or at the N- and/or C-terminus of a polypeptide corresponding to BACE, and which has substantially the same three-dimensional structure as BACE from which it is derived. By having substantially the same three-dimensional structure is meant having a set of atomic structure co-ordinates that have a root mean square deviation (r.m.s.d.) of less than or equal to about 2.0 Å (preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å) when superimposed with the atomic structure co-ordinates of the BACE from which the mutant is derived when at least about 50% to 100% of the Cα atoms of the BACE are included in the superposition. A mutant may have, but need not have, enzymatic or catalytic activity.

[0146] To produce homologues or mutants, amino acids present in the said protein can be replaced by other amino acids having similar properties, for example hydrophobicity, hydrophobic moment, antigenicity, propensity to form or break α-helical or β-sheet structures, and so. Substitutional variants of a protein are those in which at least one amino acid in the protein sequence has been removed and a different residue inserted in its place. Amino acid substitutions are typically of single residues but may be clustered depending on functional constraints e.g. at a crystal contact. Preferably amino acid substitutions will comprise conservative amino acid substitutions. Insertional amino acid variants are those in which one or more amino acids are introduced. This can be amino-terminal and/or carboxy-terminal fusion as well as intrasequence. Examples of amino-terminal and/or carboxy-terminal fusions are affinity tags, MBP tag, and epitope tags.

[0147] Deletional variants are those in which one or more amino acids are removed. This can be amino-terminal and/or carboxy-terminal, or in an internal region (for example a loop region), for example to remove or shorten that region.

[0148] Amino acid substitutions, deletions and additions that do not significantly interfere with the three-dimensional structure of the BACE will depend, in part, on the region of the BACE 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.

[0149] As explained earlier, 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.

[0150] In some instances, it may be particularly advantageous or convenient to substitute, delete and/or add amino acid residues to a BACE binding pocket or catalytic residue in order to provide convenient cloning sites in the cDNA encoding the polypeptide, to aid in purification of the polypeptide, to modify compound binding etc. Such substitutions, deletions and/or additions which do not substantially alter the three dimensional structure of BACE will be apparent to those having skills in the art.

[0151] It should be noted that the mutants (BACE muteins) contemplated herein need not exhibit enzymatic activity. Indeed, amino acid substitutions, additions or deletions that interfere with the catalytic activity of the BACE but which do not significantly alter the three-dimensional structure of the catalytic region are specifically contemplated by the invention. Such crystalline polypeptides, or the atomic structure co-ordinates obtained there from, can be used to identify compounds that bind to the protein.

[0152] The crystallization of such mutants and the determination of the three-dimensional structures by X-ray crystallography relies on the ability of the mutant proteins to yield crystals that diffract at high resolution. The mutant protein could then be used to obtain information on compound binding through the determination of mutant protein/ligand complex structures, which may be characterized using the BACE crystal structure of Table 1.

[0153] The mutations can be introduced by site-directed mutagenesis e.g. using a Stratagene QuikChange™ Site-Directed Mutagenesis Kit or cassette mutagenesis methods (see e.g. Ausubel et al., eds., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York, and Sambrook et al., Molecular Cloning: a Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989)).

[0154] To the extent that the present invention relates to BACE-ligand complexes and mutant, homologue, allelic form, species variant, derivative, mutein and analogue proteins of BACE, crystals of such proteins may be formed. The skilled person would recognize that the conditions provided herein for crystallising BACE may be used to form such crystals. Alternatively, the skilled person would use the conditions as a basis for identifying modified conditions for forming the crystals.

[0155] Thus the aspects of the invention relating to crystals of BACE, may be extended to crystals of mutant/mutein, homologue, allelic form, species variant or derivative (as defined herein).

[0156] D. Crystal Coordinates

[0157] In a further aspect, the invention also provides an apo crystal structure of BACE having the three dimensional atomic coordinates of Table 1. An advantageous feature of the structure defined by the atomic coordinates is that it has a high resolution of about 1.75 Å. A further advantageous aspect is the provision of an apo structure of BACE, which contains no ligand bound, unlike those previously described in the art. This is particularly advantageous as ligands can then be easily soaked into the crystal to provide co-complex data without the need for removal of any ligand already present, and without the need for time-consuming co-crystallisation experiments.

[0158] The BACE structure set out in Table 1 is a monomer structure. This is the first time that a monomer has been observed crystallographically for this protein.

[0159] Table 1 gives atomic coordinate data for BACE. In Table 1 the third column denotes the atom type, the fourth the residue type, the fifth the chain identification, the sixth the residue number (the atom numbering as described in Hong et al, 2000) the seventh, eighth and ninth columns are the X, Y, Z coordinates respectively of the atom in question, the tenth column the occupancy of the atom, the eleventh the temperature factor of the atom, the twelfth the chain identification, and the last, thirteenth column, the atom type.

[0160] Each of the tables is presented in an internally consistent format. For example, in Table 1 the coordinates of the atoms of each amino acid residue are listed such that the backbone nitrogen atom is first, followed by the C-alpha backbone carbon atom, designated CA, followed by the carbon and oxygen of the protein backbone and finally side chain residues (designated according to one standard convention). Alternative file formats (e.g. such as a format consistent with that of the EBI Macromolecular Structure Database (Hinxton, UK)) which may include a different ordering of these atoms, or a different designation of the side-chain residues, may be used or preferred by others of skill in the art. However it will be apparent that the use of a different file format to present or manipulate the coordinates of the Tables is within the scope of the present invention.

[0161] The coordinates of Table 1 provide a measure of atomic location in Ångstroms, to 3 decimal places. The coordinates are a relative set of positions that define a shape in three dimensions, but the skilled person would understand that an entirely different set of coordinates having a different origin and/or axes could define a similar or identical shape. Furthermore, the skilled person would understand that varying the relative atomic positions of the atoms of the structure so that the root mean square deviation of the residue backbone atoms (i.e. the nitrogen-carbon-carbon backbone atoms of the protein amino acid residues) is less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the Cα atoms or residue backbone atoms, will generally result in a structure which is substantially the same as the structure of Table 1 in terms of both its structural characteristics and usefulness for structure-based analysis of BACE-interactivity molecular structures.

[0162] Likewise the skilled person would understand that changing the number and/or positions of the water molecules and/or substrate molecules of Table 1 will not generally affect the usefulness of the structure for structure-based analysis of BACE-interacting structure. Thus for the purposes described herein as being aspects of the present invention, it is within the scope of the invention if: the Table 1 coordinates are transposed to a different origin and/or axes; the relative atomic positions of the atoms of the structure are varied so that the root mean square deviation of residue backbone atoms is less than 2.0 Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å, and most preferably less than 0.5 Å when superimposed on the coordinates provided in Table 1 for the Cα or residue backbone atoms; and/or the number and/or positions of water molecules and/or substrate molecules is varied.

[0163] Reference herein to the coordinate data of Table 1 and the like thus includes the coordinate data in which one or more individual values of the Table are varied in this way unless specified explicitly to the contrary. In a preferred aspect, reference herein to the coordinates of Table 1 or parts thereof (e.g. selected coordinates) should be taken to include coordinates having a root mean square deviation of less than 0.72 Å, and preferably less than 0.5 Å, from the Cα atoms of Table 1 or corresponding parts thereof.

[0164] By “root mean square deviation” we mean the square root of the arithmetic mean of the squares of the deviations from the mean.

[0165] Protein structure similarity is routinely expressed and measured by the root mean square deviation (r.m.s.d.), which measures the difference in positioning in space between two sets of atoms. The r.m.s.d. measures distance between equivalent atoms after their optimal superposition. The r.m.s.d. can be calculated over all atoms, over residue backbone atoms (i.e. the nitrogen-carbon-carbon backbone atoms of the protein amino acid residues), main chain atoms only (i.e. the nitrogen-carbon-oxygen-carbon backbone atoms of the protein amino acid residues), side chain atoms only or more usually over C-alpha atoms only. For the purposes of this invention, the r.m.s.d. can be calculated over any of these, using any of the methods outlined below.

[0166] Methods of comparing protein structures are discussed in Methods of Enzymology, vol 115, pg 397-420. The necessary least-squares algebra to calculate r.m.s.d. has been given by Rossman and Argos (J. Biol. Chem., vol 250, pp7525(1975)) although faster methods have been described by Kabsch (Acta Crystallogr., Section A, A92, 922 (1976); Acta Cryst. A34, 827-828 (1978)), Hendrickson (Acta Crystallogr., Section A, A35, 158 (1979) and McLachan (J. Mol. Biol., vol 128, pp49 (1979). Some algorithms use an iterative procedure in which the one molecule is moved relative to the other, such as that described by Ferro and Hermans (Ferro and Hermans, Acta Crystallographic, A33, 345-347 (1977)). Other methods e.g. Kabsch's algorithm locate the best fit directly.

[0167] It is usual to consider C-alpha atoms and the rmsd can then be calculated using programs such as LSQKAB (Collaborative Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50, (1994), 760-763), MNYFIT (part of a collection of programs called COMPOSER, Sutcliffe, M. J., Haneef, I., Carney, D. and Blundell, T. L. (1987) Protein Engineering, 1, 377-384), MAPS (Lu, G. An Approach for Multiple Alignment of Protein Structures (1998, in manuscript)), QUANTA (Jones et al., Acta Crystallography A47 (1991), 110-119 and commercially available from Accelerys, San Diego, Calif.), Insight (commercially available from Accelerys, San Diego, Calif.), Sybyl® (commercially available from Tripos, Inc., St Louis), O (Jones et al., Acta Crystallographica, A47, (1991), 110-119), and other coordinate fitting programs.

[0168] In, for example the programs LSQKAB and O, the user can define the residues in the two proteins that are to be paired for the purpose of the calculation. Alternatively, the pairing of residues can be determined by generating a sequence alignment of the two proteins, programs for sequence alignment are discussed in more detail in Section G. The atomic coordinates can then be superimposed according to this alignment and an r.m.s.d. value calculated. The program Sequoia (C. M. Bruns, I. Hubatsch, M. Ridderström, B. Mannervik, and J. A. Tainer (1999) Human Glutathione Transferase A4-4 Crystal Structures and Mutagenesis Reveal the Basis of High Catalytic Efficiency with Toxic Lipid Peroxidation Products, Journal of Molecular Biology 288(3): 427-439) performs the alignment of homologous protein sequences, and the superposition of homologous protein atomic coordinates. Once aligned, the r.m.s.d. can be calculated using programs detailed above. For sequence identical, or highly identical, the structural alignment of proteins can be done manually or automatically as outlined above. Another approach would be to generate a superposition of protein atomic coordinates without considering the sequence.

[0169] It is more normal when comparing significantly different sets of coordinates to calculate the r.m.s.d. value over C-alpha atoms only. It is particularly useful when analysing side chain movement to calculate the r.m.s.d. over all atoms and this can be done using LSQKAB and other programs.

[0170] Varying the atomic positions of the atoms of the structure by up to about 0.5 Å in a concerted way, preferably up to about 0.3 Å in any direction will result in a structure which is substantially the same as the structure of Table 1 in terms of both its structural characteristics and utility e.g. for molecular structure-based analysis.

[0171] Also, modifications in the BACE crystal structure due to e.g. mutations, additions, substitutions, and/or deletions of amino acid residues (including the deletion of one or more BACE protomers) could account for variations in the BACE atomic coordinates. However, atomic coordinate data of BACE modified so that a ligand that bound to one or more binding sites of BACE would be expected to bind to the corresponding binding sites of the modified BACE are, for the purposes described herein as being aspects of the present invention, also within the scope of the invention. Reference herein to the coordinates of Table 1 thus includes the coordinates modified in this way. Preferably, the modified coordinate data define at least one BACE binding cavity.

[0172] Those of skill in the art will appreciate that in many applications of the invention, it is not necessary to utilise all the coordinates of Table 1, but merely a portion of them. The term portion is intended to define a sub-set of the coordinates, which may or may not represent contiguous amino acid residues in the BACE structure. For example, as described below, in methods of modelling candidate compounds with BACE, selected coordinates of BACE may be used, for example at least 5, preferably at least. 10, more preferably at least 50 and even more preferably at least 100 atoms of the BACE structure. Likewise, the other applications of the invention described herein, including homology modelling and structure solution, and data storage and computer assisted manipulation of the coordinates, may also utilise all or a portion of the coordinates of Table 1.

[0173] E. Homology Modelling

[0174] The invention also provides a means for homology modelling of other proteins (referred to below as target BACE proteins). By “homology modelling”, it is meant the prediction of related BACE structures based either on X-ray crystallographic data or computer-assisted de novo prediction of structure, based upon manipulation of the coordinate data of Table 1.

[0175] “Homology modelling” extends to target BACE proteins, which are analogues or homologues of the BACE protein whose structure has been determined in the accompanying examples. It also extends to BACE protein mutants of BACE protein itself.

[0176] The term “homologous regions” describes amino acid residues in two sequences that are identical or have similar (e.g. aliphatic, aromatic, polar, negatively charged, or positively charged) side-chain chemical groups. Identical and similar residues in homologous regions are sometimes described as being respectively “invariant” and “conserved” by those skilled in the art.

[0177] In general, the method involves comparing the amino acid sequences of the BACE protein of Table 1 with a target BACE protein by aligning the amino acid sequences (Dunbrack et al., Folding and Design, 2, (1997), 27-42). Amino acids in the sequences are then compared and groups of amino acids that are homologous (conveniently referred to as “corresponding regions”) are grouped together. This method detects conserved regions of the polypeptides and accounts for amino acid insertions or deletions.

[0178] Homology between amino acid sequences can be determined using commercially available algorithms. The programs BLAST, gapped BLAST, BLASTN, PSI-BLAST and BLAST 2 sequences (provided by the National Center for Biotechnology Information) are widely used in the art for this purpose, and can align homologous regions of two amino acid sequences. These may be used with default parameters to determine the degree of homology between the amino acid sequence of the Table 1 protein and other target BACE proteins, which are to be modeled.

[0179] Analogues are defined as proteins with similar three-dimensional structures and/or functions with little evidence of a common ancestor at a sequence level.

[0180] Homologues are defined as proteins with evidence of a common ancestor, i.e. likely to be the result of evolutionary divergence and are divided into remote, medium and close sub-divisions based on the degree (usually expressed as a percentage) of sequence identity.

[0181] A homologue is defined here as a protein with at least 15% sequence identity or which has at least one functional domain, which is characteristic of BACE.

[0182] There are two types of homologue: orthologues and paralogues. Orthologues are defined as homologous genes in different organisms, i.e. the genes share a common ancestor coincident with the speciation event that generated them. Paralogues are defined as homologous genes in the same organism derived from a gene/chromosome/genome duplication, i.e. the common ancestor of the genes occurred since the last speciation event.

[0183] The homologues could also be mutants as described in section (C).

[0184] Once the amino acid sequences of the polypeptides with known and unknown structures are aligned, the structures of the conserved amino acids in a 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.

[0185] The structures of amino acids located in non-conserved regions may be assigned manually by using standard peptide geometries or by 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.

[0186] Homology modelling as such is a technique that is well known to those skilled in the art (see e.g. Greer, Science, Vol. 228, (1985), 1055, and Blundell et al, Eur. J. Biochem, Vol. 172, (1988), 513). The techniques described in these references, as well as other homology modelling techniques, generally available in the art, may be used in performing the present invention.

[0187] Thus the invention provides a method of homology modelling comprising the steps of: (a) aligning a representation of an amino acid sequence of a target BACE protein of unknown three-dimensional structure with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation (e.g. so that favorable interactions are formed within the target BACE of unknown structure and/or so that a low energy conformation is formed) for said target BACE of unknown structure which substantially preserves the structure of said matched homologous regions.

[0188] Preferably one or all of steps (a) to (c) are performed by computer modelling.

[0189] The aspects of the invention described herein which utilise the BACE structure in silico may be equally applied to homologue models of BACE obtained by the above aspect of the invention, and this application forms a further aspect of the present invention. Thus having determined a conformation of a BACE by the method described above, such a conformation may be used in a computer-based method of rational drug design as described herein.

[0190] The absence of a ligand from our structure is particularly advantageous for modelling of other proteins as this structure reveals the native structure of the protein unaffected by conformational changes upon ligand binding.

[0191] F. Structure Solution

[0192] The structure of the human BACE can also be used to solve the crystal structure of other target BACE proteins including other crystal forms of BACE, mutants, and co-complexes of BACE, where X-ray diffraction data or NMR spectroscopic data of these target BACE proteins has been generated and requires interpretation in order to provide a structure.

[0193] In the case of BACE, this protein may crystallize in more than one crystal form. The structure coordinates of BACE, or portions thereof, as provided by this invention are particularly useful to solve the structure of those other crystal forms of BACE. They may also be used to solve the structure of BACE mutants, BACE co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of BACE.

[0194] In the case of other target BACE proteins, particularly the BACE proteins referred to in Section C above, the present invention allows the structures of such targets to be obtained more readily where raw X-ray diffraction data is generated.

[0195] Thus, where X-ray crystallographic or NMR spectroscopic data is provided for target BACE-ligand complex, or a BACE homologue or analogue of unknown three-dimensional structure, the structure of BACE, as defined by Table 1, may be used to interpret that data to provide a likely structure for the other BACE by techniques which are well known in the art, e.g. phasing in the case of X-ray crystallography and assisting peak assignments in NMR spectra.

[0196] One method that may be employed for these purposes is molecular replacement. In this method, the unknown crystal structure, whether it is another crystal form of BACE, a BACE mutant, or a BACE co-complex, or the crystal of a target BACE protein with amino acid sequence homology to any functional domain of BACE, may be determined using the BACE structure coordinates of this invention as provided herein. This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

[0197] Examples of computer programs known in the art for performing molecular replacement are CNX (Brunger A. T.; Adams P. D.; Rice L. M., Current Opinion in Structural Biology, Volume 8, Issue 5, October 1998, Pages 606-611 (also commercially available from Accelerys San Diego, Calif.) or AMORE (Navaza, J. (1994). AMoRe: an automated package for molecular replacement. Acta Cryst. A50, 157-163).

[0198] Thus, in a further aspect of the invention provides a method for determining the structure of a protein, which method comprises; providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0199] In a preferred aspect of this invention the co-ordinates are used to solve the structure of target BACE particularly homologues of BACE for example aspartic proteases such as BACE2 or cathepsin E (69% and 37% similarity, respectively).

[0200] G. Computer Systems

[0201] In another aspect, the present invention provides systems, particularly a computer system, the systems containing either (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof; (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or

[0202] NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0203] For example the computer system may comprise: (i) a computer-readable data storage medium comprising data storage material encoded with the computer-readable data; (ii) a working memory for storing instructions for processing said computer-readable data; and (iii) a central-processing unit coupled to said working memory and to said computer-readable data storage medium for processing said computer-readable data and thereby generating structures and/or performing rational drug design. The computer system may further comprise a display coupled to said central-processing unit for displaying said structures.

[0204] The invention also provides such systems containing atomic coordinate data of target BACE proteins wherein such data has been generated according to the methods of the invention described herein based on the starting data provided by Table 1.

[0205] Such data is useful for a number of purposes, including the generation of structures to analyze the mechanisms of action of BACE proteins and/or to perform rational drug design of compounds which interact with BACE, such as compounds which are inhibitors of BACE.

[0206] In another aspect, the invention provides a computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion (e.g. selected coordinates as defined herein) of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the Cα or backbone atoms (nitrogen-carbonα-carbon) of Table 1 of less than 2 Å, such as not more than 1.5Å, preferably less than 1.5 Å, more preferably less than 1.0 Å, even more preferably less than 0.74 Å, even more preferably less than 0.72 Å and most preferably less than 0.5 Å.

[0207] The invention also provides a computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0208] In a further aspect, the present invention provides computer readable media with with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0209] By providing such computer readable media, the atomic coordinate data can be routinely accessed to model BACE or selected coordinates thereof. For example, RASMOL (Sayle et al., TIBS, Vol. 20, (1995), 374) is a publicly available computer software package which allows access and analysis of atomic coordinate data for structure determination and/or rational drug design.

[0210] On the other hand, structure factor data, which are derivable from atomic coordinate data (see e.g. Blundell et al., in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976)), are particularly useful for calculating e.g. difference Fourier electron density maps.

[0211] A further aspect of the invention provides a method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising:

[0212] (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0213] Thus the remote device may comprise e.g. a computer system or computer readable media of one of the previous aspects of the invention. The device may be in a different country or jurisdiction from where the computer-readable data is received. The communication may be via the internet, intranet, e-mail etc. Typically the communication will be electronic in nature, but some or all of the communication pathway may be optical, for example, over optical fibres. Additionally, the communication may be through radio signals or satellite transmissions.

[0214] H. Uses of the Crystals of the Invention

[0215] The crystal structures obtained according to the present invention (including the structure of Table 1 as well the structures of target BACE proteins obtained in accordance with the methods described herein), may be used in several ways for drug design.

[0216] By identifying conditions under which high quality crystals of apo-BACE can be produced (i.e. crystals which can diffract X-rays for the determination of atomic coordinates to a resolution of better than 2.5 Å), the present invention facilitates the identification of modulators of BACE activity.

[0217] The invention is particularly suitable for the design, screening, development and optimization of BACE inhibitor components. It is thus a preferred aspect of the invention that modulators are inhibitors.

[0218] In a further aspect, the invention provides a method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE according to the invention; (b) soaking the crystal with said compounds; and (c) determining the structure of said BACE compound complex by employing the data of Table 1.

[0219] Alternatively, the BACE and compound may be co-crystallized. Thus the invention provides a method for determining the structure of a compound bound to BACE, said method comprising; mixing the protein with the compound(s), crystallizing the protein-compound(s) complex; and determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0220] A mixture of compounds may be soaked or co-crystallized with the crystal, wherein only one or some of the compounds may be expected to bind to the BACE. As well as the structure of the complex, the identity of the complexing compound(s) is/are then determined.

[0221] In either case, substrate or a substrate analogue thereof may optionally be present.

[0222] The method may comprise the further steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0223] The analysis of such structures may employ (i) X-ray crystallographic diffraction data from the complex and (ii) a three-dimensional structure of BACE, or at least selected coordinates thereof, to generate a difference Fourier electron density map of the complex, the three-dimensional structure being defined by atomic coordinate data according to Table 1. The difference Fourier electron density map may then be analyzed, to identify the binding mode of the modulator.

[0224] Therefore, such complexes can be crystallized and analyzed using X-ray diffraction methods, e.g. according to the approach described by Greer et al., J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054, and difference Fourier electron density maps can be calculated based on X-ray diffraction patterns of soaked crystals of BACE or co-crystallized BACE and the solved structure of uncomplexed BACE. These maps can then be analyzed e.g. to determine whether and where a particular compound binds to BACE and/or changes the conformation of BACE.

[0225] Electron density maps can be calculated using programs such as those from the CCP4 computing package (Collaborative Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50, (1994), 760-763.). For map visualization and model building programs such as “O” (Jones et al., Acta Crystallographica, A47, (1991), 110-119) or “QUANTA” (1994, San Diego, Calif.: Molecular Simulations can be used.

[0226] The crystal structures of a series of complexes may then be solved by molecular replacement and compared with that of the BACE of Table 1. Potential sites for modification within the various binding sites of the enzyme may thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between BACE and a chemical entity or compound.

[0227] All of the complexes referred to above may be studied using well-known X-ray diffraction techniques and may be refined against 1.5 to 3.5 Å resolution X-ray data to an R value of about 0.30 or less using computer software, such as CNX (Brunger et al., Current Opinion in Structural Biology, Vol. 8, Issue 5, October 1998, 606-611, and commercially available from Accelerys, San Diego, Calif.), X-PLOR (Yale University, ©1992, distributed by Accelerys), as described by Blundell et al, (1976) and Methods in Enzymology, vol. 114 & 115, H. W. Wyckoff et al., eds., Academic Press (1985).

[0228] This information may thus be used to optimize known classes of BACE substrates or inhibitors, and more importantly, to design and synthesize novel classes of BACE inhibitors.

[0229] Analysing the complex by X-ray crystallography will determine the ability of the candidate compound to interact with BACE. Analysis of the co-complexes of BACE may involve e.g. phasing, molecular replacement or calculating a Fourier difference map of the complex as discussed above. However, with the high resolutions obtainable with the crystal, it can also be possible to determine the ability of the candidate modulator to interact with BACE merely by comparing the intensities and/or positions of X-ray diffraction spots from the. complex with e.g. diffraction spots of uncomplexed BACE or a previously identified BACE-ligand complex. Thus the step of analysing the complex may involve analysing the intensities and/or positions of X-ray diffraction spots from the complex to determine the ability of the candidate modulator to interact with BACE.

[0230] Having obtained and characterized a modulator compound according to the invention, the invention further provides a method for modulating the activity of BACE which method comprises: (a) providing BACE under conditions where, in the absence of modulator, the BACE is able to synthesize amyloid β-peptide from amyloid precursor protein (APP); (b) providing a modulator compound; and (c) determining the extent to which the activity of BACE is altered by the presence of said compound.

[0231] T. Structure-based Drug Design

[0232] Determination of the three-dimensional structure of BACE provides important information about the binding sites of BACE, particularly when comparisons are made with similar enzymes. This information may then be used for rational design of BACE inhibitors, e.g. by computational techniques which identify possible binding ligands for the binding sites, by enabling linked-fragment approaches to drug design, and by enabling the identification and location of bound ligands using X-ray crystallographic analysis. These techniques are discussed in more detail below.

[0233] Greer et al. (1994) describes an iterative approach to ligand design based on repeated sequences of computer modelling, protein-ligand complex formation and X-ray crystallographic or NMR spectroscopic analysis. Thus novel thymidylate synthase inhibitor series were designed de novo by Greer et al., and BACE inhibitors may also be designed in the this way. More specifically, using e.g. GRID on the solved 3D structure of BACE, a ligand (e.g. a potential inhibitor) for BACE may be designed that complements the functionalities of the BACE binding sites. The ligand can then be synthesised, formed into a complex with BACE, and the complex then analysed by X-ray crystallography to identify the actual position of the bound ligand. The structure and/or functional groups of the ligand can then be adjusted, if necessary, in view of the results of the X-ray analysis, and the synthesis and analysis sequence repeated until an optimised ligand is obtained. Related approaches to structure-based drug design are also discussed in Bohacek et al., Medicinal Research Reviews, Vol. 16, (1996), 3-50.

[0234] Linked-fragment approaches to drug design also require accurate information on the atomic coordinates of target receptors. The basic idea behind these approaches is to determine (computationally or experimentally) the binding locations of plural ligands to a target molecule, and then construct a molecular scaffold to connect the ligands together in such a way that their relative binding positions are preserved. The ligands may be provided computationally and modelled in a computer system, or provided in an experimental setting, wherein crystals according to the invention are provided and a plurality of ligands soaked separately or in mixed pools into the crystal prior to X-ray analysis and determination of their location.

[0235] The binding site of two or more ligands are determined and may be connected to form a potential lead compound that can be further refined using e.g. the iterative technique of Greer et al. For a virtual linked-fragment approach see Verlinde et al., J. of Computer-Aided Molecular Design, 6, (1992), 131-147, and for NMR and X-ray approaches see Shuker et al., Science, 274, (1996), 1531-1534 and Stout et al., Structure, 6, (1998), 839-848. The use of these approaches to design BACE inhibitors is made possible by the determination of the BACE structure.

[0236] Many of the techniques and approaches to structure-based drug design described above rely at some stage on X-ray analysis to identify the binding position of a ligand in a ligand-protein complex. A common way of doing this is to perform X-ray crystallography on the complex, produce a difference Fourier electron density map, and associate a particular pattern of electron density with the ligand. However, in order to produce the map (as explained e.g. by Blundell et al. (1976)) it is necessary to know beforehand the protein 3D structure (or at least the protein structure factors). Therefore, determination of the BACE structure also allows difference Fourier electron density maps of BACE-ligand complexes to be produced, which can greatly assist the process of rational drug design.

[0237] The provision of the crystal structures of the invention will also allow the development of compounds which interact with the binding pocket regions of BACE (for example to act as inhibitors of a BACE) based on a fragment linking or fragment growing approach.

[0238] For example, the binding of one or more molecular fragments can be determined in the protein binding pocket by X-ray crystallography. Molecular fragments are typically compounds with a molecular weight between 100 and 200 Da (Carr et al, 2002). This can then provide a starting point for medicinal chemistry to optimize the interactions using a structure-based approach. The fragments can be combined onto a template or used as the starting point for ‘growing out’ an inhibitor into other pockets of the protein (Blundell et al, 2002). The fragments can be positioned in the binding pocket of BACE and then ‘grown’ to fill the space available, exploring the electrostatic, van der Waals or hydrogen-bonding interactions that are involved in molecular recognition. The potency of the original weakly binding fragment thus can be rapidly improved using iterative structure-based chemical synthesis.

[0239] At one or more stages in the fragment growing approach, the compound may be synthesized and tested in a biological system for its activity. This can be used to guide the further growing out of the fragment.

[0240] Where two fragment-binding regions are identified, a linked fragment approach may be based upon attempting to link the two fragments directly, or growing one or both fragments in the manner described above in order to obtain a larger, linked structure, which may have the desired properties.

[0241] The previous aspects of the invention relate also to fragment linking or fragment growing approaches to rational drug design. Thus the step of providing the structure of a candidate modulator molecule in the previous aspects may be performed by providing the structures of a plurality of molecular fragments and linking the molecular fragments to form a candidate modulator molecule. Furthermore the step of fitting the structure of the candidate modulator molecule in the previous aspects may be performed by fitting the structure of each of the molecular fragments (before or after the molecular fragments are linked together).

[0242] For example, the-computer-based method of rational drug design may comprise:

[0243] (a) providing the coordinates of at least two atoms of the BACE of Table 1; (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates of the BACE; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0244] In practice, it will be desirable to model a sufficient number of atoms of the BACE as defined by the coordinates of Table 1, which represent a binding pocket. Thus, in this embodiment of the invention, there will preferably be provided the coordinates of at least 5, preferably at least 10, more preferably at least 50 and even more preferably at least 100 preferably at least 500 selected atoms of the BACE structure.

[0245] A further aspect of the invention provides a compound having a chemical structure selected using the method of any one of the previous aspects, said compound being an inhibitor of BACE.

[0246] J. Uses of the Coordinates of the Invention in In Silico Analysis and Design

[0247] Although the invention will facilitate the determination of actual crystal structures comprising BACE and a compound, which modulates BACE, current computational techniques provide a powerful alternative to the need to generate such crystals and generate and analyze diffraction data. Accordingly, a particularly preferred aspect of the invention relates to in silico methods directed to the analysis and development of compounds, which interact, with BACE structures of the present invention.

[0248] The approaches to structure-based drug design described below all require initial identification of possible compounds for interaction with target bio-molecule (in this case BACE). Sometimes these compounds are known e.g. from the research literature. However, when they are not, or when novel compounds are wanted, a first stage of the drug design program may involve computer-based in silico screening of compound databases (such as the Cambridge Structural Database) with the aim of identifying compounds which interact with the binding site or sites of the target bio-molecule. Screening selection criteria may be based on pharmacokinetic properties such as metabolic stability and toxicity. However, determination of the BACE structure allows the architecture and chemical nature of each BACE binding site to be identified, which in turn allows the geometric and functional constraints of a descriptor for the potential inhibitor to be derived. The descriptor is, therefore, a type of virtual 3-D pharmacophore, which can also be used as selection criteria or filter for database screening.

[0249] Thus as a result of the determination of the BACE three-dimensional structure, more purely computational techniques for rational drug design may also be used to design BACE inhibitors (for an overview of these techniques see e.g. Walters et al (Drug Discovery Today, Vol.3, No.4, (1998), 160-178; Abagyan, R.; Totrov, M. Curr. Opin. Chem. Biol. 2001, 5, 375-382). For example, automated ligand-receptor docking programs (discussed e.g. by Jones et al. in Current Opinion in Biotechnology, Vol.6, (1995), 652-656 and Halperin, I.; Ma, B.; Wolfson, H.; Nussinov, R. Proteins 2002, 47, 409-443), which require accurate information on the atomic coordinates of target receptors may be used to design potential BACE inhibitors.

[0250] The aspects of the invention described herein which utilize the BACE structure in silico may be equally applied to both the BACE structure of Table 1 and the models of target BACE proteins obtained by other aspects of the invention. Thus having determined a conformation of a BACE by the method described above, such a conformation may be used in a computer-based method of rational drug design as described herein. In addition the availability of the structure of the BACE will allow the generation of highly predictive pharmacophore models for virtual library screening or compound design.

[0251] Accordingly, the invention provides a computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE of the invention of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0252] In an alternative aspect, the method of the invention may utilize the coordinates of atoms of interest of BACE, which are in the vicinity of a putative molecular structure binding region, for example within 10-25 Å of the catalytic regions or within 5-10 Å of a compound bound, in order to model the pocket in which the structure binds. These coordinates may be used to define a space, which is then analyzed “in silico”. Thus the invention provides a computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure of the invention (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to said coordinates; and (c) fitting the structure to the selected coordinates of the BACE.

[0253] In practice, it will be desirable to model a sufficient number of atoms of the BACE as defined by the coordinates of Table 1, which represent a binding pocket. Thus, in this embodiment of the invention, there will preferably be provided the coordinates of at least 5, preferably at least 10, more preferably at least 50 and even more preferably at least 100 and preferably 500 selected atoms of the BACE structure.

[0254] In order to provide a three-dimensional structure of compounds to be fitted to a BACE structure of the invention, the compound structure may be modelled in three dimensions using commercially available software for this purpose or, if its crystal structure is available, the coordinates of the structure may be used to provide a representation of the compound for fitting to a BACE structure of the invention.

[0255] The step of providing the structure of a candidate modulator molecule may involve selecting the compound by computationally screening a database of compounds for interaction with the binding cavity or cavities. For example, a 3-D descriptor for the potential modulator may be derived, the descriptor including geometric and functional constraints derived from the architecture and chemical nature of the binding cavity or cavities. The descriptor may then be used to interrogate the compound database, a potential modulator being a compound that has a good match to the features of the descriptor. In effect, the descriptor is a type of virtual pharmacophore.

[0256] In any event, the determination of the three-dimensional structure of BACE provides a basis for the design of new and specific ligands for BACE. For example, knowing the three-dimensional structure of BACE, computer modelling programs may be used to design different molecules expected to interact with possible or confirmed binding cavities or other structural or functional features of BACE. Examples of this are discussed in Schneider, G.; Bohm, H. J. Drug Discov.Today 2002, 7, 64-70.

[0257] More specifically, the interaction of a compound with BACE can be examined through the use of computer modelling using a docking program such as GOLD (Jones et al., J. Mol. Biol., 245, 43-53 (1995), Jones et al., J. Mol. Biol., 267, 727-748 (1997)), GRAMM (Vakser, I. A., Proteins, Suppl., 1:226-230 (1997)), DOCK (Kuntz et al, J.Mol.Biol. 1982, 161, 269-288, Makino et al, J.Comput.Chem. 1997, 18, 1812-1825), AUTODOCK (Goodsell et al, Proteins 1990, 8, 195-202, Morris et al, J.Comput.Chem. 1998, 19, 1639-1662.), FlexX, (Rarey et al, J.Mol.Biol. 1996, 261, 470-489) or ICM (Abagyan et al, J.Comput.Chem. 1994, 15, 488-506). This procedure can include computer fitting of compounds to BACE to ascertain how well the shape and the chemical structure of the compound will bind to the BACE.

[0258] Also computer-assisted, manual examination of the binding site structure of BACE may be performed. The use of programs such as GRID (Goodford, J. Med. Chem., 28, (1985), 849-857)—a program that determines probable interaction sites between molecules with various functional groups and an enzyme surface—may also be used to analyse the binding cavity or cavities to predict partial structures of inhibiting compounds.

[0259] Computer programs can be employed to estimate the attraction, repulsion, and steric hindrance of the two binding partners (i.e. the BACE and a candidiate modulator). Generally the tighter the fit, the fewer the steric hindrances, and the greater the attractive forces, the more potent the potential modulator since these properties are consistent with a tighter binding constant. Furthermore, the more specificity in the design of a potential drug, the more likely it is that the drug will not interact with other proteins as well. This will tend to minimise potential side-effects due to unwanted interactions with other proteins.

[0260] In another aspect, the present invention provides a method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one BACE binding site and preferably a plurality of BACE binding sites; (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0261] Preferably sufficient binding sites are characterised to define a BACE binding cavity or cavities.

[0262] A plurality (for example two, three or four) of (typically spaced) BACE binding sites may be characterised and a plurality of respective compounds designed or selected. The agent compound may then be formed by linking the respective compounds into a larger compound which preferably maintains the relative positions and orientations of the respective compounds at the binding sites. The larger compound may be formed as a real molecule or by computer modelling.

[0263] In one embodiment a plurality of candidate agent compounds are screened or interrogated for interaction with the binding sites. In one example, step (b) involves providing the structures of the candidate agent compounds, each of which is then fitted in step (c) to computationally screen a database of compounds (such as the Cambridge Structural Database) for interaction with the binding sites, i.e. the candidate agent compound may be selected by computationally screening a database of compounds for interaction with the binding sites (see Martin, J. Med Chem., vol 35, 2145-2154 (1992)). In another example, a 3-D descriptor for the agent compound is derived, the descriptor including e.g. geometric and functional constraints derived from the architecture and chemical nature of the binding cavity or cavities. The descriptor may then be used to interrogate the compound database, the identified agent compound being the compound which matches with the features of the descriptor. In effect, the descriptor is a type of virtual pharmacophore.

[0264] In a related aspect, the present invention provides a method for identifying a candidate modulator (e.g. potential inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0265] Detailed structural information can then be obtained about the binding of the compound to BACE, and in the light of this information adjustments can be made to the structure or functionality of the compound, e.g. to improve its interaction with BACE. The above steps may be repeated and re-repeated as necessary.

[0266] K. Compound Selection

[0267] In another aspect, in place of in silico methods, high throughput screening of compounds to select compounds with binding activity may be undertaken, and those compounds which show binding activity may be selected as possible candidate modulators, and further crystallized with BACE (e.g. by co-crystallization or by soaking) for X-ray analysis. The resulting X-ray structure may be compared with that of Table 1 for a variety of purposes.

[0268] L. Compounds of the Invention

[0269] Having designed or selected possible binding candidate modulators (e.g. by in silico analysis, “wet” chemical methods, X-ray analysis etc.) by determining those which have favourable fitting properties (e.g. strong attraction between candidate and BACE), these can then be screened for activity.

[0270] Consequently all the methods of compound design and identification outlined above can optionally include the step of: (a) obtaining or synthesising the candidate modulator; and (b) contacting the candidate modulator with BACE to determine the ability of the candidate modulator to interact with BACE.

[0271] More preferably, in the latter step the candidate modulator is contacted with BACE under conditions to determine its function.

[0272] For example, in the contacting step above the candidate modulator is contacted with BACE in the presence of a substrate, and typically a buffer, to deter mine the ability of said candidate modulator to inhibit BACE. The substrate may be e.g. APP. So, for example, an assay mixture for BACE may be produced which comprises the candidate modulator, substrate and buffer.

[0273] Detailed structural information can be obtained about the binding of the candidate modulator to BACE, and in the light of this information adjustments can be made to the structure or functionality of the candidate modulator, e.g. to improve binding to the binding cavity or cavities. The above steps may be repeated and re-repeated as necessary.

[0274] Following identification of such compounds, it may be manufactured and/or used in the preparation, i.e. manufacture or formulation, of a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals.

[0275] Thus, the present invention extends in various aspects not only to a compound as provided by the invention, but also a pharmaceutical composition, medicament, drug or other composition comprising such a compound e.g. for treatment (which may include preventative treatment) of disease; a method comprising administration of such a composition to a patient, e.g. for treatment of disease; use of such an inhibitor in the manufacture of a composition for administration, e.g. for treatment of disease; and a method of making a pharmaceutical composition comprising admixing such an inhibitor with a pharmaceutically acceptable excipient, vehicle or carrier, and optionally other ingredients.

[0276] Thus a further aspect of the present invention provides a method for preparing a medicament, pharmaceutical composition or drug, the method comprising:

[0277] (a) identifying a BACE modulator molecule (which may thus be termed a lead compound) by a method of any one of the other aspects of the invention disclosed herein; (h) optimising the structure of the modulator molecule; and (c) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.

[0278] The above-described processes of the invention may be iterated in that the modified compound may itself be the basis for further compound design.

[0279] By “optimising the structure” we mean e.g. adding molecular scaffolding, adding or varying functional groups, or connecting the molecule with other molecules (e.g. using a fragment linking approach) such that the chemical structure of the modulator molecule is changed while its original modulating functionality is maintained or enhanced. Such optimisation is regularly undertaken during drug development programmes to e.g. enhance potency, promote pharmacological acceptability, increase chemical stability etc. of lead compounds.

[0280] Modification will be those conventional in the art known to the skilled medicinal chemist, and will include, for example, substitutions or removal of groups containing residues which interact with the amino acid side chain groups of a BACE structure of the invention. For example, the replacements may include the addition or removal of groups in order to decrease or increase the charge of a group in a test compound, the replacement of a charge group with a group of the opposite charge, or the replacement of a hydrophobic group with a hydrophilic group or vice versa. It will be understood that these are only examples of the type of substitutions considered by medicinal chemists in the development of new pharmaceutical compounds and other modifications may be made, depending upon the nature of the starting compound and its activity.

[0281] Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0282] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like may be used. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc, an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 15th Edition, 1975.

[0283] Compositions may be used, e.g. for treatment (which may include preventative treatment) of a disease such as Alzheimer's disease or Alzheimer's-type pathology in Downs syndrome. Thus the invention provides a method comprising administration of such a composition to a patient, e.g. for treatment of a disease such as Alzheimer's disease; use of such an agent compound in the manufacture of a composition for administration, e.g. for treatment of a disease such as Alzheimer's disease; and a method of making a pharmaceutical composition comprising admixing such an agent compound with a pharmaceutically acceptable excipient, vehicle or carrier, and optionally other ingredients.

EXEMPLIFICATION

[0284] The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the invention described. These examples constitute the best mode currently contemplated for practicing the invention;

[0285] BACE protease was expressed at high levels in bacterial cells as insoluble inclusion bodies. To prepare functional protein for enzyme assay and structural studies these inclusion bodies were solublised using denaturants; the slow removal of these denaturants allowed the formation of the correct tertiary structure. In the method described here, BACE was expressed as a pro-sequence and required activation by a protease before becoming fully functional. Clostripain was used as an activating protease but produced multiple species of BACE as determined by mass spectrometry. In order to obtain a uniform homogenous protein after activation by clostripain, a number of different constructs were produced. These constructs focused on the mutation of two undesireable clostripain cleavage sites (following residues R56 and R57).

[0286] Cloning of BACE WT and BACE N->Q

[0287] The full-length DNA coding sequence of BACE was cloned from human cerebellum and human dorsal root ganglion (DRG) cDNA by PCR using oligonucleotide primers based on the published BACE sequence (EMBL accession no. AF190725). The full-length template sequence was obtained by PCR amplification using the following primers: hBACE-sp1 and -ap1 I were used for primary amplification, hBACE-sp2 and -ap2 for nested PCR.

[0288] The primers were as follows:

1hBACE-sp15′-AGCTCCCTCTCCTGAGAAGCCACC-3′(SEQ ID NO: 22)hBACE-ap15′-CCACAGGTGCCATCTGTGTCTCC-3′(SEQ ID NO: 23)hBACE-sp25′-CACCAGCACCACCCAGACTTGG-3′(SEQ ID NO: 24)hBACE-ap25′-AACCACGGAGGTGTGGTCCAGG-3′(SEQ ID NO: 25)

[0289] A cDNA construct encoding a modified BACE form was made as follows. A partial BACE cDNA fragment was amplified using the full-length BACE clone as a template with primers hBACE_EC(Bam-M-14)_FOR (5′-CGG GAT CCA TGG CGG GAG TGC TGC TGC CTG CC-3′) and hBACE_EC(Bam-453)_REV (5′-CGG GAT CCT TAT GAC TCA TCT GTC TGT GGA ATG TTG TAG C-3′). The resulting 1342 bp PCR fragment was subcloned in vector pCR2.1-TOPO using the TOPO TA cloning® kit (Invitrogen) according to the manufacturer's instructions. The inserts of several resulting clones were fully sequenced and a clone containing no PCR mistakes was selected. The insert of this clone was excised from the pCR2.1-TOPO construct using the BamHI restriction endonuclease and subcloned to vector pET11a (Novagen) linearized with BamHI. The BACE coding sequence (BACE WT, SEQ ID 1) in the resulting clones was confirmed by sequence analysis and the resulting correct construct was named M-T7-RGSM(BACE14-453)/pET11a.

[0290] Plasmid M-T7-RGSM(BACE14-453)/pET11a encodes a 455 amino acid residue protein named BACE WT containing a T7 epitope tag encoded by the pET11a vector sequence (AA 1 to 11), a linker sequence (AA 12-15; RGSM) and the partial BACE amino acid sequence from residue 14 to 453 (AA 16 to 455)(numbering based on SEQ ID 2). The calculated molecular mass of the resulting protein is 50.2 kDa.

[0291] The insert from construct Plasmid M-T7-RGSM(BACE14-453)/pET11 a was amplified by PCR to incorporate a His6 tag (CAT CAC CAT CAT CAC CAC) just upstream of the stop codon and BamH1 site. Following cloning of this amplified fragment back into the original expression vector, the asparagine residues at positions -153, -172, -223 and -354 (numbers refer to the database BACE sequence BACE_HUMAN, P56817 in Swissprot) were mutated to glutamine (AAC to CAA) using the Quikchange™ mutagenesis system (Stratagene, used according to the manufacturers instructions), to generate BACE N->Q (SEQ ID 3).

[0292] Introduction of Activation Site Mutations

[0293] BACE WT and BACE N->Q, described above, were mutated using the Quickchange™ site directed mutagenesis protocol (Stratagene). Two complimentary oligonucleotides were designed which spanned the site of the mutation and which incorporated the amino acids changes to be made. These oligonucleotides were then used as primers in a PCR reaction producing each of the strands of the plasmid with the mutation present; the parental plasmid is digested with the methylation sensitive restriction endonuclease DpnI and then transformed into competent E. coli cells.

[0294] Primers were applicable for the mutation of both BACE WT and BACE N->Q due to their high sequence homology. Seven constructs were produced; these are detailed below with the oligonucleotide sequence used to make the constructs.

[0295] 1) BACE WT mutating arginine 56 to lysine and arginine 57 to lysine (SEQ ID 5)

2(SEQ ID NO: 26)5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′(SEQ ID NO: 27)5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′

[0296] 2) BACE WT mutating arginine 57 to lysine (SEQ ID 7)

3(SEQ ID NO: 28)5′-CCCGAGGAGCCCGGCCGGAAGGGCAGCTTTGTGGAGATGG-3′(SEQ ID NO: 29)5′-CCATCTCCACAAAGCTGCCCTTCCGGCCGGGCTCCTCGGG-3′

[0297] 3) BACE WT deleting arginine 57 (SEQ ID 9)

4(SEQ ID NO: 30)5′-CCCGAGGAGCCCGGCAGGGGCAGCTTTGTGGAGATGGTGGAC-3′(SEQ ID NO: 31)5′-GTCCACCATCTCCACAAAGCTGCCCCTGCCGGGCTCCTCGGG-3′

[0298] 4) BACE N->Q mutating arginine 56 to lysine and arginine 57 to lysine (SEQ ID 11)

5(SEQ ID NO: 32)5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′(SEQ ID NO: 33)5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′

[0299] 5) BACE N->Q mutating arginine 57 to lysine (SEQ ID 15)

6(SEQ ID NO: 34)5′-CCCGAGGAGCCCGGCCGGAAGGGCAGCTTTGTGGAGATGG-3′(SEQ ID NO:35)5′-CCATCTCCACAAAGCTGCCCTTCCGGCCGGGCTCCTCGGG-3′

[0300] 6) BACE N->Q deleting arginine 57 (SEQ ID 17)

7(SEQ ID NO: 36)5′-CCCGAGGAGCCCGGCAGGGGCAGCTTTGTGGAGATGGTGGAC-3′(SEQ ID NO: 37)5′-GTCCACCATCTCCACAAAGCTGCCCCTGCCGGGCTCCTCGGG-3′

[0301] 7) BACE N->Q mutating arginine 56 to lysine and arginine 57 to lysine and removing the C terminal poly histidine tag (SEQ ID 13)

8(SEQ ID NO: 38)5′-CCCGAGGAGCCCGGCAAGAAGGGCAGCTTTGTGGAGATG-3′(SEQ ID NO: 39)5′-CATCTCCACAAAGCTGCCCTTCTTGCCGGGCTCCTCGGG-3′(SEQ ID NO: 40)5′-CCACAGACAGATGAGTCATGACACCATCATCACCACTAAG-3′(SEQ ID NO: 41)5′-CTTAGTGGTGATGATGGTGTCATGACTCATCTGTCTGTGG-3′

[0302] After transformation of the plasmid the protein coding region was checked by DNA sequencing.

[0303] Protein Production (1)

[0304] Plasmid constructs were transformed into BLR(DE3) as follows: 1-2 μl DNA was added into 25 ul BLR(DE3) competent cells. Cells were then heat shocked at 42° C. for 45 secs, followed by incubation for 30 mins at 4° C. The sample was placed on ice for 2-3 mins before addition of 125-250 ul HOC medium and left for 60 mins at 37° C. Cells were plated out onto agar containing carbenicillin & incubated at 37° C. for 16 h. Transformations were stored at 4° C. Transformed cells could be used up to after 8 weeks storage.

[0305] Colonies were inoculated in 100 ml LB broth with 1 mM carbenicillin, and shaken for 16 h at 25° C. 12 ml of this culture was added to 1 L of the same medium in baffle flasks. The typical total culture volume was 12, 20 or 24 L. Cells were induced by addition of 1 mM IPTG at approximately OD600 1.0. Cells were harvested 3 to 4 hours after induction by centrifugation for 7 min at 16000 g. Cell pellets were resuspended in 1 liter TN buffer (150 mM NaCl, 50 mM Tris, pH 7.5) before addition of 10 mg lysozyme per liter of bacterial culture. The suspension was left for 20 mins under vigorous stirring then frozen at −70° C.

[0306] The lysates were thawed & adjusted to 1 mM MgCl12 and 20 μl 10 mg/ml DNAse, incubated 30-60 mins at 20° C., then 0.1% Triton X-100 was added. Inclusion body washes were performed in 11 wash steps, spun down at 13,000-16,000 g for 20 mins at room temperature then resuspended by sonication in TNT buffer (TN buffer +0.1% Triton 100). The washing step with TNT was repeated at least three times (up to seven times) until an almost homogenous dark cream precipitate was obtained. At this stage the pellet was washed twice with TN buffer. The typical yield for a 12 L culture of BACE WT constructs was 4.5 g washed inclusion body material.

[0307] Protein Refolding (1)

[0308] Each g of inclusion bodies was solubilised with 22.5 ml of 8 M urea, 50 mM Tris, 0.1 M beta-mercaptoethanol, 10 mM DTT, 1 mM EDTA. After 2 to 3 hours under gentle stirring, this was spun at 48400 g for 25 mins. This was then diluted 1 in 10 in 8 M Urea, 0.2 mM oxidized glutathione, 1.0 mM reduced glutathione. This is the starting solution for refolding

[0309] Refolding was accomplished by dilution into 20 volumes 20 mM Tris, 10 mM NDSB256 (3-(benzyldimethylammonio)propanesulfonate). The addition was achieved by slowly dripping from a burette into a strongly stirred solution. Addition was carried out at room temperature.

[0310] The pH was adjusted to approximately 9 using 13.5 ml 1 N HCl per 5 liter of refolding mix either immediately after dilution or 16 h after dilution. This was left at 4° C. for 2-3 weeks. The refolding mix was then adjusted to pH 8.2 16h before concentrating. In instances where a longer incubation was applied it appeared that yields were slightly better. No precipitation was seen when attempting to refold BACE, even in totally unsuccessful conditions. Constructs BACE WT R57K, BACE WT R57DEL, BACE N->Q R57K, and BACE R57DEL refolded with lower yields.

[0311] Protein Purification of BACE from Refolding Step (1)

[0312] The refolded protein sample was concentrated by ultrafiltration using two parallel Vivaflow 200 cells (MWCO 30 Kda), fed by a single pump. The concentration factor was not more than 200 times: if exceeded, precipitation occurred.

[0313] Concentrated refolded BACE was loaded and eluted on a 1.75 L Sephacryl 300 column run at a flow of 0.2 cm-1/min in 0.4 M Urea, 20 mM Tris, 10 mM HCl. Typical loading volume was 2% bed volume. From reconcentrated material three peaks are observed, the first one near the void volume (large aggregates), which merges into a second peak of aggregated inactive material. The third peak (elutes at approx 40% of column volume) constitutes active BACE. For BACE WT constructs, the active fraction elutes at approximately 800 ml.

[0314] Activation by Clostripain (1)

[0315] Clostripain (Cp; EC 3.4.22.8, from Worthington or Sigma C7403) was activated before use by solubilising the freeze dried material to 1.25 mg/ml in: 20 mM Calcium Acetate, 8 mM DTT, 100 mM Tris, pH 8 at 1.25 mg/ml 4 ° C for at least I h. The preparation was then stable at 4 ° C for up to four weeks.

[0316] The third peak (typically 100 ml at an average of 0.3 mg ml) from Sephacryl 300 elution was treated with activated Cp, (1/100 dilution) for between 30-90mins at room temperature.

[0317] Activation of BACE WT R56KR57K, BACE N->Q R56KR57K & BACE N->Q R56KR57K no His by clostripain was performed as described above except that prior to activation the solution was concentrated ten fold using Vivaspin 20 ml 30 KDa MWCO.

[0318] The reaction was stopped by loading onto a Mono Q HR5-5 column equilibrated in 0.4 M Urea, 20 mM Tris, 10 mM HCI, 1 mM EDTA followed by washing using the same buffer. The protein was eluted with a 0 to 1 M NaCl gradient over 10 column volumes. A typical final yield of active soluble BACE WT R56KR5!K is 1-2 mg of protein per liter of culture grown. The eluted protein was characterised and used in crystallisation assays.

Protein Production (2)

[0319] BLR (DE3) competent cells were transformed as described earlier and plated onto agar containing ampicillin (Amp). A colony was picked into 250ml LB +100 ug/ml Amp and grown overnight ( 37° C, 1 85rpm. Following overnight growth (OD600 varied between 2.0- 2.5) 10 ml of this culture was used to inoculate IL of fresh LB+100 11g/ml Amp in a 2L baffled flask. Routinely 24L of fresh LB+Amp would be inoculated from the overnight growth. Following inoculation, the 24L prep would be grown at 37° C., 185rpm until an OD600 =1.0 was obtained. Protein expression was induced by the addition of IPTG to a final concentration of 1 mM. Cultures were incubated for a further 3 hours (at 37° C., 185rpm) before harvesting by centrifugation at 8000 rpm for 10 mins (JLA 8.1000). Cell pellets could be stored at -800C or processed immediately.

[0320] All following protein production procedures were performed at room temperature unless stated otherwise. Cell pellet was re-suspended in 500ml of TN buffer (TN buffer - 1 5OmM NaCl, 50 mM Tris, pH7.5). 240mg of egg lysozyme (10 mg/L of bacterial culture) was added to the re-suspended pellet. The suspension was left stirring for 20mins. Following this, 100 ul of DNase 1 (10 mg/ml stock) was added to the suspension and this was left stirring for 20mins. This lysate was clarified by centrifugation at 8000rpm for 20mins (JLA8. l000).

[0321] The supernatant was discarded and the pellet was re-suspended in 100 ml TNT buffer (TNT buffer—150 mM NaCl, 5 mM Tris, pH7.5, 0.1% Triton X-100). Effort was made to break up any lumps present in the pellet so that a homogenous re-suspension was obtained. Following this, the re-suspension was sonicated for 2 mins (20 sec pulses). 400 ml of TNT buffer was added to bring the volume of the suspension up to ˜500 mls. This was centrifuged for 20 mins at 8000 rpm and the supernatant discarded. The re-suspension in TNT buffer and sonication steps, as described above, were repeated twice. Following these three TNT washes, the pellet was re-suspended in 100 ml of TN buffer and sonicated for 2 mins (20 second pulses). The suspension was centrifuged for 20 mins at 8000 rpm. This wash in TN buffer was repeated once. Approximately 12-15 g of inclusion bodies was obtained from the 24L of culture.

[0322] Protein Refolding (2)

[0323] The inclusion body preparation was solubilised by addition of 100 mls of solubilisation buffer (Sol. Buffer—8M urea, 50 mM Tris, 0.1M beta-mercaptoethanol, 10 mM DTT, 1 mM EDTA). Effort was made to break up the inclusion body pellet using a pipette/spatula. The solution was left stirring gently overnight. The suspension was centrifuged for 30 mins at 25,000 rpm (JA25). The supernatant (˜100 mls) was diluted by the addition of 900 mls of 8M urea, 0.2 mM oxidised glutathione, 1.0M reduced glutathione.

[0324] The 1L of solubilised inclusion bodies as prepared above were refolded by a further 20× dilution. A 250 ml aliquot of solubilised inclusion body prep was added drop-wise to 4.75L of refolding buffer (Refolding buffer—20 mM Tris, 10 mM NDSB256 (3-(benzyldimethylammonio)propanesulfonate). The 4.75L of refolding buffer was stirred vigorously (not foaming) and the 250 mls of inclusion body prep was added using a peristaltic pump. Care was taken to add the 250 mls at a fast drop rather than a continuous pour. The remaining 750 mls of inclusion body prep was diluted in the same way (250 mls into 4.75L of refolding buffer). The four 5L vessels were placed at 4° C. overnight.

[0325] Following overnight incubation at 4° C., the pH of each 5L vessel was adjusted to pH9.0 by addition of conc HCl. The vessels were then placed back at 4° C. and left for 3 weeks.

[0326] Protein Purification of BACE from Refolding Step (2)

[0327] Two parallel Vivaflow 200 cells (MWCO 30 Kda) fed by a single peristaltic pump were used. Each 5L of refolding mix was concentrated to ˜50 mls. Over concentrating leads to precipitation and should be avoided. The concentration of 5L of refolding mix took ˜2 hours. The 50 mls of concentrated refolding mix was centrifuged for 25 mins, at 25,000 rpm. The supernatant was then ready for gel filtration using a Sephacryl S-300 column (100×3.5). This method is limited by the volume of concentrated refolding mix than can be loaded onto the gel filtration column (50 mls) per run. Sephacryl S-300 column was equilibrated with 0.4M urea, 20 mM Tris, 10 mM HCl (at a flow rate of 4 ml/min). 50 ml of sample can be loaded per run. The column was run at a flow rate of 4 ml/min. SDS PAGE analysis of peaks 1,2 and 3 showed the presence of BACE (50 Kda band) however activity assay of all three peaks showed only active BACE in peak 3. Fractions from Peak 3 were pooled and kept on ice.

[0328] Activation by Clostripain (2)

[0329] Clostripain (Sigma C7403) was prepared by dissolving protein to a final concentration of 1.25 mg/ml in 20 mM Calcium acetate, 8 mM DTT, 100 mM Tris pH 8.0. The clostripain was activated by incubating on ice for 1 hour prior to use.

[0330] Pooled fractions from peak 3 (˜100 ml at 0.2 mg/ml) were activated by the addition of 1/100 dilution of 1.25 mg/ml clostripain. The reaction was incubated at 37° C. in a water bath for 90 minutes. The reaction was stopped by addition of 1 mM EDTA and placed on ice. Note: With each fresh batch of Sigma Clostripain, a time trial was performed on a small amount of BACE to verify the length of incubation needed at 37° C. The length of incubation varied from 30-90 mins. Analysis by SDS PAGE clearly showed the appearance of the lower molecular weight activated species (˜47 Kda) from the larger inactivated species (˜50 Kda).

[0331] A Mono Q 5/5 ion exchange column was pre-equilibrated in 0.4M urea, 20 mM Tris, 10 mM HCl. The activated BACE (˜50 mls at ˜0.2 mg/ml) was loaded onto the Mono Q column at a flow rate of 1.0 ml/min. Activated BACE was purified by applying a linear salt gradient (0.4M urea, 20 mM Tris, 10 mM HCl, 1.0M NaCl) over 20 column volumes. Following analysis by SDS PAGE and subsequent activity assay, fractions corresponding to activated BACE were pooled and buffer exchanged into crystallisation buffer (20 mM Tris, pH8.2, 150 mM NaCl, 1 mM DTT).

[0332] Protein Purification of BACE from Refolding Step (3)

[0333] By using method 3 in conjunction with the S-200 INDEX gel filtration column, all 20L of refolding mix could be processed in one go.

[0334] A Sartocon filtration cassette (MWCO 30 Kda) was used in conjunction with a Watson Marlow 623S high speed pump. This assembly was set up as described in the manufactures operation manual. The 20L of refolding mix was concentrated down to ˜500 mls in less than 1 hour. Due to the dead volume in the assembly tubing, the volume could not be reduced further. At this stage the 500 mls of concentrated refolding mix was filtered using a 0.2 um filter. The filtered sample was then ready for gel filtration using an S-200 INDEX gel filtration column (100×10.0). A S-200 INDEX column pre-equilibrated in 0.4M urea, 20 mm Tris, 10 mM HCl was used. The column run was at a flow rate of 10 mls/min.

[0335] SDS analysis of peaks 1,2 and 3 showed that BACE was present in all fractions. Activity assay showed that only peak 3 contain some BACE activity. Fractions from peak 3 were pooled (˜250 mls at 0.1 mg/ml).

[0336] Prior to clostripain activation, the BACE sample was concentrated using a Resource Q ion exchange column. A 6/1 Resource Q column was pre-equilibrated in 0.4M urea, 20 mM Tris, 10 mM HCl. The Bace sample was loaded onto the column at 7 ml/min. BACE was eluted off the column using a linear salt gradient (0.4M urea, 20 mM Tris, 10 mM HCl, 1M NaCl) over 5 column volumes. This step has the effect of dramatically reducing the sample volume size. Prior to clostripain activation, the protein sample is diluted with 0.4M urea, 20 mM Tris, 10 mM HCl to reduce the salt concentration to enable further purification using Mono Q. A dilution factor of 5:1 has been used successfully.

[0337] This is then followed by Clostripain Activation and Mono Q purification as outlined above.

[0338] Protein Characterization

[0339] The quality of the final preparation was evaluated by:

[0340] (a) SDS polyacrylamide gel electrophoresis, performed using commercial gels (Novagen) followed by Coomassie Brilliant Blue staining according to the manufacturer's instructions. The purity as estimated by scanning a digital image of a gel was estimated to be at least 95%.

[0341] (b) Mass Spectroscopy: The eluted peak(s) were analysed using ESI-TOF-MS. Mass spectroscopy was performed using a Bruker “BioTOF” electrospray time of flight instrument. Samples were either diluted by a factor of 1000 straight from storage buffer into methanol/water/formic acid (50:48:2 v/v/v), or subjected to reverse phase HPLC separation using a C4 column. Calibration was achieved using Bombesin and angiotensin I using the 2+ and 1+ charged states. Data were acquired between 200 and 2000 m/z range and were subsequently processed using Bruker's X-mass program. Mass accuracy was typically below 1 in 10000.

[0342] MS Analysis of BACE WT R56KR57K (SEQ ID NO: 6)

[0343] Full-length protein: MASMTGGQQMGRGSMAGVLPAHGT . . .

[0344] Predicted mass of full-length protein: 50147

[0345] Cleavage position:

[0346] MASMTGGQQMGR⇓GSMAGVLPAHGT . . .

[0347] Predicted mass of BACE protein: 48911. This is the first intermediate fragment and is obtained very quickly and can be obtained as a stable fragment at lower enzyme concentration.

[0348] Cleavage position:

9MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR↓LPRETDEEP . . .

[0349] Predicted mass of BACE protein: 45781. This is the final fragment obtained in the conditions described above. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 45783. The fragment typically elutes as a single peak from the Mono Q 5.5.

[0350] Mass Spec Analysis of BACE N->Q R56KR57K (SEQ ID NO: 12)

[0351] Predicted mass of full-length protein: 50895

[0352] Cleavage position:

10MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR↓LPRETDEEP . . .

[0353] Predicted mass of BACE protein: 46660.65. This is the final fragment obtained in the conditions described above. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 46655. The fragment typically elutes as two peaks from the Mono Q 5.5, the first corresponding to the desired fragment.

[0354] Mass Spec Analysis of BACE N->Q R56KR57K no His (SEQ ID NO: 14)

[0355] Predicted mass of full-length protein: 50072.73

[0356] Cleavage position:

11MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLR ↓LPRETDEEP . . .

[0357] Predicted mass of BACE protein: 45837.80. This is the first intermediate fragment, obtained rapidly between 30-60 minutes post activation and is suitable for crystallisation. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 45838.30. Typically elutes as 2 peaks from the Mono Q 5.5, the first peak corresponding to the desired fragment.

12MASMTGGQQMGRGSMAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGK ↓ KGSFVEMV . . .

[0358] Cleavage position:

[0359] Predicted fragment mass: 44230.11. Further digestion beyond 60 minutes promotes the formation of the above fragment, not suitable for crystallisation. Observed ES-MS spectra of this fragment deconvolutes to a parent mass of 44228.03. This typically elutes as peak 2 from the Mono Q 5.5.

[0360] Method for Determining Activity of BACE

[0361] A fluorimetric assay was used to measure the activity of the refolded proteins. Activity of the BACE enzyme was measured using the fluorescent peptide R-E(EDANS)-E-V-N-L-*D-A-E-F-K(DABCYL)-R-OH (Bachem) as substrate. Assays were carried out in 96-well black, flat-bottomed Cliniplates in a final assay volume of 100 ul. The reaction rate was monitored at room temperature on a Fluoroskan Ascent plate reader with excitation and emission wavelengths of 355 nm and 530 nm respectively.

[0362] To determine the pH profile for the enzyme 8 nM BACE was incubated with 10 μM substrate in 50 mM sodium acetate (pH 3.5-5.5) or MES (pH 5.5-6.5) buffers at varying pHs and 5% DMSO.

[0363] For kinetic characterization of the enzyme 8 nM BACE enzyme was incubated with varying concentrations of the substrate (2.5-80 μM) in 50 mM sodium acetate, pH 5, 5% DMSO and the reaction monitored as described above. Kinetic parameters were determined by the standard Michaelis-Menten equation, using Prizm (GraphPad) software. 1 mM OM 99 completely inhibits activity.

[0364] Protein Crystallisation

[0365] The sample of BACE was buffer exchanged into 20 mM Tris.HCl pH8.2, 150 mM NaCl, 1 mM DTT and concentrated down to approximately 7 mg/ml as determined by its theoretical extinction coefficient. Prior to crystallisation, the sample was spun at 55,000 rpm for 30 min using a Beckman benchtop ultracentrifuge. DMSO was added to a final concentration of 3% (v/v).

[0366] Crystals of BACE from BACE WT R56KR57K, BACE N->Q R56KR57K & BACE N->Q R56KR57K no His were obtained by the hanging-vapour diffusion method at 20° C. using 1.5 μl of protein and an equivalent volume of reservoir solution. The reservoir solution contained 20-24% PEG 5000 MME, 180-220 mM (e.g. 200 mM) ammonium iodide, 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6). In an alternative, the reservoir solution may additionally contain 2.5% v/v glycerol.

[0367] Diffraction quality single crystals of BACE WT R56KR57K were obtained by the hanging-vapour diffusion method at 20° C. using 1.5 μl of protein and an equivalent volume of reservoir solution. The reservoir solution contained 20-22.5% PEG 5000 MME, 180-220 mM (e.g. 200 mM) ammonium iodide, 180-220 mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6).

[0368] Crystals appear within the first week and grow to maximum dimensions within 14 days. The crystals were hexagonal rods with approximate dimensions of 0.2×0.05×0.05 mm. They belonged to the hexagonal space group P6122 with cell parameters a=b=103.2 Å, c=169.1 Å and accommodate one enzyme molecule per asymmetric unit, and a solvent content of 66%.

[0369] Inhibitor Soaking

[0370] BACE inhibitors were dissolved in DMSO to a concentration of 500 mM and then diluted 1 in 10 in a harvesting solution composed of 220 mM ammonium iodide, 220 mM sodium cacodylate pH 6.4 and 22% PEG 5K MME or 100-200 mM sodium citrate pH 5.0, 200 mM ammonium iodide and 30% PEG 5K MME. Apo-BACE protein crystals were transferred into the harvesting solution for a period of up to 24 hours prior to being dipped in cryoprotectant (20% PEG 5000 MME, 200 mM ammonium iodide, 200 mM sodium cacodylate pH 6.4 and 20% (v/v) glycerol or 200 mM sodium citrate pH 5.0, 200 mM ammonium iodide, 30% PEG 5K MME and 20% (v/v) glycerol) containing the inhibitor and frozen in liquid nitrogen.

[0371] Data Collection & Processing

[0372] The structure of apo-BACE was solved from BACE WT R56KR57K to 1.75 Å resolution using the method of molecular replacement. Prior to data collection, crystals were exposed, briefly, to cryoprotectant, described previously, before flash freezing. Data was collected at 100°K. on beamline ID14-1 at the European Synchrotron Radiation Facility using an ADSC Quantum4 CCD detector, with a wavelength of 0.934 Å and processed using MOSFLM (Leslie, A. G. W. (1992). In Joint CCP4 and EESF-EACMB Newsletter on Protein Crystallography, vol. 26, Warrington, Daresbury Laboratory). The dataset was scaled using SCALA (CCP4—Collaborative Computational Project 4. (1994) The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallographica D50, 760-763) and the intensities converted to structure factor amplitudes with TRUNCATE (Evans, P. R. (1997). Scaling of MAD data. In Recent Advances in Phasing (ed. K. S. Wilson, G. Davies, A. W. Ashton and S. Bailey), pp. 97-102. Council for the Central Laboratory of the Research Councils Daresbury Laboratory, Daresbury, UK), from the CCP4 suite of programs (CCP4—Collaborative Computational Project 4. (1994) The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallographica D50, 760-763). Statistics for the processing are shown in Table 2.

13TABLE 2Data collection statistics for apo-BACE.Resolution 1.75 ÅMosaicity 0.34°Completeness95.9%Multiplicity 6.3Rmerge 0.097

[0373] Structure Determination and Refinement

[0374] The structure of apo-BACE was solved by molecular replacement using the program EPMR (Kissinger C R, Gehlhaar D K, Fogel D B, Acta Crystallogr D Biol Crystallogr, 1999,vol 55 (Pt 2), 484-91). Initially, it was impossible to know whether the correct space group was P6122 or P6522, therefore molecular replacement attempts were performed against both. Default parameters and a resolution range of 15-4Å were used in conjunction with the A chain of 1FKN (Hong et al, 2000) as the search model. A solution was found for P6122 with an Rfactor of 0.458 and a correlation coefficient of 0.543. In an attempt to reduce model bias, the molecular replacement solution was used as the starting point for ARP/wARP (Morris R J, Perrakis A, Lamzin V S, Acta Crystallogr D Biol Crystallogr, 2002,vol 58,(Pt 6 No 2), 968-75) to perform automated backbone tracing using warpNtrace and side chain building via the Side_dock procedure. This produced a discontinuous model composed of 244 out of 385 residues spanning 12 amino acid chains. Cycles of structural refinement with REFMAC5 (Murshudov, G. N., Vagin, A. A. and Dodson, E. J. (1997). Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallographica, 1997 D53, 240-255) were alternated with manual rebuilding of the model using QUANTA (Jones et al., Acta Crystallography A47 (1991), 110-119 and commercially available from Accelerys, San Diego, Calif.). The model was extended to 329 residues with chain breaks between 156-170, 255-280 and 311-325. CNX (Brunger et al., Current Opinion in Structural Biology, Vol. 8, Issue 5, October 1998, 606-611, and commercially available from Accelerys, San Diego, Calif.) composite omit maps were generated to allow further building of the structure and finally water molecules added using DenInt (Astex internal software library). Refinement statistics are shown in Table 3.

14TABLE 3Final refinement statistics for apo-BACERwork0.251Rfree0.284RMS bond deviation from ideality0.011RMS bond angle deviation from ideality1.30Average Bfactor for structure32.99

[0375] This data indicates that the final structure is of good quality; the Rfactors indicating that the refined model has a good agreement with the experimental data. The RMS deviations from ideality indicate that the geometry of the model is good.

[0376] Description of the Apo Structure of BACE

[0377] The structure of BACE we present here has been solved in the absence of substrate or inhibitor. This is the first time that such a structure has been described. The solution of this structure has been possible as we have, for the first time, crystallized BACE without compound in a form suitable for diffracting X-rays, and hence allowed the determination of the apo structure of BACE. Under our conditions it crystallizes in space group P6122 with a monomer in the asymmetric unit. This is a novel crystal form of BACE.

[0378] The protein chain has been traced in the electron density from residue Phe47p to Ala157, and then from Ala168 to Asn385. There is no indication as to the position of residues 158 to 167 in the electron density map. In addition to the protein atoms, the model contains 3 iodine atoms and 285 water molecules in its present state of refinement.

[0379] The majority of the residues in this form of BACE are well defined, the exceptions being some exposed residues. Parts of the protein surface are exposed to solvent, as a consequence of the molecular packing within the crystal lattice (FIG. 1). Residues 255-259, 271-277 and 310 to 317 are exposed and have high B-factors relative to the body of the protein. In addition, residues 304 to 309 pack against an exposed loop and are poorly ordered with high b-factors. There are three disulphide bonds in BACE, two of these are well defined in the electron density, the third, between Cys269 and Cys319 has high temperature factors. This is probably a consequence of its proximity to exposed parts of the protein.

[0380] BACE as it has been solved in this form, is a compact globular protein, which is formed by two domains; domain 1 being comprised of residues 47p-146 and domain 2 of residues (146-385)(numbering from Hong et al, 2000). The active site lies between these two domains, and contains the two conserved aspartic acid residues, Asp32 and Asp228, which define the active sites of aspartic proteinases. In our structure, a single water molecule is coordinated between these two residues.

[0381] The overall fold of the protein is similar to that of 1FKN (Hong et al, 2000), with a few minor, but potentially significant changes. Residues 158-166 are ordered in the structure of BACE in the presence of OM99-2 (in the P21 form), and consist of a loop plus a short helix. In the P6122 unliganded form, these residues cannot be seen, and are assumed to be mobile. This may be a consequence of the crystal packing arrangement in this form. Residues 69-75 have a different arrangement in the crystal form described here, to their arrangement in the crystal structure of the OM99-2 complex. The residues are displaced upward relative to the active site in the structure without OM99-2. The two molecules can be superposed over all residues using the program MAPS (MAPS-Multiple Alignment of Proteins Structures Version 0.2, Sep.-7-1999, Guoguang, Lund University, Sweden and Lu, G. An Approach for Multiple Alignment of Protein Structures (1998, in manuscript) to give an r.m.s.d. of 0.74 Å. This results in close alignment of the N-terminal residue prior to residue 69 and subsequent to 75. In contrast the CA atoms of residue 71 are displaced by 3.3 Å, those of residue 72 by 4.3 Å, and those of residue 73 by 6.0 Å. (FIG. 2) The reason for this difference is postulated to be the interaction of OM99-2 backbone residues with the protein residues, in an arrangement analogous to a beta sheet. This interaction pulls the loop down over the substrate in the active site, and locks it in position. In the absence of substrate, or peptidic inhibitor, the loop moves back up again.

[0382] In addition to these local changes in structure, on binding of inhibitor, there appears to be a slight shift in the domain positions relative to each other, resulting in an average difference in position in the C-terminal domain CA atoms of about 2.0 Å, when the molecules are superposed using the N-terminal CA atoms.

[0383] The symmetry of the P6122 crystal system has resulted in a packing arrangement which brings part of a symmetry related molecule very close to the active site entrance of BACE. Gln73 from a symmetry related molecule lies very close to the entrance to the active site of BACE in this crystal form, and overlaps with the position occupied by P4 Glu in OM99-2. However, this does not interfere with the usefulness of this crystal system to soak in inhibitors, as we have shown that these crystals can be used to soak BACE inhibitors into the active site.

INCORPORATION BY REFERENCE

[0384] The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference. Particular reference is made to the references listed below:

[0385] Bennett B D, Denis P, Haniu M, Teplow D B, Kahn S, Louis J C, Citron M, Vassar R. J Biol. Chem. 2000; 275(48):37712-7.

[0386] Blundell T L, Jhoti H, Abell C, Nature Reviews Drug Discovery, 1, 45-54, 2002.

[0387] Blundell, T L and Johnson, L N, in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976)

[0388] Burton S J, Quirk A V, Wood P C, European Journal of Biochemistry, 179, 379-87, 1989.

[0389] Carr, R; Jhoti, H; Drug Discov. Today, 2002, 7(9), 522-527

[0390] Choppa R, Svenson K, Annis B, Akopian T, Bard J, Stahl M, Somers W; PCT International Publication Number WO 02/25276, (28 Mar. 2002).

[0391] Collaborative Computing Project N., 1994 Acta Crystallogr. D. 50 760-763.

[0392] Creemers J W, Ines Dominguez D, Plets E, Serneels L, Taylor N A, Multhaup G, Craessaerts K, Annaert W, De Strooper B., J Biol. Chem. (2001) 276(6), 4211-7

[0393] De Strooper, B. and Konig. G., 1999, Nature 402, 471-472.

[0394] Ghosh A K., Shin D., Downs D., Koelsch G., Lin X., Ernolieff J. and Tang J. (2000) J. Am. Chem. Soc. 122 3522-3523.

[0395] Goldberg M E, Expert-Bezancon N, Vuillard L, Rabilloud T, Folding & Design, 1, 21-27, 1996.

[0396] Greer J, Erickson J W, Baldwin J J, Varney M D, J. of Medicinal Chemistry, Vol. 37, (1994), 1035-1054,

[0397] Haniu M, Denis P, Young Y, Mendiaz E A, Fuller J, Hui J O, Bennett B D, Kahn S, Ross S. Burgess T, Katta V, Rogers G, Vassar R, Citron M., J Biol. Chem. (2000), 275(28), 21099-106.

[0398] Hong L., Koelsch G., Lin X., Wu S., Terzyan S., Ghosh A K., Zhang X C. and Tang J. (2000) SCIENCE 290 150-153.

[0399] Hussain I, Powell D, Howlett D R, Tew D G, Meek T D, Chapman C, Gloger I S, Murphy K E, Southan C D, Ryan D M, Smith T S, Simmons D L, Walsh F S, Dingwall C, Christie G., Mol. Cell Neurosci. (1999)14(6):419-27

[0400] Lin X., Koelsch G., Wu S., Downs D., Dashti A. and Tang J. (2000) PNAS 97 1456-1460.

[0401] Mallender W D, Yager D, Onstead L, Nichols M R, Eckman C, Sambamurti K, Kopcho L M, Marcinkeviciene J, Copeland R A, Rosenberry T L., Mol Pharmacol, (2001) Mar;59(3), 619-26

[0402] Navaza J., 1994 Acta Crystallogr. A. 50 157

[0403] Pflugrath, J W. (1999) Acta Crystallogr. D. 55 1718-1725 Sinha S., Anderson J P., Barbour R., Basi G S., Caccavello R., Davis D., Doan M., Dovey H F., Frigon N., Hong J., Jacobson-Croak K., Jewett N., Keim P., Knops J., Lieberburg I., Power M., Tan H., Tatsuno G., Tung J., Schenk D., Seubert P., Suomensaari S M., Wand S., Walker D., Zhoa J., McConlogue L. and Varghese J. (1999) NATURE 402 537-540

[0404] Tang J, Lin X, Koelsch G; PCT International Publication Number WO 01/00663, (04 Jan. 2001).

[0405] Vassar R., Bennett, B D., Babu-Khan S., Kahn S., Mendiaz, E A., Denis P., Teplow D B., Ross S., Amarante P., Loeloff R., Luo Y., Fisher S., Fuller J., Edenson S., Lile J., Jorosinski M A., Biere A L., Curran E., Burgess T., Louis J-C., Collins F., Treaner J., Rogers G. and Citron M. (1999) SCIENCE 286 735-741

[0406] Yan R., Bienkowski M J., Shuck M E., Miao H., Tory M C., Pauley A M., Brashier J R., Stratman N C., Mathews W R., Buhl A E., Carter D B., Tomasselli A G., Parodi L A., Heinrikson R L. and Gurney, M E. (1999) Nature, 402 533-537

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EQUIVALENTS

[0408] The foregoing description details presently preferred embodiments of the present invention which are therefore to be considered in all respects as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents, modifications and variations to the specific embodiments of the invention described specifically herein. Such equivalents, modifications and variations are intended to be (or are) encompassed in the scope of the following paragraphs:

[0409] 1. A mutant BACE protein, which protein lacks one or more proteolytic cleavage sites recognized by clostripain (or another protease which recognizes the same cleavage site as clostripain).

[0410] 2. The protein of paragraph 1 wherein BACE residues R56 and/or R57 (based on numbering of SwissProt P56817) are mutated or deleted.

[0411] 3. The protein of paragraph 2 wherein R56 or R57 are mutated by the substitution of arginine for lysine.

[0412] 4. The protein of paragraph 2 wherein R56 and R57 are mutated by the substitution of arginine for lysine.

[0413] 5. The protein of any one of the preceding paragraphs which comprises BACE residues 56 to 396 (based on numbering of SwissProt P56817).

[0414] 6. A mutant BACE protein (for example, a mutant BACE protein as defined in any one of the preceding paragraphs) which is truncated at the N-terminal up to and including R42, R45, G55, R56 or R57.

[0415]

7
. The protein of any one of paragraphs 1 to 6 truncated at the C-terminal such that at least residues 454 et seq. are absent.

[0416] 8. The protein of paragraph 7 truncated at the C-terminal such that at least residues 447 et seq. are absent.

[0417] 9. The protein of any one of the preceding paragraphs wherein the asparagine residues at positions 153, 172, 223 and 354 are mutated to glutamine residues.

[0418] 10. The protein of any one of the preceding paragraphs which is un- or deglycolsylated.

[0419] 11. A mutant BACE protein selected from: (a) SEQ ID 6; (b) SEQ ID 8; (c) SEQ ID 10; (d) SEQ ID 12; (e) SEQ ID 14; (f) SEQ ID 16; (g) SEQ ID 18; (h) SEQ ID 19; (i) SEQ ID 20; Q) SEQ ID21.

[0420] 12. Nucleic acid encoding the protein of any one of the preceding paragraphs.

[0421] 13. A vector comprising the nucleic acid of paragraph 12.

[0422] 14. A host cell comprising the vector of paragraph 13.

[0423] 15. A process for producing the protein of any one of paragraphs 1 to 11 comprising the steps of: (a) culturing the host cell of paragraph 14 under conditions suitable for expression of the protein; and optionally (b) isolating the expressed recombinant BACE protein.

[0424] 16. A process for producing refolded recombinant BACE comprising the steps of: (a) solubilising the recombinant BACE; (b) diluting the solubilised BACE into an aqueous buffer containing sulfobetaine (for example at a concentration of 10 to 50 mM); and (c) maintaining the diluted solution at low temperature (for example, 3 to 6° C.) and at high pH (e.g. 9 to 10.5) for at least 2 weeks.

[0425] 17. The process of paragraph 16 wherein the recombinant BACE is produced according to the process of paragraph 15.

[0426]

18
. Refolded recombinant BACE produced by, or obtainable by, the process of paragraph 16 or paragraph 17.

[0427]

19
. A process for producing a crystal of BACE comprising the step of refolding recombinant BACE protein according to the process of paragraph 16 or paragraph 17.

[0428]

20
. A process for producing a crystal of BACE comprising the step of growing the crystal by vapour diffusion using a reservoir buffer that contains 18-26% PEG 5000 MME (for example, 20-24% PEG 5000 MME, e.g. 20-22.5% PEG 5000 MME), 180-220 mM (e.g. 200 mM) ammonium iodide and 180-22-mM (e.g. 200 mM) tri-sodium citrate (pH 6.4-6.6).

[0429] 21. The process of paragraph 20 wherein the BACE is recombinant and the process further comprises the preliminary step of refolding the recombinant BACE according to the process of paragraph 16 or paragraph 17.

[0430] 22. The process of any one of paragraphs 18 to 20 further comprising the step of activating the BACE by clostripain digestion.

[0431] 23. The process of paragraph 21 wherein the BACE is as defined in any one of paragraphs 1 to 10.

[0432] 24. A crystal of BACE produced by, or obtainable by, the process of any one of paragraphs 18 to 22.

[0433] 25. A crystal of BACE having a hexagonal space group P6122.

[0434] 26. The crystal of paragraph 25 having unit cell dimensions of a=b=103.2 Å, c=169.1 Å, α=β60°, γ=120°, and a unit cell variability of 5% in all dimensions.

[0435] 27. The crystal of paragraph 25 or paragraph 26 which contains one copy of BACE in the asymmetric unit.

[0436] 28. A crystal of BACE (e.g. a crystal according to any one of paragraphs 24 to 27) having a resolution better than 3 Å.

[0437] 29. The crystal of paragraph 28 having a resolution better than 2.5Å.

[0438] 30. The crystal of paragraph 29 having a resolution better than 1.8Å.

[0439] 31. A crystal of BACE (e.g. a crystal according to any one of paragraphs 24 to 30) comprising a structure defined by all or a portion of the co-ordinates of Table 1.

[0440] 32. The crystal of paragraph 31 comprising a structure defined by a portion of the coordinates of Table 1 which coordinates relate to: (a) the BACE catalytic domain; and/or (b) a BACE active site; and/or (c) a BACE binding cavity; and/or (d) selected, amino acid residues of a BACE binding cavity located in a protein framework which holds the selected amino acids in a relative spatial configuration which corresponds to the spatial configuration of those amino acids in Table 1; and/or (d) a BACE binding site.

[0441] 33. The crystal of paragraph 32 wherein the portion of the coordinates of Table 1 comprise (or consist essentially of) those relating to residues SER71, GLY72, LEU91, ASP93, GLY95, SER96, VAL130, PRO131, TYR132, THR133, GLN134, ILE171, ILE179, ILE187, ALA188, ARG189, PRO190, TRP258, TYR259, ASP284, LYS285, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and ARG368 (based on the numbering of SwissProt P56817).

[0442] 34. The crystal of paragraph 33 wherein the portion of the coordinates of Table 1 comprise (or consist essentially of) those relating to residues LYS70, SER71, GLY72, GLN73, GLY74, TYR75, LEU91, VAL92, ASP93, THR94, GLY95, SER96, SER97, ASN98, TYR129, VAL130, PRO131, TYR132, THR133, GLN134, GLY135, LYS136, TRP137, LYS168, PHE169, PHE170, ILE171, ASN172, SER174, TRP176, GLY178, ILE179, LEU180, GLY181, ALA183, TYR184, ALA185, GLU186, ILE187, ALA188, ARG189, PRO190, ASP191, ASP192, ARG256, TRP258, TYR259, TYR283, ASP284, LYS285, SER286, ILE287, VAL288, ASP289, SER290, GLY291, THR292, THR293, ASN294, LEU295, ARG296, GLY325, GLU326, ARG368, VAL370, LYS382, PHE383, ALA384, ILE385, SER386, GLN387, SER388, SER389, THR390, GLY391, THR392, VAL393, GLY395, ALA396 and ILE447 (based on the numbering of SwissProt P56817).

[0443] 35. The crystal of any one of paragraphs 24 to 34 which is capable of being soaked with compound(s) to form co-complex structures.

[0444] 36. The crystal of any one of paragraphs 24 to 35 which is soaked with one or more compound(s) to form co-complex structures.

[0445] 37. The crystal of any one of paragraphs 24 to 36 wherein the BACE is co-crystallized with one or more compound(s) to form co-crystallized structures.

[0446] 38. The crystal of any one of paragraphs 24 to 35 which is an apo crystal.

[0447] 39. The crystal of any one of paragraphs 24 to 38 wherein the BACE is a wild-type BACE.

[0448] 40. The crystal of paragraph 39 wherein the BACE is a human BACE.

[0449] 41. The crystal of paragraph 40 wherein the BACE is a homologue of a human BACE.

[0450] 42. The crystal of paragraph 41 wherein the homologue is an orthologue or a paralogue of a human BACE.

[0451] 43. The crystal of any one of paragraphs 24 to 38 wherein the BACE is a mutant and/or recombinant BACE.

[0452] 44. The crystal of paragraph 43 wherein the BACE: (a) lacks the BACE transmembrane and/or cytoplasmic domain(s); and/or (b) lacks one or more glycolsylation sites; and/or (c) comprises one or more peptide tags (for example a his tag); and/or (d) lacks one or more protease cleavage site(s); and/or (e) is truncated at the N-terminus; and/or (f) is truncated at the C-terminus; and/or (f) lacks the BACE pro-sequence.

[0453] 45. The crystal of paragraph 44 wherein the BACE mutant lacks one or more clostripain cleavage sites.

[0454] 46. The crystal of paragraph 45 wherein BACE residues R56 and/or R57 (based on numbering of SwissProt P56817) are mutated or deleted.

[0455] 47. The crystal of paragraph 46 wherein R56 or R57 are mutated by the substitution of arginine for lysine.

[0456] 48. The crystal of paragraph 46 wherein R56 and R57 are mutated by the substitution of arginine for lysine.

[0457] 49. The crystal of any one of paragraphs 43 to 48 wherein the BACE mutant is truncated at the N-terminal up to and including R42.

[0458] 50. The crystal of any one of paragraphs 43 to 49 wherein the BACE mutant is truncated at the C-terminal such that at least residues 396 et seq. are absent.

[0459] 51. The crystal of paragraph 50 wherein the BACE mutant is truncated at the C-terminal such that at least residues 387 et seq. are absent.

[0460] 52. The crystal of any one of paragraphs 43 to 51 wherein the asparagine residues at positions 153, 172, 223 and 354 of the BACE mutant are mutated to glutamine residues.

[0461] 53. The crystal of any one of paragraphs 24 to 52 wherein the BACE is un- or deglycolsylated.

[0462] 54. The crystal of paragraph 43 wherein the BACE mutant is selected from: (a) SEQ ID 19; (b) SEQ ID 20; (c) SEQ ID 21.

[0463] 55. The process of any one of paragraphs 19 to 23 wherein the process produces a crystal of BACE as defined in any one of paragraphs 24 to 54.

[0464] 56. A three-dimensional representation of BACE or of a portion of BACE, which representation comprises all or a portion of the coordinates of Table 1.

[0465] 57. The three-dimensional representation of paragraph 56 which is a model constructed from all or a portion of the coordinates of Table 1.

[0466] 58. The model of paragraph 57 wherein the portion of BACE is a BACE binding cavity and the portion of the coordinates of Table 1 comprise those of atoms defining a binding site within the binding cavity (for example, wherein the coordinates are as defined in paragraph 33 or paragraph 34).

[0467] 59. A three-dimensional representation of a compound which fits the model of paragraph 57 or paragraph 58.

[0468] 60. The three-dimensional representation of paragraph 59 which is a model of the compound.

[0469] 61. The model of paragraph 60 wherein the compound is a pharmacophore.

[0470] 62. The model of any one of paragraphs 57, 58, 60 or 61 which is: (a) a wire-frame model; (b) a chicken-wire model; (c) a ball-and-stick model; (d). a space-filling model; (e) a stick-model; (f) a ribbon model; (g) a snake model; (h) an arrow and cylinder model; (i) an electron density map; (j) a molecular surface model.

[0471] 63. The model of any one of paragraphs 57, 58, 60, 61 or 62 which is in physical form.

[0472] 64. The model of any one of paragraphs 57, 58, 60, 61 or 62 which is in electronic form.

[0473] 65. The model of paragraph 64 which comprises a graphical image display on a computer screen.

[0474] 66. A computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing a BACE model as defined in paragraph 57, 58 or 62 to 65; (b) providing a molecular structure to be fitted to said BACE model; and (c) fitting the molecular structure to the BACE model to produce a compound model as defined in paragraph 60, 61 or 62 to 65.

[0475] 67. A computer-based method for the analysis of the interaction of a molecular structure with a BACE structure of the invention, which comprises: (a) providing the structure of a BACE as defined by the coordinates of Table 1; (b) providing a molecular structure to be fitted to said BACE structure; and (c) fitting the molecular structure to the BACE structure of Table 1.

[0476] 68. A computer-based method for the analysis of molecular structures which comprises: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structure of a molecular structure to be fitted to the selected coordinates; and (c) fitting the structure to the selected coordinates of the BACE structure.

[0477] 69. The method of paragraph 68 wherein the selected coordinates represent a binding pocket.

[0478] 70. The method of paragraph 68 or paragraph 69 wherein the selected coordinates are of at least 5, 10, 50 or 100 atoms.

[0479] 71. The method of paragraph 69 or paragraph 70 wherein the selected coordinates are as defined in paragraph 33 or paragraph 34.

[0480] 72. A computer-based method of rational drug design comprising the method of any one of paragraphs 66 to 71.

[0481] 73. A computer-based method of rational drug design comprising comprising: (a) providing the coordinates of at least two atoms of a BACE structure as defined in Table 1 (“selected coordinates”); (b) providing the structures of a plurality of molecular fragments; (c) fitting the structure of each of the molecular fragments to the selected coordinates; and (d) assembling the molecular fragments into a single molecule to form a candidate modulator molecule.

[0482] 74. A method for identifying a candidate modulator (e.g. candidate inhibitor) of BACE comprising the steps of: (a) employing a three-dimensional structure of BACE, at least one sub-domain thereof, or a plurality of atoms thereof, to characterise at least one BACE binding cavity, the three-dimensional structure being defined by atomic coordinate data according to Table 1; and (b) identifying the candidate modulator by designing or selecting a compound for interaction with the binding cavity.

[0483] 75. The method of paragraph 74 wherein the three-dimensional structure of BACE is a model as defined in paragraph 57 or paragraph 58.

[0484] 76. A method for identifying an agent compound (e.g. an inhibitor) which modulates BACE activity, comprising the steps of: (a) employing three-dimensional atomic coordinate data according to Table 1 to characterise at least one (e.g. a plurality of) BACE binding site(s); (b) providing the structure of a candidate agent compound; (c) fitting the candidate agent compound to the binding sites; and (d) selecting the candidate agent compound.

[0485] 77. The method of paragraph 76 wherein in step (a) the three-dimensional atomic coordinate data are employed to create a model as defined in paragraph 57, 58 or 62 to 65.

[0486] 78. The method of any one of paragraphs 73 to 77further comprising the step of: (a) obtaining or synthesising the candidate agent or modulator; and (b) contacting the candidate modulator with BACE to determine the ability of the candidate modulator to interact with BACE.

[0487] 79. A method of assessing the ability of a candidate modulator to interact with BACE which comprises the steps of: (a) obtaining or synthesising said candidate modulator; (b) forming a crystallized complex of BACE and said candidate modulator; and (c) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said candidate modulator to interact with BACE.

[0488] 80. A method for determining the structure of a compound bound to BACE, said method comprising: (a) mixing BACE with the compound to form a BACE-compound complex; (b) crystallizing the BACE-compound complex; and (c) determining the structure of said BACE-compound(s) complex by reference to the data of Table 1.

[0489] 81. A method for determining the structure of a compound bound to BACE, said method comprising: (a) providing a crystal of BACE; (b) soaking the crystal with one or more compound(s) to form a complex; and (c) determining the structure of the complex by employing the data of Table 1.

[0490] 82. A method of determining the three dimensional structure of a BACE homologue or analogue of unknown structure, the method comprising the steps of: (a) aligning a representation of an amino acid sequence of the BACE homologue or analogue with the amino acid sequence of the BACE of Table 1 to match homologous regions of the amino acid sequences; (b) modelling the structure of the matched homologous regions of said target BACE of unknown structure on the corresponding regions of the BACE structure as defined by Table 1; and (c) determining a conformation for the BACE homologue or analogue which substantially preserves the structure of said matched homologous regions.

[0491] 83. The method of paragraph 82 wherein steps (a) and/or (b) and/or (c) are performed by computer modelling.

[0492] 84. A method of providing data for generating structures and/or performing rational drug design for BACE, BACE homologues or analogues, complexes of BACE with a potential modulator, or complexes of BACE homologues or analogues with potential modulators, the method comprising: (i) establishing communication with a remote device containing computer-readable data comprising at least one of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE, at least one sub-domain of the three-dimensional structure of BACE, or the coordinates of a plurality of atoms of BACE; (b) structure factor data for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE homologue or analogue generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d); and (ii) receiving said computer-readable data from said remote device.

[0493] 85. A computer system containing one or more of: (a) atomic coordinate data according to Table 1, said data defining the three-dimensional structure of BACE or at least selected coordinates thereof, (b) structure factor data (where a structure factor comprises the amplitude and phase of the diffracted wave) for BACE, said structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a target BACE protein generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; or (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0494] 86. The computer system of paragraph 85 comprising: (i) a computer-readable data storage medium comprising data storage material encoded with the computer-readable data; (ii) a working memory for storing instructions for processing said computer-readable data; and (iii) a central-processing unit coupled to said working memory and to said computer-readable data storage medium for processing said computer-readable data and thereby generating structures and/or performing rational drug design.

[0495] 87. The computer system of paragraph 86 further comprising a display coupled to said central-processing unit for displaying said structures.

[0496] 88. A computer-readable storage medium, comprising a data storage material encoded with computer readable data, wherein the data are defined by all or a portion of the structure coordinates of BACE of Table 1, or a homologue of BACE, wherein said homologue comprises backbone atoms that have a root mean square deviation from the backbone atoms (nitrogen-carbonαcarbon) of Table 1 of not more than 1.5 Å.

[0497] 89. A computer-readable data storage medium comprising a data storage material encoded with a first set of computer-readable data comprising a Fourier transform of at least a portion (e.g. selected coordinates as defined herein) of the structural coordinates for BACE according to Table 1; which, when combined with a second set of machine readable data comprising an X-ray diffraction pattern of a molecule or molecular complex of unknown structure, using a machine programmed with the instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data.

[0498] 90. A computer readable medium with at least one of: (a) atomic coordinate data according to Table 1 recorded thereon, said data defining the three-dimensional structure of BACE, or at least selected coordinates thereof; (b) structure factor data for BACE recorded thereon, the structure factor data being derivable from the atomic coordinate data of Table 1; (c) atomic coordinate data of a target BACE protein generated by homology modelling of the target based on the data of Table 1; (d) atomic coordinate data of a BACE-ligand complex or a BACE homologue or analogue generated by interpreting X-ray crystallographic data or NMR data by reference to the data of Table 1; and (e) structure factor data derivable from the atomic coordinate data of (c) or (d).

[0499] 91. A method for determining the structure of a protein, which method comprises;

[0500] providing the co-ordinates of Table 1, and either (a) positioning the co-ordinates in the crystal unit cell of said protein so as to provide a structure for said protein or (b) assigning NMR spectra Peaks of said protein by manipulating the coordinates of Table 1.

[0501] 92. A process for producing a medicament, pharmaceutical composition or drug, the process comprising: (a) identifying a BACE modulator molecule according to the method as defined in any one of paragraphs 73 to 79; (b) optimising the structure of the modulator molecule; and (c) preparing a medicament, pharmaceutical composition or drug containing the optimised modulator molecule.

[0502] 93. A medicament, pharmaceutical composition or drug produced by, or obtainable by, the process of paragraph 92.

[0503] 94. A compound identified, produced or obtainable by the process or method of any one of paragraphs 73 to 79.

[0504] 95. A pharmaceutical composition, medicament, drug or other composition comprising the compound of paragraph 94.

[0505] 96. The medicament, pharmaceutical composition or drug of paragraph 93, compound of paragraph 94 or composition of paragraph 95 for use in medicine, for example for use in therapy or prophylaxis.

[0506] 97. The medicament, pharmaceutical composition, drug or composition of paragraph 96 wherein the therapy or prophylaxis comprises inhibiting BACE or the production of Aβ or fragments thereof or the treatment of Alzheimer's disease.

[0507] 98. A method of inhibiting BACE or the production of Aβ or fragments thereof or treating Alzheimer's disease comprising administering the miedicament, pharmaceutical composition, drug or composition of paragraph 96 to the patient.

[0508] 99. The method of paragraph 84, wherein the computer readable data is transmitted form the remove device.

[0509] 100. The method of paragraph 99, wherein the data is transmitted electronically or optically.

[0510]

15

TABLE 1

ATOM
1
N
PHE
A
47p
65.730
61.598
−17.857
1.00
56.68
A
N

ATOM
2
CA
PHE
A
47p
66.426
61.383
−16.552
1.00
54.16
A
C

ATOM
3
C
PHE
A
47p
67.801
60.738
−16.734
1.00
54.30
A
C

ATOM
4
O
PHE
A
47p
68.258
59.983
−15.869
1.00
52.46
A
O

ATOM
5
CB
PHE
A
47p
65.566
60.500
−15.635
1.00
54.61
A
C

ATOM
6
CG
PHE
A
47p
64.161
61.008
−15.429
1.00
54.65
A
C

ATOM
7
CD1
PHE
A
47p
63.110
60.508
−16.186
1.00
56.27
A
C

ATOM
8
CD2
PHE
A
47p
63.887
61.970
−14.463
1.00
55.01
A
C

ATOM
9
CE1
PHE
A
47p
61.812
60.972
−15.995
1.00
57.39
A
C

ATOM
10
CE2
PHE
A
47p
62.596
62.435
−14.266
1.00
56.06
A
C

ATOM
11
CZ
PHE
A
47p
61.556
61.938
−15.035
1.00
56.47
A
C

ATOM
12
N
VAL
A
48p
68.468
61.048
−17.845
1.00
54.26
A
N

ATOM
13
CA
VAL
A
48p
69.737
60.395
−18.200
1.00
54.45
A
C

ATOM
14
C
VAL
A
48p
70.910
60.742
−17.276
1.00
53.21
A
C

ATOM
15
O
VAL
A
48p
71.847
59.947
−17.128
1.00
56.35
A
O

ATOM
16
CB
VAL
A
48p
70.156
60.691
−19.662
1.00
57.43
A
C

ATOM
17
CG1
VAL
A
48p
69.222
59.972
−20.636
1.00
58.42
A
C

ATOM
18
CG2
VAL
A
48p
70.204
62.208
−19.944
1.00
57.43
A
C

ATOM
19
N
GLU
A
1
70.860
61.925
−16.668
1.00
49.17
A
N

ATOM
20
CA
GLU
A
1
71.845
62.329
−15.674
1.00
46.84
A
C

ATOM
21
C
GLU
A
1
71.857
61.373
−14.479
1.00
42.66
A
C

ATOM
22
O
GLU
A
1
72.901
61.125
−13.891
1.00
45.10
A
O

ATOM
23
CB
GLU
A
1
71.532
63.740
−15.171
1.00
48.32
A
C

ATOM
24
CG
GLU
A
1
70.180
64.053
−14.545
0.00
50.15
A
C

ATOM
25
CD
GLU
A
1
68.942
64.394
−15.351
0.00
51.10
A
C

ATOM
26
OE1
GLU
A
1
68.516
63.562
−16.178
0.00
51.29
A
O

ATOM
27
OE2
GLU
A
1
68.395
65.500
−15.155
0.00
51.61
A
O

ATOM
28
N
MET
A
2
70.685
60.855
−14.125
1.00
37.18
A
N

ATOM
29
CA
MET
A
2
70.525
60.001
−12.942
1.00
32.72
A
C

ATOM
30
C
MET
A
2
70.875
58.531
−13.154
1.00
29.50
A
C

ATOM
31
O
MET
A
2
71.014
57.787
−12.183
1.00
29.19
A
O

ATOM
32
CB
MET
A
2
69.099
60.111
−12.415
1.00
30.14
A
C

ATOM
33
CG
MET
A
2
68.733
61.514
−12.005
1.00
34.84
A
C

ATOM
34
SD
MET
A
2
67.103
61.723
−11.322
1.00
36.26
A
S

ATOM
35
CE
MET
A
2
66.607
63.243
−12.134
1.00
40.05
A
C

ATOM
36
N
VAL
A
3
71.008
58.079
−14.396
1.00
28.21
A
N

ATOM
37
CA
VAL
A
3
71.291
56.669
−14.611
1.00
29.18
A
C

ATOM
38
C
VAL
A
3
72.690
56.364
−14.085
1.00
27.28
A
C

ATOM
39
O
VAL
A
3
73.622
57.149
−14.298
1.00
28.33
A
O

ATOM
40
CB
VAL
A
3
71.137
56.248
−16.094
1.00
32.19
A
C

ATOM
41
CG1
VAL
A
3
71.649
54.826
−16.299
1.00
30.92
A
C

ATOM
42
CG2
VAL
A
3
69.667
56.353
−16.525
1.00
32.71
A
C

ATOM
43
N
ASP
A
4
72.803
55.254
−13.359
1.00
28.19
A
N

ATOM
44
CA
ASP
A
4
74.066
54.739
−12.825
1.00
29.50
A
C

ATOM
45
C
ASP
A
4
74.600
55.632
−11.703
1.00
27.86
A
C

ATOM
46
O
ASP
A
4
75.797
55.682
−11.454
1.00
28.77
A
O

ATOM
47
CB
ASP
A
4
75.107
54.575
−13.940
1.00
32.06
A
C

ATOM
48
CG
ASP
A
4
76.254
53.655
−13.553
1.00
37.52
A
C

ATOM
49
OD1
ASP
A
4
76.029
52.572
−12.945
1.00
38.24
A
O

ATOM
50
OD2
ASP
A
4
77.438
53.952
−13.829
1.00
45.15
A
O

ATOM
51
N
ASN
A
5
73.694
56.308
−11.015
1.00
24.98
A
N

ATOM
52
CA
ASN
A
5
74.062
57.172
−9.876
1.00
18.95
A
C

ATOM
53
C
ASN
A
5
74.270
56.415
−8.544
1.00
22.40
A
C

ATOM
54
O
ASN
A
5
74.564
57.045
−7.515
1.00
21.31
A
O

ATOM
55
CB
ASN
A
5
73.064
58.329
−9.718
1.00
21.03
A
C

ATOM
56
CG
ASN
A
5
71.677
57.870
−9.366
1.00
16.73
A
C

ATOM
57
OD1
ASN
A
5
71.424
56.673
−9.325
1.00
19.74
A
O

ATOM
58
ND2
ASN
A
5
70.801
58.808
−9.035
1.00
21.06
A
N

ATOM
59
N
LEU
A
6
74.099
55.098
−8.562
1.00
15.94
A
N

ATOM
60
CA
LEU
A
6
74.323
54.236
−7.397
1.00
16.57
A
C

ATOM
61
C
LEU
A
6
75.531
53.321
−7.510
1.00
21.72
A
C

ATOM
62
O
LEU
A
6
75.855
52.780
−8.581
1.00
21.55
A
O

ATOM
63
CB
LEU
A
6
73.109
53.352
−7.078
1.00
18.17
A
C

ATOM
64
CG
LEU
A
6
71.707
53.957
−6.866
1.00
19.32
A
C

ATOM
65
CD1
LEU
A
6
70.695
52.916
−6.521
1.00
17.46
A
C

ATOM
66
CD2
LEU
A
6
71.748
54.997
−5.797
1.00
21.42
A
C

ATOM
67
N
ARG
A
7
76.173
53.126
−6.364
1.00
21.10
A
N

ATOM
68
CA
ARG
A
7
77.333
52.266
−6.230
1.00
23.84
A
C

ATOM
69
C
ARG
A
7
77.237
51.485
−4.939
1.00
25.78
A
C

ATOM
70
O
ARG
A
7
76.424
51.808
−4.059
1.00
21.54
A
O

ATOM
71
CB
ARG
A
7
78.610
53.103
−6.226
1.00
26.25
A
C

ATOM
72
CG
ARG
A
7
78.992
53.658
−7.583
1.00
30.55
A
C

ATOM
73
CD
ARG
A
7
80.135
54.652
−7.549
1.00
37.65
A
C

ATOM
74
NE
ARG
A
7
80.063
55.407
−8.932
0.00
40.50
A
N

ATOM
75
CZ
ARG
A
7
80.997
56.306
−9.222
0.00
41.92
A
C

ATOM
76
NH1
ARG
A
7
80.991
56.911
−10.402
0.00
42.93
A
N

ATOM
77
NH2
ARG
A
7
81.937
56.601
−8.335
0.00
42.80
A
N

ATOM
78
N
GLY
A
8
78.091
50.479
−4.799
1.00
26.16
A
N

ATOM
79
CA
GLY
A
8
78.086
49.663
−3.598
1.00
29.54
A
C

ATOM
80
C
GLY
A
8
79.032
48.490
−3.639
1.00
31.18
A
C

ATOM
81
O
GLY
A
8
79.790
48.325
−4.591
1.00
33.68
A
O

ATOM
82
N
LYS
A
9
78.986
47.685
−2.587
1.00
34.88
A
N

ATOM
83
CA
LYS
A
9
79.643
48.390
−2.578
1.00
36.27
A
C

ATOM
84
C
LYS
A
9
78.625
45.337
−2.169
1.00
37.50
A
C

ATOM
85
O
LYS
A
9
77.771
45.576
−1.316
1.00
32.87
A
O

ATOM
86
CB
LYS
A
9
80.861
46.396
−1.649
1.00
39.66
A
C

ATOM
87
CG
LYS
A
9
81.975
47.324
−2.120
1.00
45.29
A
C

ATOM
88
CD
LYS
A
9
83.346
46.635
−2.207
1.00
50.21
A
C

ATOM
89
CE
LYS
A
9
84.382
47.543
−2.887
1.00
52.01
A
C

ATOM
90
NZ
LYS
A
9
85.408
48.085
−1.943
1.00
53.23
A
N

ATOM
91
N
SER
A
10
78.708
44.172
−2.805
1.00
38.65
A
N

ATOM
92
CA
SER
A
10
77.807
43.063
−2.525
1.00
39.77
A
C

ATOM
93
C
SER
A
10
77.658
42.852
−1.026
1.00
38.92
A
C

ATOM
94
O
SER
A
10
78.658
42.718
−0.316
1.00
38.89
A
O

ATOM
95
CB
SER
A
10
78.336
41.776
−3.172
1.00
41.88
A
C

ATOM
96
OG
SER
A
10
77.485
40.680
−2.879
1.00
44.59
A
O

ATOM
97
N
GLY
A
11
76.410
42.857
−0.556
1.00
36.41
A
N

ATOM
98
CA
GLY
A
11
76.097
42.627
0.843
1.00
35.71
A
C

ATOM
99
C
GLY
A
11
76.076
43.859
1.738
1.00
35.38
A
C

ATOM
100
O
GLY
A
11
75.631
43.757
2.886
1.00
37.81
A
O

ATOM
101
N
GLN
A
12
76.519
45.005
1.213
1.00
34.18
A
N

ATOM
102
CA
GLN
A
12
76.732
46.234
1.999
1.00
35.64
A
C

ATOM
103
C
GLN
A
12
75.861
47.409
1.536
1.00
35.07
A
C

ATOM
104
O
GLN
A
12
76.148
48.558
1.881
1.00
36.40
A
O

ATOM
105
CB
GLN
A
12
78.196
46.693
1.913
1.00
37.52
A
C

ATOM
106
CG
GLN
A
12
79.230
45.703
2.437
1.00
42.55
A
C

ATOM
107
CD
GLN
A
12
80.653
46.267
2.465
1.00
40.98
A
C

ATOM
108
OE1
GLN
A
12
81.562
45.623
2.984
1.00
49.77
A
O

ATOM
109
NE2
GLN
A
12
80.846
47.450
1.904
1.00
50.11
A
N

ATOM
110
N
GLY
A
13
74.824
47.132
0.749
1.00
30.97
A
N

ATOM
111
CA
GLY
A
13
73.887
48.163
0.331
1.00
27.55
A
C

ATOM
112
C
GLY
A
13
74.366
49.021
−0.820
1.00
25.65
A
C

ATOM
113
O
GLY
A
13
75.491
48.904
−1.289
1.00
26.10
A
O

ATOM
114
N
TYR
A
14
73.477
49.892
−1.275
1.00
17.01
A
N

ATOM
115
CA
TYR
A
14
73.738
50.794
−2.395
1.00
17.38
A
C

ATOM
116
C
TYR
A
14
73.722
52.218
−1.880
1.00
16.80
A
C

ATOM
117
O
TYR
A
14
72.851
52.561
−1.072
1.00
17.47
A
O

ATOM
118
CB
TYR
A
14
72.635
50.663
−3.446
1.00
18.29
A
C

ATOM
119
CG
TYR
A
14
72.651
49.339
−4.162
1.00
21.45
A
C

ATOM
120
CD1
TYR
A
14
72.134
48.194
−3.574
1.00
20.72
A
C

ATOM
121
CD2
TYR
A
14
73.201
49.239
−5.434
1.00
21.04
A
C

ATOM
122
CE1
TYR
A
14
72.164
46.981
−4.246
1.00
20.87
A
C

ATOM
123
CE2
TYR
A
14
73.233
48.043
−6.101
1.00
23.36
A
C

ATOM
124
CZ
TYR
A
14
72.723
46.935
−5.522
1.00
24.50
A
C

ATOM
125
OH
TYR
A
14
72.758
45.757
−6.229
1.00
27.32
A
O

ATOM
126
N
TYR
A
15
74.636
53.044
−2.387
1.00
18.15
A
N

ATOM
127
CA
TYR
A
15
74.727
54.431
−1.976
1.00
15.54
A
C

ATOM
128
C
TYR
A
15
74.734
55.415
−3.133
1.00
16.89
A
C

ATOM
129
O
TYR
A
15
75.171
55.108
−4.243
1.00
17.87
A
O

ATOM
130
CB
TYR
A
15
75.951
54.666
−1.064
1.00
16.46
A
C

ATOM
131
CG
TYR
A
15
77.308
54.342
−1.685
1.00
15.58
A
C

ATOM
132
CD1
TYR
A
15
77.966
55.246
−2.501
1.00
19.48
A
C

ATOM
133
CD2
TYR
A
15
77.919
53.139
−1.411
1.00
19.60
A
C

ATOM
134
CE1
TYR
A
15
79.201
54.956
−3.034
1.00
21.95
A
C

ATOM
135
CE2
TYR
A
15
79.165
52.838
−1.926
1.00
23.26
A
C

ATOM
136
CZ
TYR
A
15
79.787
53.734
−2.739
1.00
21.80
A
C

ATOM
137
OH
TYR
A
15
81.006
53.396
−3.255
1.00
26.17
A
O

ATOM
138
N
VAL
A
16
74.279
56.620
−2.823
1.00
17.50
A
N

ATOM
139
CA
VAL
A
16
74.197
57.728
−3.760
1.00
19.34
A
C

ATOM
140
C
VAL
A
16
75.077
58.862
−3.212
1.00
20.35
A
C

ATOM
141
O
VAL
A
16
75.165
59.056
−1.995
1.00
29.27
A
O

ATOM
142
CB
VAL
A
16
72.715
58.201
−3.936
1.00
18.58
A
C

ATOM
143
CG1
VAL
A
16
72.177
58.911
−2.680
1.00
18.67
A
C

ATOM
144
CG2
VAL
A
16
72.554
59.101
−5.172
1.00
21.03
A
C

ATOM
145
N
GLU
A
17
75.715
59.608
−4.101
1.00
20.07
A
N

ATOM
146
CA
GLU
A
17
76.401
60.838
−3.706
1.00
22.44
A
C

ATOM
147
C
GLU
A
17
75.398
61.943
−3.372
1.00
22.83
A
C

ATOM
148
O
GLU
A
17
74.419
62.145
−4.091
1.00
20.94
A
O

ATOM
149
CB
GLU
A
17
77.360
61.298
−4.810
1.00
23.72
A
C

ATOM
150
CG
GLU
A
17
78.246
62.482
−4.416
1.00
28.53
A
C

ATOM
151
CD
GLU
A
17
79.065
63.024
−5.580
1.00
36.53
A
C

ATOM
152
OE1
GLU
A
17
78.956
64.228
−5.878
1.00
39.02
A
O

ATOM
153
OE2
GLU
A
17
79.820
62.249
−6.201
1.00
41.99
A
O

ATOM
154
N
MET
A
18
75.616
62.632
−2.249
1.00
18.64
A
N

ATOM
155
CA
MET
A
18
74.824
63.788
−1.849
1.00
18.78
A
C

ATOM
156
C
MET
A
18
75.744
64.904
−1.365
1.00
24.24
A
C

ATOM
157
O
MET
A
18
76.919
64.671
−1.079
1.00
23.12
A
O

ATOM
158
CB
MET
A
18
73.866
63.427
−0.717
1.00
20.09
A
C

ATOM
159
CG
MET
A
18
72.884
62.284
−1.064
1.00
17.91
A
C

ATOM
160
SD
MET
A
18
71.685
61.911
0.240
1.00
20.92
A
S

ATOM
161
CE
MET
A
18
70.491
63.197
−0.005
1.00
21.35
A
C

ATOM
162
N
THR
A
19
75.229
66.121
−1.313
1.00
24.86
A
N

ATOM
163
CA
THR
A
19
75.966
67.206
−0.661
1.00
26.57
A
C

ATOM
164
C
THR
A
19
75.122
67.794
0.443
1.00
24.45
A
C

ATOM
165
O
THR
A
19
73.904
67.861
0.341
1.00
23.60
A
O

ATOM
166
CB
THR
A
19
76.392
68.292
−1.665
1.00
28.59
A
C

ATOM
167
OG1
THR
A
19
75.236
68.833
−2.311
1.00
32.78
A
O

ATOM
168
CG2
THR
A
19
77.235
67.712
−2.775
1.00
28.11
A
C

ATOM
169
N
VAL
A
20
75.775
68.213
1.531
1.00
25.61
A
N

ATOM
170
CA
VAL
A
20
75.078
68.836
2.643
1.00
22.00
A
C

ATOM
171
C
VAL
A
20
75.826
70.130
2.995
1.00
21.90
A
C

ATOM
172
O
VAL
A
20
77.040
70.183
2.841
1.00
23.44
A
O

ATOM
173
CB
VAL
A
20
75.011
67.902
3.848
1.00
25.28
A
C

ATOM
174
CG1
VAL
A
20
74.361
68.579
5.033
1.00
30.83
A
C

ATOM
175
CG2
VAL
A
20
74.245
66.611
3.495
1.00
25.14
A
C

ATOM
176
N
GLY
A
21
75.077
71.146
3.422
1.00
25.14
A
N

ATOM
177
CA
GLY
A
21
75.623
72.434
3.837
1.00
27.79
A
C

ATOM
178
C
GLY
A
21
76.015
73.417
2.752
1.00
26.88
A
C

ATOM
179
O
GLY
A
21
75.906
73.137
1.551
1.00
27.40
A
O

ATOM
180
N
SER
A
22
76.466
74.594
3.202
1.00
28.28
A
N

ATOM
181
CA
SER
A
22
76.976
75.657
2.330
1.00
29.16
A
C

ATOM
182
C
SER
A
22
78.298
76.173
2.919
1.00
28.62
A
C

ATOM
183
O
SER
A
22
78.308
76.639
4.049
1.00
29.95
A
O

ATOM
184
CB
SER
A
22
75.983
76.815
2.238
1.00
29.69
A
C

ATOM
185
OG
SER
A
22
74.675
76.366
1.925
1.00
29.77
A
O

ATOM
186
N
PRO
A
23
79.407
76.052
2.198
1.00
28.22
A
N

ATOM
187
CA
PRO
A
23
79.461
75.401
0.884
1.00
30.78
A
C

ATOM
188
C
PRO
A
23
79.227
73.886
0.976
1.00
29.87
A
C

ATOM
189
O
PRO
A
23
79.338
73.300
2.063
1.00
25.45
A
O

ATOM
190
CB
PRO
A
23
80.875
75.693
0.407
1.00
31.63
A
C

ATOM
191
CG
PRO
A
23
81.664
75.968
1.651
1.00
29.94
A
C

ATOM
192
CD
PRO
A
23
80.727
76.545
2.629
1.00
33.02
A
C

ATOM
193
N
PRO
A
24
78.894
73.258
−0.145
1.00
30.31
A
N

ATOM
194
CA
PRO
A
24
78.559
71.821
−0.139
1.00
26.63
A
C

ATOM
195
C
PRO
A
24
79.673
70.857
0.304
1.00
25.38
A
C

ATOM
196
O
PRO
A
24
80.807
70.925
−0.155
1.00
25.17
A
O

ATOM
197
CB
PRO
A
24
78.141
71.536
−1.593
1.00
28.22
A
C

ATOM
198
CG
PRO
A
24
78.576
72.715
−2.410
1.00
32.40
A
C

ATOM
199
CD
PRO
A
24
78.778
73.874
−1.484
1.00
33.13
A
C

ATOM
200
N
GLN
A
25
79.292
69.920
1.169
1.00
24.26
A
N

ATOM
201
CA
GLN
A
25
80.144
68.839
1.620
1.00
23.05
A
C

ATOM
202
C
GLN
A
25
79.617
67.576
0.992
1.00
19.90
A
C

ATOM
203
O
GLN
A
25
78.470
67.220
1.220
1.00
20.87
A
O

ATOM
204
CB
GLN
A
25
80.075
68.728
3.127
1.00
20.92
A
C

ATOM
205
CG
GLN
A
25
80.581
69.995
3.817
1.00
25.92
A
C

ATOM
206
CD
GLN
A
25
80.491
69.911
5.317
1.00
24.91
A
C

ATOM
207
OE1
GLN
A
25
80.742
68.850
5.894
1.00
21.17
A
O

ATOM
208
NE2
GLN
A
25
80.153
71.021
5.957
1.00
26.06
A
N

ATOM
209
N
THR
A
26
80.439
66.926
0.187
1.00
23.72
A
N

ATOM
210
CA
THR
A
26
80.041
65.699
−0.495
1.00
23.00
A
C

ATOM
211
C
THR
A
26
80.141
64.498
0.435
1.00
22.59
A
C

ATOM
212
O
THR
A
26
81.151
64.310
1.103
1.00
23.44
A
O

ATOM
213
CB
THR
A
26
80.943
65.456
−1.685
1.00
24.91
A
C

ATOM
214
OG1
THR
A
26
80.891
66.588
−2.566
1.00
31.54
A
O

ATOM
215
CG2
THR
A
26
80.428
64.292
−2.537
1.00
25.28
A
C

ATOM
216
N
LEU
A
27
79.107
63.666
0.430
1.00
19.15
A
N

ATOM
217
CA
LEU
A
27
79.093
62.431
1.198
1.00
18.03
A
C

ATOM
218
C
LEU
A
27
78.394
61.329
0.375
1.00
22.50
A
C

ATOM
219
O
LEU
A
27
77.511
61.636
−0.415
1.00
25.14
A
O

ATOM
220
CB
LEU
A
27
78.310
62.637
2.488
1.00
18.41
A
C

ATOM
221
CG
LEU
A
27
78.805
63.740
3.447
1.00
23.17
A
C

ATOM
222
CD1
LEU
A
27
77.737
64.155
4.429
1.00
28.47
A
C

ATOM
223
CD2
LEU
A
27
80.040
63.300
4.174
1.00
22.35
A
C

ATOM
224
N
ASN
A
28
78.804
60.075
0.562
1.00
19.63
A
N

ATOM
225
CA
ASN
A
28
78.097
58.926
−0.013
1.00
18.44
A
C

ATOM
226
C
ASN
A
28
77.098
58.404
0.985
1.00
17.41
A
C

ATOM
227
O
ASN
A
28
77.467
58.130
2.122
1.00
15.99
A
O

ATOM
228
CB
ASN
A
28
79.059
57.817
−0.346
1.00
17.43
A
C

ATOM
229
CG
ASN
A
28
79.868
58.114
−1.556
1.00
22.09
A
C

ATOM
230
OD1
ASN
A
28
79.407
58.837
−2.434
1.00
21.00
A
O

ATOM
231
ND2
ASN
A
28
81.084
57.573
−1.622
1.00
22.09
A
N

ATOM
232
N
ILE
A
29
75.848
58.222
0.566
1.00
13.33
A
N

ATOM
233
CA
ILE
A
29
74.741
57.964
1.501
1.00
15.06
A
C

ATOM
234
C
ILE
A
29
73.969
56.724
1.072
1.00
15.98
A
C

ATOM
235
O
ILE
A
29
73.495
56.628
−0.071
1.00
16.00
A
O

ATOM
236
CB
ILE
A
29
73.777
59.164
1.569
1.00
17.19
A
C

ATOM
237
CG1
ILE
A
29
74.533
60.443
1.960
1.00
16.84
A
C

ATOM
238
CG2
ILE
A
29
72.625
58.876
2.579
1.00
15.77
A
C

ATOM
239
CD1
ILE
A
29
75.147
60.409
3.359
1.00
18.72
A
C

ATOM
240
N
LEU
A
30
73.829
55.787
1.997
1.00
15.17
A
N

ATOM
241
CA
LEU
A
30
73.110
54.541
1.743
1.00
16.63
A
C

ATOM
242
C
LEU
A
30
71.623
54.825
1.455
1.00
17.89
A
C

ATOM
243
O
LEU
A
30
71.000
55.542
2.186
1.00
17.80
A
O

ATOM
244
CB
LEU
A
30
73.251
53.629
2.964
1.00
14.92
A
C

ATOM
245
CG
LEU
A
30
72.441
52.335
2.947
1.00
24.85
A
C

ATOM
246
CD1
LEU
A
30
73.456
51.336
1.962
0.00
19.90
A
C

ATOM
247
CD2
LEU
A
30
72.418
51.625
4.210
0.00
19.96
A
C

ATOM
248
N
VAL
A
31
71.059
54.224
0.405
1.00
15.67
A
N

ATOM
249
CA
VAL
A
31
69.656
54.390
0.066
1.00
17.96
A
C

ATOM
250
C
VAL
A
31
68.865
53.269
0.715
1.00
18.65
A
C

ATOM
251
O
VAL
A
31
69.101
52.060
0.440
1.00
21.01
A
O

ATOM
252
CB
VAL
A
31
69.461
54.358
−1.471
1.00
21.10
A
C

ATOM
253
CG1
VAL
A
31
67.991
54.309
−1.806
1.00
23.22
A
C

ATOM
254
CG2
VAL
A
31
70.102
55.554
−2.073
1.00
19.69
A
C

ATOM
255
N
ASP
A
32
67.936
53.656
1.591
1.00
18.25
A
N

ATOM
256
CA
ASP
A
32
67.221
52.712
2.456
1.00
20.14
A
C

ATOM
257
C
ASP
A
32
65.712
52.942
2.457
1.00
18.89
A
C

ATOM
258
O
ASP
A
32
65.217
53.839
3.144
1.00
18.73
A
O

ATOM
259
CB
ASP
A
32
67.748
52.832
3.905
1.00
20.81
A
C

ATOM
260
CG
ASP
A
32
67.163
51.747
4.850
1.00
27.29
A
C

ATOM
261
OD1
ASP
A
32
66.652
50.729
4.345
1.00
28.02
A
O

ATOM
262
OD2
ASP
A
32
67.178
51.817
6.113
1.00
29.94
A
O

ATOM
263
N
THR
A
33
64.947
52.108
1.735
1.00
15.71
A
N

ATOM
264
CA
THR
A
33
63.500
52.284
1.753
1.00
16.65
A
C

ATOM
265
C
THR
A
33
62.839
51.643
2.958
1.00
18.62
A
C

ATOM
266
O
THR
A
33
61.627
51.707
3.086
1.00
19.27
A
O

ATOM
267
CB
THR
A
33
62.855
51.726
0.459
1.00
17.78
A
C

ATOM
268
OG1
THR
A
33
63.088
50.330
0.395
1.00
17.76
A
O

ATOM
269
CG2
THR
A
33
63.526
52.289
−0.756
1.00
20.47
A
C

ATOM
270
N
GLY
A
34
63.645
51.078
3.854
1.00
19.46
A
N

ATOM
271
CA
GLY
A
34
63.137
50.457
5.065
1.00
22.82
A
C

ATOM
272
C
GLY
A
34
63.251
51.314
6.315
1.00
24.98
A
C

ATOM
273
O
GLY
A
34
63.033
50.830
7.434
1.00
24.60
A
O

ATOM
274
N
SER
A
35
63.601
52.578
6.130
1.00
18.89
A
N

ATOM
275
CA
SER
A
35
63.672
53.543
7.231
1.00
21.21
A
C

ATOM
276
C
SER
A
35
63.376
54.978
6.749
1.00
18.57
A
C

ATOM
277
O
SER
A
35
63.245
55.229
5.535
1.00
21.32
A
O

ATOM
278
CB
SER
A
35
65.045
53.420
7.880
1.00
21.69
A
C

ATOM
279
OG
SER
A
35
66.063
53.982
7.078
1.00
20.28
A
O

ATOM
280
N
SER
A
36
63.253
55.940
7.678
1.00
18.30
A
N

ATOM
281
CA
SER
A
36
62.727
57.267
7.347
1.00
20.36
A
C

ATOM
282
C
SER
A
36
63.545
58.455
7.889
1.00
21.41
A
C

ATOM
283
O
SER
A
36
63.101
59.594
7.809
1.00
19.92
A
O

ATOM
284
CB
SER
A
36
61.267
57.375
7.824
1.00
25.82
A
C

ATOM
285
OG
SER
A
36
60.485
56.344
7.230
1.00
25.30
A
O

ATOM
286
N
ASN
A
37
64.748
58.181
8.396
1.00
19.59
A
N

ATOM
287
CA
ASN
A
37
65.676
59.222
8.853
1.00
20.44
A
C

ATOM
288
C
ASN
A
37
66.852
59.444
7.907
1.00
17.40
A
C

ATOM
289
O
ASN
A
37
67.426
58.484
7.386
1.00
17.40
A
O

ATOM
290
CB
ASN
A
37
66.262
58.847
10.225
1.00
19.75
A
C

ATOM
291
CG
ASN
A
37
65.330
59.162
11.365
1.00
25.09
A
C

ATOM
292
OD1
ASN
A
37
65.323
60.288
11.888
1.00
26.01
A
O

ATOM
293
ND2
ASN
A
37
64.555
58.177
11.776
1.00
21.61
A
N

ATOM
294
N
PHE
A
38
67.217
60.704
7.697
1.00
18.60
A
N

ATOM
295
CA
PHE
A
38
68.450
61.064
7.013
1.00
17.76
A
C

ATOM
296
C
PHE
A
38
69.494
61.330
8.089
1.00
17.46
A
C

ATOM
297
O
PHE
A
38
69.356
62.288
8.837
1.00
18.26
A
O

ATOM
298
CB
PHE
A
38
68.236
62.307
6.143
1.00
17.46
A
C

ATOM
299
CG
PHE
A
38
69.466
62.776
5.366
1.00
18.60
A
C

ATOM
300
CD1
PHE
A
38
70.391
61.896
4.828
1.00
17.37
A
C

ATOM
301
CD2
PHE
A
38
69.657
64.124
5.127
1.00
24.93
A
C

ATOM
302
CE1
PHE
A
38
71.488
62.350
4.104
1.00
19.65
A
C

ATOM
303
CE2
PHE
A
38
70.747
64.586
4.384
1.00
19.49
A
C

ATOM
304
CZ
PHE
A
38
71.669
63.701
3.881
1.00
23.24
A
C

ATOM
305
N
ALA
A
39
70.467
60.430
8.224
1.00
18.71
A
N

ATOM
306
CA
ALA
A
39
71.480
60.508
9.272
1.00
18.80
A
C

ATOM
307
C
ALA
A
39
72.866
60.348
8.667
1.00
20.90
A
C

ATOM
308
O
ALA
A
39
73.104
59.439
7.862
1.00
20.32
A
O

ATOM
309
CB
ALA
A
39
71.225
59.457
10.334
1.00
17.93
A
C

ATOM
310
N
VAL
A
40
73.792
61.223
9.058
1.00
19.20
A
N

ATOM
311
CA
VAL
A
40
75.145
61.189
8.526
1.00
18.03
A
C

ATOM
312
C
VAL
A
40
76.193
61.242
9.640
1.00
18.42
A
C

ATOM
313
O
VAL
A
40
76.027
61.985
10.580
1.00
15.83
A
O

ATOM
314
CB
VAL
A
40
75.398
62.372
7.587
1.00
19.32
A
C

ATOM
315
CG1
VAL
A
40
74.430
62.354
6.382
1.00
24.72
A
C

ATOM
316
CG2
VAL
A
40
75.304
63.711
8.319
1.00
25.33
A
C

ATOM
317
N
GLY
A
41
77.272
60.490
9.488
1.00
18.41
A
N

ATOM
318
CA
GLY
A
41
78.444
60.626
10.354
1.00
13.03
A
C

ATOM
319
C
GLY
A
41
78.921
62.049
10.463
1.00
16.57
A
C

ATOM
320
O
GLY
A
41
78.986
62.780
9.486
1.00
16.35
A
O

ATOM
321
N
ALA
A
42
79.186
62.482
11.688
1.00
18.46
A
N

ATOM
322
CA
ALA
A
42
79.513
63.880
11.952
1.00
16.09
A
C

ATOM
323
C
ALA
A
42
80.745
63.987
12.843
1.00
21.94
A
C

ATOM
324
O
ALA
A
42
81.068
65.059
13.334
1.00
21.99
A
O

ATOM
325
CB
ALA
A
42
78.326
64.558
12.613
1.00
19.21
A
C

ATOM
326
N
ALA
A
43
81.444
62.873
12.985
1.00
17.43
A
N

ATOM
327
CA
ALA
A
43
82.584
62.752
13.899
1.00
19.03
A
C

ATOM
328
C
ALA
A
43
83.590
61.822
13.222
1.00
22.11
A
C

ATOM
329
O
ALA
A
43
83.186
60.977
12.414
1.00
18.84
A
O

ATOM
330
CB
ALA
A
43
82.131
62.185
15.216
1.00
20.66
A
C

ATOM
331
N
PRO
A
44
84.880
61.964
13.530
1.00
21.75
A
N

ATOM
332
CA
PRO
A
44
85.928
61.128
12.903
1.00
22.99
A
C

ATOM
333
C
PRO
A
44
86.039
59.692
13.422
1.00
21.03
A
C

ATOM
334
O
PRO
A
44
87.044
59.283
13.989
1.00
22.42
A
O

ATOM
335
CB
PRO
A
44
87.204
61.930
13.173
1.00
23.97
A
C

ATOM
336
CG
PRO
A
44
86.923
62.655
14.467
1.00
21.28
A
C

ATOM
337
CD
PRO
A
44
85.466
63.000
14.406
1.00
22.65
A
C

ATOM
338
N
HIS
A
45
85.004
58.904
13.175
1.00
19.15
A
N

ATOM
339
CA
HIS
A
45
85.011
57.491
13.493
1.00
19.87
A
C

ATOM
340
C
HIS
A
45
86.074
56.884
12.559
1.00
23.49
A
C

ATOM
341
O
HIS
A
45
86.161
57.279
11.408
1.00
18.76
A
O

ATOM
342
CB
HIS
A
45
83.600
56.898
13.231
1.00
20.18
A
C

ATOM
343
CG
HIS
A
45
83.499
55.426
13.491
1.00
20.56
A
C

ATOM
344
ND1
HIS
A
45
82.921
54.900
14.628
1.00
27.21
A
N

ATOM
345
CD2
HIS
A
45
83.911
54.369
12.753
1.00
20.97
A
C

ATOM
346
CE1
HIS
A
45
82.989
53.579
14.577
1.00
20.15
A
C

ATOM
347
NE2
HIS
A
45
83.572
53.234
13.443
1.00
26.79
A
N

ATOM
348
N
PRO
A
46
86.900
55.958
13.039
1.00
23.59
A
N

ATOM
349
CA
PRO
A
46
87.999
55.418
12.221
1.00
26.27
A
C

ATOM
350
C
PRO
A
46
87.618
54.722
10.881
1.00
23.39
A
C

ATOM
351
O
PRO
A
46
88.449
54.679
9.975
1.00
27.08
A
O

ATOM
352
CB
PRO
A
46
88.677
54.416
13.175
1.00
24.42
A
C

ATOM
353
CG
PRO
A
46
87.621
54.034
14.147
1.00
27.39
A
C

ATOM
354
CD
PRO
A
46
86.863
55.335
14.378
1.00
25.05
A
C

ATOM
355
N
PHE
A
47
86.410
54.192
10.783
1.00
25.26
A
N

ATOM
356
CA
PHE
A
47
85.924
53.538
9.560
1.00
25.03
A
C

ATOM
357
C
PHE
A
47
85.523
54.517
8.446
1.00
22.84
A
C

ATOM
358
O
PHE
A
47
85.309
54.084
7.325
1.00
25.36
A
O

ATOM
359
CB
PHE
A
47
84.678
52.671
9.832
1.00
27.84
A
C

ATOM
360
CG
PHE
A
47
84.888
51.503
10.769
1.00
32.30
A
C

ATOM
361
CD1
PHE
A
47
86.141
51.176
11.282
1.00
36.05
A
C

ATOM
362
CD2
PHE
A
47
83.794
50.722
11.134
1.00
35.59
A
C

ATOM
363
CE1
PHE
A
47
86.297
50.098
12.133
1.00
32.80
A
C

ATOM
364
CE2
PHE
A
47
83.945
49.635
12.004
1.00
36.20
A
C

ATOM
365
CZ
PHE
A
47
85.197
49.326
12.489
1.00
37.31
A
C

ATOM
366
N
LEU
A
48
85.377
55.804
8.761
1.00
19.13
A
N

ATOM
367
CA
LEU
A
48
84.818
56.789
7.835
1.00
18.71
A
C

ATOM
368
C
LEU
A
48
85.829
57.499
6.963
1.00
22.04
A
C

ATOM
369
O
LEU
A
48
86.798
58.086
7.451
1.00
22.43
A
O

ATOM
370
CB
LEU
A
48
84.019
57.848
8.602
1.00
17.69
A
C

ATOM
371
CG
LEU
A
48
82.797
57.361
9.367
1.00
14.97
A
C

ATOM
372
CD1
LEU
A
48
82.068
58.567
9.926
1.00
18.29
A
C

ATOM
373
CD2
LEU
A
48
81.839
56.567
8.517
1.00
19.80
A
C

ATOM
374
N
HIS
A
49
85.553
57.517
5.666
1.00
19.90
A
N

ATOM
375
CA
HIS
A
49
86.310
58.348
4.715
1.00
23.16
A
C

ATOM
376
C
HIS
A
49
86.115
59.862
4.903
1.00
23.74
A
C

ATOM
377
O
HIS
A
49
87.033
60.658
4.676
1.00
24.96
A
O

ATOM
378
CB
HIS
A
49
85.901
58.027
3.277
1.00
24.78
A
C

ATOM
379
CG
HIS
A
49
86.253
56.648
2.822
1.00
18.81
A
C

ATOM
380
ND1
HIS
A
49
87.368
56.386
2.054
1.00
23.64
A
N

ATOM
381
CD2
HIS
A
49
85.623
55.463
2.989
1.00
17.53
A
C

ATOM
382
CE1
HIS
A
49
87.408
55.095
1.779
1.00
20.49
A
C

ATOM
383
NE2
HIS
A
49
86.361
54.512
2.331
1.00
25.00
A
N

ATOM
384
N
ARG
A
50
84.900
60.274
5.255
1.00
23.13
A
N

ATOM
385
CA
ARG
A
50
84.603
61.682
5.496
1.00
24.92
A
C

ATOM
386
C
ARG
A
50
83.387
61.768
6.398
1.00
22.50
A
C

ATOM
387
O
ARG
A
50
82.761
60.763
6.692
1.00
20.11
A
O

ATOM
388
CB
ARG
A
50
84.335
62.435
4.200
1.00
31.00
A
C

ATOM
389
CG
ARG
A
50
84.028
61.549
3.065
1.00
30.52
A
C

ATOM
390
CD
ARG
A
50
83.871
62.231
1.758
1.00
33.45
A
C

ATOM
391
NE
ARG
A
50
83.103
61.374
0.862
1.00
35.30
A
N

ATOM
392
CZ
ARG
A
50
82.912
61.613
−0.430
1.00
41.98
A
C

ATOM
393
NH1
ARG
A
50
83.440
62.692
−1.000
1.00
41.62
A
N

ATOM
394
NH2
ARG
A
50
82.188
60.765
−1.159
1.00
41.63
A
N

ATOM
395
N
TYR
A
51
83.097
62.978
6.868
1.00
19.69
A
N

ATOM
396
CA
TYR
A
51
81.968
63.193
7.727
1.00
19.01
A
C

ATOM
397
C
TYR
A
51
81.513
64.641
7.644
1.00
17.45
A
C

ATOM
398
O
TYR
A
51
82.257
65.509
7.198
1.00
19.82
A
O

ATOM
399
CB
TYR
A
51
82.305
62.792
9.175
1.00
17.00
A
C

ATOM
400
CG
TYR
A
51
83.594
63.414
9.694
1.00
19.81
A
C

ATOM
401
CD1
TYR
A
51
84.807
62.799
9.494
1.00
22.49
A
C

ATOM
402
CD2
TYR
A
51
83.574
64.625
10.391
1.00
27.51
A
C

ATOM
403
CE1
TYR
A
51
85.996
63.363
9.962
1.00
29.01
A
C

ATOM
404
CE2
TYR
A
51
84.755
65.198
10.853
1.00
22.34
A
C

ATOM
405
CZ
TYR
A
51
85.959
64.561
10.639
1.00
26.38
A
C

ATOM
406
OH
TYR
A
51
87.153
65.103
11.102
1.00
27.75
A
O

ATOM
407
N
TYR
A
52
80.267
64.861
8.039
1.00
16.76
A
N

ATOM
408
CA
TYR
A
52
79.630
66.167
8.044
1.00
15.41
A
C

ATOM
409
C
TYR
A
52
80.251
67.057
9.094
1.00
18.19
A
C

ATOM
410
O
TYR
A
52
80.252
66.703
10.268
1.00
18.86
A
O

ATOM
411
CB
TYR
A
52
78.163
65.968
8.360
1.00
16.96
A
C

ATOM
412
CG
TYR
A
52
77.241
67.158
8.365
1.00
17.78
A
C

ATOM
413
CD1
TYR
A
52
77.491
68.311
7.617
1.00
19.54
A
C

ATOM
414
CD2
TYR
A
52
76.057
67.095
9.075
1.00
20.48
A
C

ATOM
415
CE1
TYR
A
52
76.608
69.378
7.664
1.00
17.41
A
C

ATOM
416
CE2
TYR
A
52
75.160
68.137
9.089
1.00
21.75
A
C

ATOM
417
CZ
TYR
A
52
75.443
69.280
8.373
1.00
20.07
A
C

ATOM
418
OH
TYR
A
52
74.507
70.291
8.424
1.00
24.27
A
O

ATOM
419
N
GLN
A
53
80.748
68.214
8.671
1.00
21.06
A
N

ATOM
420
CA
GLN
A
53
81.372
69.186
9.580
1.00
22.83
A
C

ATOM
421
C
GLN
A
53
80.474
70.420
9.662
1.00
18.33
A
C

ATOM
422
O
GLN
A
53
80.601
71.340
8.878
1.00
23.76
A
O

ATOM
423
CB
GLN
A
53
82.779
69.535
9.079
1.00
22.30
A
C

ATOM
424
CG
GLN
A
53
83.750
68.353
9.108
1.00
24.84
A
C

ATOM
425
CD
GLN
A
53
85.187
68.690
8.695
1.00
31.20
A
C

ATOM
426
OE1
GLN
A
53
85.490
68.915
7.504
1.00
32.31
A
O

ATOM
427
NE2
GLN
A
53
86.080
68.696
9.671
1.00
27.07
A
N

ATOM
428
N
ARG
A
54
79.537
70.385
10.597
1.00
20.86
A
N

ATOM
429
CA
ARG
A
54
78.545
71.442
10.758
1.00
21.52
A
C

ATOM
430
C
ARG
A
54
79.164
72.827
10.939
1.00
25.15
A
C

ATOM
431
O
ARG
A
54
78.568
73.828
10.536
1.00
26.20
A
O

ATOM
432
CB
ARG
A
54
77.629
71.138
11.918
1.00
21.46
A
C

ATOM
433
CG
ARG
A
54
76.652
69.995
11.655
1.00
22.36
A
C

ATOM
434
CD
ARG
A
54
75.989
69.437
12.869
1.00
24.51
A
C

ATOM
435
NE
ARG
A
54
76.919
68.779
13.780
1.00
20.24
A
N

ATOM
436
CZ
ARG
A
54
76.609
68.376
14.997
1.00
23.34
A
C

ATOM
437
NH1
ARG
A
54
75.389
68.574
15.485
1.00
26.99
A
N

ATOM
438
NH2
ARG
A
54
77.534
67.786
15.739
1.00
21.22
A
N

ATOM
439
N
GLN
A
55
80.362
72.880
11.523
1.00
25.18
A
N

ATOM
440
CA
GLN
A
55
81.055
74.153
11.741
1.00
25.49
A
C

ATOM
441
C
GLN
A
55
81.403
74.886
10.453
1.00
27.22
A
C

ATOM
442
O
GLN
A
55
81.623
76.106
10.471
1.00
31.96
A
O

ATOM
443
CB
GLN
A
55
82.342
73.951
12.586
1.00
25.44
A
C

ATOM
444
CG
GLN
A
55
83.508
73.285
11.866
1.00
26.87
A
C

ATOM
445
CD
GLN
A
55
83.607
71.787
12.100
1.00
22.47
A
C

ATOM
446
OE1
GLN
A
55
84.649
71.186
11.858
1.00
28.14
A
O

ATOM
447
NE2
GLN
A
55
82.531
71.192
12.526
1.00
19.06
A
N

ATOM
448
N
LEU
A
56
81.478
74.148
9.347
1.00
26.29
A
N

ATOM
449
CA
LEU
A
56
81.846
74.711
8.055
1.00
26.09
A
C

ATOM
450
C
LEU
A
56
80.646
75.193
7.224
1.00
28.01
A
C

ATOM
451
O
LEU
A
56
80.835
75.716
6.131
1.00
30.64
A
O

ATOM
452
CB
LEU
A
56
82.667
73.703
7.251
1.00
28.42
A
C

ATOM
453
CG
LEU
A
56
83.966
73.147
7.849
1.00
29.81
A
C

ATOM
454
CD1
LEU
A
56
84.685
72.309
6.814
1.00
33.56
A
C

ATOM
455
CD2
LEU
A
56
84.896
74.243
8.364
1.00
28.02
A
C

ATOM
456
N
SER
A
57
79.432
75.055
7.760
1.00
27.95
A
N

ATOM
457
CA
SER
A
57
78.199
75.322
7.009
1.00
27.26
A
C

ATOM
458
C
SER
A
57
77.432
76.528
7.548
1.00
26.45
A
C

ATOM
459
O
SER
A
57
76.970
76.523
8.701
1.00
27.40
A
O

ATOM
460
CB
SER
A
57
77.287
74.086
7.037
1.00
27.30
A
C

ATOM
461
OG
SER
A
57
76.004
74.353
6.482
1.00
24.82
A
O

ATOM
462
N
SER
A
58
77.250
77.541
6.704
1.00
31.30
A
N

ATOM
463
CA
SER
A
58
76.540
78.753
7.112
1.00
33.18
A
C

ATOM
464
C
SER
A
58
75.049
78.502
7.294
1.00
33.96
A
C

ATOM
465
O
SER
A
58
74.367
79.198
8.059
1.00
31.39
A
O

ATOM
466
CB
SER
A
58
76.761
79.879
6.097
1.00
35.14
A
C

ATOM
467
OG
SER
A
58
76.449
79.481
4.769
1.00
35.98
A
O

ATOM
468
N
THR
A
59
74.552
77.473
6.608
1.00
31.44
A
N

ATOM
469
CA
THR
A
59
73.128
77.222
6.528
1.00
28.82
A
C

ATOM
470
C
THR
A
59
72.637
76.209
7.545
1.00
27.75
A
C

ATOM
471
O
THR
A
59
71.431
75.989
7.648
1.00
26.38
A
O

ATOM
472
CB
THR
A
59
72.745
76.825
5.079
1.00
30.74
A
C

ATOM
473
OG1
THR
A
59
73.712
75.937
4.512
1.00
26.79
A
O

ATOM
474
CG2
THR
A
59
72.851
78.040
4.175
1.00
31.50
A
C

ATOM
475
N
TYR
A
60
73.559
75.630
8.325
1.00
25.76
A
N

ATOM
476
CA
TYR
A
60
73.204
74.716
9.405
1.00
27.01
A
C

ATOM
477
C
TYR
A
60
72.359
75.391
10.487
1.00
30.17
A
C

ATOM
478
O
TYR
A
60
72.671
76.504
10.908
1.00
32.85
A
O

ATOM
479
CB
TYR
A
60
74.475
74.108
10.024
1.00
29.24
A
C

ATOM
480
CG
TYR
A
60
74.208
73.401
11.319
1.00
32.58
A
C

ATOM
481
CD1
TYR
A
60
73.616
72.137
11.341
1.00
33.45
A
C

ATOM
482
CD2
TYR
A
60
74.507
74.016
12.539
1.00
35.22
A
C

ATOM
483
CE1
TYR
A
60
73.344
71.495
12.545
1.00
34.91
A
C

ATOM
484
CE2
TYR
A
60
74.242
73.384
13.741
1.00
35.99
A
C

ATOM
485
CZ
TYR
A
60
73.661
72.128
13.739
1.00
36.24
A
C

ATOM
486
OH
TYR
A
60
73.406
71.510
14.936
1.00
40.70
A
O

ATOM
487
N
ARG
A
61
71.302
74.710
10.934
1.00
29.78
A
N

ATOM
488
CA
ARG
A
61
70.489
75.137
12.074
1.00
32.29
A
C

ATOM
489
C
ARG
A
61
70.289
73.992
13.056
1.00
35.05
A
C

ATOM
490
O
ARG
A
61
69.781
72.931
12.695
1.00
33.45
A
O

ATOM
491
CB
ARG
A
61
69.113
75.638
11.635
1.00
34.98
A
C

ATOM
492
CG
ARG
A
61
69.146
76.790
10.663
1.00
33.55
A
C

ATOM
493
CD
ARG
A
61
67.756
77.209
10.187
1.00
39.45
A
C

ATOM
494
NE
ARG
A
61
67.802
78.053
8.991
1.00
43.50
A
N

ATOM
495
CZ
ARG
A
61
66.737
78.400
8.267
1.00
43.32
A
C

ATOM
496
NH1
ARG
A
61
65.517
77.969
8.591
1.00
43.64
A
N

ATOM
497
NH2
ARG
A
61
66.896
79.173
7.201
1.00
43.55
A
N

ATOM
498
N
ASP
A
62
70.681
74.222
14.302
1.00
32.81
A
N

ATOM
499
CA
ASP
A
62
70.488
73.277
15.385
1.00
34.32
A
C

ATOM
500
C
ASP
A
62
69.019
73.222
15.812
1.00
35.83
A
C

ATOM
501
O
ASP
A
62
68.368
74.257
15.972
1.00
37.43
A
O

ATOM
502
CB
ASP
A
62
71.385
73.703
16.561
1.00
36.21
A
C

ATOM
503
CG
ASP
A
62
71.724
72.567
17.509
1.00
37.73
A
C

ATOM
504
OD1
ASP
A
62
71.078
71.513
17.462
1.00
39.38
A
O

ATOM
505
OD2
ASP
A
62
72.632
72.654
18.366
1.00
38.06
A
O

ATOM
506
N
LEU
A
63
68.504
72.009
16.000
1.00
32.04
A
N

ATOM
507
CA
LEU
A
63
67.151
71.799
16.496
1.00
33.21
A
C

ATOM
508
C
LEU
A
63
67.155
71.580
18.003
1.00
31.37
A
C

ATOM
509
O
LEU
A
63
66.108
71.522
18.621
1.00
33.62
A
O

ATOM
510
CB
LEU
A
63
66.489
70.603
15.793
1.00
32.30
A
C

ATOM
511
CG
LEU
A
63
65.919
70.957
14.417
1.00
37.47
A
C

ATOM
512
CD1
LEU
A
63
65.566
69.688
13.604
1.00
37.52
A
C

ATOM
513
CD2
LEU
A
63
64.696
71.880
14.549
1.00
37.36
A
C

ATOM
514
N
ARG
A
64
68.345
71.460
18.580
1.00
34.84
A
N

ATOM
515
CA
ARG
A
64
68.514
71.279
20.012
1.00
34.85
A
C

ATOM
516
C
ARG
A
64
67.687
70.109
20.516
1.00
37.89
A
C

ATOM
517
O
ARG
A
64
66.925
70.220
21.474
1.00
37.04
A
O

ATOM
518
CB
ARG
A
64
68.180
72.583
20.753
1.00
37.97
A
C

ATOM
519
CG
ARG
A
64
68.865
73.821
20.152
1.00
37.97
A
C

ATOM
520
CD
ARG
A
64
68.726
75.089
21.000
1.00
41.38
A
C

ATOM
521
NE
ARG
A
64
69.447
74.699
22.367
0.00
47.96
A
N

ATOM
522
CZ
ARG
A
64
69.722
75.629
23.275
0.00
49.03
A
C

ATOM
523
NH1
ARG
A
64
69.491
76.907
23.009
0.00
49.64
A
N

ATOM
524
NH2
ARG
A
64
70.226
75.281
24.451
0.00
49.89
A
N

ATOM
525
N
LYS
A
65
67.844
68.973
19.843
1.00
34.71
A
N

ATOM
526
CA
LYS
A
65
67.212
67.732
20.266
1.00
35.06
A
C

ATOM
527
C
LYS
A
65
68.076
66.577
19.771
1.00
30.42
A
C

ATOM
528
O
LYS
A
65
68.655
66.665
18.695
1.00
31.69
A
O

ATOM
529
CB
LYS
A
65
65.801
67.642
19.676
1.00
39.80
A
C

ATOM
530
CG
LYS
A
65
64.967
66.448
20.138
1.00
43.42
A
C

ATOM
531
CD
LYS
A
65
63.513
66.564
19.672
1.00
47.97
A
C

ATOM
532
CE
LYS
A
65
62.653
65.440
20.263
1.00
50.01
A
C

ATOM
533
NZ
LYS
A
65
61.233
65.463
19.797
1.00
51.34
A
N

ATOM
534
N
GLY
A
66
68.190
65.522
20.565
1.00
31.22
A
N

ATOM
535
CA
GLY
A
66
68.910
64.339
20.149
1.00
31.55
A
C

ATOM
536
C
GLY
A
66
67.996
63.249
19.616
1.00
32.06
A
C

ATOM
537
O
GLY
A
66
66.772
63.399
19.632
1.00
33.71
A
O

ATOM
538
N
VAL
A
67
68.617
62.153
19.163
1.00
30.61
A
N

ATOM
539
CA
VAL
A
67
67.927
60.946
18.675
1.00
32.04
A
C

ATOM
540
C
VAL
A
67
68.756
59.693
18.978
1.00
32.39
A
C

ATOM
541
O
VAL
A
67
69.982
59.724
18.870
1.00
29.49
A
O

ATOM
542
CB
VAL
A
67
67.663
61.024
17.158
1.00
34.97
A
C

ATOM
543
CG1
VAL
A
67
66.568
61.988
16.878
1.00
40.45
A
C

ATOM
544
CG2
VAL
A
67
68.912
61.440
16.387
1.00
36.19
A
C

ATOM
545
N
TYR
A
68
68.108
58.602
19.384
1.00
32.50
A
N

ATOM
546
CA
TYR
A
68
68.817
57.361
19.709
1.00
36.46
A
C

ATOM
547
C
TYR
A
68
68.113
56.190
19.062
1.00
34.88
A
C

ATOM
548
O
TYR
A
68
66.962
55.916
19.383
1.00
36.97
A
O

ATOM
549
CB
TYR
A
68
68.902
57.148
21.229
1.00
36.07
A
C

ATOM
550
CG
TYR
A
68
69.801
55.993
21.670
1.00
41.81
A
C

ATOM
551
CD1
TYR
A
68
69.460
54.665
21.395
1.00
43.38
A
C

ATOM
552
CD2
TYR
A
68
70.981
56.226
22.379
1.00
44.20
A
C

ATOM
553
CE1
TYR
A
68
70.274
53.605
21.798
1.00
43.39
A
C

ATOM
554
CE2
TYR
A
68
71.805
55.167
22.789
1.00
44.55
A
C

ATOM
555
CZ
TYR
A
68
71.444
53.863
22.492
1.00
45.41
A
C

ATOM
556
OH
TYR
A
68
72.242
52.807
22.897
1.00
47.48
A
O

ATOM
557
N
VAL
A
69
68.826
55.477
18.196
1.00
33.48
A
N

ATOM
558
CA
VAL
A
69
68.249
54.404
17.376
1.08
34.57
A
C

ATOM
559
C
VAL
A
69
68.922
53.080
17.716
1.00
34.34
A
C

ATOM
560
O
VAL
A
69
69.996
52.793
17.192
1.00
28.53
A
O

ATOM
561
CB
VAL
A
69
68.440
54.691
15.866
1.00
35.13
A
C

ATOM
562
CG1
VAL
A
69
67.944
53.526
15.002
1.00
38.45
A
C

ATOM
563
CG2
VAL
A
69
67.754
56.000
15.484
1.00
36.74
A
C

ATOM
564
N
PRO
A
70
68.319
52.269
18.588
1.00
39.88
A
N

ATOM
565
CA
PRO
A
70
68.846
50.922
18.830
1.00
43.50
A
C

ATOM
566
C
PRO
A
70
68.577
50.028
17.629
1.00
47.11
A
C

ATOM
567
O
PRO
A
70
67.551
50.175
16.960
1.00
41.77
A
O

ATOM
568
CB
PRO
A
70
68.097
50.428
20.077
1.00
44.42
A
C

ATOM
569
CG
PRO
A
70
67.031
51.423
20.368
1.00
43.58
A
C

ATOM
570
CD
PRO
A
70
67.125
52.554
19.397
1.00
42.11
A
C

ATOM
571
N
TYR
A
71
69.527
49.140
17.367
1.00
51.98
A
N

ATOM
572
CA
TYR
A
71
69.474
48.179
16.276
1.00
56.73
A
C

ATOM
573
C
TYR
A
71
69.683
46.796
16.908
1.00
58.39
A
C

ATOM
574
O
TYR
A
71
69.428
46.618
18.105
1.00
57.75
A
O

ATOM
575
CB
TYR
A
71
70.558
48.519
15.229
1.00
57.66
A
C

ATOM
576
CG
TYR
A
71
70.091
49.405
14.090
1.00
59.91
A
C

ATOM
577
CD1
TYR
A
71
70.760
50.591
13.779
1.00
60.36
A
C

ATOM
578
CD2
TYR
A
71
68.995
49.049
13.304
1.00
61.59
A
C

ATOM
579
CE1
TYR
A
71
70.334
51.408
12.725
1.00
60.84
A
C

ATOM
580
CE2
TYR
A
71
68.568
49.857
12.249
1.00
62.07
A
C

ATOM
581
CZ
TYR
A
71
69.241
51.035
11.966
1.00
63.27
A
C

ATOM
582
OH
TYR
A
71
68.818
51.840
10.924
1.00
64.04
A
O

ATOM
583
N
THR
A
72
70.147
45.832
16.114
1.00
61.01
A
N

ATOM
584
CA
THR
A
72
70.319
44.444
16.556
1.00
60.90
A
C

ATOM
585
C
THR
A
72
71.093
44.294
17.877
1.00
59.74
A
C

ATOM
586
O
THR
A
72
70.491
44.060
18.931
1.00
58.04
A
O

ATOM
587
CB
THR
A
72
70.993
43.609
15.431
1.00
62.06
A
C

ATOM
588
OG1
THR
A
72
72.170
44.276
14.951
1.00
61.28
A
O

ATOM
589
CG2
THR
A
72
70.090
43.514
14.196
1.00
63.15
A
C

ATOM
590
N
GLN
A
73
72.418
44.402
17.800
1.00
57.85
A
N

ATOM
591
CA
GLN
A
73
73.287
44.461
18.971
1.00
57.41
A
C

ATOM
592
C
GLN
A
73
74.155
45.726
18.850
1.00
54.83
A
C

ATOM
593
O
GLN
A
73
75.303
45.747
19.299
1.00
57.07
A
O

ATOM
594
CB
GLN
A
73
74.153
43.194
19.060
1.00
58.83
A
C

ATOM
595
CG
GLN
A
73
73.865
42.294
20.273
1.00
60.65
A
C

ATOM
596
CD
GLN
A
73
74.720
42.630
21.504
1.00
63.27
A
C

ATOM
597
OE1
GLN
A
73
75.959
42.582
21.450
1.00
61.11
A
O

ATOM
598
NE2
GLN
A
73
74.058
42.943
22.619
1.00
61.34
A
N

ATOM
599
N
GLY
A
74
73.591
46.763
18.223
1.00
48.16
A
N

ATOM
600
CA
GLY
A
74
74.262
48.041
18.020
1.00
42.89
A
C

ATOM
601
C
GLY
A
74
73.290
49.214
18.016
1.00
38.35
A
C

ATOM
602
O
GLY
A
74
72.224
49.115
18.625
1.00
39.09
A
O

ATOM
603
N
LYS
A
75
73.656
50.320
17.360
1.00
32.71
A
N

ATOM
604
CA
LYS
A
75
72.844
51.554
17.362
1.00
31.39
A
C

ATOM
605
C
LYS
A
75
73.525
52.762
16.664
1.00
24.85
A
C

ATOM
606
O
LYS
A
75
74.685
52.698
16.338
1.00
21.55
A
O

ATOM
607
CB
LYS
A
75
72.483
51.946
18.800
1.00
34.61
A
C

ATOM
608
CG
LYS
A
75
73.667
52.144
19.731
1.00
39.32
A
C

ATOM
609
CD
LYS
A
75
74.545
53.318
19.299
1.00
39.96
A
C

ATOM
610
CE
LYS
A
75
75.034
54.144
20.451
1.00
40.91
A
C

ATOM
611
NZ
LYS
A
75
74.297
55.407
20.464
1.00
45.34
A
N

ATOM
612
N
TRP
A
76
72.782
53.843
16.434
1.00
22.44
A
N

ATOM
613
CA
TRP
A
76
73.372
55.173
16.224
1.00
25.02
A
C

ATOM
614
C
TRP
A
76
72.594
56.201
17.012
1.00
23.16
A
C

ATOM
615
O
TRP
A
76
71.429
56.007
17.353
1.00
21.34
A
O

ATOM
616
CB
TRP
A
76
73.512
55.570
14.732
1.00
24.36
A
C

ATOM
617
CG
TRP
A
76
72.243
55.752
13.957
1.00
25.79
A
C

ATOM
618
CD1
TRP
A
76
71.643
54.833
13.136
1.00
26.34
A
C

ATOM
619
CD2
TRP
A
76
71.424
56.932
13.896
1.00
21.29
A
C

ATOM
620
NE1
TRP
A
76
70.491
55.364
12.595
1.00
27.23
A
N

ATOM
621
CE2
TRP
A
76
70.348
56.656
13.030
1.00
25.91
A
C

ATOM
622
CE3
TRP
A
76
71.497
58.202
14.479
1.00
24.01
A
C

ATOM
623
CZ2
TRP
A
76
69.349
57.595
12.752
1.00
26.87
A
C

ATOM
624
CZ3
TRP
A
76
70.512
59.124
14.202
1.00
26.34
A
C

ATOM
625
CH2
TRP
A
76
69.448
58.818
13.345
1.00
25.94
A
C

ATOM
626
N
GLU
A
77
73.291
57.271
17.354
1.00
22.20
A
N

ATOM
627
CA
GLU
A
77
72.753
58.327
18.164
1.00
24.84
A
C

ATOM
628
C
GLU
A
77
73.255
59.632
17.575
1.00
22.78
A
C

ATOM
629
O
GLU
A
77
74.386
59.723
17.089
1.00
19.61
A
O

ATOM
630
CB
GLU
A
77
73.214
58.140
19.621
1.00
28.88
A
C

ATOM
631
CG
GLU
A
77
72.959
59.331
20.529
1.00
35.35
A
C

ATOM
632
CD
GLU
A
77
73.323
59.057
21.980
0.50
36.38
A
C

ATOM
633
OE1
GLU
A
77
74.397
58.470
22.222
0.50
42.18
A
O

ATOM
634
OE2
GLU
A
77
72.536
59.431
22.878
0.50
39.02
A
O

ATOM
635
N
GLY
A
78
72.418
60.651
17.573
1.00
24.09
A
N

ATOM
636
CA
GLY
A
78
72.811
61.883
16.933
1.00
25.68
A
C

ATOM
637
C
GLY
A
78
72.160
63.134
17.453
1.00
25.43
A
C

ATOM
638
O
GLY
A
78
71.328
63.116
18.350
1.00
27.93
A
O

ATOM
639
N
GLU
A
79
72.579
64.234
16.861
1.00
23.79
A
N

ATOM
640
CA
GLU
A
79
72.078
65.542
17.187
1.00
23.88
A
C

ATOM
641
C
GLU
A
79
71.283
65.981
15.979
1.00
22.32
A
C

ATOM
642
O
GLU
A
79
71.800
65.979
14.875
1.00
26.62
A
O

ATOM
643
CB
GLU
A
79
73.255
66.487
17.457
1.00
23.99
A
C

ATOM
644
CG
GLU
A
79
74.109
66.052
18.641
1.00
29.60
A
C

ATOM
645
CD
GLU
A
79
75.420
66.826
18.790
1.00
33.85
A
C

ATOM
646
OE1
GLU
A
79
76.205
66.467
19.685
1.00
34.63
A
O

ATOM
647
OE2
GLU
A
79
75.670
67.782
18.030
1.00
37.21
A
O

ATOM
648
N
LEU
A
80
70.017
66.338
16.180
1.00
22.69
A
N

ATOM
649
CA
LEU
A
80
69.184
66.809
15.075
1.00
24.78
A
C

ATOM
650
C
LEU
A
80
69.419
68.267
14.685
1.00
26.56
A
C

ATOM
651
O
LEU
A
80
69.596
69.139
15.528
1.00
26.06
A
O

ATOM
652
CB
LEU
A
80
67.704
66.617
15.403
1.00
26.07
A
C

ATOM
653
CG
LEU
A
80
67.233
65.168
15.432
1.00
31.35
A
C

ATOM
654
CD1
LEU
A
80
65.863
65.082
16.077
1.00
28.71
A
C

ATOM
655
CD2
LEU
A
80
67.212
64.609
14.015
1.00
32.32
A
C

ATOM
656
N
GLY
A
81
69.390
68.525
13.383
1.00
23.46
A
N

ATOM
657
CA
GLY
A
81
69.500
69.861
12.822
1.00
22.46
A
C

ATOM
658
C
GLY
A
81
68.854
69.916
11.448
1.00
26.63
A
C

ATOM
659
O
GLY
A
81
68.308
68.927
11.002
1.00
22.44
A
O

ATOM
660
N
THR
A
82
68.884
71.065
10.787
1.00
26.31
A
N

ATOM
661
CA
THR
A
82
68.530
71.138
9.369
1.00
28.52
A
C

ATOM
662
C
THR
A
82
69.634
71.813
8.631
1.00
25.22
A
C

ATOM
663
O
THR
A
82
70.436
72.529
9.225
1.00
27.82
A
O

ATOM
664
CB
THR
A
82
67.190
71.888
9.127
1.00
29.47
A
C

ATOM
665
OG1
THR
A
82
67.310
73.253
9.554
1.00
27.90
A
O

ATOM
666
CG2
THR
A
62
66.069
71.306
9.972
1.00
30.70
A
C

ATOM
667
N
ASP
A
83
69.704
71.567
7.326
1.00
24.75
A
N

ATOM
668
CA
ASP
A
83
70.679
72.180
6.447
1.00
22.11
A
C

ATOM
669
C
ASP
A
83
70.241
71.993
5.009
1.00
24.09
A
C

ATOM
670
O
ASP
A
83
69.261
71.285
4.741
1.00
26.17
A
O

ATOM
671
CB
ASP
A
83
72.075
71.559
6.652
1.00
24.10
A
C

ATOM
672
CG
ASP
A
83
73.213
72.542
6.376
1.00
26.19
A
C

ATOM
673
OD1
ASP
A
83
73.067
73.513
5.580
1.00
27.95
A
O

ATOM
674
OD2
ASP
A
83
74.328
72.409
6.924
1.00
25.64
A
O

ATOM
675
N
LEU
A
84
70.973
72.591
4.081
1.00
26.89
A
N

ATOM
676
CA
LEU
A
84
70.641
72.502
2.658
1.00
27.35
A
C

ATOM
677
C
LEU
A
84
71.224
71.225
2.078
1.00
28.51
A
C

ATOM
678
O
LEU
A
84
72.398
70.936
2.266
1.00
25.25
A
O

ATOM
679
CB
LEU
A
84
71.193
73.717
1.915
1.00
29.63
A
C

ATOM
680
CG
LEU
A
84
70.550
75.047
2.345
1.00
31.38
A
C

ATOM
681
CD1
LEU
A
84
71.025
76.228
1.501
1.00
30.45
A
C

ATOM
682
CD2
LEU
A
84
69.027
74.949
2.301
1.00
30.98
A
C

ATOM
683
N
VAL
A
85
70.392
70.465
1.373
1.00
25.49
A
N

ATOM
684
CA
VAL
A
85
70.790
69.203
0.768
1.00
28.08
A
C

ATOM
685
C
VAL
A
85
70.523
69.177
−0.737
1.00
27.65
A
C

ATOM
686
O
VAL
A
85
69.511
69.686
−1.213
1.00
27.43
A
O

ATOM
687
CB
VAL
A
85
70.063
68.028
1.439
1.00
27.18
A
C

ATOM
688
CG1
VAL
A
85
70.564
66.696
0.875
1.00
27.97
A
C

ATOM
689
CG2
VAL
A
85
70.273
68.084
2.950
1.00
29.93
A
C

ATOM
690
N
SER
A
86
71.451
68.587
−1.472
1.00
28.67
A
N

ATOM
691
CA
SER
A
86
71.331
68.409
−2.913
1.00
30.97
A
C

ATOM
692
C
SER
A
86
71.823
67.015
−3.293
1.00
31.51
A
C

ATOM
693
O
SER
A
86
72.512
66.354
−2.509
1.00
25.69
A
O

ATOM
694
CB
SER
A
86
72.138
69.485
−3.642
1.00
33.70
A
C

ATOM
695
OG
SER
A
86
71.607
69.737
−4.930
1.00
42.01
A
O

ATOM
696
N
ILE
A
87
71.459
66.563
−4.494
1.00
24.97
A
N

ATOM
697
CA
ILE
A
87
71.895
65.277
−5.006
1.00
25.75
A
C

ATOM
698
C
ILE
A
87
72.489
65.559
−6.384
1.00
29.06
A
C

ATOM
699
O
ILE
A
87
71.737
65.734
−7.354
1.00
27.25
A
O

ATOM
700
CB
ILE
A
87
70.713
64.275
−5.094
1.00
25.77
A
C

ATOM
701
CG1
ILE
A
87
70.062
64.090
−3.729
1.00
26.43
A
C

ATOM
702
CG2
ILE
A
87
71.187
62.939
−5.631
1.00
23.43
A
C

ATOM
703
CD1
ILE
A
87
68.758
63.332
−3.747
1.00
29.21
A
C

ATOM
704
N
PRO
A
88
73.817
65.654
−6.453
1.00
29.18
A
N

ATOM
705
CA
PRO
A
88
74.531
66.013
−7.689
1.00
30.76
A
C

ATOM
706
C
PRO
A
88
74.063
65.286
−8.956
1.00
32.20
A
C

ATOM
707
O
PRO
A
88
73.924
65.938
−9.987
1.00
33.45
A
O

ATOM
708
CB
PRO
A
88
75.971
65.632
−7.358
1.00
31.55
A
C

ATOM
709
CG
PRO
A
88
76.067
65.895
−5.896
1.00
30.46
A
C

ATOM
710
CD
PRO
A
88
74.762
65.455
−5.339
1.00
28.40
A
C

ATOM
711
N
HIS
A
89
73.857
63.972
−8.872
1.00
27.36
A
N

ATOM
712
CA
HIS
A
89
73.332
63.162
−9.978
1.00
28.26
A
C

ATOM
713
C
HIS
A
89
71.871
62.815
−9.715
1.00
29.29
A
C

ATOM
714
O
HIS
A
89
71.449
61.661
−9.847
1.00
28.09
A
O

ATOM
715
CB
HIS
A
89
74.173
61.907
−10.160
1.00
28.17
A
C

ATOM
716
CG
HIS
A
89
75.632
62.184
−10.362
1.00
38.05
A
C

ATOM
717
ND1
HIS
A
89
76.120
62.833
−11.478
1.00
41.06
A
N

ATOM
718
CD2
HIS
A
89
76.708
61.905
−9.588
1.00
38.74
A
C

ATOM
719
CE1
HIS
A
89
77.435
62.933
−11.384
1.00
40.63
A
C

ATOM
720
NE2
HIS
A
89
77.817
62.376
−10.248
1.00
41.19
A
N

ATOM
721
N
GLY
A
90
71.120
63.846
−9.334
1.00
32.50
A
N

ATOM
722
CA
GLY
A
90
69.696
63.769
−9.051
1.00
31.86
A
C

ATOM
723
C
GLY
A
90
69.005
64.963
−9.686
1.00
30.26
A
C

ATOM
724
O
GLY
A
90
69.524
65.524
−10.644
1.00
31.12
A
O

ATOM
725
N
PRO
A
91
67.861
65.382
−9.158
1.00
32.37
A
N

ATOM
726
CA
PRO
A
91
67.175
66.565
−9.691
1.00
34.88
A
C

ATOM
727
C
PRO
A
91
67.987
67.835
−9.410
1.00
39.91
A
C

ATOM
728
O
PRO
A
91
68.764
67.852
−8.458
1.00
38.58
A
O

ATOM
729
CB
PRO
A
91
65.837
66.579
−8.937
1.00
35.23
A
C

ATOM
730
CG
PRO
A
91
66.049
65.738
−7.711
1.00
34.49
A
C

ATOM
731
CD
PRO
A
91
67.164
64.807
−7.994
1.00
33.82
A
C

ATOM
732
N
ASN
A
92
67.809
68.863
−10.238
1.00
43.06
A
N

ATOM
733
CA
ASN
A
92
68.496
70.152
−10.086
1.00
45.05
A
C

ATOM
734
C
ASN
A
92
67.841
71.060
−9.034
1.00
44.59
A
C

ATOM
735
O
ASN
A
92
67.368
72.156
−9.337
1.00
44.08
A
O

ATOM
736
CB
ASN
A
92
68.546
70.860
−11.441
1.00
47.21
A
C

ATOM
737
CG
ASN
A
92
69.438
72.079
−11.431
1.00
50.71
A
C

ATOM
738
OD1
ASN
A
92
70.604
72.003
−11.044
1.00
52.68
A
O

ATOM
739
ND2
ASN
A
92
68.895
73.217
−11.863
1.00
52.24
A
N

ATOM
740
N
VAL
A
93
67.830
70.592
−7.789
1.00
41.78
A
N

ATOM
741
CA
VAL
A
93
67.205
71.310
−6.691
1.00
36.70
A
C

ATOM
742
C
VAL
A
93
68.043
71.217
−5.428
1.00
35.54
A
C

ATOM
743
O
VAL
A
93
68.907
70.353
−5.304
1.00
36.77
A
O

ATOM
744
CB
VAL
A
93
65.794
70.772
−6.374
1.00
38.91
A
C

ATOM
745
CG1
VAL
A
93
64.868
70.960
−7.573
1.00
37.74
A
C

ATOM
746
CG2
VAL
A
93
65.848
69.310
−5.921
1.00
37.34
A
C

ATOM
747
N
THR
A
94
67.772
72.139
−4.513
1.00
33.85
A
N

ATOM
748
CA
THR
A
94
68.320
72.119
−3.178
1.00
35.85
A
C

ATOM
749
C
THR
A
94
67.170
72.293
−2.216
1.00
36.41
A
C

ATOM
750
O
THR
A
94
66.283
73.119
−2.443
1.00
38.29
A
O

ATOM
751
CB
THR
A
94
69.327
73.252
−3.009
1.00
37.46
A
C

ATOM
752
OG1
THR
A
94
70.459
73.016
−3.855
1.00
37.95
A
O

ATOM
753
CG2
THR
A
94
69.910
73.256
−1.599
1.00
39.22
A
C

ATOM
754
N
VAL
A
95
67.162
71.515
−1.143
1.00
32.79
A
N

ATOM
755
CA
VAL
A
95
66.110
71.652
−0.155
1.00
32.68
A
C

ATOM
756
C
VAL
A
95
66.660
71.686
1.261
1.00
30.49
A
C

ATOM
757
O
VAL
A
95
67.762
71.240
1.499
1.00
31.56
A
O

ATOM
758
CB
VAL
A
95
65.071
70.544
−0.291
1.00
36.55
A
C

ATOM
759
CG1
VAL
A
95
64.479
70.568
−1.709
1.00
38.67
A
C

ATOM
760
CG2
VAL
A
95
65.663
69.183
0.025
1.00
33.09
A
C

ATOM
761
N
ARG
A
96
65.883
72.244
2.181
1.00
30.99
A
N

ATOM
762
CA
ARG
A
96
66.212
72.215
3.597
1.00
29.56
A
C

ATOM
763
C
ARG
A
96
65.620
70.957
4.208
1.00
28.73
A
C

ATOM
764
O
ARG
A
96
64.402
70.809
4.302
1.00
30.19
A
O

ATOM
765
CB
ARG
A
96
65.686
73.459
4.320
1.00
33.02
A
C

ATOM
766
CG
ARG
A
96
65.976
73.474
5.835
1.00
36.80
A
C

ATOM
767
CD
ARG
A
96
65.954
74.863
6.457
1.00
38.14
A
C

ATOM
768
NE
ARG
A
96
67.041
75.677
5.929
1.00
37.92
A
N

ATOM
769
CZ
ARG
A
96
68.265
75.747
6.442
1.00
37.97
A
C

ATOM
770
NH1
ARG
A
96
68.600
75.050
7.524
1.00
38.44
A
N

ATOM
771
NH2
ARG
A
96
69.160
76.512
5.846
1.00
33.62
A
N

ATOM
772
N
ALA
A
97
66.503
70.048
4.606
1.00
24.74
A
N

ATOM
773
CA
ALA
A
97
66.126
68.764
5.167
1.00
27.21
A
C

ATOM
774
C
ALA
A
97
66.541
68.668
6.614
1.00
22.38
A
C

ATOM
775
O
ALA
A
97
67.523
69.278
7.026
1.00
23.68
A
O

ATOM
776
CB
ALA
A
97
66.801
67.648
4.380
1.00
24.80
A
C

ATOM
777
N
ASN
A
98
65.796
67.884
7.378
1.00
21.67
A
N

ATOM
778
CA
ASN
A
98
66.281
67.388
8.644
1.00
22.81
A
C

ATOM
779
C
ASN
A
98
67.502
66.503
8.409
1.00
25.29
A
C

ATOM
780
O
ASN
A
98
67.538
65.738
7.451
1.00
21.43
A
O

ATOM
781
CB
ASN
A
98
65.184
66.605
9.351
1.00
23.87
A
C

ATOM
782
CG
ASN
A
98
64.033
67.503
9.805
1.00
31.55
A
C

ATOM
783
OD1
ASN
A
98
64.257
68.532
10.448
1.00
28.77
A
O

ATOM
784
ND2
ASN
A
98
62.801
67.115
9.469
1.00
29.01
A
N

ATOM
785
N
ILE
A
99
68.517
66.652
9.255
1.00
23.47
A
N

ATOM
786
CA
ILE
A
99
69.693
65.781
9.240
1.00
21.95
A
C

ATOM
787
C
ILE
A
99
70.048
65.437
10.685
1.00
19.63
A
C

ATOM
788
O
ILE
A
99
70.186
66.339
11.529
1.00
24.71
A
O

ATOM
789
CB
ILE
A
99
70.902
66.475
8.586
1.00
22.78
A
C

ATOM
790
CG1
ILE
A
99
70.571
66.968
7.184
1.00
19.57
A
C

ATOM
791
CG2
ILE
A
99
72.076
65.544
8.527
1.00
25.77
A
C

ATOM
792
CD1
ILE
A
99
71.663
67.806
6.568
1.00
26.04
A
C

ATOM
793
N
ALA
A
100
70.167
64.149
10.968
1.00
17.47
A
N

ATOM
794
CA
ALA
A
100
70.721
63.657
12.223
1.00
17.42
A
C

ATOM
795
C
ALA
A
100
72.245
63.532
12.075
1.00
21.54
A
C

ATOM
796
O
ALA
A
100
72.742
62.697
11.325
1.00
18.72
A
O

ATOM
797
CB
ALA
A
100
70.116
62.345
12.607
1.00
21.16
A
C

ATOM
798
N
ALA
A
101
72.981
64.369
12.804
1.00
18.65
A
N

ATOM
799
CA
ALA
A
101
74.436
64.308
12.819
1.00
19.52
A
C

ATOM
800
C
ALA
A
101
74.849
63.244
13.813
1.00
19.24
A
C

ATOM
801
O
ALA
A
101
74.595
63.358
15.017
1.00
22.30
A
O

ATOM
802
CB
ALA
A
101
75.052
65.702
13.163
1.00
21.40
A
C

ATOM
803
N
ILE
A
102
75.398
62.150
13.311
1.00
15.90
A
N

ATOM
804
CA
ILE
A
102
75.660
60.973
14.129
1.00
17.94
A
C

ATOM
805
C
ILE
A
102
76.952
61.245
14.892
1.00
19.52
A
C

ATOM
806
O
ILE
A
102
77.978
61.511
14.288
1.00
19.99
A
O

ATOM
807
CB
ILE
A
102
75.842
59.690
13.277
1.00
15.21
A
C

ATOM
808
CG1
ILE
A
102
74.554
59.374
12.505
1.00
16.99
A
C

ATOM
809
CG2
ILE
A
102
76.224
58.519
14.178
1.00
18.39
A
C

ATOM
810
CD1
ILE
A
102
74.673
58.276
11.472
1.00
19.74
A
C

ATOM
811
N
THR
A
103
76.866
61.146
16.212
1.00
21.46
A
N

ATOM
812
CA
THR
A
103
77.982
61.450
17.114
1.00
25.21
A
C

ATOM
813
C
THR
A
103
78.451
60.245
17.925
1.00
26.42
A
C

ATOM
814
O
THR
A
103
79.504
60.296
18.556
1.00
27.83
A
O

ATOM
815
CB
THR
A
103
77.556
62.579
18.073
1.00
24.52
A
C

ATOM
816
OG1
THR
A
103
76.344
62.216
18.746
1.00
26.84
A
O

ATOM
817
CG2
THR
A
103
77.183
63.831
17.317
1.00
25.79
A
C

ATOM
818
N
GLU
A
104
77.668
59.168
17.934
1.00
23.45
A
N

ATOM
819
CA
GLU
A
104
78.061
57.917
18.576
1.00
19.81
A
C

ATOM
820
C
GLU
A
104
77.351
56.767
17.877
1.00
21.65
A
C

ATOM
821
O
GLU
A
104
76.208
56.921
17.465
1.00
21.87
A
O

ATOM
822
CB
GLU
A
104
77.725
57.928
20.088
1.00
28.17
A
C

ATOM
823
CG
GLU
A
104
78.291
56.737
20.854
1.00
33.07
A
C

ATOM
824
CD
GLU
A
104
77.964
56.726
22.350
1.00
42.35
A
C

ATOM
825
OE1
GLU
A
104
77.594
57.785
22.928
1.00
48.99
A
O

ATOM
826
OE2
GLU
A
104
78.089
55.637
22.961
1.00
51.21
A
O

ATOM
827
N
SER
A
105
78.043
55.649
17.693
1.00
19.13
A
N

ATOM
828
CA
SER
A
105
77.446
54.481
17.026
1.00
20.88
A
C

ATOM
829
C
SER
A
105
78.126
53.167
17.421
1.00
24.82
A
C

ATOM
830
O
SER
A
105
79.260
53.151
17.929
1.00
23.75
A
O

ATOM
831
CB
SER
A
105
77.440
54.676
15.490
1.00
18.17
A
C

ATOM
832
OG
SER
A
105
78.758
54.663
15.012
1.00
21.83
A
O

ATOM
833
N
ASP
A
106
77.400
52.072
17.214
1.00
22.55
A
N

ATOM
834
CA
ASP
A
106
77.913
50.733
17.411
1.00
24.69
A
C

ATOM
835
C
ASP
A
106
77.315
49.839
16.312
1.00
23.68
A
C

ATOM
836
O
ASP
A
106
76.094
49.837
16.093
1.00
22.98
A
O

ATOM
837
CB
ASP
A
106
77.556
50.196
18.792
1.00
29.23
A
C

ATOM
838
CG
ASP
A
106
77.998
48.751
18.973
0.50
30.82
A
C

ATOM
839
OD1
ASP
A
106
79.136
48.520
19.419
0.50
35.18
A
O

ATOM
840
OD2
ASP
A
106
77.279
47.781
18.668
0.50
34.57
A
O

ATOM
841
N
LYS
A
107
78.190
49.123
15.618
1.00
25.54
A
N

ATOM
842
CA
LYS
A
107
77.820
48.161
14.572
1.00
22.36
A
C

ATOM
843
C
LYS
A
107
76.966
48.753
13.446
1.00
25.69
A
C

ATOM
844
O
LYS
A
107
76.176
48.054
12.825
1.00
22.57
A
O

ATOM
845
CB
LYS
A
107
77.139
46.935
15.195
1.00
27.43
A
C

ATOM
846
CG
LYS
A
107
78.066
46.130
16.101
1.00
32.24
A
C

ATOM
847
CD
LYS
A
107
77.314
45.034
16.835
1.00
33.50
A
C

ATOM
848
CE
LYS
A
107
78.004
44.328
17.899
0.00
31.63
A
C

ATOM
849
NZ
LYS
A
107
79.348
43.882
17.435
0.00
31.79
A
N

ATOM
850
N
PHE
A
108
77.151
50.043
13.187
1.00
22.67
A
N

ATOM
851
CA
PHE
A
108
76.412
50.770
12.161
1.00
20.97
A
C

ATOM
852
C
PHE
A
108
77.306
50.946
10.954
1.00
19.92
A
C

ATOM
853
O
PHE
A
108
77.016
50.416
9.875
1.00
21.69
A
O

ATOM
854
CB
PHE
A
108
75.946
52.125
12.691
1.00
19.57
A
C

ATOM
855
CG
PHE
A
108
75.153
52.921
11.701
1.00
20.66
A
C

ATOM
856
CD1
PHE
A
108
73.870
52.520
11.338
1.00
25.16
A
C

ATOM
857
CD2
PHE
A
108
75.688
54.053
11.107
1.00
22.61
A
C

ATOM
858
CE1
PHE
A
108
73.139
53.250
10.405
1.00
25.50
A
C

ATOM
859
CE2
PHE
A
108
74.963
54.790
10.190
1.00
22.84
A
C

ATOM
860
CZ
PHE
A
108
73.677
54.381
9.832
1.00
26.62
A
C

ATOM
861
N
PHE
A
109
78.401
51.682
11.129
1.00
20.35
A
N

ATOM
862
CA
PHE
A
109
79.372
51.887
10.044
1.00
20.96
A
C

ATOM
863
C
PHE
A
109
80.123
50.581
9.813
1.00
19.74
A
C

ATOM
864
O
PHE
A
109
80.361
49.824
10.769
1.00
24.70
A
O

ATOM
865
CB
PHE
A
109
80.325
53.065
10.348
1.00
19.85
A
C

ATOM
866
CG
PHE
A
109
79.617
54.398
10.489
1.00
16.19
A
C

ATOM
867
CD1
PHE
A
109
78.862
54.897
9.435
1.00
22.18
A
C

ATOM
868
CD2
PHE
A
109
79.726
55.162
11.633
1.00
22.85
A
C

ATOM
869
CE1
PHE
A
109
78.197
56.107
9.532
1.00
21.10
A
C

ATOM
870
CE2
PHE
A
109
79.066
56.377
11.728
1.00
21.43
A
C

ATOM
871
CZ
PHE
A
109
78.284
56.841
10.663
1.00
22.40
A
C

ATOM
872
N
ILE
A
110
80.460
50.285
8.556
1.00
24.38
A
N

ATOM
873
CA
ILE
A
110
81.176
49.060
8.204
1.00
23.73
A
C

ATOM
874
C
ILE
A
110
82.627
49.382
7.863
1.00
25.17
A
C

ATOM
875
O
ILE
A
110
82.917
50.295
7.077
1.00
21.65
A
O

ATOM
876
CB
ILE
A
110
80.510
48.364
6.998
1.00
23.43
A
C

ATOM
877
CG1
ILE
A
110
79.073
47.944
7.330
1.00
26.13
A
C

ATOM
878
CG2
ILE
A
110
81.354
47.171
6.511
1.00
27.63
A
C

ATOM
879
CD1
ILE
A
110
78.262
47.542
6.104
1.00
29.01
A
C

ATOM
880
N
ASN
A
111
83.535
48.616
8.453
1.00
24.01
A
N

ATOM
881
CA
ASN
A
111
84.958
48.786
8.213
1.00
25.66
A
C

ATOM
882
C
ASN
A
111
85.302
48.367
6.782
1.00
21.62
A
C

ATOM
883
O
ASN
A
111
85.122
47.210
6.395
1.00
24.50
A
O

ATOM
884
CB
ASN
A
111
85.762
47.950
9.219
1.00
26.77
A
C

ATOM
885
CG
ASN
A
111
87.239
48.324
9.252
1.00
30.39
A
C

ATOM
886
OD1
ASN
A
111
87.614
49.478
9.012
1.00
29.76
A
O

ATOM
887
ND2
ASN
A
111
88.081
47.348
9.588
1.00
28.98
A
N

ATOM
888
N
GLY
A
112
85.815
49.310
6.008
1.00
21.53
A
N

ATOM
889
CA
GLY
A
112
86.127
49.082
4.604
1.00
26.83
A
C

ATOM
890
C
GLY
A
112
85.073
49.602
3.630
1.00
27.54
A
C

ATOM
891
O
GLY
A
112
85.274
49.562
2.419
1.00
26.87
A
O

ATOM
892
N
SER
A
113
83.950
50.086
4.145
1.00
28.16
A
N

ATOM
893
CA
SER
A
113
82.869
50.607
3.301
1.00
23.29
A
C

ATOM
894
C
SER
A
113
83.152
52.034
2.864
1.00
22.88
A
C

ATOM
895
O
SER
A
113
83.981
52.730
3.462
1.00
22.23
A
O

ATOM
896
CB
SER
A
113
81.537
50.544
4.053
1.00
26.77
A
C

ATOM
897
OG
SER
A
113
81.450
51.622
4.968
1.00
32.46
A
O

ATOM
898
N
ASN
A
114
82.451
52.469
1.818
1.00
19.83
A
N

ATOM
899
CA
ASN
A
114
82.632
53.785
1.195
1.00
20.70
A
C

ATOM
900
C
ASN
A
114
81.400
54.686
1.349
1.00
17.94
A
C

ATOM
901
O
ASN
A
114
81.228
55.627
0.596
1.00
20.08
A
O

ATOM
902
CB
ASN
A
114
82.973
53.574
−0.303
1.00
20.54
A
C

ATOM
903
CG
ASN
A
114
83.533
54.827
−1.004
1.00
26.09
A
C

ATOM
904
OD1
ASN
A
114
83.189
55.100
−2.165
1.00
29.37
A
O

ATOM
905
ND2
ASN
A
114
84.441
55.540
−0.348
1.00
22.18
A
N

ATOM
906
N
TRP
A
115
80.558
54.414
2.354
1.00
16.89
A
N

ATOM
907
CA
TRP
A
115
79.453
55.295
2.658
1.00
16.46
A
C

ATOM
908
C
TRP
A
115
79.548
55.772
4.100
1.00
18.12
A
C

ATOM
909
O
TRP
A
115
80.184
55.126
4.943
1.00
20.65
A
O

ATOM
910
CB
TRP
A
115
78.093
54.631
2.393
1.00
18.60
A
C

ATOM
911
CG
TRP
A
115
77.869
53.335
3.061
1.00
18.81
A
C

ATOM
912
CD1
TRP
A
115
78.058
52.098
2.520
1.00
27.02
A
C

ATOM
913
CD2
TRP
A
115
77.372
53.109
4.403
1.00
19.85
A
C

ATOM
914
NE1
TRP
A
115
77.734
51.123
3.434
1.00
28.07
A
N

ATOM
915
CE2
TRP
A
115
77.311
51.716
4.597
1.00
28.04
A
C

ATOM
916
CE3
TRP
A
115
76.983
53.943
5.453
1.00
21.36
A
C

ATOM
917
CZ2
TRP
A
115
76.877
51.142
5.799
1.00
27.30
A
C

ATOM
918
CZ3
TRP
A
115
76.544
53.371
6.643
1.00
22.49
A
C

ATOM
919
CH2
TRP
A
115
76.510
51.996
6.808
1.00
24.66
A
C

ATOM
920
N
GLU
A
116
78.910
56.905
4.345
1.00
18.09
A
N

ATOM
921
CA
GLU
A
116
79.049
57.666
5.584
1.00
18.37
A
C

ATOM
922
C
GLU
A
116
77.726
58.110
6.220
1.00
21.39
A
C

ATOM
923
O
GLU
A
116
77.719
58.866
7.185
1.00
19.69
A
O

ATOM
924
CB
GLU
A
116
79.891
58.924
5.282
1.00
21.09
A
C

ATOM
925
CG
GLU
A
116
81.298
58.664
4.834
1.00
30.57
A
C

ATOM
926
CD
GLU
A
116
81.495
58.683
3.331
1.00
19.12
A
C

ATOM
927
OE1
GLU
A
116
80.945
59.571
2.609
1.00
25.47
A
O

ATOM
928
OE2
GLU
A
116
82.237
57.811
2.889
1.00
30.78
A
O

ATOM
929
N
GLY
A
117
76.601
57.670
5.680
1.00
15.48
A
N

ATOM
930
CA
GLY
A
117
75.302
58.008
6.218
1.00
14.95
A
C

ATOM
931
C
GLY
A
117
74.221
57.194
5.523
1.00
17.22
A
C

ATOM
932
O
GLY
A
117
74.517
56.329
4.686
1.00
15.79
A
O

ATOM
933
N
ILE
A
118
72.980
57.475
5.888
1.00
18.20
A
N

ATOM
934
CA
ILE
A
118
71.810
56.721
5.455
1.00
12.85
A
C

ATOM
935
C
ILE
A
118
70.668
57.692
5.108
1.00
15.45
A
C

ATOM
936
O
ILE
A
118
70.426
58.691
5.805
1.00
15.49
A
O

ATOM
937
CB
ILE
A
118
71.401
55.687
6.518
1.00
16.49
A
C

ATOM
938
CG1
ILE
A
118
70.260
54.788
6.018
1.00
20.60
A
C

ATOM
939
CG2
ILE
A
118
70.977
56.368
7.820
1.00
18.54
A
C

ATOM
940
CD1
ILE
A
118
69.959
53.672
6.975
1.00
22.49
A
C

ATOM
941
N
LEU
A
119
69.973
57.386
4.012
1.00
16.51
A
N

ATOM
942
CA
LEU
A
119
68.850
58.180
3.520
1.00
17.34
A
C

ATOM
943
C
LEU
A
119
67.605
57.332
3.631
1.00
17.57
A
C

ATOM
944
O
LEU
A
119
67.370
56.426
2.823
1.00
17.07
A
O

ATOM
945
CB
LEU
A
119
69.061
58.614
2.073
1.00
16.12
A
C

ATOM
946
CG
LEU
A
119
67.954
59.469
1.461
1.00
20.50
A
C

ATOM
947
CD1
LEU
A
119
67.744
60.734
2.237
1.00
21.51
A
C

ATOM
948
CD2
LEU
A
119
68.286
59.797
0.034
1.00
22.00
A
C

ATOM
949
N
GLY
A
120
66.817
57.600
4.659
1.00
15.26
A
N

ATOM
950
CA
GLY
A
120
65.590
56.864
4.892
1.00
16.17
A
C

ATOM
951
C
GLY
A
120
64.506
57.419
3.975
1.00
16.03
A
C

ATOM
952
O
GLY
A
120
64.131
58.593
4.102
1.00
20.14
A
O

ATOM
953
N
LEU
A
121
64.011
56.582
3.064
1.00
15.98
A
N

ATOM
954
CA
LEU
A
121
63.037
57.010
2.038
1.00
16.93
A
C

ATOM
955
C
LEU
A
121
61.586
56.616
2.330
1.00
18.71
A
C

ATOM
956
O
LEU
A
121
60.683
56.874
1.530
1.00
20.26
A
O

ATOM
957
CB
LEU
A
121
63.460
56.449
0.682
1.00
16.32
A
C

ATOM
958
CG
LEU
A
121
64.699
57.128
0.084
1.00
18.18
A
C

ATOM
959
CD1
LEU
A
121
65.208
56.418
−1.167
1.00
17.74
A
C

ATOM
960
CD2
LEU
A
121
64.505
58.626
−0.230
1.00
19.83
A
C

ATOM
961
N
ALA
A
122
61.377
55.931
3.440
1.00
17.96
A
N

ATOM
962
CA
ALA
A
122
60.037
55.568
3.916
1.00
19.62
A
C

ATOM
963
C
ALA
A
122
59.307
56.740
4.589
1.00
24.01
A
C

ATOM
964
O
ALA
A
122
59.734
57.890
4.476
1.00
24.71
A
O

ATOM
965
CB
ALA
A
122
60.130
54.361
4.829
1.00
20.17
A
C

ATOM
966
N
TYR
A
123
58.185
56.447
5.256
1.00
23.30
A
N

ATOM
967
CA
TYR
A
123
57.265
57.473
5.703
1.00
25.93
A
C

ATOM
968
C
TYR
A
123
57.492
57.894
7.163
1.00
23.41
A
C

ATOM
969
O
TYR
A
123
58.146
57.192
7.931
1.00
25.28
A
O

ATOM
970
CB
TYR
A
123
55.836
56.968
5.559
1.00
25.54
A
C

ATOM
971
CG
TYR
A
123
55.441
56.697
4.129
1.00
24.32
A
C

ATOM
972
CD1
TYR
A
123
55.015
57.724
3.310
1.00
25.79
A
C

ATOM
973
CD2
TYR
A
123
55.491
55.421
3.609
1.00
26.50
A
C

ATOM
974
CE1
TYR
A
123
54.622
57.486
1.998
1.00
28.42
A
C

ATOM
975
CE2
TYR
A
123
55.120
55.171
2.293
1.00
27.28
A
C

ATOM
976
CZ
TYR
A
123
54.678
56.195
1.501
1.00
25.25
A
C

ATOM
977
OH
TYR
A
123
54.315
55.950
0.184
1.00
26.89
A
O

ATOM
978
N
ALA
A
124
56.879
59.014
7.519
1.00
29.24
A
N

ATOM
979
CA
ALA
A
124
57.082
59.664
8.820
1.00
30.24
A
C

ATOM
980
C
ALA
A
124
56.708
58.812
10.018
1.00
35.27
A
C

ATOM
981
O
ALA
A
124
57.302
58.953
11.091
1.00
33.99
A
O

ATOM
982
CB
ALA
A
124
56.356
60.972
8.858
1.00
31.62
A
C

ATOM
983
N
GLU
A
125
55.754
57.903
9.834
1.00
34.28
A
N

ATOM
984
CA
GLU
A
125
55.295
57.003
10.894
1.00
37.92
A
C

ATOM
985
C
GLU
A
125
56.415
56.274
11.647
1.00
37.65
A
C

ATOM
986
O
GLU
A
125
56.299
56.030
12.853
1.00
38.82
A
O

ATOM
987
CB
GLU
A
125
54.330
55.968
10.293
1.00
40.24
A
C

ATOM
988
CG
GLU
A
125
53.444
55.252
11.295
1.00
45.50
A
C

ATOM
989
CD
GLU
A
125
52.121
55.962
11.496
1.00
52.07
A
C

ATOM
990
OE1
GLU
A
125
52.131
57.123
11.977
1.00
54.94
A
O

ATOM
991
OE2
GLU
A
125
51.075
55.364
11.163
1.00
57.37
A
O

ATOM
992
N
ILE
A
126
57.491
55.918
10.941
1.00
31.63
A
N

ATOM
993
CA
ILE
A
126
58.585
55.155
11.525
1.00
28.26
A
C

ATOM
994
C
ILE
A
126
59.866
55.991
11.687
1.00
26.21
A
C

ATOM
995
O
ILE
A
126
60.920
55.440
11.948
1.00
28.24
A
O

ATOM
996
CB
ILE
A
126
58.878
53.883
10.690
1.00
31.52
A
C

ATOM
997
CG1
ILE
A
126
59.197
54.235
9.234
1.00
28.75
A
C

ATOM
998
CG2
ILE
A
126
57.699
52.908
10.764
1.00
31.40
A
C

ATOM
999
CD1
ILE
A
126
59.677
53.053
8.429
1.00
29.82
A
C

ATOM
1000
N
ALA
A
127
59.751
57.298
11.493
1.00
26.38
A
N

ATOM
1001
CA
ALA
A
127
60.844
58.222
11.762
1.00
28.14
A
C

ATOM
1002
C
ALA
A
127
61.072
58.286
13.267
1.00
30.57
A
C

ATOM
1003
O
ALA
A
127
60.139
58.129
14.056
1.00
27.34
A
O

ATOM
1004
CB
ALA
A
127
60.516
59.588
11.228
1.00
26.20
A
C

ATOM
1005
N
ARG
A
128
62.323
58.479
13.650
1.00
32.29
A
N

ATOM
1006
CA
ARG
A
128
62.686
58.711
15.042
1.00
32.33
A
C

ATOM
1007
C
ARG
A
128
63.110
60.172
15.214
1.00
32.76
A
C

ATOM
1008
O
ARG
A
128
63.673
60.773
14.288
1.00
28.12
A
O

ATOM
1009
CB
ARG
A
128
63.775
57.748
15.468
1.00
33.84
A
C

ATOM
1010
CG
ARG
A
128
63.268
56.329
15.638
1.00
39.19
A
C

ATOM
1011
CD
ARG
A
128
64.006
55.302
14.843
1.00
43.32
A
C

ATOM
1012
NE
ARG
A
128
63.338
54.007
14.915
1.00
49.88
A
N

ATOM
1013
CZ
ARG
A
128
63.811
52.881
14.384
1.00
49.47
A
C

ATOM
1014
NH1
ARG
A
128
63.115
51.757
14.508
1.00
52.74
A
N

ATOM
1015
NH2
ARG
A
128
64.968
52.865
13.731
1.00
50.48
A
N

ATOM
1016
N
PRO
A
129
62.816
60.791
16.364
1.00
31.47
A
N

ATOM
1017
CA
PRO
A
129
62.218
60.159
17.553
1.00
34.71
A
C

ATOM
1018
C
PRO
A
129
60.705
59.942
17.479
1.00
34.15
A
C

ATOM
1019
O
PRO
A
129
60.172
59.122
18.229
1.00
37.59
A
O

ATOM
1020
CB
PRO
A
129
62.498
61.176
18.670
1.00
32.03
A
C

ATOM
1021
CG
PRO
A
129
62.887
62.461
18.005
1.00
33.32
A
C

ATOM
1022
CD
PRO
A
129
63.036
62.232
16.548
1.00
34.13
A
C

ATOM
1023
N
ASP
A
130
60.031
60.701
16.626
1.00
34.80
A
N

ATOM
1024
CA
ASP
A
130
58.604
60.519
16.390
1.00
38.13
A
C

ATOM
1025
C
ASP
A
130
58.234
60.967
14.976
1.00
36.50
A
C

ATOM
1026
O
ASP
A
130
59.075
61.471
14.227
1.00
36.70
A
O

ATOM
1027
CB
ASP
A
130
57.779
61.280
17.450
1.00
39.51
A
C

ATOM
1028
CG
ASP
A
130
58.154
62.756
17.558
1.00
44.22
A
C

ATOM
1029
OD1
ASP
A
130
58.795
63.139
18.571
1.00
51.20
A
O

ATOM
1030
OD2
ASP
A
130
57.839
63.614
16.705
1.00
44.98
A
O

ATOM
1031
N
ASP
A
131
56.963
60.814
14.623
1.00
38.18
A
N

ATOM
1032
CA
ASP
A
131
56.511
61.090
13.261
1.00
38.88
A
C

ATOM
1033
C
ASP
A
131
56.397
62.569
12.911
1.00
36.53
A
C

ATOM
1034
O
ASP
A
131
55.943
62.905
11.827
1.00
35.45
A
O

ATOM
1035
CB
ASP
A
131
55.191
60.346
12.950
1.00
39.38
A
C

ATOM
1036
CG
ASP
A
131
54.010
60.844
13.771
1.00
41.70
A
C

ATOM
1037
OD1
ASP
A
131
54.067
61.976
14.296
1.00
42.89
A
O

ATOM
1038
OD2
ASP
A
131
52.970
60.165
13.935
1.00
42.85
A
O

ATOM
1039
N
SER
A
132
56.801
63.462
13.815
1.00
37.22
A
N

ATOM
1040
CA
SER
A
132
56.825
64.891
13.495
1.00
34.53
A
C

ATOM
1041
C
SER
A
132
58.138
65.313
12.811
1.00
32.93
A
C

ATOM
1042
O
SER
A
132
58.242
66.415
12.301
1.00
31.50
A
O

ATOM
1043
CB
SER
A
132
56.569
65.733
14.753
1.00
36.86
A
C

ATOM
1044
OG
SER
A
132
57.784
66.236
15.282
1.00
41.97
A
O

ATOM
1045
N
LEU
A
133
59.142
64.442
12.800
1.00
33.79
A
N

ATOM
1046
CA
LEU
A
133
60.371
64.730
12.053
1.00
32.04
A
C

ATOM
1047
C
LEU
A
133
60.174
64.308
10.601
1.00
30.10
A
C

ATOM
1048
O
LEU
A
133
60.179
63.117
10.279
1.00
31.31
A
O

ATOM
1049
CB
LEU
A
133
61.586
64.035
12.652
1.00
30.30
A
C

ATOM
1050
CG
LEU
A
133
62.901
64.622
12.116
1.00
31.05
A
C

ATOM
1051
CD1
LEU
A
133
63.289
65.900
12.891
1.00
30.64
A
C

ATOM
1052
CD2
LEU
A
133
64.000
63.606
12.180
1.00
26.23
A
C

ATOM
1053
N
GLU
A
134
60.028
65.294
9.734
1.00
32.24
A
N

ATOM
1054
CA
GLU
A
134
59.630
65.044
8.362
1.00
30.89
A
C

ATOM
1055
C
GLU
A
134
60.812
64.398
7.611
1.00
30.52
A
C

ATOM
1056
O
GLU
A
134
61.938
64.919
7.650
1.00
27.23
A
O

ATOM
1057
CB
GLU
A
134
59.088
66.332
7.709
1.00
35.75
A
C

ATOM
1058
CG
GLU
A
134
59.723
66.804
6.414
1.00
41.00
A
C

ATOM
1059
CD
GLU
A
134
59.016
68.022
5.819
1.00
43.25
A
C

ATOM
1060
OE1
GLU
A
134
59.719
68.930
5.302
1.00
45.72
A
O

ATOM
1061
OE2
GLU
A
134
57.763
68.096
5.869
1.00
48.16
A
O

ATOM
1062
N
PRO
A
135
60.566
63.249
6.975
1.00
25.18
A
N

ATOM
1063
CA
PRO
A
135
61.581
62.606
6.119
1.00
24.30
A
C

ATOM
1064
C
PRO
A
135
62.039
63.453
4.958
1.00
19.94
A
C

ATOM
1065
O
PRO
A
135
61.337
64.319
4.481
1.00
23.86
A
O

ATOM
1066
CB
PRO
A
135
60.847
61.379
5.579
1.00
22.83
A
C

ATOM
1067
CG
PRO
A
135
59.796
61.109
6.573
1.00
25.70
A
C

ATOM
1068
CD
PRO
A
135
59.328
62.450
7.020
1.00
24.61
A
C

ATOM
1069
N
PHE
A
136
63.243
63.160
4.474
1.00
19.75
A
N

ATOM
1070
CA
PHE
A
136
63.850
63.848
3.367
1.00
20.77
A
C

ATOM
1071
C
PHE
A
136
62.945
64.000
2.166
1.00
25.10
A
C

ATOM
1072
O
PHE
A
136
62.798
65.099
1.632
1.00
23.63
A
O

ATOM
1073
CB
PHE
A
136
65.094
63.106
2.886
1.00
21.20
A
C

ATOM
1074
CG
PHE
A
136
65.704
63.716
1.669
1.00
19.23
A
C

ATOM
1075
CD1
PHE
A
136
66.414
64.905
1.758
1.00
26.30
A
C

ATOM
1076
CD2
PHE
A
136
65.522
63.144
0.421
1.00
23.32
A
C

ATOM
1077
CE1
PHE
A
136
66.962
65.494
0.626
1.00
25.62
A
C

ATOM
1078
CE2
PHE
A
136
66.078
63.727
−0.719
1.00
23.61
A
C

ATOM
1079
CZ
PHE
A
136
66.787
64.903
−0.615
1.00
29.48
A
C

ATOM
1080
N
PHE
A
137
62.402
62.886
1.694
1.00
21.94
A
N

ATOM
1081
CA
PHE
A
137
61.655
62.903
0.444
1.00
20.25
A
C

ATOM
1082
C
PHE
A
137
60.396
63.749
0.582
1.00
21.90
A
C

ATOM
1083
O
PHE
A
137
59.966
64.370
−0.379
1.00
24.14
A
O

ATOM
1084
CB
PHE
A
137
61.271
61.509
−0.026
1.00
18.67
A
C

ATOM
1085
CG
PHE
A
137
61.039
61.440
−1.491
1.00
20.54
A
C

ATOM
1086
CD1
PHE
A
137
62.099
61.302
−2.361
1.00
23.22
A
C

ATOM
1087
CD2
PHE
A
137
59.757
61.511
−2.003
1.00
22.93
A
C

ATOM
1088
CE1
PHE
A
137
61.900
61.241
−3.721
1.00
27.68
A
C

ATOM
1089
CE2
PHE
A
137
59.551
61.462
−3.374
1.00
20.33
A
C

ATOM
1090
CZ
PHE
A
137
60.616
61.334
−4.232
1.00
22.33
A
C

ATOM
1091
N
ASP
A
138
59.814
63.750
1.775
1.00
22.45
A
N

ATOM
1092
CA
ASP
A
138
58.649
64.582
2.081
1.00
25.79
A
C

ATOM
1093
C
ASP
A
138
59.020
66.055
1.966
1.00
27.43
A
C

ATOM
1094
O
ASP
A
138
58.296
66.825
1.326
1.00
30.80
A
O

ATOM
1095
CB
ASP
A
138
58.124
64.309
3.479
1.00
27.52
A
C

ATOM
1096
CG
ASP
A
138
57.419
62.982
3.596
1.00
33.12
A
C

ATOM
1097
OD1
ASP
A
138
56.177
63.001
3.674
1.00
41.90
A
O

ATOM
1098
OD2
ASP
A
138
58.004
61.870
3.644
1.00
36.84
A
O

ATOM
1099
N
SER
A
139
60.141
66.452
2.573
1.00
25.82
A
N

ATOM
1100
CA
SER
A
139
60.662
67.825
2.393
1.00
26.28
A
C

ATOM
1101
C
SER
A
139
60.957
68.169
0.940
1.00
26.44
A
C

ATOM
1102
O
SER
A
139
60.719
69.293
0.496
1.00
28.87
A
O

ATOM
1103
CB
SER
A
139
61.951
68.049
3.204
1.00
21.06
A
C

ATOM
1104
OG
SER
A
139
61.769
67.663
4.541
1.00
25.91
A
O

ATOM
1105
N
LEU
A
140
61.493
67.212
0.188
1.00
24.71
A
N

ATOM
1106
CA
LEU
A
140
61.816
67.443
−1.209
1.00
24.32
A
C

ATOM
1107
C
LEU
A
140
60.547
67.732
−2.019
1.00
26.78
A
C

ATOM
1108
O
LEU
A
140
60.555
68.649
−2.851
1.00
28.93
A
O

ATOM
1109
CB
LEU
A
140
62.555
66.253
−1.819
1.00
25.33
A
C

ATOM
1110
CG
LEU
A
140
62.797
66.212
−3.332
1.00
27.48
A
C

ATOM
1111
CD1
LEU
A
140
63.903
67.142
−3.762
1.00
30.78
A
C

ATOM
1112
CD2
LEU
A
140
63.124
64.795
−3.764
1.00
32.40
A
C

ATOM
1113
N
VAL
A
141
59.482
66.964
−1.774
1.00
27.82
A
N

ATOM
1114
CA
VAL
A
141
58.236
67.121
−2.539
1.00
27.51
A
C

ATOM
1115
C
VAL
A
141
57.548
68.440
−2.159
1.00
33.11
A
C

ATOM
1116
O
VAL
A
141
57.054
69.159
−3.024
1.00
34.42
A
O

ATOM
1117
CB
VAL
A
141
57.268
65.953
−2.319
1.00
30.35
A
C

ATOM
1118
CG1
VAL
A
141
55.923
66.224
−2.980
1.00
31.75
A
C

ATOM
1119
CG2
VAL
A
141
57.849
64.666
−2.885
1.00
30.79
A
C

ATOM
1120
N
LYS
A
142
57.541
68.747
−0.868
1.00
32.37
A
N

ATOM
1121
CA
LYS
A
142
56.876
69.931
−0.338
1.00
37.06
A
C

ATOM
1122
C
LYS
A
142
57.527
71.211
−0.828
1.00
34.32
A
C

ATOM
1123
O
LYS
A
142
56.826
72.191
−1.091
1.00
35.77
A
O

ATOM
1124
CB
LYS
A
142
56.876
69.897
1.187
1.00
37.65
A
C

ATOM
1125
CG
LYS
A
142
56.135
71.055
1.850
1.00
44.63
A
C

ATOM
1126
CD
LYS
A
142
55.689
70.702
3.264
1.00
46.28
A
C

ATOM
1127
CE
LYS
A
142
54.644
71.684
3.779
1.00
49.93
A
C

ATOM
1128
NZ
LYS
A
142
54.400
71.364
5.250
0.00
45.29
A
N

ATOM
1129
N
GLN
A
143
58.848
71.196
−0.999
1.00
30.71
A
N

ATOM
1130
CA
GLN
A
143
59.602
72.415
−1.260
1.00
32.98
A
C

ATOM
1131
C
GLN
A
143
59.948
72.655
−2.726
1.00
31.39
A
C

ATOM
1132
O
GLN
A
143
60.393
73.754
−3.071
1.00
35.65
A
O

ATOM
1133
CB
GLN
A
143
60.900
72.429
−0.443
1.00
29.67
A
C

ATOM
1134
CG
GLN
A
143
60.712
72.505
1.045
1.00
29.86
A
C

ATOM
1135
CD
GLN
A
143
62.033
72.359
1.785
1.00
22.99
A
C

ATOM
1136
OE1
GLN
A
143
62.072
71.774
2.871
1.00
32.84
A
O

ATOM
1137
NE2
GLN
A
143
63.100
72.879
1.202
1.00
24.10
A
N

ATOM
1138
N
THR
A
144
59.767
71.650
−3.588
1.00
30.44
A
N

ATOM
1139
CA
THR
A
144
60.095
71.786
−5.011
1.00
31.63
A
C

ATOM
1140
C
THR
A
144
58.950
71.268
−5.887
1.00
32.37
A
C

ATOM
1141
O
THR
A
144
57.910
70.882
−5.368
1.00
35.67
A
O

ATOM
1142
CB
THR
A
144
61.405
71.032
−5.365
1.00
35.08
A
C

ATOM
1143
OG1
THR
A
144
61.169
69.613
−5.395
1.00
34.32
A
O

ATOM
1144
CG2
THR
A
144
62.458
71.221
−4.298
1.00
34.68
A
C

ATOM
1145
N
HIS
A
145
59.165
71.247
−7.203
1.00
36.14
A
N

ATOM
1146
CA
HIS
A
145
58.193
70.682
−8.155
1.00
39.38
A
C

ATOM
1147
C
HIS
A
145
58.512
69.232
−8.562
1.00
37.43
A
C

ATOM
1148
O
HIS
A
145
57.961
68.715
−9.544
1.00
33.33
A
O

ATOM
1149
CB
HIS
A
145
58.097
71.563
−9.409
1.00
43.05
A
C

ATOM
1150
CG
HIS
A
145
57.493
72.910
−9.154
1.00
47.15
A
C

ATOM
1151
ND1
HIS
A
145
56.200
73.072
−8.703
1.00
50.46
A
N

ATOM
1152
CD2
HIS
A
145
58.006
74.157
−9.284
1.00
49.69
A
C

ATOM
1153
CE1
HIS
A
145
55.941
74.361
−8.570
1.00
51.63
A
C

ATOM
1154
NE2
HIS
A
145
57.021
75.041
−8.913
1.00
51.86
A
N

ATOM
1155
N
VAL
A
146
59.379
68.565
−7.798
1.00
33.76
A
N

ATOM
1156
CA
VAL
A
146
59.705
67.163
−8.059
1.00
29.14
A
C

ATOM
1157
C
VAL
A
146
58.472
66.301
−7.774
1.00
22.43
A
C

ATOM
1158
O
VAL
A
146
57.885
66.398
−6.697
1.00
24.83
A
O

ATOM
1159
CB
VAL
A
146
60.921
66.695
−7.206
1.00
27.14
A
C

ATOM
1160
CG1
VAL
A
146
61.151
65.185
−7.339
1.00
27.28
A
C

ATOM
1161
CG2
VAL
A
146
62.178
67.468
−7.626
1.00
26.85
A
C

ATOM
1162
N
PRO
A
147
58.045
65.483
−8.744
1.00
26.48
A
N

ATOM
1163
CA
PRO
A
147
56.864
64.637
−8.557
1.00
26.08
A
C

ATOM
1164
C
PRO
A
147
57.049
63.662
−7.403
1.00
22.97
A
C

ATOM
1165
O
PRO
A
147
58.185
63.217
−7.166
1.00
27.41
A
O

ATOM
1166
CB
PRO
A
147
56.749
63.885
−9.882
1.00
25.30
A
C

ATOM
1167
CG
PRO
A
147
57.462
64.717
−10.865
1.00
27.21
A
C

ATOM
1168
CD
PRO
A
147
58.636
65.310
−10.089
1.00
25.24
A
C

ATOM
1169
N
ASN
A
148
55.963
63.339
−6.711
1.00
21.69
A
N

ATOM
1170
CA
ASN
A
148
56.014
62.466
−5.551
1.00
21.05
A
C

ATOM
1171
C
ASN
A
148
56.167
60.969
−5.908
1.00
21.77
A
C

ATOM
1172
O
ASN
A
148
55.305
60.152
−5.607
1.00
21.62
A
O

ATOM
1173
CB
ASN
A
148
54.797
62.717
−4.670
1.00
23.86
A
C

ATOM
1174
CG
ASN
A
148
54.878
62.024
−3.338
1.00
22.10
A
C

ATOM
1175
OD1
ASN
A
148
55.967
61.652
−2.885
1.00
20.69
A
O

ATOM
1176
ND2
ASN
A
148
53.716
61.795
−2.710
1.00
25.43
A
N

ATOM
1177
N
LEU
A
149
57.291
60.629
−6.524
1.00
20.43
A
N

ATOM
1178
CA
LEU
A
149
57.666
59.252
−6.775
1.00
22.50
A
C

ATOM
1179
C
LEU
A
149
59.152
59.110
−7.020
1.00
21.20
A
C

ATOM
1180
O
LEU
A
149
59.838
60.073
−7.389
1.00
19.54
A
O

ATOM
1181
CB
LEU
A
149
56.859
58.654
−7.927
1.00
25.03
A
C

ATOM
1182
CG
LEU
A
149
57.349
58.789
−9.346
1.00
28.60
A
C

ATOM
1183
CD1
LEU
A
149
56.502
57.899
−10.267
1.00
30.70
A
C

ATOM
1184
CD2
LEU
A
149
57.237
60.237
−9.725
1.00
30.68
A
C

ATOM
1185
N
PHE
A
150
59.678
57.919
−6.745
1.00
18.27
A
N

ATOM
1186
CA
PHE
A
150
61.044
57.586
−7.149
1.00
18.21
A
C

ATOM
1187
C
PHE
A
150
61.116
56.104
−7.566
1.00
17.26
A
C

ATOM
1188
O
PHE
A
150
60.229
55.324
−7.235
1.00
17.41
A
O

ATOM
1189
CB
PHE
A
150
62.054
57.925
−6.045
1.00
16.20
A
C

ATOM
1190
CG
PHE
A
150
61.904
57.072
−4.808
1.00
15.43
A
C

ATOM
1191
CD1
PHE
A
150
61.042
57.450
−3.805
1.00
18.11
A
C

ATOM
1192
CD2
PHE
A
150
62.614
55.885
−4.681
1.00
17.12
A
C

ATOM
1193
CE1
PHE
A
150
60.883
56.655
−2.694
1.00
16.60
A
C

ATOM
1194
CE2
PHE
A
150
62.477
55.092
−3.564
1.00
16.66
A
C

ATOM
1195
CZ
PHE
A
150
61.588
55.468
−2.576
1.00
18.98
A
C

ATOM
1196
N
SER
A
151
62.143
55.741
−8.320
1.00
15.58
A
N

ATOM
1197
CA
SER
A
151
62.353
54.360
−8.764
1.00
13.42
A
C

ATOM
1198
C
SER
A
151
63.779
53.904
−8.612
1.00
15.43
A
C

ATOM
1199
O
SER
A
151
64.717
54.708
−8.638
1.00
17.96
A
O

ATOM
1200
CB
SER
A
151
61.880
54.171
−10.200
1.00
18.86
A
C

ATOM
1201
OG
SER
A
151
62.440
55.169
−11.021
1.00
19.88
A
O

ATOM
1202
N
LEU
A
152
63.932
52.603
−8.401
1.00
15.64
A
N

ATOM
1203
CA
LEU
A
152
65.213
51.992
−8.105
1.00
16.25
A
C

ATOM
1204
C
LEU
A
152
65.456
50.817
−9.015
1.00
17.29
A
C

ATOM
1205
O
LEU
A
152
64.596
49.925
−9.143
1.09
17.99
A
O

ATOM
1206
CB
LEU
A
152
65.248
51.493
−6.650
1.00
16.35
A
C

ATOM
1207
CG
LEU
A
152
65.317
52.590
−5.590
1.00
18.65
A
C

ATOM
1208
CD1
LEU
A
152
65.177
51.994
−4.208
1.00
19.71
A
C

ATOM
1209
CD2
LEU
A
152
66.585
53.418
−5.725
1.00
19.60
A
C

ATOM
1210
N
GLN
A
153
66.618
50.820
−9.646
1.00
19.70
A
N

ATOM
1211
CA
GLN
A
153
67.115
49.692
−10.419
1.00
19.09
A
C

ATOM
1212
C
GLN
A
153
68.422
49.296
−9.747
1.00
17.61
A
C

ATOM
1213
O
GLN
A
153
69.438
49.964
−9.921
1.00
22.26
A
O

ATOM
1214
CB
GLN
A
153
67.368
50.078
−11.883
1.00
23.44
A
C

ATOM
1215
CG
GLN
A
153
67.771
48.873
−12.721
1.00
24.58
A
C

ATOM
1216
CD
GLN
A
153
68.573
49.194
−13.957
1.00
26.89
A
C

ATOM
1217
OE1
GLN
A
153
69.610
49.863
−13.895
1.00
32.38
A
O

ATOM
1218
NE2
GLN
A
153
68.116
48.681
−15.089
1.00
27.76
A
N

ATOM
1219
N
LEU
A
154
68.392
48.247
−8.941
1.00
17.74
A
N

ATOM
1220
CA
LEU
A
154
69.618
47.726
−8.329
1.00
21.30
A
C

ATOM
1221
C
LEU
A
154
70.186
46.576
−9.166
1.00
28.90
A
C

ATOM
1222
O
LEU
A
154
69.479
45.609
−9.464
1.00
29.97
A
O

ATOM
1223
CB
LEU
A
154
69.339
47.276
−6.898
1.00
21.73
A
C

ATOM
1224
CG
LEU
A
154
68.556
48.277
−6.046
1.00
22.21
A
C

ATOM
1225
CD1
LEU
A
154
68.239
47.712
−4.686
1.00
25.89
A
C

ATOM
1226
CD2
LEU
A
154
69.266
49.619
−5.888
1.00
22.60
A
C

ATOM
1227
N
CYS
A
155
71.461
46.678
−9.537
1.00
32.67
A
N

ATOM
1228
CA
CYS
A
155
72.096
45.709
−10.442
1.00
36.54
A
C

ATOM
1229
C
CYS
A
155
73.103
44.805
−9.720
1.00
41.47
A
C

ATOM
1230
O
CYS
A
155
72.719
43.815
−9.116
1.00
43.64
A
O

ATOM
1231
CB
CYS
A
155
72.744
46.440
−11.616
1.09
36.93
A
C

ATOM
1232
SG
CYS
A
155
71.580
47.462
−12.528
1.00
37.02
A
S

ATOM
1233
N
GLY
A
156
74.389
45.122
−9.802
1.00
49.66
A
N

ATOM
1234
CA
GLY
A
156
75.416
44.312
−9.170
1.00
52.13
A
C

ATOM
1235
C
GLY
A
156
75.784
43.035
−9.897
1.00
54.64
A
C

ATOM
1226
O
GLY
A
156
75.586
41.937
−9.372
1.00
55.03
A
O

ATOM
1237
N
ALA
A
157
76.323
43.196
−11.106
1.00
58.96
A
N

ATOM
1238
CA
ALA
A
157
76.935
42.104
−11.872
1.00
59.70
A
C

ATOM
1239
C
ALA
A
157
76.142
40.799
−11.808
1.00
61.26
A
C

ATOM
1240
O
ALA
A
157
76.543
39.845
−11.131
1.00
63.37
A
O

ATOM
1241
CB
ALA
A
157
78.377
41.881
−11.396
1.00
61.07
A
C

ATOM
1242
N
ALA
A
168
81.887
41.703
−5.577
1.00
52.10
A
N

ATOM
1243
CA
ALA
A
168
82.673
42.857
−6.011
1.00
51.66
A
C

ATOM
1244
C
ALA
A
168
81.807
44.132
−6.026
1.00
49.66
A
C

ATOM
1245
O
ALA
A
168
80.833
44.234
−5.270
1.00
47.62
A
O

ATOM
1246
CB
ALA
A
168
83.302
42.585
−7.389
1.00
52.14
A
C

ATOM
1247
N
SER
A
169
82.169
45.100
−6.865
1.00
48.50
A
N

ATOM
1248
CA
SER
A
169
81.455
46.373
−6.933
1.00
47.11
A
C

ATOM
1249
C
SER
A
169
80.128
46.241
−7.693
1.00
45.49
A
C

ATOM
1250
O
SER
A
169
80.102
45.793
−8.833
1.00
42.21
A
O

ATOM
1251
CB
SER
A
169
82.336
47.432
−7.596
1.00
48.06
A
C

ATOM
1252
OG
SER
A
169
81.625
48.637
−7.812
1.00
53.03
A
O

ATOM
1253
N
VAL
A
170
79.036
46.648
−7.048
1.00
40.36
A
N

ATOM
1254
CA
VAL
A
170
77.714
46.662
−7.675
1.00
36.88
A
C

ATOM
1255
C
VAL
A
170
77.329
48.074
−8.121
1.00
33.45
A
C

ATOM
1256
O
VAL
A
170
77.980
49.050
−7.751
1.00
27.09
A
O

ATOM
1257
CB
VAL
A
170
76.636
46.100
−6.714
1.00
35.68
A
C

ATOM
1258
CG1
VAL
A
170
76.978
44.662
−6.301
1.00
38.27
A
C

ATOM
1259
CG2
VAL
A
170
76.471
46.986
−5.476
1.00
36.83
A
C

ATOM
1260
N
GLY
A
171
76.256
48.174
−8.905
1.00
30.02
A
N

ATOM
1261
CA
GLY
A
171
75.760
49.457
−9.360
1.00
28.27
A
C

ATOM
1262
C
GLV
A
171
74.250
49.511
−9.521
1.00
23.99
A
C

ATOM
1263
O
GLY
A
171
73.567
48.502
−9.456
1.00
30.07
A
O

ATOM
1264
N
GLY
A
172
73.748
50.704
−9.785
1.00
22.93
A
N

ATOM
1265
CA
GLY
A
172
72.321
50.912
−9.960
1.00
24.79
A
C

ATOM
1266
C
GLY
A
172
71.921
52.328
−10.318
1.00
21.72
A
C

ATOM
1267
O
GLY
A
172
72.755
53.177
−10.586
1.00
20.97
A
O

ATOM
1268
N
SER
A
173
70.615
52.576
−10.323
1.00
20.55
A
N

ATOM
1269
CA
SER
A
173
70.056
53.881
−10.618
1.00
19.75
A
C

ATOM
1270
C
SER
A
173
68.934
54.169
−9.642
1.00
17.92
A
C

ATOM
1271
O
SER
A
173
68.098
53.318
−9.396
1.00
19.13
A
O

ATOM
1272
CB
SER
A
173
69.490
53.959
−12.045
1.00
20.34
A
C

ATOM
1273
OG
SER
A
173
70.498
53.718
−13.025
1.00
23.31
A
O

ATOM
1274
N
MET
A
174
68.935
55.371
−9.085
1.09
19.22
A
N

ATOM
1275
CA
MET
A
174
67.794
55.904
−8.368
1.00
19.42
A
C

ATOM
1276
C
MET
A
174
67.284
57.099
−9.164
1.00
20.07
A
C

ATOM
1277
O
MET
A
174
67.936
58.150
−9.226
1.00
18.63
A
O

ATOM
1278
CB
MET
A
174
68.156
56.332
−6.953
1.00
19.01
A
C

ATOM
1279
CG
MET
A
174
66.982
56.914
−6.230
1.00
22.45
A
C

ATOM
1280
SD
MET
A
174
67.349
57.388
−4.532
1.00
24.52
A
S

ATOM
1281
CE
MET
A
174
68.659
58.440
−4.766
1.00
27.89
A
C

ATOM
1282
N
ILE
A
175
66.135
56.904
−9.818
1.00
21.08
A
N

ATOM
1283
CA
ILE
A
175
65.469
57.972
−10.548
1.00
16.99
A
C

ATOM
1284
C
ILE
A
175
64.484
58.690
−9.642
1.00
16.84
A
C

ATOM
1285
O
ILE
A
175
63.468
58.119
−9.242
1.00
19.54
A
O

ATOM
1286
CB
ILE
A
175
64.740
57.415
−11.800
1.00
22.71
A
C

ATOM
1287
CG1
ILE
A
175
65.645
56.492
−12.632
1.00
21.64
A
C

ATOM
1288
CG2
ILE
A
175
64.160
58.559
−12.633
1.00
22.47
A
C

ATOM
1289
CD1
ILE
A
175
66.942
57.124
−13.192
1.00
21.34
A
C

ATOM
1290
N
ILE
A
176
64.820
59.929
−9.276
1.00
22.11
A
N

ATOM
1291
CA
ILE
A
176
64.012
60.750
−8.396
1.00
22.51
A
C

ATOM
1292
C
ILE
A
176
63.045
61.581
−9.230
1.00
23.28
A
C

ATOM
1293
O
ILE
A
176
63.464
62.397
−10.056
1.00
27.99
A
O

ATOM
1294
CB
ILE
A
176
64.908
61.703
−7.567
1.00
24.59
A
C

ATOM
1295
CG1
ILE
A
176
65.914
60.917
−6.718
1.00
27.72
A
C

ATOM
1296
CG2
ILE
A
176
64.059
62.601
−6.699
1.00
26.83
A
C

ATOM
1297
CD1
ILE
A
176
65.274
60.104
−5.618
1.00
30.97
A
C

ATOM
1298
N
GLY
A
177
61.762
61.359
−9.003
1.00
23.04
A
N

ATOM
1299
CA
GLY
A
177
60.711
62.169
−9.578
1.00
23.58
A
C

ATOM
1300
C
GLY
A
177
60.114
61.540
−10.810
1.00
27.69
A
C

ATOM
1301
O
GLY
A
177
59.224
62.125
−11.428
1.00
29.57
A
O

ATOM
1302
N
GLY
A
178
60.561
60.340
−11.160
1.00
24.14
A
N

ATOM
1303
CA
GLY
A
178
60.023
59.706
−12.342
1.00
26.72
A
C

ATOM
1304
C
GLY
A
178
60.460
58.295
−12.586
1.00
27.37
A
C

ATOM
1305
O
GLY
A
178
61.017
57.610
−11.712
1.00
24.67
A
O

ATOM
1306
N
ILE
A
179
60.153
57.861
−13.800
1.00
24.35
A
N

ATOM
1307
CA
ILE
A
179
60.475
56.541
−14.300
1.00
28.10
A
C

ATOM
1308
C
ILE
A
179
61.277
56.703
−15.591
1.00
30.00
A
C

ATOM
1309
O
ILE
A
179
61.031
57.640
−16.367
1.00
29.66
A
O

ATOM
1310
CB
ILE
A
179
59.174
55.751
−14.552
1.00
28.71
A
C

ATOM
1311
CG1
ILE
A
179
58.240
55.833
−13.314
1.00
31.09
A
C

ATOM
1312
CG2
ILE
A
179
59.480
54.319
−14.890
1.00
32.54
A
C

ATOM
1313
CD1
ILE
A
179
56.941
55.086
−13.456
1.00
35.50
A
C

ATOM
1314
N
ASP
A
180
62.241
55.806
−15.795
1.00
29.78
A
N

ATOM
1315
CA
ASP
A
180
63.094
55.783
−16.983
1.00
32.20
A
C

ATOM
1316
C
ASP
A
180
62.895
54.450
−17.703
1.00
30.45
A
C

ATOM
1317
O
ASP
A
180
63.345
53.399
−17.240
1.00
27.79
A
O

ATOM
1318
CB
ASP
A
180
64.566
55.955
−16.576
1.00
31.37
A
C

ATOM
1319
CG
ASP
A
180
65.488
56.151
−17.759
1.00
37.38
A
C

ATOM
1320
OD1
ASP
A
180
65.155
55.692
−18.868
1.00
40.09
A
O

ATOM
1321
OD2
ASP
A
180
66.577
56.746
−17.670
1.00
37.04
A
O

ATOM
1322
N
HIS
A
181
62.235
54.504
−18.856
1.00
34.60
A
N

ATOM
1323
CA
HIS
A
181
61.829
53.298
−19.592
1.00
34.97
A
C

ATOM
1324
C
HIS
A
181
62.986
52.434
−20.108
1.00
35.24
A
C

ATOM
1325
O
HIS
A
181
62.825
51.229
−20.323
1.00
34.58
A
O

ATOM
1326
CB
HIS
A
181
60.868
53.695
−20.721
1.00
38.80
A
C

ATOM
1327
CG
HIS
A
181
59.662
54.442
−20.233
0.50
38.66
A
C

ATOM
1328
ND1
HIS
A
181
58.846
53.959
−19.234
0.50
38.35
A
N

ATOM
1329
CD2
HIS
A
181
59.158
55.649
−20.580
0.50
40.41
A
C

ATOM
1330
CE1
HIS
A
181
57.880
54.828
−18.998
0.50
40.15
A
C

ATOM
1331
NE2
HIS
A
181
58.045
55.863
−19.803
0.50
40.15
A
N

ATOM
1332
N
SER
A
182
64.167
53.026
−20.244
1.00
33.98
A
N

ATOM
1333
CA
SER
A
182
65.369
52.269
−20.589
1.00
34.19
A
C

ATOM
1334
C
SER
A
182
65.834
51.304
−19.484
1.00
31.16
A
C

ATOM
1335
O
SER
A
182
66.638
50.418
−19.736
1.00
29.95
A
O

ATOM
1336
CB
SER
A
182
66.507
53.230
−20.966
1.00
36.56
A
C

ATOM
1337
OG
SER
A
182
66.853
54.088
−19.886
1.00
39.80
A
O

ATOM
1338
N
LEU
A
183
65.318
51.458
−18.261
1.00
28.19
A
N

ATOM
1339
CA
LEU
A
183
65.719
50.607
−17.156
1.00
26.88
A
C

ATOM
1340
C
LEU
A
183
64.920
49.310
−17.012
1.00
26.28
A
C

ATOM
1341
O
LEU
A
183
65.267
48.479
−16.178
1.00
21.62
A
O

ATOM
1342
CB
LEU
A
183
65.646
51.397
−15.838
1.00
26.71
A
C

ATOM
1343
CG
LEU
A
183
66.557
52.620
−15.805
1.00
30.09
A
C

ATOM
1344
CD1
LEU
A
183
66.413
53.360
−14.479
1.00
28.34
A
C

ATOM
1345
CD2
LEU
A
183
67.997
52.185
−16.027
1.00
33.43
A
C

ATOM
1346
N
TYR
A
184
63.865
49.130
−17.822
1.00
26.39
A
N

ATOM
1347
CA
TYR
A
184
63.038
47.935
−17.710
1.00
22.78
A
C

ATOM
1348
C
TYR
A
184
62.486
47.453
−19.040
1.00
22.69
A
C

ATOM
1349
O
TYR
A
184
62.380
48.227
−19.990
1.00
23.92
A
O

ATOM
1350
CB
TYR
A
184
61.856
48.135
−16.742
1.00
22.73
A
C

ATOM
1351
CG
TYR
A
184
60.726
49.040
−17.193
1.00
20.79
A
C

ATOM
1352
CD1
TYR
A
184
59.540
48.523
−17.735
1.00
21.72
A
C

ATOM
1353
CD2
TYR
A
184
60.812
50.410
−17.035
1.00
23.49
A
C

ATOM
1354
CE1
TYR
A
184
58.500
49.357
−18.123
1.00
23.85
A
C

ATOM
1355
CE2
TYR
A
184
59.776
51.250
−17.395
1.00
21.72
A
C

ATOM
1356
CZ
TYR
A
184
58.616
50.718
−17.949
1.00
23.96
A
C

ATOM
1357
OH
TYR
A
184
57.603
51.567
−18.306
1.00
27.89
A
O

ATOM
1358
N
THR
A
185
62.082
46.190
−19.048
1.00
26.60
A
N

ATOM
1359
CA
THR
A
185
61.397
45.590
−20.194
1.00
23.12
A
C

ATOM
1360
C
THR
A
185
60.012
45.120
−19.777
1.00
26.64
A
C

ATOM
1361
O
THR
A
185
59.754
44.849
−18.608
1.00
24.65
A
O

ATOM
1362
CB
THR
A
185
62.215
44.414
−20.801
1.00
25.79
A
C

ATOM
1363
OG1
THR
A
185
62.261
43.299
−19.906
1.00
28.94
A
O

ATOM
1364
CG2
THR
A
185
63.702
44.791
−20.980
1.00
32.36
A
C

ATOM
1365
N
GLY
A
186
59.127
44.998
−20.762
1.00
30.22
A
N

ATOM
1366
CA
GLY
A
186
57.765
44.602
−20.489
1.00
28.03
A
C

ATOM
1367
C
GLY
A
186
57.019
45.726
−19.805
1.00
24.17
A
C

ATOM
1368
O
GLY
A
186
57.380
46.894
−19.927
1.00
29.37
A
O

ATOM
1369
N
SER
A
187
55.952
45.365
−19.102
1.00
23.81
A
N

ATOM
1370
CA
SER
A
187
55.062
46.328
−18.488
1.00
21.71
A
C

ATOM
1371
C
SER
A
187
55.311
46.342
−16.996
1.00
19.66
A
C

ATOM
1372
O
SER
A
187
55.732
45.342
−16.426
1.00
20.42
A
O

ATOM
1373
CB
SER
A
187
53.601
45.940
−18.750
1.00
23.20
A
C

ATOM
1374
OG
SER
A
187
52.695
46.740
−18.000
1.00
25.16
A
O

ATOM
1375
N
LEU
A
188
55.046
47.493
−16.390
1.00
18.89
A
N

ATOM
1376
CA
LEU
A
188
54.965
47.608
−14.928
1.00
17.77
A
C

ATOM
1377
C
LEU
A
188
53.629
47.054
−14.466
1.00
19.39
A
C

ATOM
1378
O
LEU
A
188
52.601
47.299
−15.082
1.00
21.63
A
O

ATOM
1379
CB
LEU
A
188
55.067
49.054
−14.470
1.00
18.74
A
C

ATOM
1380
CG
LEU
A
188
56.433
49.736
−14.522
1.00
18.45
A
C

ATOM
1381
CD1
LEU
A
188
56.311
51.222
−14.556
1.00
20.69
A
C

ATOM
1382
CD2
LEU
A
188
57.295
49.273
−13.305
1.00
19.48
A
C

ATOM
1383
N
TRP
A
189
53.670
46.295
−13.384
1.00
13.99
A
N

ATOM
1384
CA
TRP
A
189
52.524
45.838
−12.633
1.00
15.66
A
C

ATOM
1385
C
TRP
A
189
52.595
46.453
−11.245
1.00
16.26
A
C

ATOM
1386
O
TRP
A
189
53.650
46.442
−10.633
1.00
17.41
A
O

ATOM
1387
CB
TRP
A
189
52.542
44.325
−12.516
1.00
15.88
A
C

ATOM
1388
CG
TRP
A
189
52.121
43.681
−13.817
1.00
18.59
A
C

ATOM
1389
CD1
TRP
A
189
52.916
43.461
−14.898
1.00
21.85
A
C

ATOM
1390
CD2
TRP
A
189
50.800
43.262
−14.200
1.00
18.24
A
C

ATOM
1391
NE1
TRP
A
189
52.189
42.888
−15.919
1.00
23.05
A
N

ATOM
1392
CE2
TRP
A
189
50.885
42.772
−15.522
1.00
19.78
A
C

ATOM
1393
CE3
TRP
A
189
49.552
43.264
−13.570
1.00
15.96
A
C

ATOM
1394
CZ2
TRP
A
189
49.777
42.292
−16.224
1.00
20.18
A
C

ATOM
1395
CZ3
TRP
A
189
48.436
42.778
−14.274
1.00
17.80
A
C

ATOM
1396
CH2
TRP
A
189
48.570
42.298
−15.590
1.00
16.72
A
C

ATOM
1397
N
TYR
A
190
51.467
46.920
−10.739
1.00
14.59
A
N

ATOM
1398
CA
TYR
A
190
51.425
47.625
−9.453
1.00
14.85
A
C

ATOM
1399
C
TYR
A
190
50.631
46.901
−8.353
1.00
17.95
A
C

ATOM
1400
O
TYR
A
190
49.564
46.289
−8.586
1.00
13.30
A
O

ATOM
1401
CB
TYR
A
190
50.864
49.021
−9.636
1.00
13.88
A
C

ATOM
1402
CG
TYR
A
190
51.635
49.973
−10.515
1.00
15.59
A
C

ATOM
1403
CD1
TYR
A
190
52.573
50.842
−9.977
1.00
15.38
A
C

ATOM
1404
CD2
TYR
A
190
51.339
50.092
−11.866
1.00
17.42
A
C

ATOM
1405
CE1
TYR
A
190
53.237
51.770
−10.760
1.00
17.56
A
C

ATOM
1406
CE2
TYR
A
190
52.018
51.038
−12.685
1.00
14.93
A
C

ATOM
1407
CZ
TYR
A
190
52.954
51.873
−12.107
1.00
18.74
A
C

ATOM
1408
OH
TYR
A
190
53.638
52.785
−12.865
1.00
17.23
A
O

ATOM
1409
N
THR
A
191
51.182
46.980
−7.139
1.00
16.74
A
N

ATOM
1410
CA
THR
A
191
50.568
46.429
−5.953
1.00
15.64
A
C

ATOM
1411
C
THR
A
191
50.304
47.626
−5.008
1.00
17.89
A
C

ATOM
1412
O
THR
A
191
51.106
48.544
−4.975
1.00
16.52
A
O

ATOM
1413
CB
THR
A
191
51.520
45.392
−5.357
1.00
16.95
A
C

ATOM
1414
OG1
THR
A
191
50.861
44.672
−4.325
1.00
19.32
A
O

ATOM
1415
CG2
THR
A
191
52.768
46.057
−4.680
1.00
16.37
A
C

ATOM
1416
N
PRO
A
192
49.168
47.686
−4.309
1.00
20.12
A
N

ATOM
1417
CA
PRO
A
192
48.944
48.801
−3.365
1.00
21.23
A
C

ATOM
1418
C
PRO
A
192
49.911
48.871
−2.178
1.00
17.60
A
C

ATOM
1419
O
PRO
A
192
50.370
47.856
−1.643
1.00
24.36
A
O

ATOM
1420
CB
PRO
A
192
47.504
48.585
−2.876
1.00
21.11
A
C

ATOM
1421
CG
PRO
A
192
46.881
47.748
−3.955
1.00
22.26
A
C

ATOM
1422
CD
PRO
A
192
47.980
46.828
−4.424
1.00
23.51
A
C

ATOM
1423
N
ILE
A
193
50.235
50.099
−1.797
1.00
21.72
A
N

ATOM
1424
CA
ILE
A
193
50.881
50.339
−0.515
1.00
22.71
A
C

ATOM
1425
C
ILE
A
193
49.758
50.230
0.508
1.00
23.63
A
C

ATOM
1426
O
ILE
A
193
48.881
51.079
0.568
1.00
29.68
A
O

ATOM
1427
CB
ILE
A
193
51.550
51.713
−0.453
1.00
24.36
A
C

ATOM
1428
CG1
ILE
A
193
52.730
51.781
−1.438
1.00
24.14
A
C

ATOM
1429
CG2
ILE
A
193
52.036
51.993
0.987
1.00
24.12
A
C

ATOM
1430
CD1
ILE
A
193
53.313
53.171
−1.629
1.00
22.49
A
C

ATOM
1431
N
ARG
A
194
49.764
49.145
1.257
1.00
29.07
A
N

ATOM
1432
CA
ARG
A
194
48.696
48.887
2.199
1.00
32.57
A
C

ATOM
1433
C
ARG
A
194
48.547
50.005
3.219
1.00
33.92
A
C

ATOM
1434
O
ARG
A
194
47.446
50.517
3.435
1.00
36.50
A
O

ATOM
1435
CB
ARG
A
194
48.940
47.592
2.930
1.00
31.65
A
C

ATOM
1436
CG
ARG
A
194
47.768
47.245
3.797
1.00
32.32
A
C

ATOM
1437
CD
ARG
A
194
48.031
46.137
4.719
1.00
34.05
A
C

ATOM
1438
NE
ARG
A
194
46.832
45.833
5.482
1.00
37.69
A
N

ATOM
1439
CZ
ARG
A
194
46.774
44.914
6.424
1.00
43.49
A
C

ATOM
1440
NH1
ARG
A
194
47.853
44.211
6.726
1.00
45.66
A
N

ATOM
1441
NH2
ARG
A
194
45.636
44.700
7.079
1.00
44.35
A
N

ATOM
1442
N
ARG
A
195
49.668
50.353
3.839
1.00
35.28
A
N

ATOM
1443
CA
ARG
A
195
49.740
51.436
4.817
1.00
35.11
A
C

ATOM
1444
C
ARG
A
195
51.059
52.190
4.631
1.00
32.34
A
C

ATOM
1445
O
ARG
A
195
52.089
51.576
4.401
1.00
28.84
A
O

ATOM
1446
CB
ARG
A
195
49.683
50.857
6.226
1.00
35.59
A
C

ATOM
1447
CG
ARG
A
195
49.645
51.910
7.339
1.00
40.30
A
C

ATOM
1448
CD
ARG
A
195
48.907
51.460
8.591
1.00
43.51
A
C

ATOM
1449
NE
ARG
A
195
49.734
50.619
9.458
1.00
44.69
A
N

ATOM
1450
CZ
ARG
A
195
50.582
51.069
10.387
1.00
46.19
A
C

ATOM
1451
NH1
ARG
A
195
50.753
52.371
10.585
1.00
46.87
A
N

ATOM
1452
NH2
ARG
A
195
51.274
50.201
11.124
1.00
46.12
A
N

ATOM
1453
N
GLU
A
196
51.016
53.508
4.766
1.00
33.16
A
N

ATOM
1454
CA
GLU
A
196
52.167
54.353
4.500
1.00
34.04
A
C

ATOM
1455
C
GLU
A
196
52.963
54.554
5.774
1.00
31.83
A
C

ATOM
1456
O
GLU
A
196
52.790
55.566
6.460
1.00
35.74
A
O

ATOM
1457
CB
GLU
A
196
51.728
55.699
3.953
1.00
33.34
A
C

ATOM
1458
CG
GLU
A
196
50.986
55.643
2.624
1.00
38.79
A
C

ATOM
1459
CD
GLU
A
196
50.230
56.927
2.341
1.00
42.74
A
C

ATOM
1460
OE1
GLU
A
196
49.199
57.182
3.009
1.00
47.60
A
O

ATOM
1461
OE2
GLU
A
196
50.661
57.688
1.450
1.00
42.51
A
O

ATOM
1462
N
TRP
A
197
53.805
53.567
6.075
1.00
29.99
A
N

ATOM
1463
CA
TRP
A
197
54.773
53.629
7.184
1.00
32.01
A
C

ATOM
1464
C
TRP
A
197
56.104
53.059
6.668
1.00
29.04
A
C

ATOM
1465
O
TRP
A
197
56.938
53.829
6.210
1.00
30.54
A
O

ATOM
1466
CB
TRP
A
197
54.229
52.970
8.474
1.00
31.92
A
C

ATOM
1467
CG
TRP
A
197
53.800
51.538
8.412
1.00
36.08
A
C

ATOM
1468
CD1
TRP
A
197
53.091
50.926
7.418
1.00
36.38
A
C

ATOM
1469
CD2
TRP
A
197
54.023
50.532
9.414
1.00
40.65
A
C

ATOM
1470
NE1
TRP
A
197
52.887
49.605
7.726
1.00
40.70
A
N

ATOM
1471
CE2
TRP
A
197
53.446
49.337
8.948
1.00
41.77
A
C

ATOM
1472
CE3
TRP
A
197
54.672
50.518
10.658
1.00
41.22
A
C

ATOM
1473
CZ2
TRP
A
197
53.486
48.146
9.680
1.00
43.13
A
C

ATOM
1474
CZ3
TRP
A
197
54.720
49.337
11.381
1.00
40.93
A
C

ATOM
1475
CH2
TRP
A
197
54.129
48.166
10.891
1.00
42.69
A
C

ATOM
1476
N
TYR
A
198
56.303
51.746
6.699
1.00
24.59
A
N

ATOM
1477
CA
TYR
A
198
57.184
51.077
5.740
1.00
25.69
A
C

ATOM
1478
C
TYR
A
198
56.456
51.094
4.391
1.00
22.71
A
C

ATOM
1479
O
TYR
A
198
55.317
51.519
4.305
1.00
25.15
A
O

ATOM
1480
CB
TYR
A
198
57.455
49.620
6.110
1.00
28.07
A
C

ATOM
1481
CG
TYR
A
198
58.137
49.394
7.453
1.00
32.69
A
C

ATOM
1482
CD1
TYR
A
198
59.514
49.273
7.541
1.00
36.04
A
C

ATOM
1483
CD2
TYR
A
198
57.393
49.289
8.627
1.00
35.45
A
C

ATOM
1484
CE1
TYR
A
198
60.146
49.054
8.769
1.00
35.82
A
C

ATOM
1485
CE2
TYR
A
198
58.015
49.079
9.865
1.00
36.80
A
C

ATOM
1486
CZ
TYR
A
198
59.385
48.962
9.927
1.00
38.75
A
C

ATOM
1487
OH
TYR
A
198
60.007
48.744
11.143
1.00
38.81
A
O

ATOM
1488
N
TYR
A
199
57.142
50.654
3.347
1.00
21.11
A
N

ATOM
1489
CA
TYR
A
199
56.497
50.364
2.048
1.00
21.41
A
C

ATOM
1490
C
TYR
A
199
55.866
48.991
2.152
1.00
18.46
A
C

ATOM
1491
O
TYR
A
199
56.471
47.969
1.784
1.00
18.42
A
O

ATOM
1492
CB
TYR
A
199
57.521
50.484
0.914
1.00
21.15
A
C

ATOM
1493
CG
TYR
A
199
57.861
51.927
0.640
1.00
18.31
A
C

ATOM
1494
CD1
TYR
A
199
56.965
52.770
−0.020
1.00
17.27
A
C

ATOM
1495
CD2
TYR
A
199
59.078
52.478
1.059
1.00
17.06
A
C

ATOM
1496
CE1
TYR
A
199
57.275
54.106
−0.239
1.00
18.14
A
C

ATOM
1497
CE2
TYR
A
199
59.394
53.799
0.816
1.00
14.53
A
C

ATOM
1498
CZ
TYR
A
199
58.510
54.608
0.178
1.00
17.63
A
C

ATOM
1499
OH
TYR
A
199
58.822
55.911
−0.024
1.00
17.71
A
O

ATOM
1500
N
GLU
A
200
54.664
48.979
2.742
1.00
21.57
A
N

ATOM
1501
CA
GLU
A
200
54.004
47.722
3.098
1.00
22.77
A
C

ATOM
1502
C
GLU
A
200
53.206
47.182
1.904
1.00
16.75
A
C

ATOM
1503
O
GLU
A
200
52.457
47.916
1.322
1.00
24.39
A
O

ATOM
1504
CB
GLU
A
200
53.030
47.909
4.260
1.00
24.90
A
C

ATOM
1505
CG
GLU
A
200
52.680
46.604
4.946
1.00
27.85
A
C

ATOM
1506
CD
GLU
A
200
51.514
46.716
5.919
1.00
28.16
A
C

ATOM
1507
OE1
GLU
A
200
51.081
47.840
6.278
1.00
35.16
A
O

ATOM
1508
OE2
GLU
A
200
50.987
45.649
6.300
1.00
34.56
A
O

ATOM
1509
N
VAL
A
201
53.386
45.920
1.596
1.00
22.87
A
N

ATOM
1510
CA
VAL
A
201
52.595
45.240
0.554
1.00
21.15
A
C

ATOM
1511
C
VAL
A
201
52.057
43.892
1.045
1.00
26.77
A
C

ATOM
1512
O
VAL
A
201
52.462
43.402
2.103
1.00
26.68
A
O

ATOM
1513
CB
VAL
A
201
53.455
44.997
−0.684
1.00
22.52
A
C

ATOM
1514
CG1
VAL
A
201
54.012
46.314
−1.198
1.00
22.34
A
C

ATOM
1515
CG2
VAL
A
201
54.593
43.991
−0.400
1.00
23.70
A
C

ATOM
1516
N
ILE
A
202
51.187
43.262
0.248
1.00
20.41
A
N

ATOM
1517
CA
ILE
A
202
50.579
41.984
0.632
1.00
24.08
A
C

ATOM
1518
C
ILE
A
262
50.901
40.908
−0.404
1.00
23.18
A
C

ATOM
1519
O
ILE
A
202
50.569
41.064
−1.572
1.00
21.92
A
O

ATOM
1520
CB
ILE
A
202
49.041
42.119
0.801
1.00
24.91
A
C

ATOM
1521
CG1
ILE
A
202
48.697
43.058
1.967
1.00
28.97
A
C

ATOM
1522
CG2
ILE
A
202
48.410
40.742
1.042
1.00
26.55
A
C

ATOM
1523
CD1
ILE
A
202
47.237
43.384
2.081
1.00
28.35
A
C

ATOM
1524
N
ILE
A
203
51.552
39.836
0.037
1.00
20.58
A
N

ATOM
1525
CA
ILE
A
203
51.806
38.642
−0.749
1.00
23.06
A
C

ATOM
1526
C
ILE
A
203
50.600
37.712
−0.588
1.00
23.74
A
C

ATOM
1527
O
ILE
A
203
50.113
37.480
0.521
1.00
25.10
A
O

ATOM
1528
CB
ILE
A
203
53.097
37.940
−0.293
1.00
24.14
A
C

ATOM
1529
CG1
ILE
A
203
54.310
38.807
−0.656
1.00
25.32
A
C

ATOM
1530
CG2
ILE
A
203
53.196
36.561
−0.924
1.00
23.21
A
C

ATOM
1531
CD1
ILE
A
203
55.655
38.280
−0.193
1.00
30.24
A
C

ATOM
1532
N
VAL
A
204
50.065
37.249
−1.705
1.00
24.79
A
N

ATOM
1533
CA
VAL
A
204
48.827
36.465
−1.685
1.00
22.84
A
C

ATOM
1534
C
VAL
A
204
49.050
34.992
−2.011
1.00
27.15
A
C

ATOM
1535
O
VAL
A
204
48.192
34.158
−1.721
1.00
28.57
A
O

ATOM
1536
CB
VAL
A
204
47.764
37.091
−2.640
1.00
21.80
A
C

ATOM
1537
CG1
VAL
A
204
47.505
38.524
−2.253
1.00
20.60
A
C

ATOM
1538
CG2
VAL
A
204
48.210
36.970
−4.075
1.00
24.51
A
C

ATOM
1539
N
ARG
A
205
50.191
34.678
−2.612
1.00
24.48
A
N

ATOM
1540
CA
ARG
A
205
50.540
33.330
−3.018
1.00
27.35
A
C

ATOM
1541
C
ARG
A
205
52.049
33.204
−3.207
1.00
32.98
A
C

ATOM
1542
O
ARG
A
205
52.755
34.167
−3.563
1.00
24.15
A
O

ATOM
1543
CB
ARG
A
205
49.815
32.977
−4.325
1.00
30.35
A
C

ATOM
1544
CG
ARG
A
205
49.857
31.540
−4.763
1.00
33.44
A
C

ATOM
1545
CD
ARG
A
205
49.122
31.314
−6.095
1.00
36.40
A
C

ATOM
1546
NE
ARG
A
205
49.502
30.060
−6.747
1.00
40.66
A
N

ATOM
1547
CZ
ARG
A
205
48.730
28.978
−6.838
1.00
44.96
A
C

ATOM
1548
NH1
ARG
A
205
47.510
28.961
−6.312
1.00
49.55
A
N

ATOM
1549
NH2
ARG
A
205
49.185
27.893
−7.457
1.00
48.81
A
N

ATOM
1550
N
VAL
A
206
52.548
32.004
−2.961
1.00
31.90
A
N

ATOM
1551
CA
VAL
A
206
53.955
31.713
−3.133
1.00
31.00
A
C

ATOM
1552
C
VAL
A
206
54.077
30.348
−3.747
1.00
36.19
A
C

ATOM
1553
O
VAL
A
206
53.523
29.380
−3.227
1.00
37.64
A
O

ATOM
1554
CB
VAL
A
206
54.727
31.762
−1.786
1.00
34.34
A
C

ATOM
1555
CG1
VAL
A
206
56.208
31.653
−2.026
1.00
38.60
A
C

ATOM
1556
CG2
VAL
A
206
54.407
33.029
−1.020
1.00
34.28
A
C

ATOM
1557
N
GLU
A
207
54.746
30.296
−4.889
1.00
35.57
A
N

ATOM
1558
CA
GLU
A
207
55.129
29.059
−5.525
1.00
40.01
A
C

ATOM
1559
C
GLU
A
207
56.630
28.880
−5.382
1.00
43.14
A
C

ATOM
1560
O
GLU
A
207
57.371
29.858
−5.263
1.00
38.43
A
O

ATOM
1561
CB
GLU
A
207
54.766
29.102
−7.007
1.00
41.74
A
C

ATOM
1562
CG
GLU
A
207
53.270
29.123
−7.274
1.00
41.66
A
C

ATOM
1563
CD
GLU
A
207
52.934
29.348
−8.733
1.00
41.56
A
C

ATOM
1564
OE1
GLU
A
207
53.854
29.540
−9.548
1.00
40.42
A
O

ATOM
1565
OE2
GLU
A
207
51.733
29.347
−9.071
1.00
47.50
A
O

ATOM
1566
N
ILE
A
208
57.063
27.620
−5.371
1.00
44.90
A
N

ATOM
1567
CA
ILE
A
208
58.462
27.260
−5.592
1.00
48.28
A
C

ATOM
1568
C
ILE
A
208
58.488
26.248
−6.737
1.00
50.10
A
C

ATOM
1569
O
ILE
A
208
57.926
25.155
−6.628
1.00
48.21
A
O

ATOM
1570
CB
ILE
A
208
59.106
26.692
−4.312
1.00
48.76
A
C

ATOM
1571
CG1
ILE
A
208
59.185
27.770
−3.227
1.00
50.92
A
C

ATOM
1572
CG2
ILE
A
208
60.499
26.179
−4.607
1.00
50.10
A
C

ATOM
1573
CD1
ILE
A
208
59.221
27.225
−1.835
1.00
52.20
A
C

ATOM
1574
N
ASN
A
209
59.102
26.647
−7.846
1.00
51.40
A
N

ATOM
1575
CA
ASN
A
209
59.111
25.882
−9.091
1.00
56.38
A
C

ATOM
1576
C
ASN
A
209
57.756
25.851
−9.827
1.00
56.68
A
C

ATOM
1577
O
ASN
A
209
57.689
25.425
−10.982
1.00
55.91
A
O

ATOM
1578
CB
ASN
A
209
59.636
24.456
−8.847
1.00
58.04
A
C

ATOM
1579
CG
ASN
A
209
60.332
23.865
−10.064
1.00
60.28
A
C

ATOM
1580
OD1
ASN
A
209
60.251
22.656
−10.316
1.00
65.04
A
O

ATOM
1581
ND2
ASN
A
209
61.025
24.707
−10.820
1.00
62.80
A
N

ATOM
1582
N
GLY
A
210
56.696
26.338
−9.181
1.00
56.56
A
N

ATOM
1583
CA
GLY
A
210
55.345
26.202
−9.699
1.00
56.62
A
C

ATOM
1584
C
GLY
A
210
54.374
25.584
−8.708
1.00
57.30
A
C

ATOM
1585
O
GLY
A
210
53.169
25.564
−8.959
1.00
58.65
A
O

ATOM
1586
N
GLN
A
211
54.885
25.094
−7.582
1.00
56.04
A
N

ATOM
1587
CA
GLN
A
211
54.071
24.409
−6.589
1.00
56.19
A
C

ATOM
1588
C
GLN
A
211
53.873
25.311
−5.383
1.00
55.79
A
C

ATOM
1589
O
GLN
A
211
54.839
25.720
−4.748
1.00
51.74
A
O

ATOM
1590
CB
GLN
A
211
54.761
23.112
−6.168
1.00
58.40
A
C

ATOM
1591
CG
GLN
A
211
54.940
22.113
−7.308
1.00
60.83
A
C

ATOM
1592
CD
GLN
A
211
55.915
20.988
−6.973
1.00
64.24
A
C

ATOM
1593
OE1
GLN
A
211
56.594
20.463
−7.863
1.00
64.43
A
O

ATOM
1594
NE2
GLN
A
211
55.983
20.614
−5.694
1.00
66.64
A
N

ATOM
1595
N
ASP
A
212
52.628
25.626
−5.048
1.00
54.01
A
N

ATOM
1596
CA
ASP
A
212
52.407
26.569
−3.959
1.00
56.91
A
C

ATOM
1597
C
ASP
A
212
52.447
25.914
−2.575
1.00
57.30
A
C

ATOM
1598
O
ASP
A
212
52.369
24.693
−2.454
1.00
55.10
A
O

ATOM
1599
CB
ASP
A
212
51.157
27.428
−4.209
1.00
56.98
A
C

ATOM
1600
CG
ASP
A
212
49.890
26.788
−3.737
1.00
57.67
A
C

ATOM
1601
OD1
ASP
A
212
49.566
25.680
−4.212
1.00
57.46
A
O

ATOM
1602
OD2
ASP
A
212
49.139
27.347
−2.909
1.00
59.70
A
O

ATOM
1603
N
LEU
A
213
52.623
26.738
−1.545
1.00
58.77
A
N

ATOM
1604
CA
LEU
A
213
52.860
26.263
−0.176
1.00
60.89
A
C

ATOM
1605
C
LEU
A
213
51.546
26.024
0.566
1.00
61.05
A
C

ATOM
1606
O
LEU
A
213
51.518
25.356
1.596
1.00
58.81
A
O

ATOM
1607
CB
LEU
A
213
53.725
27.270
0.598
1.00
61.26
A
C

ATOM
1608
CG
LEU
A
213
55.223
27.312
0.263
1.00
62.51
A
C

ATOM
1609
CD1
LEU
A
213
55.490
27.170
−1.234
1.00
62.99
A
C

ATOM
1610
CD2
LEU
A
213
55.857
28.602
0.793
1.00
63.51
A
C

ATOM
1611
N
LYS
A
214
50.470
26.602
0.039
1.00
62.93
A
N

ATOM
1612
CA
LYS
A
214
49.107
26.273
0.441
1.00
65.41
A
C

ATOM
1613
C
LYS
A
214
48.812
26.553
1.915
1.00
64.81
A
C

ATOM
1614
O
LYS
A
214
47.985
25.872
2.523
1.00
66.72
A
O

ATOM
1615
CB
LYS
A
214
48.781
24.808
0.083
1.00
66.77
A
C

ATOM
1616
CG
LYS
A
214
47.364
24.625
−0.469
1.00
69.56
A
C

ATOM
1617
CD
LYS
A
214
46.931
23.158
−0.553
1.00
70.85
A
C

ATOM
1618
CE
LYS
A
214
45.423
23.023
−0.346
1.00
70.83
A
C

ATOM
1619
NZ
LYS
A
214
44.873
21.747
−0.879
1.00
72.20
A
N

ATOM
1620
N
MET
A
215
49.465
27.568
2.480
1.00
62.76
A
N

ATOM
1621
CA
MET
A
215
49.187
27.959
3.862
1.00
61.10
A
C

ATOM
1622
C
MET
A
215
48.402
29.267
3.925
1.00
57.64
A
C

ATOM
1623
O
MET
A
215
48.495
30.102
3.024
1.00
57.95
A
O

ATOM
1624
CB
MET
A
215
50.474
28.035
4.701
1.00
62.37
A
C

ATOM
1625
CG
MET
A
215
51.555
28.957
4.190
1.00
63.11
A
C

ATOM
1626
SD
MET
A
215
53.067
28.833
5.203
1.00
62.67
A
S

ATOM
1627
CE
MET
A
215
54.211
28.376
3.978
1.00
62.72
A
C

ATOM
1628
N
ASP
A
216
47.599
29.420
4.976
1.00
53.34
A
N

ATOM
1629
CA
ASP
A
216
46.873
30.660
5.220
1.00
52.79
A
C

ATOM
1630
C
ASP
A
216
47.755
31.819
4.770
1.00
51.45
A
C

ATOM
1631
O
ASP
A
216
48.861
32.008
5.283
1.00
45.58
A
O

ATOM
1632
CB
ASP
A
216
46.517
30.792
6.705
1.00
53.42
A
C

ATOM
1633
CG
ASP
A
216
45.523
31.911
6.981
1.00
55.05
A
C

ATOM
1634
OD1
ASP
A
216
45.109
32.639
6.045
1.00
53.37
A
O

ATOM
1635
OD2
ASP
A
216
45.096
32.134
8.132
1.00
59.33
A
O

ATOM
1636
N
CYS
A
217
47.285
32.567
3.779
1.00
49.19
A
N

ATOM
1637
CA
CYS
A
217
48.119
33.601
3.172
1.00
49.39
A
C

ATOM
1638
C
CYS
A
217
48.345
34.770
4.144
1.00
48.78
A
C

ATOM
1639
O
CYS
A
217
49.274
35.554
3.966
1.00
49.38
A
O

ATOM
1640
CB
CYS
A
217
47.515
34.072
1.843
1.00
46.23
A
C

ATOM
1641
SG
CYS
A
217
45.917
34.862
2.016
1.00
48.31
A
S

ATOM
1642
N
LYS
A
218
47.489
34.869
5.166
1.00
48.17
A
N

ATOM
1643
CA
LYS
A
218
47.671
35.792
6.291
1.00
46.87
A
C

ATOM
1644
C
LYS
A
218
49.055
35.646
6.937
1.00
44.90
A
C

ATOM
1645
O
LYS
A
218
49.632
36.624
7.446
1.00
37.36
A
O

ATOM
1646
CB
LYS
A
218
46.585
35.551
7.345
1.00
48.51
A
C

ATOM
1647
CG
LYS
A
218
46.222
36.772
8.167
1.00
52.96
A
C

ATOM
1648
CD
LYS
A
218
44.760
36.731
8.616
1.00
54.70
A
C

ATOM
1649
CE
LYS
A
218
44.287
38.081
9.134
1.00
56.36
A
C

ATOM
1650
NZ
LYS
A
218
42.812
38.224
8.965
1.00
58.19
A
N

ATOM
1651
N
GLU
A
219
49.579
34.425
6.899
1.00
41.30
A
N

ATOM
1652
CA
GLU
A
219
50.894
34.118
7.460
1.00
41.57
A
C

ATOM
1653
C
GLU
A
219
52.043
34.739
6.674
1.00
41.40
A
C

ATOM
1654
O
GLU
A
219
53.112
35.003
7.245
1.00
38.39
A
O

ATOM
1655
CB
GLU
A
219
51.129
32.603
7.526
1.00
42.52
A
C

ATOM
1656
CG
GLU
A
219
50.072
31.806
8.284
1.00
43.99
A
C

ATOM
1657
CD
GLU
A
219
50.103
32.015
9.793
1.00
49.15
A
C

ATOM
1658
OE1
GLU
A
219
49.422
31.235
10.503
1.00
49.54
A
O

ATOM
1659
OE2
GLU
A
219
50.786
32.950
10.276
1.00
47.89
A
O

ATOM
1660
N
TYR
A
220
51.851
34.902
5.364
1.00
35.85
A
N

ATOM
1661
CA
TYR
A
220
52.867
35.487
4.479
1.00
35.18
A
C

ATOM
1662
C
TYR
A
220
53.164
36.913
4.830
1.00
28.13
A
C

ATOM
1663
O
TYR
A
220
54.185
37.465
4.445
1.00
34.25
A
O

ATOM
1664
CB
TYR
A
220
52.413
35.452
3.004
1.00
36.98
A
C

ATOM
1665
CG
TYR
A
220
52.256
34.069
2.389
1.00
37.36
A
C

ATOM
1666
CD1
TYR
A
220
51.233
33.809
1.478
1.00
37.78
A
C

ATOM
1667
CD2
TYR
A
220
53.132
33.026
2.702
1.00
40.58
A
C

ATOM
1668
CE1
TYR
A
220
51.093
32.557
0.894
1.00
38.43
A
C

ATOM
1669
CE2
TYR
A
220
52.996
31.775
2.136
1.00
40.55
A
C

ATOM
1670
CZ
TYR
A
220
51.962
31.539
1.233
1.00
41.11
A
C

ATOM
1671
OH
TYR
A
220
51.819
30.299
0.656
1.00
42.27
A
O

ATOM
1672
N
ASN
A
221
52.230
37.542
5.520
1.00
33.23
A
N

ATOM
1673
CA
ASN
A
221
52.322
38.933
5.865
1.00
35.09
A
C

ATOM
1674
C
ASN
A
221
52.201
39.102
7.363
1.00
31.87
A
C

ATOM
1675
O
ASN
A
221
51.682
40.126
7.831
1.00
33.51
A
O

ATOM
1676
CB
ASN
A
221
51.201
39.649
5.143
1.00
36.43
A
C

ATOM
1677
CG
ASN
A
221
51.102
39.213
3.695
1.00
37.85
A
C

ATOM
1678
OD1
ASN
A
221
50.157
38.521
3.300
1.00
33.97
A
O

ATOM
1679
ND2
ASN
A
221
52.119
39.561
2.910
1.00
28.28
A
N

ATOM
1680
N
TYR
A
222
52.668
38.088
8.091
1.00
39.46
A
N

ATOM
1681
CA
TYR
A
222
52.401
37.971
9.525
1.00
42.38
A
C

ATOM
1682
C
TYR
A
222
53.237
39.004
10.244
1.00
43.57
A
C

ATOM
1683
O
TYR
A
222
54.475
38.894
10.348
1.00
33.19
A
O

ATOM
1684
CB
TYR
A
222
52.673
36.559
10.071
1.00
45.87
A
C

ATOM
1685
CG
TYR
A
222
52.591
36.428
11.592
1.00
48.19
A
C

ATOM
1686
CD1
TYR
A
222
51.870
37.337
12.382
1.00
51.26
A
C

ATOM
1687
CD2
TYR
A
222
53.241
35.392
12.236
1.00
51.18
A
C

ATOM
1688
CE1
TYR
A
222
51.815
37.204
13.774
1.00
52.32
A
C

ATOM
1689
CE2
TYR
A
222
53.192
35.245
13.616
1.00
52.66
A
C

ATOM
1690
CZ
TYR
A
222
52.481
36.154
14.381
1.00
54.09
A
C

ATOM
1691
OH
TYR
A
222
52.436
36.004
15.751
1.00
56.15
A
O

ATOM
1692
N
ASP
A
223
52.486
39.968
10.768
1.00
46.73
A
N

ATOM
1693
CA
ASP
A
223
52.934
41.294
11.099
1.00
47.06
A
C

ATOM
1694
C
ASP
A
223
52.865
42.194
9.864
1.00
43.47
A
C

ATOM
1695
O
ASP
A
223
52.008
43.088
9.777
1.00
45.70
A
O

ATOM
1696
CB
ASP
A
223
54.339
41.289
11.693
1.00
50.64
A
C

ATOM
1697
CG
ASP
A
223
54.663
42.585
12.348
1.00
48.82
A
C

ATOM
1698
OD1
ASP
A
223
54.041
42.879
13.392
1.00
56.19
A
O

ATOM
1699
OD2
ASP
A
223
55.483
43.386
11.871
1.00
54.79
A
O

ATOM
1700
N
LYS
A
224
53.745
41.920
8.908
1.00
43.90
A
N

ATOM
1701
CA
LYS
A
224
54.128
42.889
7.872
1.00
43.50
A
C

ATOM
1702
C
LYS
A
224
54.720
42.221
6.651
1.00
38.65
A
C

ATOM
1703
O
LYS
A
224
55.321
41.177
6.749
1.00
37.31
A
O

ATOM
1704
CB
LYS
A
224
55.234
43.791
8.425
1.00
44.84
A
C

ATOM
1705
CG
LYS
A
224
54.814
45.182
8.824
1.00
49.52
A
C

ATOM
1706
CD
LYS
A
224
56.030
46.109
8.874
1.00
50.93
A
C

ATOM
1707
CE
LYS
A
224
56.970
45.783
10.029
1.00
52.43
A
C

ATOM
1708
NZ
LYS
A
224
58.303
45.329
9.550
1.00
53.74
A
N

ATOM
1709
N
SER
A
225
54.605
42.855
5.487
1.00
34.67
A
N

ATOM
1710
CA
SER
A
225
55.428
42.463
4.347
1.00
29.36
A
C

ATOM
1711
C
SER
A
225
55.923
43.766
3.727
1.00
23.18
A
C

ATOM
1712
O
SER
A
225
55.109
44.637
3.491
1.00
24.20
A
O

ATOM
1713
CB
SER
A
225
54.634
41.642
3.319
1.00
33.54
A
C

ATOM
1714
OG
SER
A
225
54.443
40.303
3.737
1.00
31.33
A
O

ATOM
1715
N
ILE
A
226
57.235
43.914
3.514
1.00
24.65
A
N

ATOM
1716
CA
ILE
A
226
57.814
45.209
3.080
1.00
24.70
A
C

ATOM
1717
C
ILE
A
226
58.879
45.132
1.973
1.00
20.50
A
C

ATOM
1718
O
ILE
A
226
59.568
44.138
1.762
1.00
22.18
A
O

ATOM
1719
CB
ILE
A
226
58.378
46.052
4.318
1.00
26.96
A
C

ATOM
1720
CG1
ILE
A
226
59.715
45.495
4.804
1.00
29.94
A
C

ATOM
1721
CG2
ILE
A
226
57.350
46.153
5.417
1.00
29.80
A
C

ATOM
1722
CD1
ILE
A
226
60.392
46.347
5.918
1.00
30.64
A
C

ATOM
1723
N
VAL
A
227
59.046
46.229
1.249
1.00
21.76
A
N

ATOM
1724
CA
VAL
A
227
60.073
46.314
0.221
1.00
20.70
A
C

ATOM
1725
C
VAL
A
227
61.187
47.177
0.820
1.00
22.68
A
C

ATOM
1726
O
VAL
A
227
60.949
48.339
1.114
1.00
25.66
A
O

ATOM
1727
CB
VAL
A
227
59.486
46.982
−1.036
1.00
22.09
A
C

ATOM
1728
CG1
VAL
A
227
60.466
46.919
−2.217
1.00
22.41
A
C

ATOM
1729
CG2
VAL
A
227
58.172
46.322
−1.385
1.00
22.10
A
C

ATOM
1730
N
ASP
A
228
62.377
46.598
1.025
1.00
25.94
A
N

ATOM
1731
CA
ASP
A
228
63.488
47.250
1.750
1.00
26.69
A
C

ATOM
1732
C
ASP
A
228
64.859
47.181
1.053
1.00
25.68
A
C

ATOM
1733
O
ASP
A
228
65.552
46.160
1.089
1.00
28.14
A
O

ATOM
1734
CB
ASP
A
228
63.610
46.628
3.151
1.00
30.80
A
C

ATOM
1735
CG
ASP
A
228
64.507
47.435
4.073
1.00
36.12
A
C

ATOM
1736
OD1
ASP
A
228
65.240
48.316
3.575
1.00
32.68
A
O

ATOM
1737
OD2
ASP
A
228
64.544
47.261
5.315
1.00
43.13
A
O

ATOM
1738
N
SER
A
229
65.273
48.283
0.448
1.00
20.40
A
N

ATOM
1739
CA
SER
A
229
66.534
48.352
0.261
1.00
19.83
A
C

ATOM
1740
C
SER
A
229
67.766
48.269
0.668
1.00
20.00
A
C

ATOM
1741
O
SER
A
229
68.848
47.998
0.202
1.00
20.19
A
O

ATOM
1742
CB
SER
A
229
66.608
49.641
−1.084
1.00
19.70
A
C

ATOM
1743
OG
SER
A
229
66.651
50.793
−0.239
1.00
20.04
A
O

ATOM
1744
N
GLY
A
230
67.582
48.539
1.955
1.00
24.02
A
N

ATOM
1745
CA
GLY
A
230
68.666
48.429
2.928
1.00
30.23
A
C

ATOM
1746
C
GLY
A
230
69.016
46.983
3.270
1.00
32.91
A
C

ATOM
1747
O
GLY
A
230
70.179
46.641
3.517
1.00
37.27
A
O

ATOM
1748
N
THR
A
231
67.998
46.129
3.290
1.00
35.70
A
N

ATOM
1749
CA
THR
A
231
68.157
44.736
3.700
1.00
36.19
A
C

ATOM
1750
C
THR
A
231
68.647
43.943
2.502
1.00
36.17
A
C

ATOM
1751
O
THR
A
231
68.125
44.098
1.392
1.00
36.88
A
O

ATOM
1752
CB
THR
A
231
66.811
44.203
4.216
1.00
36.06
A
C

ATOM
1753
OG1
THR
A
231
66.371
44.988
5.333
1.00
41.33
A
O

ATOM
1754
CG2
THR
A
231
66.931
42.806
4.770
1.00
39.41
A
C

ATOM
1755
N
THR
A
232
69.676
43.117
2.701
1.00
34.96
A
N

ATOM
1756
CA
THR
A
232
70.213
42.299
1.624
1.00
31.73
A
C

ATOM
1757
C
THR
A
232
69.299
41.111
1.311
1.00
35.19
A
C

ATOM
1758
O
THR
A
232
69.149
40.754
0.150
1.00
34.98
A
O

ATOM
1759
CB
THR
A
232
71.612
41.737
1.968
1.00
36.41
A
C

ATOM
1760
OG1
THR
A
232
72.502
42.796
2.338
1.00
33.05
A
O

ATOM
1761
CG2
THR
A
232
72.274
41.136
0.735
1.00
36.22
A
C

ATOM
1762
N
ASN
A
233
68.735
40.502
2.352
1.00
38.19
A
N

ATOM
1763
CA
ASN
A
233
68.029
39.230
2.211
1.00
41.17
A
C

ATOM
1764
C
ASN
A
233
66.520
39.365
2.052
1.00
40.23
A
C

ATOM
1765
O
ASN
A
233
65.922
40.416
2.327
1.00
39.76
A
O

ATOM
1766
CB
ASN
A
233
68.307
38.323
3.420
1.00
43.40
A
C

ATOM
1767
CG
ASN
A
233
69.767
37.864
3.503
1.00
44.47
A
C

ATOM
1768
OD1
ASN
A
233
70.293
37.678
4.593
1.00
53.39
A
O

ATOM
1769
ND2
ASN
A
233
70.409
37.667
2.360
1.00
47.21
A
N

ATOM
1770
N
LEU
A
234
65.927
38.259
1.613
1.00
39.45
A
N

ATOM
1771
CA
LEU
A
234
64.497
38.025
1.667
1.00
35.83
A
C

ATOM
1772
C
LEU
A
234
64.178
37.466
3.035
1.00
31.21
A
C

ATOM
1773
O
LEU
A
234
64.504
36.342
3.319
1.00
35.53
A
O

ATOM
1774
CB
LEU
A
234
64.119
37.022
0.562
1.00
41.31
A
C

ATOM
1775
CG
LEU
A
234
62.727
36.992
−0.082
1.00
42.04
A
C

ATOM
1776
CD1
LEU
A
234
62.447
35.596
−0.613
1.00
45.40
A
C

ATOM
1777
CD2
LEU
A
234
61.630
37.429
0.851
1.00
42.45
A
C

ATOM
1778
N
ARG
A
235
63.564
38.263
3.906
1.00
39.51
A
N

ATOM
1779
CA
ARG
A
235
63.200
37.811
5.254
1.00
37.00
A
C

ATOM
1780
C
ARG
A
235
61.737
37.315
5.290
1.00
38.00
A
C

ATOM
1781
O
ARG
A
235
60.863
37.918
4.699
1.00
31.41
A
O

ATOM
1782
CB
ARG
A
235
63.434
38.930
6.278
1.00
40.50
A
C

ATOM
1783
CG
ARG
A
235
64.843
39.557
6.210
1.00
43.67
A
C

ATOM
1784
CD
ARG
A
235
65.208
40.478
7.378
1.00
46.74
A
C

ATOM
1785
NE
ARG
A
235
65.177
39.774
8.659
1.00
49.76
A
N

ATOM
1786
CZ
ARG
A
235
64.729
40.272
9.823
1.00
52.94
A
C

ATOM
1787
NH1
ARG
A
235
64.272
41.522
9.918
1.00
51.18
A
N

ATOM
1788
NH2
ARG
A
235
64.743
39.503
10.914
1.00
51.36
A
N

ATOM
1789
N
LEU
A
236
61.473
36.226
6.008
1.00
37.36
A
N

ATOM
1790
CA
LEU
A
236
60.156
35.571
5.992
1.00
37.98
A
C

ATOM
1791
C
LEU
A
236
59.691
35.254
7.408
1.00
39.27
A
C

ATOM
1792
O
LEU
A
236
60.503
34.847
8.230
1.00
37.29
A
O

ATOM
1793
CB
LEU
A
236
60.238
34.271
5.210
1.00
37.66
A
C

ATOM
1794
CG
LEU
A
236
60.689
34.363
3.745
1.00
36.72
A
C

ATOM
1795
CD1
LEU
A
236
60.713
32.994
3.135
1.00
34.34
A
C

ATOM
1796
CD2
LEU
A
236
59.784
35.269
2.922
1.00
37.91
A
C

ATOM
1797
N
PRO
A
237
58.399
35.408
7.719
1.00
37.12
A
N

ATOM
1798
CA
PRO
A
237
57.939
35.039
9.061
1.00
35.72
A
C

ATOM
1799
C
PRO
A
237
58.324
33.600
9.304
1.00
36.04
A
C

ATOM
1800
O
PRO
A
237
58.364
32.870
8.326
1.00
31.43
A
O

ATOM
1801
CB
PRO
A
237
56.425
35.222
8.985
1.00
36.23
A
C

ATOM
1802
CG
PRO
A
237
56.243
36.263
7.917
1.00
36.72
A
C

ATOM
1803
CD
PRO
A
237
57.297
35.918
6.887
1.00
37.44
A
C

ATOM
1804
N
LYS
A
238
58.647
33.213
10.538
1.00
34.49
A
N

ATOM
1805
CA
LYS
A
238
59.098
31.839
10.805
1.00
34.56
A
C

ATOM
1806
C
LYS
A
238
58.322
30.780
10.051
1.00
32.78
A
C

ATOM
1807
O
LYS
A
238
58.908
29.860
9.452
1.00
32.03
A
O

ATOM
1808
CB
LYS
A
238
58.881
31.433
12.243
1.09
34.24
A
C

ATOM
1809
CG
LYS
A
238
59.299
32.363
13.281
1.00
30.75
A
C

ATOM
1810
CD
LYS
A
238
58.868
31.768
14.539
1.00
5.80
A
C

ATOM
1811
CE
LYS
A
238
57.493
31.846
14.975
1.00
27.32
A
C

ATOM
1812
NZ
LYS
A
238
57.007
31.123
16.239
1.00
32.55
A
N

ATOM
1813
N
LYS
A
239
56.998
30.879
10.142
1.00
28.36
A
N

ATOM
1814
CA
LYS
A
239
56.149
29.747
9.735
1.00
37.49
A
C

ATOM
1815
C
LYS
A
239
56.292
29.508
8.233
1.00
35.49
A
C

ATOM
1816
O
LYS
A
239
56.310
28.360
7.762
1.00
30.89
A
O

ATOM
1817
CB
LYS
A
239
54.675
29.990
10.108
1.00
39.29
A
C

ATOM
1818
CG
LYS
A
239
54.110
28.997
11.108
1.00
46.03
A
C

ATOM
1819
CD
LYS
A
239
52.700
29.406
11.566
1.00
48.69
A
C

ATOM
1820
CE
LYS
A
239
51.634
28.404
11.117
1.00
50.81
A
C

ATOM
1821
NZ
LYS
A
239
50.243
28.846
11.463
1.00
49.91
A
N

ATOM
1822
N
VAL
A
240
56.411
30.614
7.497
1.00
32.65
A
N

ATOM
1823
CA
VAL
A
240
56.599
30.569
6.057
1.00
32.95
A
C

ATOM
1824
C
VAL
A
240
58.018
30.172
5.684
1.00
28.03
A
C

ATOM
1825
O
VAL
A
240
58.201
29.484
4.704
1.00
26.73
A
O

ATOM
1826
CB
VAL
A
240
56.323
31.928
5.390
1.00
28.86
A
C

ATOM
1827
CG1
VAL
A
240
56.411
31.801
3.908
1.00
29.02
A
C

ATOM
1828
CG2
VAL
A
240
54.963
32.517
5.818
1.00
33.40
A
C

ATOM
1829
N
PHE
A
241
59.019
30.655
6.430
1.00
31.69
A
N

ATOM
1830
CA
PHE
A
241
60.402
30.267
6.159
1.00
34.11
A
C

ATOM
1831
C
PHE
A
241
60.559
28.745
6.338
1.00
32.98
A
C

ATOM
1832
O
PHE
A
241
61.100
28.029
5.470
1.00
29.40
A
O

ATOM
1833
CB
PHE
A
241
61.360
30.997
7.095
1.00
35.69
A
C

ATOM
1834
CG
PHE
A
241
62.748
30.459
7.057
1.00
39.37
A
C

ATOM
1835
CD1
PHE
A
241
63.601
30.785
6.012
1.00
42.58
A
C

ATOM
1836
CD2
PHE
A
241
63.197
29.583
8.047
1.00
42.39
A
C

ATOM
1837
CE1
PHE
A
241
64.895
30.272
5.968
1.00
43.06
A
C

ATOM
1838
CE2
PHE
A
241
64.479
29.073
8.007
1.00
38.87
A
C

ATOM
1839
CZ
PHE
A
241
65.329
29.419
6.964
1.00
43.23
A
C

ATOM
1840
N
GLU
A
242
60.075
28.249
7.468
1.00
32.78
A
N

ATOM
1841
CA
GLU
A
242
60.011
26.800
7.696
1.00
36.60
A
C

ATOM
1842
C
GLU
A
242
59.505
26.025
6.487
1.00
33.79
A
C

ATOM
1843
O
GLU
A
242
60.160
25.083
6.053
1.00
35.48
A
O

ATOM
1844
CB
GLU
A
242
59.123
26.473
8.899
1.00
37.43
A
C

ATOM
1845
CG
GLU
A
242
59.830
26.686
10.217
1.00
43.87
A
C

ATOM
1846
CD
GLU
A
242
60.878
25.635
10.508
1.00
45.01
A
C

ATOM
1847
OE1
GLU
A
242
61.759
25.906
11.358
1.00
45.07
A
O

ATOM
1848
OE2
GLU
A
242
60.818
24.545
9.888
1.00
52.08
A
O

ATOM
1849
N
ALA
A
243
58.358
26.437
5.942
1.00
34.61
A
N

ATOM
1850
CA
ALA
A
243
57.752
25.723
4.804
1.00
36.67
A
C

ATOM
1851
C
ALA
A
243
58.531
25.984
3.523
1.00
35.54
A
C

ATOM
1852
O
ALA
A
243
58.735
25.093
2.706
1.00
30.69
A
O

ATOM
1853
CB
ALA
A
243
56.307
26.138
4.615
1.00
36.74
A
C

ATOM
1854
N
ALA
A
244
58.961
27.231
3.375
1.00
36.29
A
N

ATOM
1855
CA
ALA
A
244
59.717
27.682
2.224
1.00
36.28
A
C

ATOM
1856
C
ALA
A
244
60.970
26.841
2.063
1.00
36.59
A
C

ATOM
1857
O
ALA
A
244
61.133
26.184
1.058
1.00
35.35
A
O

ATOM
1858
CB
ALA
A
244
60.073
29.142
2.383
1.00
34.54
A
C

ATOM
1859
N
VAL
A
245
61.853
26.884
3.064
1.00
38.90
A
N

ATOM
1860
CA
VAL
A
245
63.002
25.982
3.143
1.00
42.56
A
C

ATOM
1861
C
VAL
A
245
62.658
24.500
2.899
1.00
40.13
A
C

ATOM
1862
O
VAL
A
245
63.341
23.835
2.114
1.00
40.38
A
O

ATOM
1863
CB
VAL
A
245
63.742
26.130
4.515
1.00
43.37
A
C

ATOM
1864
CG1
VAL
A
245
64.651
24.918
4.821
1.09
47.23
A
C

ATOM
1865
CG2
VAL
A
245
64.541
27.420
4.534
1.00
44.13
A
C

ATOM
1866
N
LYS
A
246
61.627
23.974
3.556
1.00
39.54
A
N

ATOM
1867
CA
LYS
A
246
61.270
22.556
3.352
1.00
44.44
A
C

ATOM
1868
C
LYS
A
246
61.172
22.215
1.859
1.00
43.12
A
C

ATOM
1869
O
LYS
A
246
61.745
21.233
1.407
1.00
40.51
A
O

ATOM
1870
CB
LYS
A
246
59.965
22.180
4.068
1.00
46.80
A
C

ATOM
1871
CG
LYS
A
246
59.575
20.695
3.924
1.00
50.38
A
C

ATOM
1872
CD
LYS
A
246
58.263
20.380
4.653
1.00
52.29
A
C

ATOM
1873
CE
LYS
A
246
57.530
19.182
4.042
1.00
54.52
A
C

ATOM
1874
NZ
LYS
A
246
58.452
18.072
3.656
1.00
53.80
A
N

ATOM
1875
N
SER
A
247
60.473
23.051
1.097
1.00
44.68
A
N

ATOM
1876
CA
SER
A
247
60.282
22.809
−0.337
1.00
45.24
A
C

ATOM
1877
C
SER
A
247
61.505
23.062
−1.226
1.00
43.18
A
C

ATOM
1878
O
SER
A
247
61.653
22.423
−2.258
1.00
38.59
A
O

ATOM
1879
CB
SER
A
247
59.126
23.654
−0.869
1.00
45.97
A
C

ATOM
1880
OG
SER
A
247
59.035
23.478
−2.266
1.00
42.87
A
O

ATOM
1881
N
ILE
A
248
62.345
24.027
−0.861
1.00
47.83
A
N

ATOM
1882
CA
ILE
A
248
63.534
24.348
−1.658
1.00
50.81
A
C

ATOM
1883
C
ILE
A
248
64.570
23.241
−1.475
1.00
52.35
A
C

ATOM
1884
O
ILE
A
248
65.200
22.787
−2.440
1.00
48.20
A
O

ATOM
1885
CB
ILE
A
248
64.116
25.716
−1.260
1.00
51.35
A
C

ATOM
1886
CG1
ILE
A
248
63.101
26.823
−1.548
1.00
50.95
A
C

ATOM
1887
CG2
ILE
A
248
65.428
25.983
−2.015
1.00
51.10
A
C

ATOM
1888
CD1
ILE
A
248
63.447
28.154
−0.913
1.00
51.52
A
C

ATOM
1889
N
LYS
A
249
64.725
22.814
−0.227
1.00
53.72
A
N

ATOM
1890
CA
LYS
A
249
65.451
21.585
0.108
1.00
59.31
A
C

ATOM
1891
C
LYS
A
249
65.021
20.377
−0.745
1.00
61.00
A
C

ATOM
1892
O
LYS
A
249
65.871
19.634
−1.233
1.00
58.84
A
O

ATOM
1893
CB
LYS
A
249
65.260
21.257
1.598
1.00
61.17
A
C

ATOM
1894
CG
LYS
A
249
66.419
20.522
2.240
1.00
63.43
A
C

ATOM
1895
CD
LYS
A
249
66.187
20.317
3.740
1.00
65.86
A
C

ATOM
1896
CE
LYS
A
249
66.299
21.620
4.530
1.00
67.19
A
C

ATOM
1897
NZ
LYS
A
249
66.791
21.417
5.929
1.00
68.30
A
N

ATOM
1898
N
ALA
A
250
63.711
20.207
−0.942
1.00
63.51
A
N

ATOM
1899
CA
ALA
A
250
63.160
19.006
−1.589
1.00
66.01
A
C

ATOM
1900
C
ALA
A
250
63.564
18.839
−3.059
1.00
67.43
A
C

ATOM
1901
O
ALA
A
250
64.214
17.861
−3.408
1.00
67.59
A
O

ATOM
1902
CB
ALA
A
250
61.635
18.974
−1.455
1.00
65.47
A
C

ATOM
1903
N
ALA
A
251
63.185
19.783
−3.917
1.00
69.93
A
N

ATOM
1904
CA
ALA
A
251
63.539
19.694
−5.342
1.00
70.60
A
C

ATOM
1905
C
ALA
A
251
64.985
20.123
−5.633
1.00
70.50
A
C

ATOM
1906
O
ALA
A
251
65.364
20.268
−6.794
1.00
69.29
A
O

ATOM
1907
CB
ALA
A
251
62.547
20.488
−6.212
1.00
70.96
A
C

ATOM
1908
N
SER
A
252
65.778
20.338
−4.582
1.00
70.95
A
N

ATOM
1909
CA
SER
A
252
67.213
20.562
−4.718
1.00
72.23
A
C

ATOM
1910
C
SER
A
252
68.016
19.483
−3.985
1.00
73.46
A
C

ATOM
1911
O
SER
A
252
69.189
19.680
−3.661
1.00
71.37
A
O

ATOM
1912
CB
SER
A
252
67.582
21.951
−4.189
1.00
72.68
A
C

ATOM
1913
OG
SER
A
252
67.505
21.999
−2.775
1.00
73.18
A
O

ATOM
1914
N
SER
A
253
67.389
18.332
−3.756
1.00
75.44
A
N

ATOM
1915
CA
SER
A
253
68.011
17.239
−3.011
1.00
77.44
A
C

ATOM
1916
C
SER
A
253
69.079
16.491
−3.819
1.00
79.67
A
C

ATOM
1917
O
SER
A
253
69.783
15.645
−3.263
1.00
79.72
A
O

ATOM
1918
CB
SER
A
253
66.944
16.250
−2.532
1.00
77.46
A
C

ATOM
1919
OG
SER
A
253
66.037
16.870
−1.637
1.00
76.30
A
O

ATOM
1920
N
THR
A
254
69.196
16.799
−5.116
1.00
81.88
A
N

ATOM
1921
CA
THR
A
254
70.232
16.215
−5.983
1.00
83.80
A
C

ATOM
1922
C
THR
A
254
71.624
16.245
−5.334
1.00
85.34
A
C

ATOM
1923
O
THR
A
254
72.423
15.330
−5.538
1.00
85.86
A
O

ATOM
1924
CB
THR
A
254
70.270
16.936
−7.360
1.00
83.52
A
C

ATOM
1925
OG1
THR
A
254
68.992
16.851
−7.999
1.00
83.21
A
O

ATOM
1926
CG2
THR
A
254
71.205
16.228
−8.342
1.00
83.62
A
C

ATOM
1927
N
GLU
A
255
71.909
17.296
−4.565
1.00
86.72
A
N

ATOM
1928
CA
GLU
A
255
73.121
17.354
−3.746
1.00
87.75
A
C

ATOM
1929
C
GLU
A
255
72.785
17.714
−2.302
1.00
88.51
A
C

ATOM
1930
O
GLU
A
255
72.017
18.643
−2.048
1.00
89.05
A
O

ATOM
1931
CB
GLU
A
255
74.103
18.379
−4.307
1.00
87.94
A
C

ATOM
1932
CG
GLU
A
255
74.553
18.101
−5.731
1.00
88.21
A
C

ATOM
1933
CD
GLU
A
255
75.403
19.222
−6.297
1.00
88.85
A
C

ATOM
1934
OE1
GLU
A
255
76.162
19.847
−5.521
1.00
88.18
A
O

ATOM
1935
OE2
GLU
A
255
75.308
19.478
−7.518
1.00
89.16
A
O

ATOM
1936
N
LYS
A
256
73.367
16.973
−1.361
1.00
89.37
A
N

ATOM
1937
CA
LYS
A
256
73.181
17.233
0.066
1.00
89.70
A
C

ATOM
1938
C
LYS
A
256
74.060
18.406
0.515
1.00
89.43
A
C

ATOM
1939
O
LYS
A
256
75.211
18.519
0.090
1.00
90.96
A
O

ATOM
1940
CB
LYS
A
256
73.524
15.976
0.878
1.00
89.79
A
C

ATOM
1941
CG
LYS
A
256
73.344
16.118
2.390
1.00
89.80
A
C

ATOM
1942
CD
LYS
A
256
73.488
14.778
3.106
1.00
89.76
A
C

ATOM
1943
CE
LYS
A
256
74.916
14.250
3.037
1.00
89.66
A
C

ATOM
1944
NZ
LYS
A
256
75.135
13.099
3.955
1.00
89.59
A
N

ATOM
1945
N
PHE
A
257
73.509
19.278
1.359
1.00
88.33
A
N

ATOM
1946
CA
PHE
A
257
74.277
20.358
1.988
1.00
87.80
A
C

ATOM
1947
C
PHE
A
257
73.957
20.434
3.486
1.00
85.90
A
C

ATOM
1948
O
PHE
A
257
72.901
19.963
3.916
1.00
84.62
A
O

ATOM
1949
CB
PHE
A
257
73.977
21.698
1.307
1.00
88.75
A
C

ATOM
1950
CG
PHE
A
257
74.158
21.672
−0.188
1.00
90.18
A
C

ATOM
1951
CD1
PHE
A
257
73.128
22.071
−1.035
1.00
90.73
A
C

ATOM
1952
CD2
PHE
A
257
75.358
21.243
−0.747
1.00
90.65
A
C

ATOM
1953
CE1
PHE
A
257
73.295
22.043
−2.417
1.00
91.50
A
C

ATOM
1954
CE2
PHE
A
257
75.530
21.208
−2.125
1.00
91.35
A
C

ATOM
1955
CZ
PHE
A
257
74.499
21.611
−2.961
1.00
91.69
A
C

ATOM
1956
N
PRO
A
258
74.857
21.019
4.282
1.00
84.41
A
N

ATOM
1957
CA
PRO
A
258
74.671
21.079
5.743
1.00
83.94
A
C

ATOM
1958
C
PRO
A
258
73.334
21.697
6.182
1.00
83.10
A
C

ATOM
1959
O
PRO
A
258
72.764
22.519
5.459
1.00
82.64
A
O

ATOM
1960
CB
PRO
A
258
75.840
21.957
6.218
1.00
83.97
A
C

ATOM
1961
CG
PRO
A
258
76.862
21.878
5.141
1.00
84.54
A
C

ATOM
1962
CD
PRO
A
258
76.116
21.664
3.861
1.00
84.44
A
C

ATOM
1963
N
ASP
A
259
72.852
21.302
7.360
1.00
81.28
A
N

ATOM
1964
CA
ASP
A
259
71.608
21.847
7.916
1.00
79.36
A
C

ATOM
1965
C
ASP
A
259
71.767
23.327
8.300
1.00
76.80
A
C

ATOM
1966
O
ASP
A
259
70.804
24.097
8.228
1.00
75.77
A
O

ATOM
1967
CB
ASP
A
259
71.140
21.025
9.133
1.00
80.43
A
C

ATOM
1968
CG
ASP
A
259
69.749
20.420
8.947
1.00
81.62
A
C

ATOM
1969
OD1
ASP
A
259
69.433
19.944
7.832
1.00
81.91
A
O

ATOM
1970
OD2
ASP
A
259
68.906
20.364
9.870
1.00
82.81
A
O

ATOM
1971
N
GLY
A
260
72.981
23.716
8.694
1.00
72.15
A
N

ATOM
1972
CA
GLY
A
260
73.280
25.095
9.051
1.00
68.23
A
C

ATOM
1973
C
GLY
A
260
73.394
26.055
7.873
1.00
65.01
A
C

ATOM
1974
O
GLY
A
260
73.306
27.266
8.055
1.00
62.06
A
O

ATOM
1975
N
PHE
A
261
73.601
25.529
6.670
1.00
61.00
A
N

ATOM
1976
CA
PHE
A
261
73.582
26.350
5.456
1.00
59.12
A
C

ATOM
1977
C
PHE
A
261
72.247
27.101
5.311
1.00
57.30
A
C

ATOM
1978
O
PHE
A
261
72.217
28.296
5.013
1.00
47.15
A
O

ATOM
1979
CB
PHE
A
261
73.833
25.475
4.222
1.00
59.54
A
C

ATOM
1980
CG
PHE
A
261
73.504
26.148
2.920
1.00
58.56
A
C

ATOM
1981
CD1
PHE
A
261
74.289
27.187
2.447
1.00
57.89
A
C

ATOM
1982
CD2
PHE
A
261
72.415
25.741
2.169
1.00
58.88
A
C

ATOM
1983
CE1
PHE
A
261
73.996
27.807
1.259
1.00
56.77
A
C

ATOM
1984
CE2
PHE
A
261
72.118
26.359
0.972
1.00
58.83
A
C

ATOM
1985
CZ
PHE
A
261
72.912
27.393
0.516
1.00
58.32
A
C

ATOM
1986
N
TRP
A
262
71.151
26.389
5.557
1.00
56.79
A
N

ATOM
1987
CA
TRP
A
262
69.813
26.949
5.396
1.00
58.03
A
C

ATOM
1988
C
TRP
A
262
69.475
27.995
6.467
1.00
58.02
A
C

ATOM
1989
O
TRP
A
262
68.525
28.760
6.296
1.00
57.45
A
O

ATOM
1990
CB
TRP
A
262
68.759
25.832
5.406
1.00
59.10
A
C

ATOM
1991
CG
TRP
A
262
69.026
24.721
4.432
1.00
60.40
A
C

ATOM
1992
CD1
TRP
A
262
69.372
23.430
4.730
1.00
61.96
A
C

ATOM
1993
CD2
TRP
A
262
68.974
24.800
3.003
1.00
61.91
A
C

ATOM
1994
NE1
TRP
A
262
69.535
22.704
3.574
1.00
60.97
A
N

ATOM
1995
CE2
TRP
A
262
69.298
23.520
2.498
1.00
61.58
A
C

ATOM
1996
CE3
TRP
A
262
68.688
25.824
2.092
1.00
62.89
A
C

ATOM
1997
CZ2
TRP
A
262
69.343
23.240
1.132
1.00
62.27
A
C

ATOM
1998
CZ3
TRP
A
262
68.729
25.543
0.731
1.00
63.90
A
C

ATOM
1999
CH2
TRP
A
262
69.057
24.260
0.267
1.00
63.92
A
C

ATOM
2000
N
LEU
A
263
70.236
28.025
7.563
1.00
56.89
A
N

ATOM
2001
CA
LEU
A
263
70.040
29.026
8.626
1.00
57.55
A
C

ATOM
2002
C
LEU
A
263
71.038
30.204
8.576
1.00
55.97
A
C

ATOM
2003
O
LEU
A
263
71.084
31.020
9.501
1.00
51.83
A
O

ATOM
2004
CB
LEU
A
263
70.102
28.355
10.010
1.00
58.30
A
C

ATOM
2005
CG
LEU
A
263
68.913
27.494
10.470
1.00
61.17
A
C

ATOM
2006
CD1
LEU
A
263
67.569
28.209
10.298
1.00
62.02
A
C

ATOM
2007
CD2
LEU
A
263
68.900
26.160
9.759
1.00
61.49
A
C

ATOM
2008
N
GLY
A
264
71.821
30.300
7.501
1.00
54.23
A
N

ATOM
2009
CA
GLY
A
264
72.793
31.378
7.352
1.00
55.51
A
C

ATOM
2010
C
GLY
A
264
73.964
31.272
8.318
1.00
53.62
A
C

ATOM
2011
O
GLY
A
264
74.657
32.259
8.582
1.00
52.01
A
O

ATOM
2012
N
GLU
A
265
74.180
30.057
8.822
1.00
52.02
A
N

ATOM
2013
CA
GLU
A
265
75.202
29.749
9.818
1.00
52.34
A
C

ATOM
2014
C
GLU
A
265
76.498
29.185
9.216
1.00
51.88
A
C

ATOM
2015
O
GLU
A
265
77.521
29.092
9.902
1.00
50.86
A
O

ATOM
2016
CB
GLU
A
265
74.620
28.757
10.823
1.00
53.23
A
C

ATOM
2017
CG
GLU
A
265
73.484
29.351
11.651
1.00
56.42
A
C

ATOM
2018
CD
GLU
A
265
72.811
28.342
12.572
1.00
59.67
A
C

ATOM
2019
OE1
GLU
A
265
73.053
27.121
12.415
1.00
62.41
A
O

ATOM
2020
OE2
GLU
A
265
72.029
28.777
13.451
1.00
58.43
A
O

ATOM
2021
N
GLN
A
266
76.444
28.781
7.951
1.00
48.71
A
N

ATOM
2022
CA
GLN
A
266
77.650
28.438
7.197
1.00
50.93
A
C

ATOM
2023
C
GLN
A
266
77.436
28.743
5.726
1.00
50.91
A
C

ATOM
2024
O
GLN
A
266
76.300
28.790
5.262
1.00
48.81
A
O

ATOM
2025
CB
GLN
A
266
77.919
26.957
7.385
1.00
51.13
A
C

ATOM
2026
CG
GLN
A
266
79.152
26.489
6.603
0.00
20.00
A
C

ATOM
2027
CD
GLN
A
266
79.377
25.016
6.849
0.00
20.00
A
C

ATOM
2028
OE1
GLN
A
266
79.286
24.174
5.970
0.00
20.00
A
O

ATOM
2029
NE2
GLN
A
266
79.677
24.718
8.129
0.00
20.00
A
N

ATOM
2030
N
LEU
A
267
78.523
28.947
4.988
1.00
52.35
A
N

ATOM
2031
CA
LEU
A
267
78.414
29.197
3.555
1.00
55.74
A
C

ATOM
2032
C
LEU
A
267
78.794
27.955
2.759
1.00
55.94
A
C

ATOM
2033
O
LEU
A
267
79.623
27.161
3.189
1.00
55.10
A
O

ATOM
2034
CB
LEU
A
267
79.228
30.427
3.117
1.00
57.95
A
C

ATOM
2035
CG
LEU
A
267
80.592
30.763
3.719
1.00
59.40
A
C

ATOM
2036
CD1
LEU
A
267
81.667
29.797
3.226
1.00
61.73
A
C

ATQM
2037
CD2
LEU
A
267
80.966
32.199
3.379
1.00
59.25
A
C

ATOM
2038
N
VAL
A
268
78.141
27.778
1.614
1.00
59.08
A
N

ATOM
2039
CA
VAL
A
268
78.394
26.635
0.734
1.00
63.27
A
C

ATOM
2040
C
VAL
A
268
79.437
27.028
−0.317
1.00
65.28
A
C

ATOM
2041
O
VAL
A
268
79.581
28.206
−0.628
1.00
65.73
A
O

ATOM
2042
CB
VAL
A
268
77.072
26.103
0.084
1.00
63.60
A
C

ATOM
2043
CG1
VAL
A
268
76.461
27.114
−0.900
1.00
64.14
A
C

ATOM
2044
CG2
VAL
A
268
77.302
24.759
−0.593
1.00
63.65
A
C

ATOM
2045
N
CYS
A
269
80.182
26.050
−0.830
1.00
67.59
A
N

ATOM
2046
CA
CYS
A
269
81.255
26.315
−1.794
1.00
70.85
A
C

ATOM
2047
C
CYS
A
269
81.288
25.302
−2.943
1.00
71.91
A
C

ATOM
2048
O
CYS
A
269
81.068
24.106
−2.740
1.00
70.92
A
O

ATOM
2049
CB
CYS
A
269
82.618
26.330
−1.086
1.00
71.01
A
C

ATOM
2050
SG
CYS
A
269
82.804
27.634
0.160
1.00
73.46
A
S

ATOM
2051
N
TRP
A
270
81.560
25.804
−4.147
1.00
73.59
A
N

ATQM
2052
CA
TRP
A
270
81.768
24.975
−5.335
1.00
74.68
A
C

ATOM
2053
C
TRP
A
270
83.036
25.412
−6.065
1.00
75.66
A
C

ATOM
2054
O
TRP
A
270
83.455
26.563
−5.952
1.00
74.31
A
O

ATOM
2055
CB
TRP
A
270
80.584
25.108
−6.289
1.00
75.03
A
C

ATOM
2056
CG
TRP
A
270
79.330
24.451
−5.812
1.00
74.79
A
C

ATOM
2057
CD1
TRP
A
270
79.034
23.118
−5.848
1.00
74.58
A
C

ATOM
2058
CD2
TRP
A
270
78.191
25.099
−5.239
1.00
74.13
A
C

ATOM
2059
NE1
TRP
A
270
77.781
22.898
−5.329
1.00
74.78
A
N

ATOM
2060
CE2
TRP
A
270
77.241
24.098
−4.946
1.00
74.47
A
C

ATOM
2061
CE3
TRP
A
270
77.875
26.431
−4.939
1.00
73.49
A
C

ATOM
2062
CZ2
TRP
A
270
76.000
24.386
−4.372
1.00
74.22
A
C

ATOM
2063
CZ3
TRP
A
270
76.649
26.715
−4.371
1.00
73.73
A
C

ATOM
2064
CH2
TRP
A
270
75.727
25.696
−4.088
1.00
73.99
A
C

ATOM
2065
N
GLN
A
271
83.633
24.497
−6.827
1.00
77.31
A
N

ATOM
2066
CA
GLN
A
271
84.835
24.808
−7.603
1.00
78.64
A
C

ATOM
2067
C
GLN
A
271
84.559
25.956
−8.579
1.00
79.98
A
C

ATOM
2068
O
GLN
A
271
83.424
26.136
−9.025
1.00
79.95
A
O

ATOM
2069
CB
GLN
A
271
85.233
23.565
−8.378
1.00
78.38
A
C

ATOM
2070
CG
GLN
A
271
85.694
22.427
−7.461
0.00
20.00
A
C

ATOM
2071
CD
GLN
A
271
86.108
21.239
−8.297
0.00
20.00
A
C

ATOM
2072
OE1
GLN
A
271
86.517
20.197
−7.812
0.00
20.00
A
O

ATOM
2073
NE2
GLN
A
271
85.995
21.443
−9.624
0.00
20.00
A
N

ATOM
2074
N
ALA
A
272
85.596
26.733
−8.891
1.00
81.27
A
N

ATOM
2075
CA
ALA
A
272
85.467
27.927
−9.736
1.00
82.23
A
C

ATOM
2076
C
ALA
A
272
84.604
27.706
−10.989
1.00
82.74
A
C

ATOM
2077
O
ALA
A
272
85.006
27.012
−11.926
1.00
82.97
A
O

ATOM
2078
CB
ALA
A
272
86.850
28.443
−10.131
1.00
82.17
A
C

ATOM
2079
N
GLY
A
273
83.408
28.289
−10.977
1.00
83.80
A
N

ATOM
2080
CA
GLY
A
273
82.523
28.301
−12.132
1.00
84.66
A
C

ATOM
2081
C
GLY
A
273
81.761
27.008
−12.373
1.00
84.93
A
C

ATOM
2082
O
GLY
A
273
81.383
26.720
−13.511
1.00
86.15
A
O

ATOM
2083
N
THR
A
274
81.509
26.250
−11.305
1.00
84.63
A
N

ATOM
2084
CA
THR
A
274
80.861
24.940
−11.396
1.00
84.75
A
C

ATOM
2085
C
THR
A
274
79.570
24.921
−10.581
1.00
84.35
A
C

ATOM
2086
O
THR
A
274
79.158
23.880
−10.064
1.00
82.91
A
O

ATOM
2087
CB
THR
A
274
81.812
23.828
−10.895
1.00
85.61
A
C

ATOM
2088
OG1
THR
A
274
82.135
24.043
−9.514
1.00
85.37
A
O

ATOM
2089
CG2
THR
A
274
83.162
23.879
−11.618
1.00
86.24
A
C

ATOM
2090
N
THR
A
275
78.929
26.079
−10.480
1.00
84.51
A
N

ATOM
2091
CA
THR
A
275
77.719
26.213
−9.688
1.00
85.22
A
C

ATOM
2092
C
THR
A
275
76.535
25.616
−10.451
1.00
84.97
A
C

ATOM
2093
O
THR
A
275
76.311
25.959
−11.614
1.00
83.74
A
O

ATOM
2094
CB
THR
A
275
77.450
27.690
−9.370
1.00
85.63
A
C

ATOM
2095
OG1
THR
A
275
78.649
28.313
−8.889
1.00
87.20
A
O

ATOM
2096
CG2
THR
A
275
76.472
27.827
−8.210
1.00
86.40
A
C

ATOM
2097
N
PRO
A
276
75.790
24.718
−9.808
1.00
84.86
A
N

ATOM
2098
CA
PRO
A
276
74.591
24.138
−10.420
1.00
84.84
A
C

ATOM
2099
C
PRO
A
276
73.386
25.087
−10.330
1.00
84.60
A
C

ATOM
2100
O
PRO
A
276
72.759
25.213
−9.270
1.00
83.40
A
O

ATOM
2101
CB
PRO
A
276
74.363
22.864
−9.599
1.00
85.26
A
C

ATOM
2102
CG
PRO
A
276
74.945
23.160
−8.247
1.00
84.89
A
C

ATOM
2103
CD
PRO
A
276
76.033
24.178
−8.456
1.00
84.87
A
C

ATOM
2104
N
TRP
A
277
73.084
25.757
−11.441
1.00
83.87
A
N

ATOM
2105
CA
TRP
A
277
71.945
26.671
−11.512
1.00
82.59
A
C

ATOM
2106
C
TRP
A
277
70.645
25.914
−11.259
1.00
78.91
A
C

ATOM
2107
O
TRP
A
277
69.868
26.253
−10.361
1.00
76.37
A
O

ATOM
2108
CB
TRP
A
277
71.852
27.327
−12.903
1.00
84.62
A
C

ATOM
2109
CG
TRP
A
277
72.863
28.426
−13.258
1.00
86.23
A
C

ATOM
2110
CD1
TRP
A
277
73.299
28.743
−14.520
1.00
86.71
A
C

ATOM
2111
CD2
TRP
A
277
73.518
29.358
−12.371
1.00
86.55
A
C

ATOM
2112
NE1
TRP
A
277
74.186
29.792
−14.473
1.00
86.87
A
N

ATOM
2113
CE2
TRP
A
277
74.340
30.190
−13.171
1.00
87.19
A
C

ATOM
2114
CE3
TRP
A
277
73.503
29.573
−10.982
1.00
86.48
A
C

ATOM
2115
CZ2
TRP
A
277
75.129
31.211
−12.632
1.00
87.46
A
C

ATOM
2116
CZ3
TRP
A
277
74.291
30.587
−10.449
1.00
86.65
A
C

ATOM
2117
CH2
TRP
A
277
75.092
31.392
−11.273
1.00
87.15
A
C

ATOM
2118
N
ASN
A
278
70.450
24.864
−12.052
1.00
75.16
A
N

ATOM
2119
CA
ASN
A
278
69.149
24.232
−12.228
1.00
71.96
A
C

ATOM
2120
C
ARN
A
278
68.678
23.332
−11.094
1.00
68.53
A
C

ATOM
2121
O
ASN
A
278
67.516
22.952
−11.057
1.00
65.41
A
O

ATOM
2122
CB
ASN
A
278
69.145
23.456
−13.544
1.00
71.99
A
C

ATOM
2123
CG
ASN
A
278
69.124
24.372
−14.749
1.00
73.02
A
C

ATOM
2124
OD1
ASN
A
278
68.090
24.528
−15.397
1.00
75.67
A
O

ATOM
2125
ND2
ASN
A
278
70.261
25.002
−15.043
1.00
71.03
A
N

ATOM
2126
N
ILE
A
279
69.567
23.002
−10.164
1.00
67.52
A
N

ATOM
2127
CA
ILE
A
279
69.188
22.191
−9.006
1.00
66.60
A
C

ATOM
2128
C
ILE
A
279
68.277
22.978
−8.046
1.00
63.12
A
C

ATOM
2129
O
ILE
A
279
67.509
22.382
−7.293
1.00
61.43
A
O

ATOM
2130
CB
ILE
A
279
70.451
21.673
−8.266
1.00
69.14
A
C

ATOM
2131
CG1
ILE
A
279
71.311
20.801
−9.196
1.00
70.33
A
C

ATOM
2132
CG2
ILE
A
279
70.069
20.890
−7.004
1.00
70.79
A
C

ATOM
2133
CD1
ILE
A
279
70.601
19.582
−9.773
1.00
71.75
A
C

ATOM
2134
N
PHE
A
280
68.364
24.310
−8.089
1.00
58.16
A
N

ATOM
2135
CA
PHE
A
280
67.577
25.184
−7.215
1.00
54.73
A
C

ATOM
2136
C
PHE
A
280
66.327
25.723
−7.929
1.00
48.44
A
C

ATOM
2137
O
PHE
A
280
66.404
26.160
−9.065
1.00
42.63
A
O

ATOM
2138
CB
PHE
A
280
68.440
26.352
−6.737
1.00
54.07
A
C

ATOM
2139
CG
PHE
A
280
69.641
25.934
−5.950
1.00
56.01
A
C

ATOM
2140
CD1
PHE
A
280
70.860
25.735
−6.582
1.00
56.28
A
C

ATOM
2141
CD2
PHE
A
280
69.554
25.741
−4.578
1.00
56.86
A
C

ATOM
2142
CE1
PHE
A
280
71.975
25.351
−5.861
1.00
58.79
A
C

ATOM
2143
CE2
PHE
A
280
70.663
25.351
−3.846
1.00
58.48
A
C

ATOM
2144
CZ
PHE
A
280
71.880
25.158
−4.487
1.00
58.24
A
C

ATOM
2145
N
PRO
A
281
65.183
25.713
−7.253
1.00
46.45
A
N

ATOM
2146
CA
PRO
A
281
63.933
26.153
−7.873
1.00
45.34
A
C

ATOM
2147
C
PRO
A
281
63.830
27.670
−7.930
1.00
46.32
A
C

ATOM
2148
O
PRO
A
281
64.540
28.377
−7.209
1.00
44.85
A
O

ATOM
2149
CB
PRO
A
281
62.875
25.625
−6.911
1.00
47.02
A
C

ATOM
2159
CG
PRO
A
281
63.552
25.707
−5.574
1.00
48.68
A
C

ATOM
2151
CD
PRO
A
281
64.985
25.312
−5.845
1.00
47.62
A
C

ATOM
2152
N
VAL
A
282
62.942
28.158
−8.783
1.00
44.02
A
N

ATOM
2153
CA
VAL
A
282
62.594
29.567
−8.785
1.00
44.12
A
C

ATOM
2154
C
VAL
A
282
61.625
29.811
−7.650
1.00
44.35
A
C

ATOM
2155
O
VAL
A
282
60.976
28.886
−7.174
1.00
43.30
A
O

ATOM
2156
CB
VAL
A
282
61.977
30.021
−10.119
1.00
44.10
A
C

ATOM
2157
CG1
VAL
A
282
62.930
29.754
−11.259
1.00
40.34
A
C

ATOM
2158
CG2
VAL
A
282
60.621
29.359
−10.368
1.00
48.29
A
C

ATOM
2159
N
ILE
A
283
61.555
31.048
−7.186
1.00
40.14
A
N

ATOM
2160
CA
ILE
A
283
60.502
31.421
−6.273
1.00
42.52
A
C

ATOM
2161
C
ILE
A
283
59.656
32.479
−6.970
1.00
39.13
A
C

ATOM
2162
O
ILE
A
283
60.171
33.297
−7.743
1.00
35.09
A
O

ATOM
2163
CB
ILE
A
283
61.043
31.847
−4.878
1.00
43.69
A
C

ATOM
2164
CG1
ILE
A
283
59.925
32.432
−4.023
1.00
46.75
A
C

ATOM
2165
CG2
ILE
A
283
62.174
32.818
−4.984
1.00
47.57
A
C

ATOM
2166
CD1
ILE
A
283
60.216
32.406
−2.547
1.00
47.98
A
C

ATOM
2167
N
SER
A
284
58.350
32.359
−6.758
1.00
35.81
A
N

ATOM
2168
CA
SER
A
284
57.354
33.282
−7.292
1.00
33.91
A
C

ATOM
2169
C
SER
A
284
56.555
33.814
−6.121
1.00
32.23
A
C

ATOM
2170
O
SER
A
284
56.080
33.051
−5.274
1.00
31.03
A
O

ATOM
2171
CB
SER
A
284
56.457
32.574
−8.313
1.00
31.65
A
C

ATOM
2172
OG
SER
A
284
57.075
32.546
−9.585
1.00
35.60
A
O

ATOM
2173
N
LEU
A
285
56.455
35.137
−6.028
1.00
25.42
A
N

ATOM
2174
CA
LEU
A
285
55.588
35.760
−5.069
1.00
24.59
A
C

ATOM
2175
C
LEU
A
285
54.478
36.397
−5.890
1.00
21.13
A
C

ATOM
2176
O
LEU
A
285
54.770
37.108
−6.839
1.00
19.53
A
O

ATOM
2177
CB
LEU
A
285
56.348
36.799
−4.263
1.00
27.87
A
C

ATOM
2178
CG
LEU
A
285
57.674
36.297
−3.682
1.00
27.04
A
C

ATOM
2179
CD1
LEU
A
285
58.356
37.456
−3.002
1.00
31.32
A
C

ATOM
2180
CD2
LEU
A
285
57.428
35.159
−2.702
1.00
29.67
A
C

ATOM
2181
N
TYR
A
286
53.233
36.065
−5.587
1.00
22.23
A
N

ATOM
2182
CA
TYR
A
286
52.112
36.768
−6.196
1.00
22.87
A
C

ATOM
2183
C
TYR
A
286
51.807
37.909
−5.280
1.00
20.51
A
C

ATOM
2184
O
TYR
A
286
51.686
37.712
−4.069
1.00
23.12
A
O

ATOM
2185
CB
TYR
A
286
50.871
35.898
−6.336
1.00
18.84
A
C

ATOM
2186
CG
TYR
A
286
50.989
34.755
−7.339
1.00
20.36
A
C

ATOM
2187
CD1
TYR
A
286
51.857
33.691
−7.125
1.00
27.97
A
C

ATOM
2188
CD2
TYR
A
286
50.168
34.720
−8.477
1.00
22.74
A
C

ATOM
2189
CE1
TYR
A
286
51.937
32.641
−8.024
1.00
28.14
A
C

ATOM
2190
CE2
TYR
A
286
50.243
33.661
−9.393
1.00
19.26
A
C

ATOM
2191
CZ
TYR
A
286
51.125
32.630
−9.148
1.00
24.29
A
C

ATOM
2192
OH
TYR
A
286
51.198
31.595
−10.033
1.00
23.89
A
O

ATOM
2193
N
LEU
A
287
51.672
39.113
−5.849
1.00
17.57
A
N

ATOM
2194
CA
LEU
A
287
51.327
40.293
−5.084
1.00
18.37
A
C

ATOM
2195
C
LEU
A
287
49.902
40.714
−5.367
1.00
19.30
A
C

ATOM
2196
O
LEU
A
287
49.413
40.525
−6.486
1.00
17.31
A
O

ATOM
2197
CB
LEU
A
287
52.291
41.429
−5.435
1.00
16.99
A
C

ATOM
2198
CG
LEU
A
287
53.759
41.076
−5.143
1.00
19.76
A
C

ATOM
2199
CD1
LEU
A
287
54.689
42.131
−5.672
1.00
21.23
A
C

ATOM
2200
CD2
LEU
A
287
53.943
40.852
−3.653
1.00
27.06
A
C

ATOM
2201
N
MET
A
288
49.250
41.310
−4.369
1.00
17.49
A
N

ATOM
2202
CA
MET
A
288
47.906
41.869
−4.524
1.00
14.88
A
C

ATOM
2203
C
MET
A
288
47.938
42.861
−5.688
1.00
17.43
A
C

ATOM
2204
O
MET
A
288
48.833
43.675
−5.798
1.00
16.72
A
O

ATOM
2205
CB
MET
A
288
47.471
42.597
−3.242
1.00
19.44
A
C

ATOM
2206
CG
MET
A
288
46.150
43.315
−3.360
1.00
21.18
A
C

ATOM
2207
SD
MET
A
288
45.656
44.123
−1.787
1.00
27.75
A
S

ATOM
2208
CE
MET
A
288
45.045
42.809
−0.930
1.00
26.84
A
C

ATOM
2209
N
GLY
A
289
46.961
42.792
−6.574
1.00
15.66
A
N

ATOM
2210
CA
GLY
A
289
46.942
43.753
−7.664
1.00
17.02
A
C

ATOM
2211
C
GLY
A
289
46.143
45.000
−7.381
1.00
16.69
A
C

ATOM
2212
O
GLY
A
289
45.655
45.211
−6.267
1.00
16.95
A
O

ATOM
2213
N
GLU
A
290
45.922
45.786
−8.425
1.00
16.66
A
N

ATOM
2214
CA
GLU
A
290
45.190
47.057
−8.298
1.00
17.93
A
C

ATOM
2215
C
GLU
A
290
43.656
46.888
−8.251
1.00
18.47
A
C

ATOM
2216
O
GLU
A
290
42.944
47.782
−7.800
1.00
20.92
A
O

ATOM
2217
CB
GLU
A
290
45.541
47.958
−9.465
1.00
21.26
A
C

ATOM
2292
O
THR
A
299
61.614
36.337
−11.139
1.00
28.84
A
O

ATOM
2293
CB
THR
A
299
59.291
34.640
−11.560
1.00
27.03
A
C

ATOM
2294
OG1
THR
A
299
57.902
34.287
−11.572
1.00
32.46
A
O

ATOM
2295
CG2
THR
A
299
60.001
33.283
−11.620
1.00
28.77
A
C

ATOM
2296
N
ILE
A
300
61.803
35.268
−9.175
1.00
31.26
A
N

ATOM
2297
CA
ILE
A
300
63.270
35.393
−9.098
1.00
33.70
A
C

ATOM
2298
C
ILE
A
300
63.938
34.033
−9.195
1.00
39.02
A
C

ATOM
2299
O
ILE
A
300
63.273
32.989
−9.287
1.00
37.86
A
O

ATOM
2300
CB
ILE
A
300
63.729
36.107
−7.793
1.00
35.95
A
C

ATOM
2301
CG1
ILE
A
300
63.443
35.258
−6.566
1.00
37.33
A
C

ATOM
2302
CG2
ILE
A
300
63.049
37.457
−7.639
1.00
35.67
A
C

ATOM
2303
CD1
ILE
A
300
64.152
35.715
−5.318
1.00
39.22
A
C

ATOM
2304
N
LEU
A
301
65.265
34.067
−9.161
1.00
39.05
A
N

ATOM
2305
CA
LEU
A
301
66.093
32.901
−9.421
1.00
37.54
A
C

ATOM
2306
C
LEU
A
301
67.013
32.602
−8.255
1.00
38.40
A
C

ATOM
2307
O
LEU
A
301
67.182
33.428
−7.371
1.00
36.53
A
O

ATOM
2308
CB
LEU
A
301
66.933
33.169
−10.664
1.00
36.30
A
C

ATOM
2309
CG
LEU
A
301
66.126
33.447
−11.937
1.00
34.74
A
C

ATOM
2310
CD1
LEU
A
301
67.030
33.935
−13.022
1.00
32.47
A
C

ATOM
2311
CD2
LEU
A
301
65.387
32.196
−12.430
1.00
39.84
A
C

ATOM
2312
N
PRO
A
302
67.619
31.420
−8.264
1.00
39.73
A
N

ATOM
2313
CA
PRO
A
302
68.706
31.113
−7.335
1.00
41.84
A
C

ATOM
2314
C
PRO
A
302
69.828
32.157
−7.387
1.00
41.87
A
C

ATOM
2315
O
PRO
A
302
70.427
32.420
−6.356
1.00
45.40
A
O

ATOM
2316
CB
PRO
A
302
69.208
29.759
−7.834
1.00
41.99
A
C

ATOM
2317
CG
PRO
A
302
68.031
29.157
−8.495
1.00
42.63
A
C

ATOM
2318
CD
PRO
A
302
67.321
30.285
−9.150
1.00
40.17
A
C

ATOM
2319
N
GLN
A
303
70.094
32.759
−8.546
1.00
40.21
A
N

ATOM
2320
CA
GLN
A
303
71.197
33.721
−8.659
1.00
41.56
A
C

ATOM
2321
C
GLN
A
303
70.933
34.984
−7.824
1.00
43.24
A
C

ATOM
2322
O
GLN
A
303
71.837
35.788
−7.598
1.00
38.56
A
O

ATOM
2323
CB
GLN
A
303
71.523
34.117
−10.119
1.00
44.66
A
C

ATOM
2324
CG
GLN
A
303
70.564
33.666
−11.201
1.00
47.40
A
C

ATOM
2325
CD
GLN
A
303
70.716
32.201
−11.545
1.00
50.63
A
C

ATOM
2326
OE1
GLN
A
303
69.911
31.372
−11.120
1.00
55.64
A
O

ATOM
2327
NE2
GLN
A
303
71.742
31.877
−12.332
1.00
51.86
A
N

ATOM
2328
N
GLN
A
304
69.689
35.145
−7.382
1.00
41.50
A
N

ATOM
2329
CA
GLN
A
304
69.273
36.282
−6.589
1.00
46.43
A
C

ATOM
2330
C
GLN
A
304
69.293
35.906
−5.100
1.00
47.20
A
C

ATOM
2331
O
GLN
A
304
69.738
36.705
−4.270
1.00
45.43
A
O

ATOM
2332
CB
GLN
A
304
67.871
36.735
−7.046
1.00
49.88
A
C

ATOM
2333
CG
GLN
A
304
67.862
37.811
−8.157
1.00
51.33
A
C

ATOM
2334
CD
GLN
A
304
68.273
37.315
−9.548
1.00
54.63
A
C

ATOM
2335
OE1
GLN
A
304
67.918
37.933
−10.556
1.00
54.99
A
O

ATOM
2336
NE2
GLN
A
304
69.031
36.224
−9.607
1.00
57.60
A
N

ATOM
2337
N
TYR
A
305
68.838
34.694
−4.760
1.00
47.73
A
N

ATOM
2338
CA
TYR
A
305
68.895
34.241
−3.364
1.00
51.85
A
C

ATOM
2339
C
TYR
A
305
70.132
33.385
−3.029
1.00
53.38
A
C

ATOM
2340
O
TYR
A
305
70.267
32.911
−1.903
1.00
53.57
A
O

ATOM
2341
CB
TYR
A
305
67.573
33.577
−2.910
1.00
52.81
A
C

ATOM
2342
CG
TYR
A
305
67.247
32.202
−3.471
1.00
53.16
A
C

ATOM
2343
CD1
TYR
A
305
67.828
31.052
−2.943
1.00
52.42
A
C

ATOM
2344
CD2
TYR
A
305
66.309
32.053
−4.494
1.00
52.93
A
C

ATOM
2345
CE1
TYR
A
305
67.515
29.789
−3.446
1.00
53.23
A
C

ATOM
2346
CE2
TYR
A
305
65.985
30.796
−5.002
1.00
53.91
A
C

ATOM
2347
CZ
TYR
A
305
66.592
29.669
−4.474
1.00
53.62
A
C

ATOM
2348
OH
TYR
A
305
66.272
28.425
−4.971
1.00
53.84
A
O

ATOM
2349
N
LEU
A
306
71.033
33.228
−3.997
1.00
55.03
A
N

ATOM
2350
CA
LEU
A
306
72.355
32.633
−3.777
1.00
61.56
A
C

ATOM
2351
C
LEU
A
306
73.390
33.700
−4.150
1.00
63.69
A
C

ATOM
2352
O
LEU
A
306
73.663
33.946
−5.332
1.00
64.04
A
O

ATOM
2353
CB
LEU
A
306
72.559
31.361
−4.610
1.00
62.70
A
C

ATOM
2354
CG
LEU
A
306
72.418
29.992
−3.934
1.00
65.11
A
C

ATOM
2355
CD1
LEU
A
306
71.256
29.932
−2.950
1.00
65.92
A
C

ATOM
2356
CD2
LEU
A
306
72.262
28.920
−5.001
1.00
65.99
A
C

ATOM
2357
N
ARG
A
307
73.965
34.321
−3.126
1.00
67.42
A
N

ATOM
2358
CA
ARG
A
307
74.753
35.546
−3.285
1.00
69.54
A
C

ATOM
2359
C
ARG
A
307
76.226
35.241
−3.045
1.00
70.36
A
C

ATOM
2360
O
ARG
A
307
76.568
34.726
−1.981
1.00
69.95
A
O

ATOM
2361
CB
ARG
A
307
74.270
36.631
−2.302
1.00
70.52
A
C

ATOM
2362
CG
ARG
A
307
73.942
36.126
−0.885
1.00
71.76
A
C

ATOM
2363
CD
ARG
A
307
73.347
37.158
0.060
1.00
71.91
A
C

ATOM
2364
NE
ARG
A
307
74.308
37.604
1.064
1.00
71.58
A
N

ATOM
2365
CZ
ARG
A
307
75.160
38.609
0.900
1.00
72.31
A
C

ATOM
2440
OD2
ASP
A
317
87.616
26.284
−4.381
1.00
83.59
A
O

ATOM
2441
N
ASP
A
318
84.113
29.504
−5.421
1.00
77.10
A
N

ATOM
2442
CA
ASP
A
318
82.894
30.315
−5.525
1.00
76.86
A
C

ATOM
2443
C
ASP
A
318
81.909
29.982
−4.398
1.00
75.04
A
C

ATOM
2444
O
ASP
A
318
81.025
29.137
−4.565
1.00
76.20
A
O

ATOM
2445
CB
ASP
A
318
82.212
30.093
−6.880
1.00
76.77
A
C

ATOM
2446
CG
ASP
A
318
83.043
30.590
−8.044
1.00
77.69
A
C

ATOM
2447
OD1
ASP
A
318
84.270
30.781
−7.874
1.00
78.53
A
O

ATOM
2448
OD2
ASP
A
318
82.550
30.811
−9.170
1.00
77.17
A
O

ATOM
2449
N
CYS
A
319
82.065
30.653
−3.259
1.00
73.01
A
N

ATOM
2450
CA
CYS
A
319
81.211
30.428
−2.094
1.00
71.05
A
C

ATOM
2451
C
CYS
A
319
80.044
31.414
−2.062
1.00
68.67
A
C

ATOM
2452
O
CYS
A
319
80.235
32.611
−2.258
1.00
66.66
A
O

ATOM
2453
CB
CYS
A
319
82.026
30.554
−0.803
1.00
71.92
A
C

ATOM
2454
SG
CYS
A
319
83.414
29.394
−0.686
1.00
74.09
A
S

ATOM
2455
N
TYR
A
320
78.839
30.899
−1.832
1.00
66.44
A
N

ATOM
2456
CA
TYR
A
320
77.645
31.728
−1.691
1.00
64.22
A
C

ATOM
2457
C
TYR
A
320
77.013
31.498
−0.320
1.00
62.66
A
C

ATOM
2458
O
TYR
A
320
77.332
30.523
0.365
1.00
61.41
A
O

ATOM
2459
CB
TYR
A
320
76.611
31.384
−2.764
1.00
64.24
A
C

ATOM
2460
CG
TYR
A
320
77.108
31.323
−4.198
1.00
64.74
A
C

ATOM
2461
CD1
TYR
A
320
77.957
30.302
−4.632
1.00
64.73
A
C

ATOM
2462
CD2
TYR
A
320
76.682
32.260
−5.139
1.00
64.78
A
C

ATOM
2463
CE1
TYR
A
320
78.390
30.239
−5.961
1.00
64.57
A
C

ATOM
2464
CE2
TYR
A
320
77.106
32.202
−6.465
1.00
64.30
A
C

ATOM
2465
CZ
TYR
A
320
77.957
31.193
−6.871
1.00
64.35
A
C

ATOM
2466
OH
TYR
A
320
78.374
31.146
−8.185
1.00
62.89
A
O

ATOM
2467
N
LYS
A
321
76.111
32.392
0.076
1.00
59.11
A
N

ATOM
2468
CA
LYS
A
321
75.320
32.189
1.286
1.00
58.36
A
C

ATOM
2469
C
LYS
A
321
73.816
32.265
0.996
1.00
55.24
A
C

ATOM
2470
O
LYS
A
321
73.353
33.065
0.181
1.00
47.87
A
O

ATOM
2471
CB
LYS
A
321
75.747
33.160
2.398
1.00
59.88
A
C

ATOM
2472
CG
LYS
A
321
74.853
34.371
2.629
1.00
62.72
A
C

ATOM
2473
CD
LYS
A
321
75.277
35.120
3.888
1.00
64.37
A
C

ATOM
2474
CE
LYS
A
321
74.699
34.483
5.145
1.00
64.91
A
C

ATOM
2475
NZ
LYS
A
321
74.999
35.289
6.363
1.00
66.23
A
N

ATOM
2476
N
PHE
A
322
73.062
31.401
1.664
1.00
51.88
A
N

ATOM
2477
CA
PHE
A
322
71.619
31.397
1.531
1.00
49.73
A
C

ATOM
2478
C
PHE
A
322
71.087
32.737
2.019
1.00
49.06
A
C

ATOM
2479
O
PHE
A
322
71.346
33.148
3.154
1.00
45.51
A
O

ATOM
2480
CB
PHE
A
322
70.999
30.235
2.321
1.00
49.10
A
C

ATOM
2481
CG
PHE
A
322
69.573
29.925
1.935
1.00
44.63
A
C

ATOM
2482
CD1
PHE
A
322
68.563
29.921
2.894
1.00
45.73
A
C

ATOM
2483
CD2
PHE
A
322
69.248
29.629
0.623
1.00
39.25
A
C

ATOM
2484
CE1
PHE
A
322
67.252
29.634
2.539
1.00
44.70
A
C

ATOM
2485
CE2
PHE
A
322
67.950
29.351
0.261
1.00
41.50
A
C

ATOM
2486
CZ
PHE
A
322
66.947
29.353
1.218
1.00
42.07
A
C

ATOM
2487
N
ALA
A
323
70.339
33.399
1.142
1.00
47.94
A
N

ATOM
2488
CA
ALA
A
323
69.901
34.771
1.336
1.00
46.61
A
C

ATOM
2489
C
ALA
A
323
68.426
34.839
1.712
1.00
44.07
A
C

ATOM
2490
O
ALA
A
323
67.809
35.887
1.548
1.00
33.93
A
O

ATOM
2491
CB
ALA
A
323
70.133
35.564
0.054
1.00
49.38
A
C

ATOM
2492
N
ILE
A
324
67.853
33.725
2.169
1.00
37.73
A
N

ATOM
2493
CA
ILE
A
324
66.520
33.746
2.739
1.00
38.21
A
C

ATOM
2494
C
ILE
A
324
66.643
33.442
4.214
1.00
34.73
A
C

ATOM
2495
O
ILE
A
324
67.442
32.611
4.619
1.00
36.43
A
O

ATOM
2496
CB
ILE
A
324
65.577
32.736
2.038
1.00
38.89
A
C

ATOM
2497
CG1
ILE
A
324
65.714
32.862
0.518
1.00
38.34
A
C

ATOM
2498
CG2
ILE
A
324
64.126
32.960
2.495
1.00
40.76
A
C

ATOM
2499
CD1
ILE
A
324
64.684
32.110
−0.277
1.00
41.65
A
C

ATOM
2500
N
SER
A
325
65.840
34.112
5.020
1.00
32.69
A
N

ATOM
2501
CA
SER
A
325
66.013
34.031
6.460
1.00
38.71
A
C

ATOM
2502
C
SER
A
325
64.722
34.407
7.139
1.00
39.64
A
C

ATOM
2503
O
SER
A
325
63.792
34.883
6.509
1.00
40.29
A
O

ATOM
2504
CB
SER
A
325
67.150
34.953
6.925
1.00
40.03
A
C

ATOM
2505
OG
SER
A
325
66.788
36.327
6.838
1.00
38.81
A
O

ATOM
2506
N
GLN
A
326
64.677
34.221
8.440
1.00
38.99
A
N

ATOM
2507
CA
GLN
A
326
63.414
34.244
9.134
1.00
39.09
A
C

ATOM
2508
C
GLN
A
326
63.294
35.561
9.885
1.00
36.76
A
C

ATOM
2509
O
GLN
A
326
64.259
36.297
10.004
1.00
39.83
A
O

ATOM
2510
CB
GLN
A
326
63.287
33.011
10.037
1.00
41.88
A
C

ATOM
2511
CG
GLN
A
326
64.481
32.024
9.957
1.00
45.10
A
C

ATOM
2512
CD
GLN
A
326
64.374
30.817
10.892
1.00
50.52
A
C

ATOM
2513
OE1
GLN
A
326
65.393
30.286
11.322
1.00
51.97
A
O

ATOM
2514
NE2
GLN
A
326
63.151
30.388
11.202
1.00
51.73
A
N

ATOM
2515
N
SER
A
327
62.108
35.878
10.374
1.00
30.92
A
N

ATOM
2516
CA
SER
A
327
61.904
37.188
10.988
1.00
35.17
A
C

ATOM
2517
C
SER
A
327
60.788
37.140
11.993
1.00
36.09
A
C

ATOM
2518
O
SER
A
327
59.978
36.208
12.018
1.00
38.75
A
O

ATOM
2519
CB
SER
A
327
61.578
38.259
9.921
1.00
35.42
A
C

ATOM
2520
OG
SER
A
327
60.882
39.380
10.482
1.00
33.54
A
O

ATOM
2521
N
SER
A
328
60.723
38.174
12.808
1.00
31.04
A
N

ATOM
2522
CA
SER
A
328
59.597
38.328
13.697
1.00
37.93
A
C

ATOM
2523
C
SER
A
328
58.868
39.654
13.520
1.00
39.07
A
C

ATOM
2524
O
SER
A
328
57.960
39.967
14.296
1.00
43.35
A
O

ATOM
2525
CB
SER
A
328
60.086
38.167
15.123
1.00
41.74
A
C

ATOM
2526
OG
SER
A
328
60.967
39.227
15.485
1.00
45.41
A
O

ATOM
2527
N
THR
A
329
59.257
40.409
12.492
1.00
37.31
A
N

ATOM
2528
CA
THR
A
329
58.675
41.715
12.186
1.00
40.83
A
C

ATOM
2529
C
THR
A
329
58.020
41.703
10.797
1.00
39.53
A
C

ATOM
2530
O
THR
A
329
57.814
42.771
10.218
1.00
37.06
A
O

ATOM
2531
CB
THR
A
329
59.770
42.814
12.193
1.00
42.95
A
C

ATOM
2532
OG1
THR
A
329
60.831
42.455
11.287
1.00
41.26
A
O

ATOM
2533
CG2
THR
A
329
60.441
42.933
13.558
1.00
44.90
A
C

ATOM
2534
N
GLY
A
330
57.724
40.510
10.270
1.00
37.04
A
N

ATOM
2535
CA
GLY
A
330
57.032
40.358
8.988
1.00
35.68
A
C

ATOM
2536
C
GLY
A
330
57.929
39.930
7.836
1.00
34.85
A
C

ATOM
2537
O
GLY
A
330
59.067
39.526
8.047
1.00
32.50
A
O

ATOM
2538
N
THR
A
331
57.398
39.974
6.605
1.00
33.39
A
N

ATOM
2539
CA
THR
A
331
58.207
39.709
5.419
1.00
28.89
A
C

ATOM
2540
C
THR
A
331
58.979
40.971
4.998
1.00
27.79
A
C

ATOM
2541
O
THR
A
331
58.496
42.086
5.175
1.00
33.40
A
O

ATOM
2542
CB
THR
A
331
57.320
39.267
4.249
1.00
30.99
A
C

ATOM
2543
OG1
THR
A
331
56.695
38.020
4.561
1.00
30.88
A
O

ATOM
2544
CG2
THR
A
331
58.157
38.989
2.983
1.00
33.73
A
C

ATOM
2545
N
VAL
A
332
60.177
40.764
4.470
1.00
22.23
A
N

ATOM
2546
CA
VAL
A
332
61.065
41.847
3.989
1.00
27.82
A
C

ATOM
2547
C
VAL
A
332
61.630
41.466
2.632
1.00
24.10
A
C

ATOM
2548
O
VAL
A
332
62.394
40.540
2.501
1.00
26.31
A
O

ATOM
2549
CB
VAL
A
332
62.274
42.139
4.935
1.00
28.52
A
C

ATOM
2550
CG1
VAL
A
332
63.138
43.293
4.367
1.00
32.83
A
C

ATOM
2551
CG2
VAL
A
332
61.801
42.468
6.329
1.00
30.87
A
C

ATOM
2552
N
MET
A
333
61.242
42.199
1.591
1.00
29.37
A
N

ATOM
2553
CA
MET
A
333
61.760
41.968
0.251
1.00
23.35
A
C

ATOM
2554
C
MET
A
333
63.012
42.813
−0.015
1.00
26.09
A
C

ATOM
2555
O
MET
A
333
62.920
43.935
−0.512
1.00
22.66
A
O

ATOM
2556
CB
MET
A
333
60.687
42.296
−0.804
1.00
26.84
A
C

ATOM
2557
CG
MET
A
333
59.550
41.295
−0.855
1.00
28.90
A
C

ATOM
2558
SD
MET
A
333
58.086
41.883
−1.807
1.00
33.93
A
S

ATOM
2559
CE
MET
A
333
58.640
41.701
−3.325
1.00
30.83
A
C

ATOM
2560
N
GLY
A
334
64.179
42.265
0.294
1.00
26.44
A
N

ATOM
2561
CA
GLY
A
334
65.428
43.015
0.190
1.00
28.29
A
C

ATOM
2562
C
GLY
A
334
66.044
43.002
−1.185
1.00
28.85
A
C

ATOM
2563
O
GLY
A
334
65.370
42.791
−2.185
1.00
28.04
A
O

ATOM
2564
N
ALA
A
335
67.350
43.220
−1.243
1.00
29.46
A
N

ATOM
2565
CA
ALA
A
335
68.097
43.214
−2.489
1.00
28.30
A
C

ATOM
2566
C
ALA
A
335
67.939
41.952
−3.330
1.00
31.11
A
C

ATOM
2567
O
ALA
A
335
68.001
42.021
−4.563
1.00
29.82
A
O

ATOM
2568
CB
ALA
A
335
69.578
43.470
−2.206
1.00
34.20
A
C

ATOM
2569
N
VAL
A
336
67.738
40.805
−2.671
1.00
31.66
A
N

ATOM
2570
CA
VAL
A
336
67.506
39.532
−3.349
1.00
35.42
A
C

ATOM
2571
C
VAL
A
336
66.412
39.733
−4.393
1.00
32.46
A
C

ATOM
2572
O
VAL
A
336
66.626
39.464
−5.574
1.00
36.08
A
O

ATOM
2573
CB
VAL
A
336
67.096
38.405
−2.341
1.00
38.14
A
C

ATOM
2574
CG1
VAL
A
336
66.466
37.196
−3.057
1.00
41.63
A
C

ATOM
2575
CG2
VAL
A
336
68.294
37.960
−1.518
1.00
42.38
A
C

ATOM
2576
N
ILE
A
337
65.271
40.248
−3.944
1.00
32.57
A
N

ATOM
2577
CA
ILE
A
337
64.130
40.507
−4.832
1.00
31.81
A
C

ATOM
2578
C
ILE
A
337
64.389
41.687
−5.760
1.00
29.91
A
C

ATOM
2579
O
ILE
A
337
64.231
41.592
−6.969
1.00
27.22
A
O

ATOM
2580
CB
ILE
A
337
62.835
40.731
−4.005
1.00
34.05
A
C

ATOM
2581
CG1
ILE
A
337
62.466
39.472
−3.216
1.00
37.53
A
C

ATOM
2582
CG2
ILE
A
337
61.668
41.174
−4.903
1.00
34.31
A
C

ATOM
2583
CD1
ILE
A
337
61.814
38.383
−4.043
1.00
39.14
A
C

ATOM
2584
N
MET
A
338
64.813
42.816
−5.202
1.00
28.42
A
N

ATOM
2585
CA
MET
A
338
64.909
44.038
−5.998
1.00
27.14
A
C

ATOM
2586
C
MET
A
338
65.914
43.969
−7.154
1.00
28.91
A
C

ATOM
2587
O
MET
A
338
65.753
44.650
−8.166
1.00
28.30
A
O

ATOM
2588
CB
MET
A
338
65.195
45.214
−5.067
1.00
25.93
A
C

ATOM
2589
CG
MET
A
338
64.083
45.457
−4.082
1.00
27.03
A
C

ATOM
2590
SD
MET
A
338
64.367
46.907
−3.076
1.00
25.07
A
S

ATOM
2591
CE
MET
A
338
64.174
48.235
−4.312
1.00
20.81
A
C

ATOM
2592
N
GLU
A
339
66.954
43.142
−7.040
1.00
29.81
A
N

ATOM
2593
CA
GLU
A
339
67.909
43.018
−8.142
1.00
32.30
A
C

ATOM
2594
C
GLU
A
339
67.318
42.371
−9.403
1.00
30.06
A
C

ATOM
2595
O
GLU
A
339
67.874
42.502
−10.488
1.00
33.61
A
O

ATOM
2596
CB
GLU
A
339
69.174
42.269
−7.704
1.00
33.90
A
C

ATOM
2597
CG
GLU
A
339
70.197
43.177
−7.027
1.00
38.40
A
C

ATOM
2598
CD
GLU
A
339
71.139
42.424
−6.107
1.00
42.07
A
C

ATOM
2599
OE1
GLU
A
339
71.439
41.242
−6.391
1.00
39.96
A
O

ATOM
2600
OE2
GLU
A
339
71.570
43.015
−5.095
1.00
43.98
A
O

ATOM
2601
N
GLY
A
340
66.187
41.687
−9.259
1.00
30.73
A
N

ATOM
2602
CA
GLY
A
340
65.475
41.165
−10.411
1.00
29.00
A
C

ATOM
2603
C
GLY
A
340
64.626
42.169
−11.162
1.00
25.72
A
C

ATOM
2604
O
GLY
A
340
64.289
41.949
−12.331
1.00
25.52
A
O

ATOM
2605
N
PHE
A
341
64.278
43.281
−10.509
1.00
21.32
A
N

ATOM
2606
CA
PHE
A
341
63.243
44.173
−11.017
1.00
17.05
A
C

ATOM
2607
C
PHE
A
341
63.561
45.656
−10.971
1.00
19.54
A
C

ATOM
2608
O
PHE
A
341
64.379
46.111
−10.174
1.00
20.37
A
O

ATOM
2609
CB
PHE
A
341
61.961
43.899
−10.222
1.00
18.19
A
C

ATOM
2610
CG
PHE
A
341
61.630
42.440
−10.137
1.00
20.96
A
C

ATOM
2611
CD1
PHE
A
341
61.108
41.770
−11.237
1.00
22.17
A
C

ATOM
2612
CD2
PHE
A
341
61.910
41.717
−8.998
1.00
23.21
A
C

ATOM
2613
CE1
PHE
A
341
60.853
40.399
−11.160
1.00
17.74
A
C

ATOM
2614
CE2
PHE
A
341
61.650
40.351
−8.939
1.00
23.34
A
C

ATOM
2615
CZ
PHE
A
341
61.134
39.705
−10.012
1.00
24.23
A
C

ATOM
2616
N
TYR
A
342
62.952
46.413
−11.875
1.00
17.67
A
N

ATOM
2617
CA
TYR
A
342
62.820
47.837
−11.702
1.00
17.52
A
C

ATOM
2618
C
TYR
A
342
61.608
48.077
−10.810
1.00
22.25
A
C

ATOM
2619
O
TYR
A
342
60.494
47.620
−11.100
1.00
19.30
A
O

ATOM
2620
CB
TYR
A
342
62.656
48.485
−13.040
1.00
17.92
A
C

ATOM
2621
CG
TYR
A
342
62.654
49.980
−13.067
1.00
18.37
A
C

ATOM
2622
CD1
TYR
A
342
63.668
50.730
−12.467
1.00
19.68
A
C

ATOM
2623
CD2
TYR
A
342
61.681
50.654
−13.765
1.00
23.05
A
C

ATOM
2624
CE1
TYR
A
342
63.684
52.115
−12.562
1.00
22.84
A
C

ATOM
2625
CE2
TYR
A
342
61.693
52.006
−13.868
1.00
22.40
A
C

ATOM
2626
CZ
TYR
A
342
62.693
52.750
−13.264
1.00
22.81
A
C

ATOM
2627
OH
TYR
A
342
62.667
54.131
−13.385
1.00
26.20
A
O

ATOM
2628
N
VAL
A
343
61.840
48.777
−9.705
1.00
15.05
A
N

ATOM
2629
CA
VAL
A
343
60.827
49.008
−8.688
1.00
17.53
A
C

ATOM
2630
C
VAL
A
343
60.510
50.494
−8.598
1.00
14.20
A
C

ATOM
2631
O
VAL
A
343
61.378
51.334
−8.376
1.00
15.91
A
O

ATOM
2632
CB
VAL
A
343
61.259
48.442
−7.305
1.00
15.41
A
C

ATOM
2633
CG1
VAL
A
343
60.123
48.560
−6.267
1.00
18.03
A
C

ATOM
2634
CG2
VAL
A
343
61.704
47.022
−7.473
1.00
18.07
A
C

ATOM
2635
N
VAL
A
344
59.231
50.791
−8.767
1.00
11.66
A
N

ATOM
2636
CA
VAL
A
344
58.682
52.123
−8.783
1.00
12.22
A
C

ATOM
2637
C
VAL
A
344
57.903
52.401
−7.510
1.00
13.35
A
C

ATOM
2638
O
VAL
A
344
56.875
51.802
−7.235
1.00
16.24
A
O

ATOM
2639
CB
VAL
A
344
57.774
52.308
−10.027
1.00
15.89
A
C

ATOM
2640
CG1
VAL
A
344
57.159
53.685
−10.035
1.00
18.74
A
C

ATOM
2641
CG2
VAL
A
344
58.587
52.106
−11.280
1.00
18.50
A
C

ATOM
2642
N
PHE
A
345
58.418
53.322
−6.713
1.00
16.40
A
N

ATOM
2643
CA
PHE
A
345
57.771
53.763
−5.483
1.00
15.06
A
C

ATOM
2644
C
PHE
A
345
56.833
54.934
−5.754
1.00
15.39
A
C

ATOM
2645
O
PHE
A
345
57.192
56.113
−5.655
1.00
17.43
A
O

ATOM
2646
CB
PHE
A
345
58.846
54.062
−4.416
1.00
17.40
A
C

ATOM
2647
CG
PHE
A
345
59.670
52.855
−4.040
1.00
15.11
A
C

ATOM
2648
CD1
PHE
A
345
60.702
52.386
−4.863
1.00
13.07
A
C

ATOM
2649
CD2
PHE
A
345
59.402
52.153
−2.882
1.00
13.71
A
C

ATOM
2650
CE1
PHE
A
345
61.446
51.242
−4.510
1.00
15.84
A
C

ATOM
2651
CE2
PHE
A
345
60.169
51.040
−2.507
1.00
11.40
A
C

ATOM
2652
CZ
PHE
A
345
61.186
50.581
−3.327
1.00
15.67
A
C

ATOM
2653
N
ASP
A
346
55.633
54.601
−6.206
1.00
16.44
A
N

ATOM
2654
CA
ASP
A
346
54.671
55.593
−6.672
1.00
15.35
A
C

ATOM
2655
C
ASP
A
346
53.855
56.101
−5.495
1.00
16.03
A
C

ATOM
2656
O
ASP
A
346
52.711
55.700
−5.254
1.00
19.50
A
O

ATOM
2657
CB
ASP
A
346
53.800
54.986
−7.778
1.00
18.03
A
C

ATOM
2658
CG
ASP
A
346
52.872
55.995
−8.420
1.00
25.99
A
C

ATOM
2659
OD1
ASP
A
346
52.844
57.166
−7.967
1.00
28.56
A
O

ATOM
2660
OD2
ASP
A
346
52.120
55.680
−9.382
1.00
23.57
A
O

ATOM
2661
N
ARG
A
347
54.491
56.978
−4.725
1.00
17.55
A
N

ATOM
2662
CA
ARG
A
347
53.908
57.497
−3.499
1.00
21.29
A
C

ATOM
2663
C
ARG
A
347
52.632
58.294
−3.785
1.00
18.95
A
C

ATOM
2664
O
ARG
A
347
51.701
58.266
−2.991
1.00
22.26
A
O

ATOM
2665
CB
ARG
A
347
54.932
58.369
−2.765
1.00
19.24
A
C

ATOM
2666
CG
ARG
A
347
56.184
57.635
−2.282
1.00
22.31
A
C

ATOM
2667
CD
ARG
A
347
57.359
58.594
−2.059
1.00
23.46
A
C

ATOM
2668
NE
ARG
A
347
57.009
59.652
−1.092
1.00
23.99
A
N

ATOM
2669
CZ
ARG
A
347
57.403
59.691
0.183
1.00
30.72
A
C

ATOM
2670
NH1
ARG
A
347
57.031
60.700
0.959
1.00
32.59
A
N

ATOM
2671
NH2
ARG
A
347
58.174
58.745
0.696
1.00
27.96
A
N

ATOM
2672
N
ALA
A
348
52.590
58.959
−4.936
1.00
21.83
A
N

ATOM
2673
CA
ALA
A
348
51.439
59.780
−5.327
1.00
24.64
A
C

ATOM
2674
C
ALA
A
348
50.148
58.953
−5.399
1.00
28.25
A
C

ATOM
2675
O
ALA
A
348
49.056
59.426
−5.028
1.00
24.96
A
O

ATOM
2676
CB
ALA
A
348
51.721
60.425
−6.668
1.00
24.31
A
C

ATOM
2677
N
ARG
A
349
50.282
57.724
−5.896
1.00
25.65
A
N

ATOM
2678
CA
ARG
A
349
49.151
56.806
−6.029
1.00
25.84
A
C

ATOM
2679
C
ARG
A
349
49.168
55.627
−5.077
1.00
25.58
A
C

ATOM
2680
O
ARG
A
349
48.460
54.653
−5.319
1.00
25.28
A
O

ATOM
2681
CB
ARG
A
349
49.100
56.276
−7.459
1.00
29.93
A
C

ATOM
2682
CG
ARG
A
349
49.176
57.344
−8.488
1.00
33.60
A
C

ATOM
2683
CD
ARG
A
349
48.502
57.000
−9.775
1.00
36.74
A
C

ATOM
2684
NE
ARG
A
349
48.827
58.016
−10.763
1.00
42.71
A
N

ATOM
2685
CZ
ARG
A
349
48.278
59.227
−10.814
1.00
48.30
A
C

ATOM
2686
NH1
ARG
A
349
47.316
59.600
−9.964
1.00
46.44
A
N

ATOM
2687
NH2
ARG
A
349
48.686
60.072
−11.751
1.00
50.26
A
N

ATOM
2688
N
LYS
A
350
49.954
55.721
−3.989
1.00
23.32
A
N

ATOM
2689
CA
LYS
A
350
50.022
54.700
−2.945
1.00
24.27
A
C

ATOM
2690
C
LYS
A
350
50.163
53.310
−3.549
1.00
19.69
A
C

ATOM
2691
O
LYS
A
350
49.374
52.429
−3.260
1.00
20.60
A
O

ATOM
2692
CB
LYS
A
350
48.757
54.704
−2.079
1.00
28.78
A
C

ATOM
2693
CG
LYS
A
350
48.522
55.929
−1.231
1.00
34.60
A
C

ATOM
2694
CD
LYS
A
350
47.436
55.639
−0.141
1.00
37.26
A
C

ATOM
2695
CE
LYS
A
350
47.719
54.361
0.695
1.00
36.46
A
C

ATOM
2696
NZ
LYS
A
350
46.822
54.210
1.887
1.00
40.30
A
N

ATOM
2697
N
ARG
A
351
51.147
53.140
−4.420
1.00
19.35
A
N

ATOM
2698
CA
ARG
A
351
51.371
51.855
−5.063
1.00
17.19
A
C

ATOM
2699
C
ARG
A
351
52.842
51.641
−5.383
1.00
15.48
A
C

ATOM
2700
O
ARG
A
351
53.609
52.576
−5.490
1.00
17.66
A
O

ATOM
2701
CB
ARG
A
351
50.501
51.758
−6.328
1.00
15.07
A
C

ATOM
2702
CG
ARG
A
351
50.851
52.687
−7.388
1.00
17.01
A
C

ATOM
2703
CD
ARG
A
351
49.837
52.667
−8.565
1.00
17.81
A
C

ATOM
2704
NE
ARG
A
351
50.304
53.485
−9.674
1.00
17.24
A
N

ATOM
2705
CZ
ARG
A
351
49.711
53.543
−10.862
1.00
23.21
A
C

ATOM
2706
NH1
ARG
A
351
48.651
52.804
−11.095
1.00
21.30
A
N

ATOM
2707
NH2
ARG
A
351
50.213
54.312
−11.831
1.00
24.26
A
N

ATOM
2708
N
ILE
A
352
53.240
50.376
−5.500
1.00
17.16
A
N

ATOM
2709
CA
ILE
A
352
54.581
50.022
−5.928
1.00
16.38
A
C

ATOM
2710
C
ILE
A
352
54.510
49.221
−7.208
1.00
15.28
A
C

ATOM
2711
O
ILE
A
352
53.800
48.234
−7.277
1.00
15.77
A
O

ATOM
2712
CB
ILE
A
352
55.303
49.167
−4.857
1.00
17.10
A
C

ATOM
2713
CG1
ILE
A
352
55.387
49.937
−3.540
1.00
24.67
A
C

ATOM
2714
CG2
ILE
A
352
56.740
48.790
−5.322
1.00
17.46
A
C

ATOM
2715
CD1
ILE
A
352
55.844
49.129
−2.381
1.00
28.46
A
C

ATOM
2716
N
GLY
A
353
55.291
49.633
−8.199
1.00
14.93
A
N

ATOM
2717
CA
GLY
A
353
55.345
48.949
−9.481
1.00
14.98
A
C

ATOM
2718
C
GLY
A
353
56.559
48.090
−9.631
1.00
15.46
A
C

ATOM
2719
O
GLY
A
353
57.649
48.466
−9.185
1.00
14.60
A
O

ATOM
2720
N
PHE
A
354
56.385
46.936
−10.290
1.00
15.06
A
N

ATOM
2721
CA
PHE
A
354
57.469
46.043
−10.577
1.00
14.45
A
C

ATOM
2722
C
PHE
A
354
57.482
45.781
−12.064
1.00
15.57
A
C

ATOM
2723
O
PHE
A
354
56.431
45.590
−12.685
1.00
17.67
A
O

ATOM
2724
CB
PHE
A
354
57.285
44.716
−9.860
1.00
16.68
A
C

ATOM
2725
CG
PHE
A
354
57.443
44.793
−8.362
1.00
16.38
A
C

ATOM
2726
CD1
PHE
A
354
56.371
45.164
−7.563
1.00
16.54
A
C

ATOM
2727
CD2
PHE
A
354
58.640
44.430
−7.756
1.00
19.54
A
C

ATOM
2728
CE1
PHE
A
354
56.490
45.231
−6.177
1.00
20.88
A
C

ATOM
2729
CE2
PHE
A
354
58.771
44.487
−6.362
1.00
19.27
A
C

ATOM
2730
CZ
PHE
A
354
57.684
44.906
−5.571
1.00
15.66
A
C

ATOM
2731
N
ALA
A
355
58.684
45.766
−12.606
1.00
18.28
A
N

ATOM
2732
CA
ALA
A
355
58.922
45.384
−13.999
1.00
16.49
A
C

ATOM
2733
C
ALA
A
355
60.245
44.644
−14.081
1.00
19.90
A
C

ATOM
2734
O
ALA
A
355
61.106
44.777
−13.211
1.00
21.15
A
O

ATOM
2735
CB
ALA
A
355
58.922
46.569
−14.878
1.00
17.48
A
C

ATOM
2736
N
VAL
A
356
60.399
43.827
−15.120
1.00
20.94
A
N

ATOM
2737
CA
VAL
A
356
61.650
43.107
−15.305
1.00
21.72
A
C

ATOM
2738
C
VAL
A
356
62.776
44.111
−15.553
1.00
19.54
A
C

ATOM
2739
O
VAL
A
356
62.672
44.989
−16.402
1.00
21.35
A
O

ATOM
2740
CB
VAL
A
356
61.562
42.087
−16.473
1.00
19.47
A
C

ATOM
2741
CG1
VAL
A
356
62.936
41.435
−16.724
1.00
20.92
A
C

ATOM
2742
CG2
VAL
A
356
60.517
41.025
−16.174
1.00
23.31
A
C

ATOM
2743
N
SER
A
357
63.853
43.982
−14.793
1.00
24.48
A
N

ATOM
2744
CA
SER
A
357
64.963
44.919
−14.883
1.00
26.30
A
C

ATOM
2745
C
SER
A
357
65.767
44.633
−16.142
1.00
26.78
A
C

ATOM
2746
O
SER
A
357
66.071
43.481
−16.420
1.00
30.47
A
O

ATOM
2747
CB
SER
A
357
65.896
44.775
−13.676
1.00
25.63
A
C

ATOM
2748
OG
SER
A
357
67.009
45.645
−13.815
1.00
30.40
A
O

ATOM
2749
N
ALA
A
358
66.128
45.682
−16.867
1.00
32.11
A
N

ATOM
2750
CA
ALA
A
358
67.012
45.567
−18.029
1.00
36.75
A
C

ATOM
2751
C
ALA
A
358
68.445
45.147
−17.666
1.00
38.55
A
C

ATOM
2752
O
ALA
A
358
69.233
44.838
−18.560
1.00
42.49
A
O

ATOM
2753
CB
ALA
A
358
67.025
46.881
−18.802
1.00
37.17
A
C

ATOM
2754
N
CYS
A
359
68.782
45.129
−16.374
1.00
39.61
A
N

ATOM
2755
CA
CYS
A
359
70.124
44.742
−15.920
1.00
41.87
A
C

ATOM
2756
C
CYS
A
359
70.169
43.490
−15.049
1.00
42.74
A
C

ATOM
2757
O
CYS
A
359
71.241
43.132
−14.550
1.00
45.60
A
O

ATOM
2758
CB
CYS
A
359
70.801
45.913
−15.175
1.00
41.64
A
C

ATOM
2759
SG
CYS
A
359
70.275
46.154
−13.447
1.00
42.44
A
S

ATOM
2760
N
HIS
A
360
69.040
42.811
−14.847
1.00
42.50
A
N

ATOM
2761
CA
HIS
A
360
69.071
41.569
−14.081
1.00
43.24
A
C

ATOM
2762
C
HIS
A
360
69.903
40.538
−14.848
1.00
44.08
A
C

ATOM
2763
O
HIS
A
360
69.932
40.545
−16.089
1.00
37.43
A
O

ATOM
2764
CB
HIS
A
360
67.665
41.037
−13.772
1.00
43.88
A
C

ATOM
2765
CG
HIS
A
360
67.018
40.307
−14.909
1.00
42.46
A
C

ATOM
2766
ND1
HIS
A
360
66.587
40.941
−16.054
1.00
43.80
A
N

ATOM
2767
CD2
HIS
A
360
66.711
38.997
−15.067
1.00
43.40
A
C

ATOM
2768
CE1
HIS
A
360
66.053
40.053
−16.876
1.00
42.29
A
C

ATOM
2769
NE2
HIS
A
360
66.107
38.867
−16.295
1.00
40.67
A
N

ATOM
2770
N
VAL
A
361
70.604
39.688
−14.108
1.00
46.31
A
N

ATOM
2771
CA
VAL
A
361
71.444
38.671
−14.736
1.00
53.46
A
C

ATOM
2772
C
VAL
A
361
70.569
37.519
−15.208
1.00
55.15
A
C

ATOM
2773
O
VAL
A
361
69.788
36.965
−14.433
1.00
55.26
A
O

ATOM
2774
CB
VAL
A
361
72.584
38.144
−13.812
1.00
55.33
A
C

ATOM
2775
CG1
VAL
A
361
73.724
39.146
−13.769
1.00
58.02
A
C

ATOM
2776
CG2
VAL
A
361
72.086
37.824
−12.392
1.00
57.18
A
C

ATOM
2777
N
HIS
A
362
70.687
37.191
−16.491
1.00
58.23
A
N

ATOM
2778
CA
HIS
A
362
69.957
36.071
−17.078
1.00
61.27
A
C

ATOM
2779
C
HIS
A
362
70.886
35.268
−17.991
1.00
63.90
A
C

ATOM
2780
O
HIS
A
362
72.106
35.470
−17.978
1.00
63.06
A
O

ATOM
2781
CB
HIS
A
362
68.707
36.570
−17.820
1.00
61.80
A
C

ATOM
2782
CG
HIS
A
362
68.987
37.603
−18.869
1.00
64.30
A
C

ATOM
2783
ND1
HIS
A
362
69.075
38.949
−18.582
1.00
65.54
A
N

ATOM
2784
CD2
HIS
A
362
69.176
37.491
−20.206
1.00
66.55
A
C

ATOM
2785
CE1
HIS
A
362
69.318
39.621
−19.694
1.00
66.26
A
C

ATOM
2786
NE2
HIS
A
362
69.384
38.760
−20.694
1.00
67.04
A
N

ATOM
2787
N
ASP
A
363
70.311
34.348
−18.765
1.00
66.38
A
N

ATOM
2788
CA
ASP
A
363
71.086
33.477
−19.645
1.00
68.15
A
C

ATOM
2789
C
ASP
A
363
70.180
32.971
−20.779
1.00
69.51
A
C

ATOM
2790
O
ASP
A
363
69.558
33.787
−21.466
1.00
68.87
A
O

ATOM
2791
CB
ASP
A
363
71.711
32.343
−18.820
1.00
67.85
A
C

ATOM
2792
CG
ASP
A
363
70.722
31.702
−17.869
1.00
67.03
A
C

ATOM
2793
OD1
ASP
A
363
71.157
31.015
−16.923
1.00
67.42
A
O

ATOM
2794
OD2
ASP
A
363
69.490
31.839
−17.981
1.00
67.25
A
O

ATOM
2795
N
GLU
A
364
70.111
31.651
−20.981
1.00
71.44
A
N

ATOM
2796
CA
GLU
A
364
69.186
31.037
−21.944
1.00
71.30
A
C

ATOM
2977
C
GLU
A
364
68.223
30.026
−21.289
1.00
69.20
A
C

ATOM
2798
O
GLU
A
364
67.280
29.569
−21.938
1.00
70.14
A
O

ATOM
2799
CB
GLU
A
364
69.980
30.351
−23.069
1.00
73.26
A
C

ATOM
2800
CG
GLU
A
364
69.968
31.097
−24.399
1.00
74.89
A
C

ATOM
2801
CD
GLU
A
364
70.651
32.451
−24.320
1.00
76.70
A
C

ATOM
2802
OE1
GLU
A
364
71.868
32.494
−24.028
1.00
77.66
A
O

ATOM
2803
OE2
GLU
A
364
69.969
33.476
−24.549
1.00
79.09
A
O

ATOM
2804
N
PHE
A
365
68.455
29.685
−20.017
1.00
66.67
A
N

ATOM
2805
CA
PHE
A
365
67.630
28.704
−19.299
1.00
64.31
A
C

ATOM
2806
C
PHE
A
365
66.403
29.347
−18.633
1.00
61.08
A
C

ATOM
2807
O
PHE
A
365
65.266
29.082
−19.026
1.00
62.40
A
O

ATOM
2808
CB
PHE
A
365
68.464
27.959
−18.245
1.00
65.86
A
C

ATOM
2809
CG
PHE
A
365
69.365
26.886
−18.819
1.00
67.96
A
C

ATOM
2810
CD1
PHE
A
365
70.557
27.227
−19.461
1.00
68.71
A
C

ATOM
2811
CD2
PHE
A
365
69.029
25.538
−18.705
1.00
68.02
A
C

ATOM
2812
CE1
PHE
A
365
71.395
26.241
−19.989
1.00
68.45
A
C

ATOM
2813
CE2
PHE
A
365
69.860
24.545
−19.232
1.00
68.28
A
C

ATOM
2814
CZ
PHE
A
365
71.045
24.899
−19.874
1.00
68.33
A
C

ATOM
2815
N
ARG
A
366
66.636
30.183
−17.624
1.00
54.06
A
N

ATOM
2816
CA
ARG
A
366
65.544
30.804
−16.874
1.00
49.84
A
C

ATOM
2817
C
ARG
A
366
65.747
32.305
−16.729
1.00
48.18
A
C

ATOM
2818
O
ARG
A
366
66.867
32.816
−16.857
1.00
47.96
A
O

ATOM
2819
CB
ARG
A
366
65.424
30.159
−15.490
1.00
47.56
A
C

ATOM
2820
CG
ARG
A
366
65.240
28.655
−15.525
1.00
43.64
A
C

ATOM
2821
CD
ARG
A
366
64.974
28.012
−14.174
1.00
38.98
A
C

ATOM
2822
NE
ARG
A
366
66.159
27.987
−13.327
1.00
41.26
A
N

ATOM
2823
CZ
ARG
A
366
66.242
27.371
−12.147
1.00
36.86
A
C

ATOM
2824
NH1
ARG
A
366
65.203
26.718
−11.644
1.00
42.11
A
N

ATOM
2825
NH2
ARG
A
366
67.375
27.413
−11.471
1.00
36.33
A
N

ATOM
2826
N
THR
A
367
64.654
33.009
−16.446
1.00
46.71
A
N

ATOM
2827
CA
THR
A
367
64.675
34.468
−16.397
1.00
46.92
A
C

ATOM
2828
C
THR
A
367
63.746
35.043
−15.331
1.00
44.72
A
C

ATOM
2829
O
THR
A
367
62.744
34.435
−14.973
1.00
42.54
A
O

ATOM
2830
CB
THR
A
367
64.306
35.019
−17.783
1.00
46.57
A
C

ATOM
2831
OG1
THR
A
367
65.143
34.406
−18.774
1.00
49.10
A
O

ATOM
2832
CG2
THR
A
367
64.628
36.484
−17.902
1.00
48.33
A
C

ATOM
2833
N
ALA
A
368
64.105
36.219
−14.819
1.00
43.12
A
N

ATOM
2834
CA
ALA
A
368
63.206
36.976
−13.962
1.00
37.88
A
C

ATOM
2835
C
ALA
A
368
61.990
37.417
−14.772
1.00
31.67
A
C

ATOM
2836
O
ALA
A
368
62.091
37.780
−15.946
1.00
33.05
A
O

ATOM
2837
CB
ALA
A
368
63.920
38.185
−13.359
1.00
37.36
A
C

ATOM
2838
N
ALA
A
369
60.827
37.407
−14.133
1.00
30.27
A
N

ATOM
2839
CA
ALA
A
369
59.608
37.776
−14.828
1.00
25.65
A
C

ATOM
2840
C
ALA
A
369
58.590
38.454
−13.917
1.00
18.85
A
C

ATOM
2841
O
ALA
A
369
58.574
38.264
−12.707
1.00
26.84
A
O

ATOM
2842
CB
ALA
A
369
58.988
36.559
−15.484
1.00
26.18
A
C

ATOM
2843
N
VAL
A
370
57.772
39.267
−14.543
1.00
21.79
A
N

ATOM
2844
CA
VAL
A
370
56.623
39.891
−13.921
1.00
22.63
A
C

ATOM
2845
C
VAL
A
370
55.460
39.580
−14.864
1.00
23.34
A
C

ATOM
2846
O
VAL
A
370
55.491
39.970
−16.007
1.00
23.37
A
O

ATOM
2847
CB
VAL
A
370
56.806
41.403
−13.783
1.00
24.21
A
C

ATOM
2848
CG1
VAL
A
370
55.606
42.016
−13.069
1.00
20.64
A
C

ATOM
2849
CG2
VAL
A
370
58.091
41.738
−13.021
1.00
24.95
A
C

ATOM
2850
N
GLU
A
371
54.435
38.890
−14.367
1.00
23.45
A
N

ATOM
2851
CA
GLU
A
371
53.364
38.364
−15.208
1.00
26.07
A
C

ATOM
2852
C
GLU
A
371
52.005
38.601
−14.556
1.00
21.52
A
C

ATOM
2853
O
GLU
A
371
51.886
38.584
−13.346
1.00
22.32
A
O

ATOM
2854
CB
GLU
A
371
53.593
36.859
−15.452
1.00
29.04
A
C

ATOM
2855
CG
GLU
A
371
54.667
36.583
−16.508
1.00
37.79
A
C

ATOM
2856
CD
GLU
A
371
55.383
35.235
−16.373
1.00
42.98
A
C

ATOM
2857
OE1
GLU
A
371
55.957
34.768
−17.389
1.00
47.96
A
O

ATOM
2858
OE2
GLU
A
371
55.428
34.655
−15.271
1.00
46.63
A
O

ATOM
2859
N
GLY
A
372
50.997
38.849
−15.375
1.00
23.24
A
N

ATOM
2860
CA
GLY
A
372
49.629
38.995
−14.902
1.00
20.28
A
C

ATOM
2861
C
GLY
A
372
48.652
39.097
−16.060
1.00
21.84
A
C

ATOM
2862
O
GLY
A
372
49.087
39.076
−17.231
1.00
23.46
A
O

ATOM
2863
N
PRO
A
373
47.355
39.219
−15.790
1.00
20.69
A
N

ATOM
2864
CA
PRO
A
373
46.758
39.117
−14.455
1.00
18.48
A
C

ATOM
2865
C
PRO
A
373
46.427
37.686
−14.050
1.00
19.08
A
C

ATOM
2866
O
PRO
A
373
46.197
36.821
−14.906
1.00
22.98
A
O

ATOM
2867
CB
PRO
A
373
45.466
39.923
−14.607
1.00
20.66
A
C

ATOM
2868
CG
PRO
A
373
45.050
39.692
−16.023
1.00
22.14
A
C

ATOM
2869
CD
PRO
A
373
46.328
39.516
−16.811
1.00
21.78
A
C

ATOM
2870
N
PHE
A
374
46.385
37.445
−12.742
1.00
15.75
A
N

ATOM
2871
CA
PHE
A
374
45.882
36.206
−12.195
1.00
16.86
A
C

ATOM
2872
C
PHE
A
374
44.622
36.442
−11.376
1.00
21.99
A
C

ATOM
2873
O
PHE
A
374
44.370
37.554
−10.943
1.00
19.16
A
O

ATOM
2874
CB
PHE
A
374
46.973
35.539
−11.360
1.00
16.65
A
C

ATOM
2875
CG
PHE
A
374
48.148
35.118
−12.170
1.00
19.99
A
C

ATOM
2876
CD1
PHE
A
374
48.097
33.957
−12.936
1.00
23.38
A
C

ATOM
2877
CD2
PHE
A
374
49.294
35.894
−12.221
1.00
22.80
A
C

ATOM
2878
CE1
PHE
A
374
49.189
33.565
−13.711
1.00
27.21
A
C

ATOM
2879
CE2
PHE
A
374
50.385
35.503
−12.980
1.00
22.14
A
C

ATOM
2880
CZ
PHE
A
374
50.341
34.340
−13.722
1.00
25.11
A
C

ATOM
2881
N
VAL
A
375
43.822
35.392
−11.207
1.00
21.84
A
N

ATOM
2882
CA
VAL
A
375
42.614
35.458
−10.407
1.00
22.25
A
C

ATOM
2883
C
VAL
A
375
42.948
34.876
−9.049
1.00
20.48
A
C

ATOM
2884
O
VAL
A
375
43.281
33.695
−8.943
1.00
24.24
A
O

ATOM
2885
CB
VAL
A
375
41.439
34.656
−11.016
1.00
24.98
A
C

ATOM
2886
CG1
VAL
A
375
40.206
34.758
−10.119
1.00
22.92
A
C

ATOM
2887
CG2
VAL
A
375
41.117
35.152
−12.404
1.00
23.43
A
C

ATOM
2888
N
THR
A
376
42.881
35.710
−8.023
1.00
22.65
A
N

ATOM
2889
CA
THR
A
376
43.104
35.291
−6.637
1.00
22.10
A
C

ATOM
2890
C
THR
A
376
42.027
35.873
−5.737
1.00
17.23
A
C

ATOM
2891
O
THR
A
376
41.856
37.081
−5.647
1.00
20.58
A
O

ATOM
2892
CB
THR
A
376
44.490
35.777
−6.137
1.00
23.66
A
C

ATOM
2893
OG1
THR
A
376
45.515
35.417
−7.080
1.00
25.31
A
O

ATOM
2894
CG2
THR
A
376
44.873
35.046
−4.844
1.00
26.58
A
C

ATOM
2895
N
LEU
A
377
41.265
35.010
−5.080
1.00
22.23
A
N

ATOM
2896
CA
LEU
A
377
40.199
35.472
−4.205
1.00
23.50
A
C

ATOM
2897
C
LEU
A
377
40.708
35.632
−2.776
1.00
27.50
A
C

ATOM
2898
O
LEU
A
377
41.710
35.019
−2.401
1.00
28.12
A
O

ATOM
2899
CB
LEU
A
377
39.046
34.481
−4.217
1.00
26.48
A
C

ATOM
2900
CG
LEU
A
377
38.541
34.109
−5.622
1.00
29.26
A
C

ATOM
2901
CD1
LEU
A
377
37.314
33.287
−5.496
1.00
30.60
A
C

ATOM
2902
CD2
LEU
A
377
38.247
35.344
−6.466
1.00
29.52
A
C

ATOM
2903
N
ASP
A
378
39.981
36.441
−2.014
1.00
29.13
A
N

ATOM
2904
CA
ASP
A
378
40.177
36.631
−0.574
1.00
35.27
A
C

ATOM
2905
C
ASP
A
378
41.540
37.210
−0.251
1.00
33.60
A
C

ATOM
2906
O
ASP
A
378
42.134
36.858
0.760
1.00
36.99
A
O

ATOM
2907
CB
ASP
A
378
40.002
35.325
0.196
1.00
33.08
A
C

ATOM
2908
CG
ASP
A
378
38.627
34.762
0.070
1.00
36.04
A
C

ATOM
2909
OD1
ASP
A
378
37.654
35.549
−0.049
1.00
31.19
A
O

ATOM
2910
OD2
ASP
A
378
38.441
33.532
0.097
1.00
41.39
A
O

ATOM
2911
N
MET
A
379
42.026
38.096
−1.110
1.00
34.47
A
N

ATOM
2912
CA
MET
A
379
43.349
38.682
−0.933
1.00
33.96
A
C

ATOM
2913
C
MET
A
379
43.396
39.613
0.270
1.00
34.59
A
C

ATOM
2914
O
MET
A
379
44.449
39.755
0.871
1.00
37.56
A
O

ATOM
2915
CB
MET
A
379
43.782
39.449
−2.186
1.00
30.92
A
C

ATOM
2916
CG
MET
A
379
44.041
38.562
−3.375
1.00
28.94
A
C

ATOM
2917
SD
MET
A
379
44.749
39.489
−4.761
1.00
26.10
A
S

ATOM
2918
CE
MET
A
379
43.486
40.462
−5.207
1.00
25.48
A
C

ATOM
2919
N
GLU
A
380
42.268
40.233
0.615
1.00
41.66
A
N

ATOM
2920
CA
GLU
A
380
42.182
41.091
1.805
1.00
46.13
A
C

ATOM
2921
C
GLU
A
380
42.498
40.308
3.080
1.00
47.68
A
C

ATOM
2922
O
GLU
A
380
43.208
40.810
3.957
1.00
50.01
A
O

ATOM
2923
CB
GLU
A
380
40.803
41.741
1.927
1.00
48.86
A
C

ATOM
2924
CG
GLU
A
380
40.743
43.189
1.446
1.00
51.99
A
C

ATOM
2925
CD
GLU
A
380
40.851
43.338
−0.066
1.00
55.58
A
C

ATOM
2926
OE1
GLU
A
380
40.498
42.385
−0.799
1.00
56.65
A
O

ATOM
2927
OE2
GLU
A
380
41.282
44.426
−0.524
1.00
57.63
A
O

ATOM
2928
N
ASP
A
381
41.997
39.075
3.169
1.00
46.10
A
N

ATOM
2929
CA
ASP
A
381
42.296
38.192
4.309
1.00
46.90
A
C

ATOM
2930
C
ASP
A
381
43.774
37.804
4.428
1.00
44.71
A
C

ATOM
2931
O
ASP
A
381
44.167
37.175
5.402
1.00
45.68
A
O

ATOM
2932
CB
ASP
A
381
41.448
36.911
4.254
1.00
45.21
A
C

ATOM
2933
CG
ASP
A
381
40.052
37.059
3.994
0.00
50.29
A
C

ATOM
2934
OD1
ASP
A
381
39.485
37.731
4.881
0.00
50.63
A
O

ATOM
2935
OD2
ASP
A
381
39.440
36.553
3.030
0.00
50.70
A
O

ATOM
2936
N
CYS
A
382
44.587
38.137
3.429
1.00
43.03
A
N

ATOM
2937
CA
CYS
A
382
46.026
37.939
3.526
1.00
42.15
A
C

ATOM
2938
C
CYS
A
382
46.693
39.021
4.400
1.00
41.50
A
C

ATOM
2939
O
CYS
A
382
47.808
38.827
4.855
1.00
43.47
A
O

ATOM
2940
CB
CYS
A
382
46.669
37.897
2.137
1.00
41.83
A
C

ATOM
2941
SG
CYS
A
382
45.985
36.643
1.026
1.00
38.22
A
S

ATOM
2942
N
GLY
A
383
45.999
40.133
4.645
1.00
43.76
A
N

ATOM
2943
CA
GLY
A
383
46.521
41.233
5.447
1.00
47.67
A
C

ATOM
2944
C
GLY
A
383
46.200
41.165
6.939
1.00
51.51
A
C

ATOM
2945
O
GLY
A
383
45.034
41.086
7.329
1.00
52.22
A
O

ATOM
2946
N
TYR
A
384
47.239
41.220
7.772
1.00
55.14
A
N

ATOM
2947
CA
TYR
A
384
47.092
41.146
9.227
1.00
57.40
A
C

ATOM
2948
C
TYR
A
384
46.613
42.453
9.878
1.00
58.55
A
C

ATOM
2949
O
TYR
A
384
47.216
43.508
9.687
1.00
56.79
A
O

ATOM
2950
CB
TYR
A
384
48.414
40.719
9.865
1.00
57.72
A
C

ATOM
2951
CG
TYR
A
384
48.357
40.643
11.375
1.00
60.49
A
C

ATOM
2952
CD1
TYR
A
384
47.657
39.623
12.015
1.00
61.73
A
C

ATOM
2953
CD2
TYR
A
384
48.994
41.598
12.167
1.00
62.68
A
C

ATOM
2954
CE1
TYR
A
384
47.597
39.551
13.408
1.00
61.50
A
C

ATOM
2955
CE2
TYR
A
384
48.941
41.536
13.561
1.00
62.87
A
C

ATOM
2956
CZ
TYR
A
384
48.242
40.510
14.173
1.00
62.60
A
C

ATOM
2957
OH
TYR
A
384
48.188
40.443
15.548
1.00
62.41
A
O

ATOM
2958
N
ASN
A
385
45.540
42.359
10.666
1.00
60.14
A
N

ATOM
2959
CA
ASN
A
385
45.049
43.478
11.471
1.00
62.13
A
C

ATOM
2960
C
ASN
A
385
45.450
43.295
12.938
1.00
63.14
A
C

ATOM
2961
1OCT
ASN
A
385
46.043
44.168
13.582
1.00
64.31
A
O

ATOM
2962
CB
ASN
A
385
43.524
43.592
11.362
1.00
62.36
A
C

ATOM
2963
CG
ASN
A
385
43.037
43.666
9.918
1.00
63.95
A
C

ATOM
2964
OD1
ASN
A
385
42.654
42.654
9.326
1.00
64.71
A
O

ATOM
2965
ND2
ASN
A
385
43.043
44.866
9.351
1.00
63.38
A
N

ATOM
2966
2OCT
ASN
A
385
45.193
42.257
13.550
1.00
63.30
A
O

ATOM
2967
O
HOH
W
1
79.629
68.206
12.595
1.00
19.21
W
O

ATOM
2968
O
HOH
W
2
49.015
47.109
−12.447
1.00
16.55
W
O

ATOM
2969
O
HOH
W
3
85.976
52.179
5.603
1.00
21.59
W
O

ATOM
2970
O
HOH
W
4
80.248
66.497
15.419
1.00
25.04
W
O

ATOM
2971
O
HOH
W
5
75.516
59.444
−7.006
1.00
20.45
W
O

ATOM
2972
O
HOH
W
6
64.679
60.731
5.508
1.00
20.67
W
O

ATOM
2973
O
HOH
W
7
52.200
57.481
−0.615
1.00
36.49
W
O

ATOM
2974
O
HOH
W
8
52.125
39.097
−18.355
1.00
30.59
W
O

ATOM
2975
O
HOH
W
9
66.983
62.454
10.671
1.00
21.40
W
O

ATOM
2976
O
HOH
W
10
44.515
33.044
−12.767
1.00
22.53
W
O

ATOM
2977
O
HOH
W
11
80.173
73.603
4.481
1.00
33.04
W
O

ATOM
2978
O
HOH
W
12
47.807
50.724
−13.972
1.00
20.13
W
O

ATOM
2979
O
HOH
W
13
80.860
59.315
0.203
1.00
26.62
W
O

ATOM
2980
O
HOH
W
14
55.473
70.139
−4.604
1.00
53.88
W
O

ATOM
2981
O
HOH
W
15
74.472
71.225
−0.260
1.00
39.12
W
O

ATOM
2982
O
HOH
W
16
40.544
39.218
−3.509
1.00
31.61
W
O

ATOM
2983
O
HOH
W
17
80.450
59.844
12.764
1.00
26.37
W
O

ATOM
2984
O
HOH
W
18
66.075
77.514
3.855
1.00
38.59
W
O

ATOM
2985
O
HOH
W
19
85.138
68.322
12.518
1.00
27.81
W
O

ATOM
2986
O
HOH
W
20
87.998
70.949
7.571
1.00
53.38
W
O

ATOM
2987
O
HOH
W
21
87.495
66.754
13.176
1.00
21.08
W
O

ATOM
2988
O
HOH
W
22
49.756
30.124
−1.047
1.00
45.82
W
O

ATOM
2989
O
HOH
W
23
49.361
33.536
13.751
1.00
66.10
W
O

ATOM
2990
O
HOH
W
24
67.788
54.838
10.862
1.00
28.51
W
O

ATOM
2991
O
HOH
W
25
50.160
45.140
−1.881
1.00
27.20
W
O

ATOM
2992
O
HOH
W
26
82.766
67.175
5.119
1.00
34.54
W
O

ATOM
2993
O
HOH
W
27
45.592
32.973
−7.823
1.00
33.43
W
O

ATOM
2994
O
HOH
W
28
81.090
55.720
18.331
1.00
22.44
W
O

ATOM
2995
O
HOH
W
29
43.057
33.861
0.341
1.00
80.20
W
O

ATOM
2996
O
HOH
W
30
61.780
27.615
13.286
1.00
58.09
W
O

ATOM
2997
O
HOH
W
31
50.466
45.953
8.884
1.00
40.45
W
O

ATOM
2998
O
HOH
W
32
83.327
58.106
0.741
1.00
25.84
W
O

ATOM
2999
O
HOH
W
33
81.327
48.709
18.206
1.00
36.23
W
O

ATOM
3000
O
HOH
W
34
72.944
38.241
4.000
1.00
50.15
W
O

ATOM
3001
O
HOH
W
35
48.453
40.727
−19.960
1.00
41.17
W
O

ATOM
3002
O
HOH
W
36
66.664
48.548
5.951
1.00
33.26
W
O

ATOM
3003
O
HOH
W
37
58.083
43.778
−17.062
1.00
24.83
W
O

ATOM
3004
O
HOH
W
38
55.799
60.814
5.110
1.00
39.72
W
O

ATOM
3005
O
HOH
W
39
79.293
52.119
13.860
1.00
21.39
W
O

ATOM
3006
O
HOH
W
40
77.511
45.900
20.280
1.00
50.24
W
O

ATOM
3007
O
HOH
W
41
50.802
43.439
−20.117
1.00
42.67
W
O

ATOM
3008
O
HOH
W
42
66.106
19.960
−9.172
1.00
47.01
W
O

ATOM
3009
O
HOH
W
43
63.894
58.910
−19.204
1.00
76.51
W
O

ATOM
3010
O
HOH
W
44
76.257
41.684
15.651
1.00
62.92
W
O

ATOM
3011
O
HOH
W
45
54.819
50.279
−18.015
1.00
21.51
W
O

ATOM
3012
O
HOH
W
46
65.401
64.403
6.138
1.00
24.60
W
O

ATOM
3013
O
HOH
W
47
53.853
55.150
−11.636
1.00
29.65
W
O

ATOM
3014
O
HOH
W
48
68.908
67.519
−5.703
1.00
33.79
W
O

ATOM
3015
O
HOH
W
49
79.968
52.673
6.743
1.00
26.80
W
O

ATOM
3016
O
HOH
W
50
48.181
44.979
−10.637
1.00
17.31
W
O

ATOM
3017
O
HOH
W
51
53.488
60.669
−0.029
1.00
31.52
W
O

ATOM
3018
O
HOH
W
52
62.724
61.887
9.306
1.00
24.34
W
O

ATOM
3019
O
HOH
W
53
64.870
59.282
19.837
1.00
40.43
W
O

ATOM
3020
O
HOH
W
54
67.034
55.997
8.478
1.00
18.91
W
O

ATOM
3021
O
HOH
W
55
81.783
69.009
13.884
1.00
24.02
W
O

ATOM
3022
O
HOH
W
56
62.338
60.129
2.848
1.00
20.26
W
O

ATOM
3023
O
HOH
W
57
59.948
49.626
3.509
1.00
20.58
W
O

ATOM
3024
O
HOH
W
58
74.315
61.973
−6.807
1.00
24.90
W
O

ATOM
3025
O
HOH
W
59
72.754
44.483
0.023
1.00
30.57
W
O

ATOM
3026
O
HOH
W
60
85.756
65.674
6.462
1.00
34.66
W
O

ATOM
3027
O
HOH
W
61
65.197
62.897
8.395
1.00
24.15
W
O

ATOM
3028
O
HOH
W
62
83.185
55.955
4.621
1.00
21.13
W
O

ATOM
3029
O
HOH
W
63
68.666
31.435
6.797
1.00
32.75
W
O

ATOM
3030
O
HOH
W
64
70.959
50.115
−0.021
1.00
24.74
W
O

ATOM
3031
O
HOH
W
65
70.634
69.168
18.081
1.00
35.02
W
O

ATOM
3032
O
HOH
W
66
83.133
65.815
2.329
1.00
28.15
W
O

ATOM
3033
O
HOH
W
67
81.369
47.920
15.072
1.00
41.54
W
O

ATOM
3034
O
HOH
W
68
87.299
59.567
9.845
1.00
38.69
W
O

ATOM
3035
O
HOH
W
69
41.854
32.167
−5.319
1.00
34.05
W
O

ATOM
3036
O
HOH
W
70
87.742
64.125
6.529
1.00
68.19
W
O

ATOM
3037
O
HOH
W
71
72.460
68.092
12.019
1.00
27.07
W
O

ATOM
3038
O
HOH
W
72
65.274
42.384
−19.635
1.00
61.51
W
O

ATOM
3039
O
HOH
W
73
85.768
65.313
2.708
1.00
45.28
W
O

ATOM
3040
O
HOH
W
74
62.071
26.325
−12.323
1.00
30.75
W
O

ATOM
3041
O
HOH
W
75
53.548
58.246
7.753
1.00
35.77
W
O

ATOM
3042
O
HOH
W
76
48.415
35.384
−17.283
1.00
49.88
W
O

ATOM
3043
O
HOH
W
77
63.389
66.452
6.071
1.00
24.26
W
O

ATOM
3044
O
HOH
W
78
82.811
58.045
−3.976
1.00
49.01
W
O

ATOM
3045
O
HOH
W
79
73.849
44.456
−1.977
1.00
46.53
W
O

ATOM
3046
O
HOH
W
80
45.102
52.297
−10.384
1.00
27.65
W
O

ATOM
3047
O
HOH
W
81
65.497
47.590
−7.949
1.00
22.50
W
O

ATOM
3048
O
HOH
W
82
60.385
50.571
−20.969
1.00
35.94
W
O

ATOM
3049
O
HOH
W
83
73.977
51.153
−13.532
1.00
42.34
W
O

ATOM
3050
O
HOH
W
84
73.807
75.017
−0.696
1.00
45.17
W
O

ATOM
3051
O
HOH
W
85
89.302
56.875
9.021
1.00
36.01
W
O

ATOM
3052
O
HOH
W
86
59.573
59.896
2.947
1.00
37.55
W
O

ATOM
3053
O
HOH
W
87
69.343
40.980
6.123
1.00
33.99
W
O

ATOM
3054
O
HOH
W
88
52.716
58.960
−10.022
1.00
38.62
W
O

ATOM
3055
O
HOH
W
89
71.368
68.265
20.363
1.00
40.93
W
O

ATOM
3056
O
HOH
W
90
58.025
24.259
10.874
1.00
64.35
W
O

ATOM
3057
O
HOH
W
91
79.324
57.854
−5.249
1.00
28.34
W
O

ATOM
3058
O
HOH
W
92
52.049
42.888
4.777
1.00
33.22
W
O

ATOM
3059
O
HOH
W
93
58.572
51.240
−21.845
1.00
39.18
W
O

ATOM
3060
O
HOH
W
94
58.399
59.801
−15.372
1.00
34.06
W
O

ATOM
3061
O
HOH
W
95
51.199
63.163
−3.700
1.00
34.26
W
O

ATOM
3062
O
HOH
W
96
39.751
42.093
5.333
1.00
63.63
W
O

ATOM
3063
O
HOH
W
97
62.377
69.523
12.319
1.00
37.67
W
O

ATOM
3064
O
HOH
W
98
57.972
57.007
14.799
1.00
35.19
W
O

ATOM
3065
O
HOH
W
99
62.896
33.477
−11.943
1.00
76.49
W
O

ATOM
3066
O
HOH
W
100
77.078
56.466
−5.817
1.00
21.61
W
O

ATOM
3067
O
HOH
W
101
58.723
72.174
10.770
1.00
45.78
W
O

ATOM
3068
O
HOH
W
102
82.563
53.786
6.291
1.08
28.84
W
O

ATOM
3069
O
HOH
W
103
59.353
71.034
3.910
1.00
33.97
W
O

ATOM
3070
O
HOH
W
104
64.748
30.333
−21.491
1.00
39.71
W
O

ATOM
3071
O
HOH
W
105
74.634
59.328
−12.866
1.00
40.33
W
O

ATOM
3072
O
HOH
W
106
55.438
42.543
−19.877
1.00
35.74
W
O

ATOM
3073
O
HOH
W
107
77.532
77.780
−0.830
1.00
47.95
W
O

ATOM
3074
O
HOH
W
108
65.148
68.989
−11.545
1.00
51.49
W
O

ATOM
3075
O
HOH
W
109
57.778
41.274
−18.333
1.00
41.55
W
O

ATOM
3076
O
HOH
W
110
55.086
59.049
16.334
1.00
47.49
W
O

ATOM
3077
O
HOH
W
111
81.228
50.040
13.406
1.00
68.55
W
O

ATOM
3078
O
HOH
W
112
39.213
39.599
−0.284
1.00
54.99
W
O

ATOM
3079
O
HOH
W
113
58.054
38.933
−17.692
1.00
30.12
W
O

ATOM
3080
O
HOH
W
114
46.682
50.824
−7.093
1.00
27.96
W
O

ATOM
3081
O
HOH
W
115
56.111
63.217
−0.389
1.00
31.05
W
O

ATOM
3082
O
HOH
W
116
83.364
67.774
0.538
1.00
32.16
W
O

ATOM
3083
O
HOH
W
117
48.343
27.854
7.458
1.00
45.35
W
O

ATOM
3084
O
HOH
W
118
62.036
71.098
6.922
1.00
37.49
W
O

ATOM
3085
O
HOH
W
119
50.470
55.859
8.484
1.00
50.28
W
O

ATOM
3086
O
HOH
W
120
59.219
48.282
−21.628
1.00
49.61
W
O

ATOM
3087
O
HOH
W
121
70.795
46.171
0.982
1.00
42.89
W
O

ATOM
3088
O
HOH
W
122
67.725
50.769
8.365
1.00
44.67
W
O

ATOM
3089
O
HOH
W
123
62.717
69.639
−10.878
1.00
52.07
W
O

ATOM
3090
O
HOH
W
124
60.253
41.588
−20.165
1.00
31.75
W
O

ATOM
3091
O
HOH
W
125
40.595
48.954
−7.729
1.00
24.22
W
O

ATOM
3092
O
HOH
W
126
60.544
37.484
−18.077
1.00
33.87
W
O

ATOM
3093
O
HOH
W
127
65.662
55.956
21.772
1.00
33.55
W
O

ATOM
3094
O
HOH
W
128
65.944
31.897
−19.969
1.00
51.23
W
O

ATOM
3095
O
HOH
W
129
61.793
76.127
1.749
1.00
56.51
W
O

ATOM
3096
O
HOH
W
130
85.302
59.460
0.012
1.00
36.81
W
O

ATOM
3097
O
HOH
W
131
51.594
64.021
−6.048
1.00
58.01
W
O

ATOM
3098
O
HOH
W
132
54.042
66.667
−6.161
1.00
63.77
W
O

ATOM
3099
O
HOH
W
133
62.332
75.297
4.414
1.00
55.75
W
O

ATOM
3100
O
HOH
W
134
50.042
46.059
−20.292
1.00
73.57
W
O

ATOM
3101
O
HOH
W
135
79.366
53.491
−11.459
1.00
45.91
W
O

ATOM
3102
O
HOH
W
136
62.077
57.368
−20.403
1.00
50.99
W
O

ATOM
3103
O
HOH
W
137
70.534
49.754
8.111
1.00
67.69
W
O

ATOM
3104
O
HOH
W
138
78.803
66.881
19.280
1.00
33.48
W
O

ATOM
3105
O
HOH
W
139
83.041
34.659
−5.519
1.00
42.03
W
O

ATOM
3106
O
HOH
W
140
77.602
56.674
−9.068
1.00
43.32
W
O

ATOM
3107
O
HOH
W
141
80.073
75.620
15.238
1.00
30.64
W
O

ATOM
3108
O
HOH
W
142
80.099
63.907
−8.340
1.00
39.92
W
O

ATOM
3109
O
HOH
W
143
56.033
68.239
−6.044
1.00
52.71
W
O

ATOM
3110
O
HOH
W
144
53.413
63.896
−8.009
1.00
35.96
W
O

ATOM
3111
O
HOH
W
145
89.147
64.107
9.192
1.00
45.54
W
O

ATOM
3112
O
HOH
W
146
37.356
37.399
−3.003
1.00
37.40
W
O

ATOM
3113
O
HOH
W
147
71.841
68.945
−7.695
1.00
67.24
W
O

ATOM
3114
O
HOH
W
148
65.710
25.459
1.815
1.00
68.03
W
O

ATOM
3115
O
HOH
W
149
54.563
32.460
14.878
1.00
45.89
W
O

ATOM
3116
O
HOH
W
150
69.771
32.591
−13.970
1.00
38.39
W
O

ATOM
3117
O
HOH
W
151
40.372
41.672
−3.643
1.00
35.36
W
O

ATOM
3118
O
HOH
W
152
67.233
45.846
−10.950
1.00
26.82
W
O

ATOM
3119
O
HOH
W
153
38.766
47.051
−8.023
1.00
28.56
W
O

ATOM
3120
O
HOH
W
154
81.319
69.504
−2.622
1.00
45.91
W
O

ATOM
3121
O
HOH
W
155
53.761
29.575
−15.833
1.00
38.29
W
O

ATOM
3122
O
HOH
W
156
56.342
73.135
−5.405
1.00
68.20
W
O

ATOM
3123
O
HOH
W
157
53.773
72.306
−0.902
1.00
67.09
W
O

ATOM
3124
O
HOH
W
158
79.692
66.676
−5.072
1.00
50.12
W
O

ATOM
3125
O
HOH
W
159
73.232
38.089
−7.677
1.00
45.17
W
O

ATOM
3126
O
HOH
W
160
46.657
52.288
−3.310
1.00
36.02
W
O

ATOM
3127
O
HOH
W
161
68.327
19.772
−0.212
1.00
70.84
W
O

ATOM
3128
O
HOH
W
162
57.706
29.223
−8.479
1.00
39.36
W
O

ATOM
3129
O
HOH
W
163
80.380
78.795
5.802
1.00
56.31
W
O

ATOM
3130
O
HOH
W
164
56.675
59.728
−19.716
1.00
51.35
W
O

ATOM
3131
O
HOH
W
165
72.021
78.865
10.956
1.00
57.63
W
O

ATOM
3132
O
HOH
W
166
61.187
22.723
11.672
1.00
52.43
W
O

ATOM
3133
O
HOH
W
167
52.637
65.982
−3.596
1.00
43.55
W
O

ATOM
3134
O
HOH
W
168
77.094
59.049
−11.764
1.00
53.68
W
O

ATOM
3135
O
HOH
W
169
82.297
55.117
−5.408
1.00
56.75
W
O

ATOM
3136
O
HOH
W
170
44.896
54.140
−2.621
1.00
44.26
W
O

ATOM
3137
O
HOH
W
171
75.662
48.265
9.068
1.00
31.34
W
O

ATOM
3138
O
HOH
W
172
62.322
26.608
−15.255
1.00
73.50
W
O

ATOM
3139
O
HOH
W
173
70.503
79.530
7.957
1.00
46.42
W
O

ATOM
3140
O
HOH
W
174
78.756
79.738
3.636
1.00
57.59
W
O

ATOM
3141
O
HOH
W
175
63.567
48.079
7.690
1.00
56.49
W
O

ATOM
3142
O
HOH
W
176
73.105
50.182
8.251
1.00
62.98
W
O

ATOM
3143
O
HOH
W
177
74.155
72.309
−2.546
1.00
63.14
W
O

ATOM
3144
O
HOH
W
178
65.269
74.588
10.615
1.00
38.50
W
O

ATOM
3145
O
HOH
W
179
77.404
52.712
−10.561
1.00
40.86
W
O

ATOM
3146
O
HOH
W
180
53.494
69.486
−1.573
1.00
61.27
W
O

ATOM
3147
O
HOH
W
181
44.408
43.630
15.946
1.00
63.55
W
O

ATOM
3148
O
HOH
W
182
45.148
46.355
9.428
1.00
58.76
W
O

ATOM
3149
O
HOH
W
183
78.021
49.570
−0.246
1.00
32.19
W
O

ATOM
3150
O
HOH
W
184
81.804
50.829
−2.607
1.00
38.10
W
O

ATOM
3151
O
HOH
W
185
88.410
73.240
7.564
1.00
56.30
W
O

ATOM
3152
O
HOH
W
186
61.080
66.476
15.948
1.00
68.96
W
O

ATOM
3153
O
HOH
W
187
45.110
31.905
1.445
1.00
67.43
W
O

ATOM
3154
O
HOH
W
188
49.200
55.926
12.964
1.00
72.28
W
O

ATOM
3155
O
HOH
W
189
71.187
76.958
15.269
1.00
39.87
W
O

ATOM
3156
O
HOH
W
190
73.886
47.482
4.081
1.00
53.55
W
O

ATOM
3157
O
HOH
W
191
69.355
68.996
−15.162
1.00
61.52
W
O

ATOM
3158
O
HOH
W
192
82.777
65.787
−8.682
1.00
62.77
W
O

ATOM
3159
O
HOH
W
193
39.736
46.583
7.480
1.00
62.23
W
O

ATOM
3160
O
HOH
W
194
52.055
40.044
−22.266
1.00
55.63
W
O

ATOM
3161
O
HOH
W
195
71.314
50.785
−16.556
1.00
49.70
W
O

ATOM
3162
O
HOH
W
196
61.950
38.755
−19.713
1.00
70.81
W
O

ATOM
3163
O
HOH
W
197
84.051
69.275
5.460
1.00
48.64
W
O

ATOM
3164
O
HOH
W
198
76.032
60.681
20.880
1.00
69.12
W
O

ATOM
3165
O
HOH
W
199
73.266
44.918
4.326
1.00
68.75
W
O

ATOM
3166
O
HOH
W
200
82.129
50.468
−5.451
1.00
59.02
W
O

ATOM
3167
O
HOH
W
201
83.221
72.917
3.600
1.00
40.04
W
O

ATOM
3168
O
HOH
W
202
59.652
75.257
4.275
1.00
57.30
W
O

ATOM
3169
O
HOH
W
203
78.123
47.635
22.706
1.00
45.73
W
O

ATOM
3170
O
HOH
W
204
77.637
76.375
11.568
1.00
43.51
W
O

ATOM
3171
O
HOH
W
205
58.555
48.938
13.305
1.00
48.92
W
O

ATOM
3172
O
HOH
W
206
57.638
66.927
18.153
1.00
50.79
W
O

ATOM
3173
O
HOH
W
207
58.312
43.498
7.697
1.00
33.77
W
O

ATOM
3174
O
HOH
W
208
44.538
28.297
3.536
1.00
55.65
W
O

ATOM
3175
O
HOH
W
209
59.595
53.833
19.308
1.00
58.04
W
O

ATOM
3176
O
HOH
W
210
57.084
51.317
14.707
1.00
51.78
W
O

ATOM
3177
O
HOH
W
211
49.436
21.830
−1.938
1.00
62.41
W
O

ATOM
3178
O
HOH
W
212
60.734
77.657
4.018
1.00
73.34
W
O

ATOM
3179
O
HOH
W
213
79.123
83.308
3.898
1.00
63.20
W
O

ATOM
3180
O
HOH
W
214
57.523
61.921
−13.519
1.00
37.25
W
O

ATOM
3181
O
HOH
W
215
71.168
43.072
5.167
1.00
41.82
W
O

ATOM
3182
O
HOH
W
216
76.653
84.242
3.301
1.00
78.23
W
O

ATOM
3183
O
HOH
W
217
42.382
40.135
17.622
1.00
61.51
W
O

ATOM
3184
O
HOH
W
218
78.733
69.517
−5.343
1.00
61.81
W
O

ATOM
3185
O
HOH
W
219
62.986
22.749
−4.555
1.00
42.82
W
O

ATOM
3186
O
HOH
W
220
60.743
44.247
9.220
1.00
48.58
W
O

ATOM
3187
O
HOH
W
221
57.413
29.275
−13.554
1.00
41.77
W
O

ATOM
3188
O
HOH
W
222
71.784
39.808
−3.358
1.00
49.72
W
O

ATOM
3189
O
HOH
W
223
74.571
63.700
−13.618
1.00
53.93
W
O

ATOM
3190
O
HOH
W
224
71.261
51.431
−13.741
1.00
41.48
W
O

ATOM
3191
O
HOH
W
225
78.559
79.217
0.998
1.00
50.39
W
O

ATOM
3192
O
HOH
W
226
68.431
42.241
17.534
1.00
51.33
W
O

ATOM
3193
O
HOH
W
227
74.858
56.378
23.475
1.00
62.51
W
O

ATOM
3194
O
HOH
W
228
79.307
60.745
22.219
1.00
40.98
W
O

ATOM
3195
O
HOH
W
229
60.314
68.573
10.249
1.00
29.74
W
O

ATOM
3196
O
HOH
W
230
61.602
71.621
−9.518
1.00
51.81
W
O

ATOM
3197
O
HOH
W
231
49.899
42.585
7.057
1.00
35.46
W
O

ATOM
3198
O
HOH
W
232
46.590
57.769
2.535
1.00
69.32
W
O

ATOM
3199
O
HOH
W
233
45.044
34.173
−1.541
1.00
50.34
W
O

ATOM
3200
O
HOH
W
234
71.447
46.668
−18.182
1.00
58.66
W
O

ATOM
3201
O
HOH
W
235
73.000
43.214
−18.003
1.00
45.06
W
O

ATOM
3202
O
HOH
W
236
43.370
55.663
−1.011
1.00
61.60
W
O

ATOM
3203
O
HOH
W
237
74.007
57.458
−17.330
1.00
59.05
W
O

ATOM
3204
O
HOH
W
238
78.277
52.906
−16.612
1.00
65.63
W
O

ATOM
3205
O
HOH
W
239
77.796
59.191
−8.755
1.00
45.94
W
O

ATOM
3206
O
HOH
W
240
84.436
60.164
−3.135
1.00
53.03
W
O

ATOM
3207
O
HOH
W
241
65.112
49.259
9.447
1.00
53.21
W
O

ATOM
3208
O
HOH
W
242
63.207
51.425
10.118
1.00
42.58
W
O

ATOM
3209
O
HOH
W
243
89.242
51.621
10.559
1.00
37.79
W
O

ATOM
3210
O
HOH
W
244
88.861
58.033
−1.500
1.00
63.56
W
O

ATOM
3211
O
HOH
W
245
80.840
77.800
12.517
1.00
43.88
W
O

ATOM
3212
O
HOH
W
246
77.216
83.653
0.754
1.00
66.92
W
O

ATOM
3213
O
HOH
W
247
69.579
67.222
23.238
1.00
67.75
W
O

ATOM
3214
O
HOH
W
248
75.887
51.320
21.816
1.00
72.66
W
O

ATOM
3215
O
HOH
W
249
68.191
78.916
4.291
1.00
52.82
W
O

ATOM
3216
O
HOH
W
250
82.004
63.181
21.579
1.00
30.60
W
O

ATOM
3217
O
HOH
W
251
76.390
67.886
21.910
1.00
51.17
W
O

ATOM
3218
O
HOH
W
252
53.503
60.921
17.416
1.00
72.58
W
O

ATOM
3219
O
HOH
W
253
60.509
46.370
−23.693
1.00
62.40
W
O

ATOM
3220
O
HOH
W
254
53.842
41.622
−18.205
1.00
43.31
W
O

ATOM
3221
O
HOH
W
255
48.037
45.876
−0.170
1.00
42.34
W
O

ATOM
3222
O
HOH
W
256
44.592
45.050
2.573
1.00
46.37
W
O

ATOM
3223
O
HOH
W
257
40.130
44.608
4.624
1.00
61.11
W
O

ATOM
3224
O
HOH
W
258
69.355
47.143
5.898
1.00
60.82
W
O

ATOM
3225
O
HOH
W
259
34.957
32.570
1.397
1.00
47.77
W
O

ATOM
3226
O
HOH
W
260
61.555
31.492
−14.640
1.00
63.05
W
O

ATOM
3227
O
HOH
W
261
43.862
53.451
−5.566
1.00
71.67
W
O

ATOM
3228
O
HOH
W
262
84.234
48.309
0.364
1.00
54.03
W
O

ATOM
3229
O
HOH
W
263
87.932
51.816
−3.215
1.00
57.80
W
O

ATOM
3230
O
HOH
W
264
82.425
63.456
−6.283
1.00
62.42
W
O

ATOM
3231
O
HOH
W
265
80.271
28.172
9.463
1.00
40.70
W
O

ATOM
3232
O
HOH
W
266
73.963
30.020
4.302
1.00
26.30
W
O

ATOM
3233
O
HOH
W
267
83.112
71.680
1.066
1.00
51.04
W
O

ATOM
3234
O
HOH
W
268
63.047
54.124
10.355
1.00
50.34
W
O

ATOM
3235
O
HOH
W
269
83.682
62.329
−4.165
1.00
42.75
W
O

ATOM
3236
O
HOH
W
270
61.547
73.522
−7.931
1.00
47.36
W
O

ATOM
3237
O
HOH
W
271
60.577
53.517
13.966
1.00
53.55
W
O

ATOM
3238
O
HOH
W
272
54.580
71.014
−6.905
1.00
46.69
W
O

ATOM
3239
O
HOH
W
273
77.926
39.031
−0.508
1.00
49.59
W
O

ATOM
3240
O
HOH
W
274
69.669
49.137
−17.891
1.00
45.33
W
O

ATOM
3241
O
HOH
W
275
44.777
49.840
1.964
1.00
44.62
W
O

ATOM
3242
O
HOH
W
276
48.453
54.600
5.308
1.00
39.43
W
O

ATOM
3243
O
HOH
W
277
51.764
32.262
13.155
1.00
71.42
W
O

ATOM
3244
O
HOH
W
278
60.951
29.296
11.161
1.00
53.99
W
O

ATOM
3245
O
HOH
W
279
68.206
23.452
8.777
1.00
50.70
W
O

ATOM
3246
O
HOH
W
280
87.567
24.412
−10.981
1.00
49.42
W
O

ATOM
3247
O
HOH
W
281
81.650
24.690
−15.233
1.00
46.79
W
O

ATOM
3248
O
HOH
W
282
83.121
29.023
−15.678
1.00
59.22
W
O

ATOM
3249
O
HOH
W
283
81.854
31.654
−13.384
1.00
44.68
W
O

ATOM
3250
O
HOH
W
284
43.424
43.922
−5.261
1.00
38.18
W
O

ATOM
3251
O
HOH
W
285
80.484
32.987
−6.395
1.00
39.87
W
O

ATOM
3252
I
IOD
J
1
80.243
57.842
15.501
0.75
23.63
J
I

ATOM
3253
I
IOD
J
2
81.546
50.334
15.785
0.50
35.87
J
I

ATOM
3254
I
IOD
J
3
51.528
57.888
−13.233
0.50
56.82
J
I

END

[0511]

Crystal structure of beta site APP cleaving enzyme (BACE) and methods of use thereof

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

RELATED APPLICATIONS

Provisional Applications (1)