Mycobacterium tuberculosis CYP51 high resolution structure, polypeptides and nucleic acids, and therapeutic and screening methods relating to same

TECHNICAL FIELD

[0003] The present invention relates generally to isolated and purified polypeptides, to isolated and purified nucleic acids encoding such polypeptides, and to high resolution x-ray structures of these polypeptides. More particularly, the present invention relates to isolated and purified Mycobacterium tuberculosis CYP51 polypeptides, to isolated and purified nucleic acid molecules encoding the same, and to high resolution x-ray structures of these polypeptides.

[0004] The present invention also relates generally to the structure of Mycobacterium tuberculosis CYP51, and more particularly to the crystalline structure of Mycobacterium tuberculosis CYP51 complexed with 4-phenylimidazole and the crystalline structure of Mycobacterium tuberculosis CYP51 complexed with fluconazole. The invention further relates to methods by which modulators and ligands of Mycobacterium tuberculosis CYP51, can be identified.

1Table of AbbreviationsBMPBone morphogenetic proteinBSABovine serum albuminCOR(s)Complementarity determining region(s)CYP450Cytochrome P450CYP45014DMCytochrome P450 14α-demethyIaseCYP51Cytochrome P450 14α-demethylaseDHL24,25-dihydrolanosterolFdrEscherichia coil flavodoxin reductaseFdxMycobacterium tuberculosis ferredoxinFidEscherichia coli flavodoxinFLUFluconazoleFnrSpinach ferredoxin reductaseGC-MSGas chromatography-Mass spectroscopyHATCell culture media comprising hypoxanthine,aminopterin, and thymidineHPLCHigh pressure liquid chromatographyKLHKeyhole limpet hemocyaninMIRASMultiple isomorphous replacement anomalousscatteringMTMycobacterium tuberculosisNMRNuclear magnetic resonancePORPolymerase chain reaction4-PI4-phenylimidazoleRMSRoot mean squareSRSSubstrate recognition sequence

BACKGROUND ART

[0005] The cytochrome P450 enzyme cytochrome P450 14α-demethylase (CYP45014DM) catalyzes 14α-demethylation of different sterols via three successive oxidations at the C-32 methyl group. CYP45014DM is thus involved in cholesterol, ergosterol and phytosterol biosynthesis in animals, fungi and plants, respectively. In animals, for example, the demethylation reaction catalyzed by CYP45014DM results in the formation of formic acid and 4,4-dimethyl-5α cholesta-8,14-,24-trien-3β-ol from lanosterol.

[0006] Although the function of this enzyme has been conserved between different species, CYP45014DM substrate specificity is narrow. It has been reported that yeast and animals utilize lanosterol and dihydrolanosterol while filimentus fungi utilize eburicol (24-methylene lanosterol). Plant CYP45014DM's, however, use only obtusifoliol as a substrate. Currently, this enzyme is the only CYP450 enzyme found in three different phyla: animals, fungi and plants.

[0007] Thus, CYP45014DM enzymes are present in a wide variety of organisms. But, prior to the the studies of the present invention, no bacterial CYP4504DM has been fully characterized. Moreover, given the key sterol metabolic pathway in which this enzyme is involved, there is a continuing need in the art for further characterization of CYP45014DM enzymes in general. In particular, there remains a continuing need for the characterization of substrate specificity and the elucidation of crystalline structures.

SUMMARY OF THE INVENTION

[0008] A crystalline form of a substantially pure MT CYP51 domain polypeptide is disclosed. In a preferred embodiment, the crystalline form of a substantially pure MT CYP51 domain polypeptide is complexed with at least one modulator molecule is disclosed. Preferably, the crystalline form is an orthorhombic crystalline form. Even more preferably, the crystalline form has a space group of P212121. Still more preferably, the MT CYP51 polypeptide has the amino acid sequence shown in SEQ ID NOs:2, 4, 6 or 8.

[0009] A method for determining the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one modulator molecule to a resolution of about 2.2 Å or better is disclosed. The method comprises: (a) crystallizing an MT CYP51 polypeptide in the presence of at least one modulator molecule, whereby a crystallized MTCY51 polypeptide complexed with at least one modulator is formed; (b) analyzing the crystallized MTCY51 polypeptide complexed with at least one modulator molecule to determine the three-dimensional structure of the crystallized MT CYP51 polypeptide, whereby the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one modulator molecule to a resolution of about 2.2 Å or better is determined.

[0010] A method of generating a crystallized MT CYP51 polypeptide complexed with at least one modulator molecule is disclosed. The method comprises: (a) incubating a solution comprising an MT CYP51 polypeptide with an equal volume of reservoir liquid, the reservoir liquid comprising an modulator solution; and (b) crystallizing the MT CYP51 polypeptide using the hanging drop method, whereby a crystallized MT CYP51 polypeptide complexed with at least one modulator molecule is generated.

[0011] A crystalline form of a substantially pure MTCYP51MT CYP51 domain polypeptide complexed with at least one 4-phenylimidazole molecule is disclosed. Preferably, the crystalline form has lattice constants of a=46.14 Å, b=83.86 Å, c=109.56 Å, α=90°, β=90°, γ=90°. More preferably, the crystalline form is an orthorhombic crystalline form. Even more preferably, the crystalline form has a space group of P212121. Still more preferably, the MT CYP51 polypeptide has the amino acid sequence shown in SEQ ID NOs:2, 4, 6 or 8.

[0012] A crystalline form of a substantially pure MT CYP51 domain polypeptide complexed with at least one fluconazole molecule is also disclosed. Preferably, the crystalline form has lattice constants of a=46.19 Å, b=84.26 Å, c=109.75 Å, α=90°, β=90°, γ=90°. More preferably, the crystalline form is an orthorhombic crystalline form. Even more preferably, the crystalline form has a space group of P212121. Still more preferably, the MT CYP51 polypeptide has the amino acid sequence shown in SEQ ID NOs:2, 4, 6 or 8.

[0013] Additionally, a method for determining the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one 4-phenylimidazole molecule to a resolution of about 2.1 Å or better is disclosed. The method comprises: (a) crystallizing an MT CYP51 polypeptide in the presence of 4-phenylimidazole, whereby a crystallized MTCY51 polypeptide complexed with 4-phenylimidazole is formed; (b) analyzing the crystallized MTCY51 polypeptide complexed with 4-phenylimidazole to determine the three-dimensional structure of the crystallized MT CYP51 polypeptide, whereby the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one 4-phenylimidazole molecule to a resolution of about 2.1 Å or better is determined.

[0014] A method for determining the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one fluconazole molecule to a resolution of about 2.2 Å or better is further disclosed. The method comprises: (a) crystallizing an MT CYP51 polypeptide complexed with at least one complexedfluconazole molecule; and (b) analyzing the complex to determine the three-dimensional structure of the crystallized MT CYP51 polypeptide, whereby the three-dimensional structure of a crystallized MT CYP51 polypeptide complexed with at least one fluconazole molecule to a resolution of about 2.2 Å or better is determined.

[0015] In addition, a method of generating a crystallized MT CYP51 polypeptide complexed with at least one 4-phenylimidazole molecule is also disclosed. The method comprises: (a) incubating a solution comprising an MT CYP51 polypeptide with an equal volume of reservoir liquid, the reservoir liquid comprising 4-phenylimidazole; and (b) crystallizing the MT CYP51 polypeptide using the hanging drop method, whereby a crystallized MT CYP51 polypeptide is generated.

[0016] A method of generating a crystallized MT CYP51 polypeptide complexed with at least one fluconazole molecule is also disclosed. The method comprises: (a) incubating a solution comprising an MT CYP51 polypeptide with an equal volume of reservoir liquid, the reservoir liquid comprising 4-phenylimidazole, to form MT CYP51/4-phenylimidazole complex; (b) crystallizing the MT CYP51/4-phenylimidazole complex using the hanging drop method; (c) incubating the MT CYP51/4-phenylimidazole crystals with a solution of about 0.5 mM fluconazole to form a MT CYP51/4-phenylimidazole/fluconazole crystals.

[0017] A method of designing a modulator of an MT CYP51 polypeptide is also disclosed. The method comprises: (a) designing a potential modulator of an MT CYP51 polypeptide that will form bonds with amino acids in a substrate binding site based upon a crystalline structure of an MT CYP51 polypeptide; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the MT CYP51 polypeptide, whereby a modulator of an MT CYP51 polypeptide is designed.

[0018] Yet another method of designing a modulator of an MT CYP51 polypeptide is disclosed. The method comprises: (a) designing a potential modulator of an MT CYP51 polypeptide that will form bonds with amino acids in a substrate binding site based upon a crystalline structure of an MT CYP51 polypeptide complexed with 4-phenylimidazole or with fluconazole; (b) synthesizing the modulator; and (c) determining whether the potential modulator modulates the activity of the MT CYP51 polypeptide, whereby a modulator of an MT CYP51 polypeptide is designed.

[0019] In addition, a method of designing a modulator that selectively modulates the activity of an MT CYP51 polypeptide is disclosed. The method comprises: (a) obtaining a crystalline form of a MT CYP51 polypeptide; (b) evaluating the three-dimensional structure of the crystallized MT CYP51 polypeptide; and (c) synthesizing a potential modulator based on the three-dimensional crystal structure of the crystallized MT CYP51 polypeptide, whereby a modulator that selectively modulates the activity of an MT CYP51 polypeptide is designed.

[0020] A method of designing a modulator that selectively modulates the activity of an MT CYP51 polypeptide is disclosed as well. The method comprises: (a) obtaining a crystalline form of an MT CYP51 polypeptide complexed with at least one 4-phenylimidazole or with at least one fluconazole molecule; (b) evaluating the three-dimensional structure of the crystallized MT CYP51 polypeptide complexed with at least one 4-phenylimidazole or with at least one fluconazole molecule; and (c) synthesizing a potential modulator based on the three-dimensional crystal structure of the crystallized MT CYP51 polypeptide complexed with at least one 4-phenylimidazole or with at least one fluconazole molecule, whereby a modulator that selectively modulates the activity of an MT CYP51 polypeptide is designed.

[0021] A method for identifying an MT CYP51 modulator is also disclosed. The method comprises: (a) providing atomic coordinates of an MT CYP51 polypeptide to a computerized modeling system; and (b) modeling ligands that bind the MT CYP51 polypeptide, whereby an MT CYP51 modulator is identified.

[0022] A method for identifying an MT CYP51 modulator is disclosed. The method comprises: (a) providing atomic coordinates of an MT CYP51 polypeptide complexed with at least one 4-phenylimidazole or with at least one fluconazole molecule to a computerized modeling system; and (b) modeling ligands that bind the MT CYP51 polypeptide, whereby an MT CYP51 modulator is identified.

[0023] A method of screening a plurality of compounds for a modulator of a MT CYP51 polypeptide is disclosed. The method comprises: (a) providing a library of test samples; (b) contacting a crystalline form of a MT CYP51 polypeptide complexed with an modulator molecule with each test sample; (c) detecting an interaction between a test sample and the crystalline MT CYP51 polypeptide; (d) identifying a test sample that interacts with the crystalline MT CYP51 polypeptide; and (e) isolating a test sample that interacts with the crystalline MT CYP51 polypeptide, whereby a plurality of compounds is screened for a modulator of a MT CYP51 polypeptide.

[0024] Some of the aspects and objects of the invention having been stated herein above, other aspects and objects will become evident as the description proceeds, when taken in connection with the accompanying Drawings and Laboratory Examples as best described hereinbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025]
FIG. 1 is a schematic depicting the activity of CYP45014DM in sterol biosynthesis. Note that the 14α-methyl group which is removed by this enzyme is indicated in each substrate.

[0026]
FIG. 2 is a schematic depicting alignment of the amino acid sequence of Mycobacterium tuberculosis (MT) CYP51 gene product with Homo sapiens (H.s); Penicilium italicum (P.i.); Triticum aevestivum (T.a.); and Candida albicans (C.a.) sequences. The boxed residues correspond to the substrate recognition sequence (SRS) elements, expected to be found in all cytochrome P450 enzymes. The arrow corresponds to the cysteine heme-ligand. No homology is observed in the N-terminal sequence between the other CYP51 isoforms and the MT CYP51 gene product. This is because the MT CYP51 gene product is a soluble protein and the others are anchored in cellular membranes.

[0027]
FIG. 3 pertains to sterol molecule structures and DHL 14α-demethylation.

[0028]
FIG. 3A depicts sterol molecule structures: (1) lanosterol, (2) cycloartenol, (3) parkeol, (4) DHL, (5) zymosterol and (6) obtusifoliol.

[0029]
FIG. 3B is a reaction schematic for DHL 14α-demethylation, that is, conversion of DHL to 4,4-dimethyl-5α-cholesta-8,14-diene-3β-ol in the presence of MT P45014DM, NADPH and molecular oxygen.

[0030]
FIG. 3C is a line graph depicting GLC profile of overnight conversion of 2 mg DHL. The E. coli Fld/Fdr system was used as P450 electron donor. The peaks at 16.38 min and 17 min correspond to the DHL and metabolite retention times, respectively.

[0031]
FIG. 4 depicts sequence and absorbence characteristics of the MT CYP51 gene and gene product.

[0032]
FIG. 4A depicts a potential Shine-Dalgarno sequence (shadowed box) of the MT CYP51 gene, the ATG is represented in bold character.

[0033]
FIG. 4B depicts absorbance of purified MT P45014DM (400 pmol), absolute oxidized form (regular trace), sodium hydrosulfite reduced form (dashed trace). The inset shows the α and β bands for the oxidized and the reduced forms.

[0034]
FIG. 4C depicts differential CO-reduced P450 spectrum of purified MT P45014DM (400 pmol).

[0035]
FIG. 4D depicts (1) silver staining and (2) immunoblot analysis using 1 pmol and 0.4 pmol of purified MT P45014DM, respectively. MT P45014DM antibody prepared with TiterMax@gold™ as adjuvant was used at 1:5000 dilution. Protein G-horseradish peroxidase conjugate (BIO-RAD) was used as a second antibody and ECL kit for detection.

[0036]
FIG. 5 depicts comparison of MT P45014DM activities supported by either Fld/Fdr or Fdx/Fnr. [24-3H]DHL was converted overnight at 30° C. by 1 nmole of MT P45014DM with either 20 nmoles Fld and 2 nmoles Fdr (panel A) or 20 nmoles Fdx and 2 nmoles Fnr (panel B) (30). Peaks S and P correspond to DHL and its 14α-demethylated product, respectively. Peaks U are unidentified products. MT P45014DM used in this experiment was further purified by HLPC (BIOCAD®/Sprint, PerSeptive Biosystems, Inc., Framingham, Mass.) using Poros HS and HQ columns (PerSeptive Biosystems, Inc., Framingham, Mass.). The HS flow-through is loaded on an HQ column and eluted using a NaCl gradient (150 to 500 mM).

[0037]
FIG. 6 depicts MT P45014DM binding spectra.

[0038]
FIG. 6A depicts MT P45014DM type I binding spectrum for obtusifoliol (100 nM−5 μM).

[0039]
FIG. 6B depicts double reciprocal plot for obtusifoliol (&Circlesolid;), DHL (▴) and lanosterol (▪) binding with 10 μM of MT P45014DM

[0040]
FIG. 6C. MT P45014DM type II binding spectrum in presence of clotrimazole (500 nM−100 μM).

[0041]
FIG. 6D. Double reciprocal plot for clotrimazole (◯), ketoconazole (&Circlesolid;) and fluconazole (▴) binding with 5 μM of MT P45014DM.

[0042]
FIG. 7 is a western blot analysis of 0.4 pmol of purified recombinant MT P45014DM (lanes 1 and 3) and 100 μg of MT cytosolic fraction (lanes 2 and 4) using complete (lanes 1 and 2) and the depleted (lanes 3 and 4) antisera. The antiserum raised using Freund's adjuvant was purified using a MT P45014DM sepharose affinity column followed by batch chromatography with the same resin (Gough & Adams, (1978) Biochemistry 17: 5560-6). The antiserum was depleted by overnight incubation with 6 nmole of purified MT P45014DM at 4° C.

[0043]
FIG. 8 is a ribbon representation of the MT CYP51 structures with the inhibitors bound. (A), front, and (B), top, views of the 4-PI-(yellow) and FLU-(blue) bound MT CYP51 superimposed with an RMS deviation of 0.45 D. Heme is shown in red, 4-PI in orange, FLU in light blue color. The I-helix is also in red. A large cavity of 2600 Å3, shown in blue leads from the substrate binding site to the molecular surface along the protein domain interface (channel 2). Structural elements significantly deviating among P450 structures are labeled. All figures, if not otherwise indicated, are generated using SWISS-PDB VIEWER (Guex & Peitsch, (1997) Electrophoresis 18:2714-2723)

[0044]
FIG. 9 is a diagram depicting the superimposition and alignment of the I-helix in known P450 structures. (A), front, and (B), top, views of the I-helix from superimposed P450 structures assigned in sequence alignment panel (C). Each structure was pair wise superimposed with MT CYP51 so that the RMS deviation for the most structurally homologous regions did not exceed 1.2 Å. The I-helix bends in its central part where conserved residues A256 and G257 are located. Bending results in displacement of the N-terminus while position of C-terminus is not affected. MT CYP51 shows largest displacement of the I-helix N-terminus away from the heme, which creates more space in the substrate binding site and releases the BC loop from closed conformation. (C) Alignment of the I-helix sequences performed using BCM Search Launcher (Smith et al., (1996) Genome Res. 6: 454-62). Residues identical or homologous in at least half of compared sequences are shaded in dark or light, respectively. Position of conserved glycine is marked according to MT CYP51 sequence (P77901).

[0045]
FIG. 10A is a diagram depicting the surface representation of MT CYP51 structure. Heme, shown in red, is accessible from the surface through the open mouth of the substrate entry channel 1. Surface was generated with GRASP (Nicholls et al., (1991) Proteins 11: 281-96).

[0046]
FIG. 10B is a diagram depicting a view of substrate binding site from direction of the substrate entry along channel 1. Gray ribbon represents the P450BM3 (Li & Poulos (1997) Nature Struct. Biol. 4: 140-46), and yellow MT CYP51. Both structures were superimposed so that the RMS deviation for the most homologous regions is 0.98 Å. MT CYP51 BC loop is open and lies above N-terminus of the bent I-helix which is pulled away from the structural core.

[0047]
FIG. 11 is a diagram depicting regions adjacent to the N-terminus of the I-helix, the H, G, and F helices and loops in between, exhibit the largest structural deviations between MT CYP51 and P450BM3. Temperature factors in MT CYP51 indicate GH and BC loops and the C helix as the most dynamic regions within the protein that could enable conformational changes required for the synchronized opening and closing of channels 1 and 2.

[0048]
FIG. 12A is a diagram depicting the MT CYP51 active site chamber. Structural elements and residues constituting the dome of the active site are indicated.

[0049]
FIG. 12B is a diagram depicting the interaction of 4-Pt and FLU in the binding site of MT CYP51. Residues located within 4.1 Å of each ligand are shown.

[0050]
FIG. 12C is a diagram depicting the interaction of 4-PI and FLU in the binding site of MT CYP51. In FIG. 12C, region 96-100 is seen to be displaced toward the substrate binding site as a result of conformational changes in the C helix upon fluconazole binding. Fragments of simulated annealing omit 2Fo-Fc map contoured at 1.5 σ are shown.

[0051]
FIG. 13 is a ribbon diagram depicting the mapping of C. albicans mutations in azole resistant isolates onto MT CYP51 structure. 4-PI-bound MT CYP51 is colored according to B-factor values from blue (low) to red (high). Red and yellow colors correspond to the most dynamic regions of MT CYP51. Four mutation hotspots are indicated by different colors. In magenta are shown mutations associated with the “cysteine-pocket”, the region of contacts between β-sheet and helical domains. In rose are shown mutations associated with C-terminus of the G helix and with the H helix. In yellow are shown mutations that associate with interdomain interface. Mutations that associate with the substrate entry loop are shown in white color. Substitutions, which have been experimentally demonstrated to be important for azole affinity are underlined. Numbering of residues in the figure is according to C. albicans.

DETAILED DESCRIPTION OF THE INVENTION

[0052] Disclosed herein is the cloning and isolation of a MT CYP51 gene and a polypeptide encoded by this gene. During the isolation and cloning of the gene, four histidine codons were added at the 3′ end. The polypeptide was expressed in E. coli at a level of about 500 nmol of soluble CYP51 per liter of culture. The polypeptide was subsequently purified using a Ni+2 affinity column, and the purified enzyme showed oxidized, reduced and reduced-CO spectra typical for a biologically active CYP450.

[0053] The purified polypeptide was biologically active in that it was able to convert dihydrolanosterol to its 14α-demethylated product. This reaction was inhibited by ketoconazole. The purified biologically active polypeptide demonstrated substrate specificity for lanosterol, dihydrolanosterol and obtusifoliol. Particularly, dihydrolanosterol and obtusifoliol were metabolized by the purified biologically active polypeptide. The disclosure of the present invention demonstrates the existence of a CYP450 14α-demethylase in a fourth phylum, bacteria. Unlike eukaryotic forms, the bacterial CYP450 14α-demethylase is a soluble CYP450.

[0054] The present invention also relates generally to the structure of Mycobacterium tuberculosis CYP51, and more particularly to the crystalline structure of Mycobacterium tuberculosis CYP51 complexed with 4-phenylimidazole and the crystalline structure of Mycobacterium tuberculosis CYP51 complexed with fluconazole. The invention further relates to methods by which modulators and ligands of Mycobacterium tuberculosis CYP51, can be identified.

[0055] I. Definitions

[0056] As used herein, the terms “structure coordinates” and “structural coordinates” mean mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a molecule in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.

[0057] Those of skill in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this invention, any set of structure coordinates for MT CYP51 or an MT CYP51 mutant that have a root mean square (RMS) deviation from ideal of no more than 1.2 Å when superimposed, using the polypeptide backbone atoms, on the structure coordinates listed in Table 2 and/or Table 3 shall be considered identical.

[0058] As used herein, the term “space group” means the arrangement of symmetry elements of a crystal.

[0059] As used herein, the term “molecular replacement” means a method that involves generating a preliminary model of a wild-type MT CYP51 polypeptide, or an MT CYP51 mutant crystal whose structure coordinates are unknown, by orienting and positioning a molecule whose structure coordinates are known within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal. See, e.g., Lattman, (1985) Method Enzymol, 115: 55-77; Rossmann, ed, (1972) The Molecular Replacement Method, Gordon & Breach, New York.) Using the structure coordinates of the MT CYP51 polypeptide provided by this invention, molecular replacement can be used to determine the structure coordinates of a crystalline mutant an ortholog or a homologue of the MT CYP51 polypeptide, or of a different crystal form of the MT CYP51 polypeptide.

[0060] As used herein, the term “isomorphous replacement” means a method of using heavy atom derivative crystals to obtain the phase information necessary to elucidate the three-dimensional structure of a native crystal (Blundell et al., (1976) Protein Crystallography, Academic Press; Otwinowski, (1991), in Isomorphous Replacement and Anomalous Scattering, (Evans & Leslie, eds.), pp. 80-86, Daresbury Laboratory, Daresbury, United Kingdom). The phrase “heavy-atom derivatization” is synonymous with the term “isomorphous replacement”.

[0061] As used herein, the terms “β-sheet” and “beta-sheet” mean the conformation of a polypeptide chain stretched into an extended zig-zig conformation. Portions of polypeptide chains that run “parallel” all run in the same direction. Polypeptide chains that are “antiparallel” run in the opposite direction from the parallel chains.

[0062] As used herein, the terms “α-helix” and “alpha-helix” mean the conformation of a polypeptide chain wherein the polypeptide backbone is wound around the long axis of the molecule in a left-handed or right-handed direction, and the R groups of the amino acids protrude outward from the helical backbone, wherein the repeating unit of the structure is a single turnoff the helix, which extends about 0.56 nm along the long axis.

[0063] As used herein, the term “unit cell” means a basic parallelepiped shaped block. The entire volume of a crystal can be constructed by regular assembly of such blocks. Each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal. Thus, the term “unit cell” means the fundamental portion of a crystal structure that is repeated infinitely by translation in three dimensions. A unit cell is characterized by three vectors a, b, and c, not located in one plane, which form the edges of a parallelepiped. Angles α, β and γ define the angles between the vectors: angle α is the angle between vectors b and c; angle β is the angle between vectors a and c; and angle γ is the angle between vectors a and b. The entire volume of a crystal can be constructed by regular assembly of unit cells; each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal.

[0064] As used herein, the term “orthorhombic unit cell” means a unit cell wherein a≠b≠c; and α=β=γ=90°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles.

[0065] As used herein, the term “crystal lattice” means the array of points defined by the vertices of packed unit cells.

[0066] As used herein, the term “active site” means that site in a polypeptide where substrate binding occurs.

[0067] As used herein, the terms “chimeric protein” or “fusion protein” are used interchangeably and mean a fusion of a first amino acid sequence encoding an MT CYP51 polypeptide with a second amino acid sequence defining a polypeptide domain foreign to, and not homologous with, any domain of one of an MT CYP51 polypeptide. A chimeric protein can present a foreign domain which is found in an organism which also expresses the first protein, or it can be an “interspecies” or “intergenic” fusion of protein structures expressed by different kinds of organisms. In general, a fusion protein can be represented by the general formula X-MT CYP51-Y, wherein MT CYP51 represents a portion of the protein which is derived from an MT CYP51 polypeptide, and X and Y are independently absent or represent amino acid sequences which are not related to an MT CYP51 sequence in an organism, which includes naturally occurring mutants.

[0068] II. Definitions and Techniques Affecting Gene Products and Genes

[0069] The present invention concerns DNA segments, isolatable from bacterial cells, which are free from genomic DNA and which are capable of conferring CYP450 14α-demethylase biological activity in a recombinant host cell when incorporated into the recombinant host cell. DNA segments capable of conferring CYP450 14α-demethylase biological activity can encode complete MT CYP51 polypeptides, cleavage products and biologically active functional domains thereof.

[0070] The terms “MT CYP51 protein”, “MT CYP51 polypeptide”, “MT CYP51 gene product”, “MT CYP51”, “MT CYP45014DM protein”, “MT CYP45014DM polypeptide”, and “MT CYP45014DM”, as used in the specification and in the claims, are meant to be synonymous and to refer to proteins having amino acid sequences which are substantially identical to the respective native MT CYP45014DM amino acid sequences and which have CYP450 14α-demethylase biological activity or are capable of cross-reacting with an anti-MT CYP51 antibody raised against MT CYP51. Such sequences are disclosed herein. The terms “MT CYP51 protein”, “MT CYP51 polypeptide”, “MT CYP51 gene product”, “MT CYP51”, “MT CYP45014DM protein”, “MT CYP45014DM polypeptide”, and “MT CYP45014DM” also include analogs of MT P45014DM molecules which exhibit at least some biological activity in common with native MT CYP45014DM.

[0071] Furthermore, those skilled in the art of mutagenesis will appreciate that other analogs, as yet undisclosed or undiscovered, can be used to construct MT CYP51 analogs. There is no need for a “MT CYP51 protein”, “MT CYP51 polypeptide”, “MT CYP51 gene product”, “MT CYP51”, “MT CYP45014DM protein”, “MT CYP45014DM polypeptide”, and “MT CYP45014DM” to comprise all, or substantially all, of the amino acid sequence encoded by the native MT CYP51 gene. Shorter or longer sequences are anticipated to be of use in the invention. The term “fragment” refers to any subject polypeptide having an amino acid residue sequence shorter than that of a polypeptide whose amino acid residue sequence is shown herein.

[0072] The terms “MT CYP51 gene”, “MT CYP51 gene sequence” and “MT CYP51 gene segment” refer to any DNA sequence that is substantially identical to a DNA sequence encoding a MT CYP51 polypeptide or MT CYP51 as defined above. The terms also refer to RNA, or antisense sequences, compatible with such DNA sequences. A “MT CYP51 gene”, “MT CYP51 gene sequence” and “MT CYP51 gene segment” can also comprise any combination of associated control sequences.

[0073] The term “substantially identical”, when used to define either a MT CYP51 or MT CYP51 amino acid sequence, or a MT CYP51 gene or MT CYP51 nucleic acid sequence, means that a particular sequence, for example, a mutant sequence, varies from the sequence of a natural MT CYP51 by one or more deletions, substitutions, or additions, the net effect of which is to retain at least some of biological activity of MT CYP51. Alternatively, DNA analog sequences are “substantially identical” to specific DNA sequences disclosed herein if: (a) the DNA analog sequence is derived from coding regions for the natural MT CYP51 or from the natural MT CYP51 gene; or (b) the DNA analog sequence is capable of hybridization of DNA sequences of (a) under moderately stringent conditions and which encode biologically active MT CYP51; or (c) the DNA sequences are degenerative as a result of the genetic code to the DNA analog sequences defined in (a) and/or (b).

[0074] Substantially identical analog proteins will be greater than about 60% identical to the corresponding sequence of the native protein. Sequences having lesser degrees of similarity but comparable biological activity are considered to be equivalents. In determining nucleic acid sequences, all subject nucleic acid sequences capable of encoding substantially similar amino acid sequences are considered to be substantially similar to a reference nucleic acid sequence, regardless of differences in codon sequences.

[0075] II.A. Percent Similarity

[0076] Percent similarity can be determined, for example, by comparing sequence information using the GAP computer program, available from the University of Wisconsin Geneticist Computer Group. The GAP program utilizes the alignment method of Needleman et al., (1970), as revised by Smith et al., (Smith et al., Adv. Appl. Math. 2:482 (1981)). Briefly, the GAP program defines similarity as the number of aligned symbols (i.e. nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences. The preferred default parameters for the GAP program include: (1) a unitary comparison matrix (containing a value of 1 for identities and 0 for non-identities) of nucleotides and the weighted comparison matrix of Gribskov et al., (Gribskov et al. (1986) Nucl. Acids. Res. 14:6745.), as described by Schwartz et al., (Schwartz et al., eds. (1979) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, pp. 357-358.); (2) a penalty of 3.0 for each gap and an additional 0.01 penalty for each symbol and each gap; and (3) no penalty for end gaps.

[0077] The term “homology” describes a mathematically based comparison of sequence similarities which is used to identify genes or proteins with similar functions or motifs. Accordingly, the term “homology” is synonymous with the term “similarity” and “percent similarity” as defined above. Thus, the phrases “substantial homology” or “substantial similarity” have similar meanings.

[0078] II.B. Nucleic Acid Sequences

[0079] In certain embodiments, the invention concerns the use of MT CYP51 genes and gene products that include within their respective sequences a sequence which is essentially that of the MT CYP51 gene, or the corresponding protein. The term “a sequence essentially as that of MT CYP51 or MT CYP51 gene”, means that the sequence substantially corresponds to a portion of a MT CYP51 or MT CYP51 gene and has relatively few bases or amino acids (whether DNA or protein) which are not identical to those of a MT CYP51 or MT CYP51 gene, (or a biologically functional equivalent of, when referring to proteins). The term “biologically functional equivalent” is well understood in the art and is further defined in detail herein. Accordingly, sequences which have between about 70% and about 80%; or more preferably, between about 81% and about 90%; or even more preferably, between about 91% and about 99%; of amino acids which are identical or functionally equivalent to the amino acids of a MT CYP51 or MT CYP51 gene, will be sequences which are “essentially the same”.

[0080] MT CYP51 encoding nucleic acid sequences which have functionally equivalent codons are also covered by the invention. The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six codons for arginine or serine. Thus, when referring to the sequence examples presented in SEQ ID NO's:1-10 applicants contemplate substitution of functionally equivalent codons disclosed in the Table into the sequence examples of SEQ ID NO's:1-10. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience.

[0081] The term “functionally equivalent codon” is also used herein to refer to codons that encode biologically equivalent amino acids (see Table immediately below). Thus, when referring to the sequence examples presented in SEQ ID NO's:1-10 applicants contemplate substitution from the table of codons that encode biologically equivalent amino acids as described herein into the sequence examples of SEQ ID NO's:1-10. Thus, applicants are in possession of amino acid and nucleic acids sequences which include such substitutions but which are not set forth herein in their entirety for convenience.

2Table of Functionally Equivalent Codons.Amino AcidsCodonsAlanineAlaAGCA GCC GCG GCUCysteineCysCUGC UGUAspartic AcidAspDGAC GAUGlumatic acidGluEGAA GAGPhenylalaninePheFUUC UUUGlycineGlyGGGA GGC GGG GGUHistidineHisHCAC CAUIsoleucineIleIAUA AUC AUULysineLysKAAA AAGLeucineLeuLUUA UUG CUA CUC CUG CUUMethionineMetMAUGAsparagineAsnNAAC AAUProlineProPCCA CCC CCG CCUGlutamineGlnQCAA CAGArginineArgRAGA AGG CGA CGC CGG CGUSerineSerSACG AGU UCA UCC UCG UCUThreonineThrTACA ACC ACG ACUValineValVGUA GUC GUG GUUTryptophanTrpWUGGTyrosineTyrYUAC UAU

[0082] It will also be understood that amino acid and nucleic acid sequences can include additional residues, such as additional or C-terminal amino acids or 5′ or 3′ sequences, and yet still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences which can, for example, include various non-coding sequences flanking either of the 5′ or 3′ portions of the coding region or can include various internal sequences which are known to occur within genes.

[0083] The present invention also encompasses the use of DNA segments which are complementary, or essentially complementary, to the sequences set forth in the specification. Nucleic acid sequences which are “complementary” are those which are base-pairing according to the standard Watson-Crick complementarity rules. As used herein, the term “complementary sequences” means nucleic acid sequences which are substantially complementary, as can be assessed by the same nucleotide comparison set forth above, or as defined as being capable of hybridizing to the nucleic acid segment in question under relatively stringent conditions such as those described herein. A particular example of a contemplated complementary nucleic acid segment is an antisense oligonucleotide.

[0084] Nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. Stringent temperature conditions will generally include temperatures in excess of 30° C., typically in excess of 37° C., and preferably in excess of 45° C. Stringent salt conditions will ordinarily be less than 1,000 mM, typically less than 500 mM, and preferably less than 200 mM. However, the combination of parameters is much more important than the measure of any single parameter. (See, e.g., Wetmur & Davidson (1968) J. Mol. Biol. 31:349-370).

[0085] Probe sequences can also hybridize specifically to duplex DNA under certain conditions to form triplex or other higher order DNA complexes. The preparation of such probes and suitable hybridization conditions are well known in the art.

[0086] As used herein, the term “DNA segment” refers to a DNA molecule which has been isolated free of total genomic DNA of a particular species. Furthermore, a DNA segment encoding a MT CYP51 refers to a DNA segment which contains MT CYP51 coding sequences, yet is isolated away from, or purified free from, total genomic DNA of Mycobacterium tuberculosis. Included within the term “DNA segment” are DNA segments and smaller fragments of such segments, and also recombinant vectors, including, for example, plasmids, cosmids, phages, viruses, and the like.

[0087] Similarly, a DNA segment comprising an isolated or purified MT CYP51 gene refers to a DNA segment including MT CYP51 coding sequences isolated substantially away from other naturally occurring genes or protein encoding sequences. In this respect, the term “gene” is used for simplicity to refer to a functional protein, polypeptide or peptide encoding unit. “Isolated substantially away from other coding sequences” means that the gene of interest, in this case, the MT CYP51 gene, forms the significant part of the coding region of the DNA segment, and that the DNA segment does not contain large portions of naturally-occurring coding DNA, such as large chromosomal fragments or other functional genes or coding regions. Of course, this refers to the DNA segment as originally isolated, and does not exclude genes or coding regions later added to the segment by the hand of man.

[0088] In particular embodiments, the invention concerns isolated DNA segments and recombinant vectors incorporating DNA sequences which encode a MT CYP51 that includes within its amino acid sequence the amino acid sequence of any of SEQ ID NO's:2, 4, 6, 8 and 10.

[0089] It will also be understood that this invention is not limited to the particular nucleic acid and amino acid sequences of SEQ ID NOs:1 and 2. Recombinant vectors and isolated DNA segments can therefore variously include the MT CYP51-encoding region itself, include coding regions bearing selected alterations or modifications in the basic coding region, or include encoded larger polypeptides which nevertheless include MT CYP51-encoding regions or can encode biologically functional equivalent proteins or peptides which have variant amino acid sequences.

[0090] In certain embodiments, the invention concerns isolated DNA segments and recombinant vectors which encode a protein or peptide that includes within its amino acid sequence an amino acid sequence essentially as set forth in Of any of SEQ ID NO's:2, 4, 6, 8 and 10. Naturally, where the DNA segment or vector encodes a full length MT CYP51 gene product, the most preferred sequence is that which is essentially as set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9 and which encode a protein that exhibits CYP450 14α-demethylase metabolic activity in, for example, bacterial cells, as can be determined by, for example, sterol metabolism assays as disclosed herein.

[0091] The term “a sequence essentially as set forth in Of any of SEQ ID NO's:2, 4, 6, 8 and 10” means that the sequence substantially corresponds to a portion of any of SEQ ID NO's:2, 4, 6, 8 and 10 and has relatively few amino acids which are not identical to, or a biologically functional equivalent of, the amino acids of any of SEQ ID NO's:2, 4, 6, 8 and 10. The term “biologically functional equivalent” is well understood in the art and is further defined in detail herein. Accordingly, sequences, which have between about 70% and about 80%; or more preferably, between about 81% and about 90%; or even more preferably, between about 91% and about 99%; of amino acids which are identical or functionally equivalent to the amino acids of any of SEQ ID NO's:2, 4, 6, 8 and 10, will be sequences which are “essentially as set forth in any of SEQ ID NO's:2, 4, 6, 8 and 10”.

[0092] In certain other embodiments, the invention concerns isolated DNA segments and recombinant vectors that include within their sequence a nucleic acid sequence essentially as set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9. The term “essentially as set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9” is used in the same sense as described above and means that the nucleic acid sequence substantially corresponds to a portion of any of SEQ ID NO's:1, 3, 5, 7 and 9, respectively, and has relatively few codons which are not identical, or functionally equivalent, to the codons of any of SEQ ID NO's:1, 3, 5, 7 and 9, respectively. Again, DNA segments which encode gene products exhibiting CYP450 14α-demethylase activity of the MT CYP51 gene product will be most preferred. The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six codons for arginine or serine, and also to refer to codons that encode biologically equivalent amino acids.

[0093] The nucleic acid segments of the present invention, regardless of the length of the coding sequence itself, can be combined with other DNA sequences, such as promoters, enhancers, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length can vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length can be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant DNA protocol. For example, nucleic acid fragments can be prepared which include a short stretch complementary to any of SEQ ID NO's:1, 3, 5, 7 and 9, such as about 10 nucleotides, and which are up to 10,000 or 5,000 base pairs in length, with segments of 3,000 being preferred in certain cases. DNA segments with total lengths of about 1,000, 500, 200, 100 and about 50 base pairs in length are also contemplated to be useful.

[0094] The DNA segments of the present invention encompass biologically functional equivalent MT CYP51 proteins and peptides. Such sequences can rise as a consequence of codon redundancy and functional equivalency which are known to occur naturally within nucleic acid sequences and the proteins thus encoded. Alternatively, functionally equivalent proteins or peptides can be created via the application of recombinant DNA technology, in which changes in the protein structure can be engineered, based on considerations of the properties of the amino acids being exchanged. Changes designed by man can be introduced through the application of site-directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test MT CYP51 mutants in order to examine CYP450 14α-demethylase activity at the molecular level.

[0095] If desired, one can also prepare fusion proteins and peptides, e.g., where the MT CYP51 coding region is aligned within the same expression unit with other proteins or peptides having desired functions, such as for purification or immunodetection purposes (e.g., proteins which can be purified by affinity chromatography and enzyme label coding regions, respectively).

[0096] Recombinant vectors form important further aspects of the present invention. Particularly useful vectors are contemplated to be those vectors in which the coding portion of the DNA segment is positioned under the control of a promoter. The promoter can be in the form of the promoter which is naturally associated with the MT CYP51 gene, e.g., in MT cells, as can be obtained by isolating the 5′ non-coding sequences located upstream of the coding segment, for example, using recombinant cloning and/or PCR technology, in connection with the compositions disclosed herein.

[0097] In other embodiments, it is contemplated that certain advantages will be gained by positioning the coding DNA segment under the control of a recombinant, or heterologous, promoter. As used herein, a recombinant or heterologous promoter is intended to refer to a promoter that is not normally associated with a MT CYP51 gene in its natural environment. Such promoters can include promoters isolated from bacterial, viral, eukaryotic, or mammalian cells. Naturally, it will be important to employ a promoter that effectively directs the expression of the DNA segment in the cell type chosen for expression. The use of promoter and cell type combinations for protein expression is generally known to those of skill in the art of molecular biology, for example, see, e.g., Sambrook et al., (1989), specifically incorporated herein by reference. The promoters employed can be constitutive, or inducible, and can be used under the appropriate conditions to direct high level expression of the introduced DNA segment, such as is advantageous in the large-scale production of recombinant proteins or peptides. Appropriate promoter systems contemplated for use in high-level expression include, but are not limited to, the vaccina virus promoter and the baculovirus promoter, which are more fully described below.

[0098] In an alternative embodiment, the present invention provides an expression vector comprising a polynucleotide that encodes a MT CYP51 polypeptide having CYP450 14α-demethylase metabolic activity. Also preferably, an expression vector of the present invention comprises a polynucleotide that encodes human MT CYP51. More preferably, an expression vector of the present invention comprises a polynucleotide that encodes a polypeptide comprising the amino acid residue sequence of any of SEQ ID NO's:2, 4, 6, 8 and 10. More preferably, an expression vector of the present invention comprises a polynucleotide comprising the nucleotide base sequence of any of SEQ ID NO's:1, 3, 5, 7 and 9. Even more preferably, an expression vector of the invention comprises a polynucleotide operatively linked to an enhancer-promoter. More preferably still, an expression vector of the invention comprises a polynucleotide operatively linked to a prokaryotic promoter. Alternatively, an expression vector of the present invention comprises a polynucleotide operatively linked to an enhancer-promoter that is a eukaryotic promoter, and the expression vector further comprises a polyadenylation signal that is positioned 3′ of the carboxy-terminal amino acid and within a transcriptional unit of the encoded polypeptide.

[0099] In yet another embodiment, the present invention provides a recombinant host cell transfected with a polynucleotide that encodes a MT CYP51 polypeptide having CYP450 14α-demethylase metabolic activity. SEQ ID NO's:1-10 set forth exemplary nucleotide and amino acid sequences from MT. Also provided by the present invention are homologous or biologically equivalent MT CYP51 polynucleotides and polypeptides. Preferably, a recombinant host cell of the present invention is transfected with the polynucleotide sequence of any of SEQ ID NO's:1, 3, 5, 7 and 9.

[0100] In another aspect, a recombinant host cell of the present invention is a prokaryotic host cell. Preferably, a recombinant host cell of the invention is a bacterial cell, preferably a strain of Escherichia coli. More preferably, a recombinant host cell comprises a polynucleotide under the transcriptional control of regulatory signals functional in the recombinant host cell, wherein the regulatory signals appropriately control expression of the MT CYP51 polypeptide in a manner to enable all necessary transcriptional and post-transcriptional modification.

[0101] In yet another embodiment, the present invention provides a process of preparing an MT CYP51 polypeptide comprising transfecting a cell with polynucleotide that encodes an MT CYP51 polypeptide having CYP450 14α-demethylase activity to produce a transformed host cell; and maintaining the transformed host cell under biological conditions sufficient for expression of the polypeptide. More preferably, the host cell is a prokaryotic cell. More preferably, the prokaryotic cell is a bacterial cell of the HMS174 strain of Escherichia coli. Even more preferably, a polynucleotide transfected into the transformed cell comprises the nucleotide base sequence of any of SEQ ID NO's:1, 3, 5, 7 and 9. SEQ ID NO's:1-10 set forth nucleotide and amino acid sequences for MT. Also contemplated by the present invention are homologues, orthologs or biologically equivalent CYP51 polynucleotides and polypeptides found in other bacterial species.

[0102] As mentioned above, in connection with expression embodiments to prepare recombinant MT CYP51 proteins and peptides, it is contemplated that longer DNA segments will most often be used, with DNA segments encoding the entire MT CYP51 protein, functional domains or cleavage products thereof, being most preferred. However, it will be appreciated that the use of shorter DNA segments to direct the expression of MT CYP51 peptides or epitopic core regions, such as can be used to generate anti-MT CYP51 antibodies, also falls within the scope of the invention.

[0103] DNA segments which encode peptide antigens from about 15 to about 50 amino acids in length, or more preferably, from about 15 to about 30 amino acids in length are contemplated to be particularly useful. DNA segments encoding peptides will generally have a minimum coding length in the order of about 45 to about 150, or to about 90 nucleotides. DNA segments encoding full length proteins preferably have a coding length on the order of about 1353 nucleotides for a protein in accordance with any of SEQ ID NO's:2, 4, 6, 8 and 10.

[0104] Naturally, the present invention also encompasses DNA segments which are complementary, or essentially complementary, to the sequence set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9. The terms “complementary” and “essentially complementary” are defined above. Excepting flanking regions, and allowing for the degeneracy of the genetic code, sequences which have between about 70% and about 80%; or more preferably, between about 81% and about 90%; or even more preferably, between about 91% and about 99%; of nucleotides which are identical or functionally equivalent (i.e. encoding the same amino acid) of nucleotides of any of SEQ ID NO's:1, 3, 5, 7 and 9, will be sequences which are “essentially as set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9”. Sequences which are essentially the same as those set forth in any of SEQ ID NO's:1, 3, 5, 7 and 9 can also be functionally defined as sequences which are capable of hybridizing to a nucleic acid segment containing the complement of any of SEQ ID NO's:1, 3, 5, 7 and 9 under relatively stringent conditions. Suitable relatively stringent hybridization conditions are described herein and will be well known to those of skill in the art.

[0105] II.C. Biologically Functional Equivalents

[0106] As mentioned above, modification and changes can be made in the structure of the MT CYP51 proteins and peptides described herein and still obtain a molecule having like or otherwise desirable characteristics. For example, certain amino acids can be substituted for other amino acids in a protein structure without appreciable loss of interactive capacity with lanosterol, dihydrolanosterol and other substrates. Since it is the interactive capacity and nature of a protein that defines that protein's biological activity, certain amino acid sequence substitutions can be made in a protein sequence (or, of course, its underlying DNA coding sequence) and nevertheless obtain a protein with like or even countervailing properties (e.g., antagonistic v. agonistic). It is thus contemplated by the inventors that various changes can be made in the sequence of the MT CYP51 proteins and peptides (or underlying DNA) without appreciable loss of their biological utility or activity.

[0107] It is also well understood by the skilled artisan that, inherent in the definition of a biologically functional equivalent protein or peptide, is the concept that there is a limit to the number of changes that can be made within a defined portion of the molecule and still result in a molecule with an acceptable level of equivalent biological activity. Biologically functional equivalent peptides are thus defined herein as those peptides in which certain, not most or all, of the amino acids can be substituted. Of course, a plurality of distinct proteins/peptides with different substitutions can easily be made and used in accordance with the invention.

[0108] It is also well understood that where certain residues are shown to be particularly important to the biological or structural properties of a protein or peptide, e.g., residues in active sites, such residues should not generally be exchanged. This is the case in the present invention, where if any changes, for example, SRS elements or cysteine-heme ligands, could result in a loss of an aspect of the utility of the resulting peptide for the present invention.

[0109] Amino acid substitutions, such as those which might be employed in modifying the MT CYP51 proteins and peptides described herein, are generally based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. An analysis of the size, shape and type of the amino acid side-chain substituents reveals that arginine, lysine and histidine are all positively charged residues; that alanine, glycine and serine are all a similar size; and that phenylalanine, tryptophan and tyrosine all have a generally similar shape. Therefore, based upon these considerations, arginine, lysine and histidine; alanine, glycine and serine; and phenylalanine, tryptophan and tyrosine; are defined herein as biologically functional equivalents.

[0110] In making such changes, the hydropathic index of amino acids can be considered. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics, these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5).

[0111] The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art (Kyte & Doolittle, (1982) J. Mol. Biol. 157: 105. incorporated herein by reference). It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred.

[0112] It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No. 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e. with a biological property of the protein. It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent protein.

[0113] As detailed in U.S. Pat. No. 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5±1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); tryptophan (−3.4).

[0114] In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred.

[0115] While discussion has focused on functionally equivalent polypeptides arising from amino acid changes, it will be appreciated that these changes can be effected by alteration of the encoding DNA, taking into consideration also that the genetic code is degenerate and that two or more codons can code for the same amino acid.

[0116] II.D. Sequence Modification Techniques

[0117] Modifications to the MT CYP51 proteins and peptides described herein can be carried out using techniques such as site directed mutagenesis. Site-specific mutagenesis is a technique useful in the preparation of individual peptides, or biologically functional equivalent proteins or peptides, through specific mutagenesis of the underlying DNA. The technique further provides a ready ability to prepare and test sequence variants, for example, incorporating one or more of the foregoing considerations, by introducing one or more nucleotide sequence changes into the DNA. Site-specific mutagenesis allows the production of mutants through the use of specific oligonucleotide sequences which encode the DNA sequence of the desired mutation, as well as a sufficient number of adjacent nucleotides, to provide a primer sequence of sufficient size and sequence complexity to form a stable duplex on both sides of the deletion junction being traversed. Typically, a primer of about 17 to 30 nucleotides in length is preferred, with about 5 to 10 residues on both sides of the junction of the sequence being altered.

[0118] In general, the technique of site-specific mutagenesis is well known in the art as exemplified by publications (e.g., Adelman et al., (1983) DNA 2:183). As will be appreciated, the technique typically employs a phage vector which exists in both a single stranded and double stranded form. Typical vectors useful in site-directed mutagenesis include vectors such as the M13 phage (Messing et al., (1981) Third Cleveland Symposium on Macromolecules and Recombinant DNA, Ed. A. Walton, (Elsevier, Amsterdam).). These phage are readily commercially available and their use is generally well known to those skilled in the art. Double stranded plasmids are also routinely employed in site directed mutagenesis which eliminates the step of transferring the gene of interest from a plasmid to a phage.

[0119] In general, site-directed mutagenesis in accordance herewith is performed by first obtaining a single-stranded vector or melting apart the two strands of a double stranded vector which includes within its sequence a DNA sequence which encodes, for example, the MT CYP51 gene. An oligonucleotide primer bearing the desired mutated sequence is prepared, generally synthetically, for example by the method of Crea et al., (1978) Proc. Natl. Acad. Sci. U.S.A, 75:5765. This primer is then annealed with the single-stranded vector, and subjected to DNA polymerizing enzymes such as E. coli polymerase I Klenow fragment, in order to complete the synthesis of the mutation-bearing strand. Thus, a heteroduplex is formed wherein one strand encodes the original non-mutated sequence and the second strand bears the desired mutation. This heteroduplex vector is then used to transform appropriate cells, such as E. coli cells, and clones are selected which include recombinant vectors bearing the mutated sequence arrangement.

[0120] The preparation of sequence variants of the selected gene using site-directed mutagenesis is provided as a way of producing potentially useful MT CYP51 or other biologically active species and is not meant to be limiting as there are other ways in which sequence variants of these peptides can be obtained. For example, recombinant vectors encoding the desired genes can be treated with mutagenic agents to obtain sequence variants (see, e.g., a method described by Eichenlaub et al., (1979) R. J. Bacteriol 138:559-566) for the mutagenesis of plasmid DNA using hydroxylamine.

[0121] II.E. Other Structural Equivalents

[0122] Applicants also contemplate that sterically similar compounds can be formulated to mimic the key portions of the peptide structure. Such compounds can be used in the same manner as the peptides of the invention and hence are also functional equivalents. The generation of a structural and functional equivalent can be achieved by the techniques of modeling and chemical design known to those of skill in the art. It will be understood that all such sterically similar constructs fall within the scope of the present invention.

[0123] III. Introduction of Gene Products

[0124] Where the gene itself is employed to introduce the gene products, a convenient method of introduction will be through the use of a recombinant vector which incorporates the desired gene, together with its associated control sequences. The preparation of recombinant vectors is well known to those of skill in the art and described in many references, such as, for example, Sambrook et al., (1989), specifically incorporated herein by reference.

[0125] In vectors, it is understood that the DNA coding sequences to be expressed, in this case those encoding the MT CYP51 gene products, are positioned adjacent to and under the control of a promoter. It is understood in the art that to bring a coding sequence under the control of such a promoter, one generally positions the 5′ end of the transcription initiation site of the transcriptional reading frame of the gene product to be expressed between about 1 and about 50 nucleotides “downstream” of (i.e., 3′ of) the chosen promoter. One can also desire to incorporate into the transcriptional unit of the vector an appropriate polyadenylation site (e.g., 5′-AATAAA-3′), if one was not contained within the original inserted DNA. Typically, these poly A addition sites are placed about 30 to 2000 nucleotides “downstream” of the coding sequence at a position prior to transcription termination.

[0126] While use of the control sequences of the specific gene (i.e., the MT CYP51 promoter for MT CYP51) will be preferred, there is no reason why other control sequences could not be employed, so long as they are compatible with the genotype of the cell into which gene products are being introduced. Thus, one can mention other useful promoters by way of example, including, e.g., a simian virus 40 (SV40) early promoter, a long terminal repeat promoter from retrovirus, an actin promoter, a heat shock promoter, a metallothionein promoter, and the like.

[0127] As is known in the art, a promoter is a region of a DNA molecule typically within about 100 nucleotide pairs in front of (upstream of) the point at which transcription begins (i.e., a transcription start site). That region typically contains several types of DNA sequence elements that are located in similar relative positions in different genes. As used herein, the term “promoter” includes what is referred to in the art as an upstream promoter region, a promoter region or a promoter of a generalized eukaryotic RNA Polymerase II transcription unit.

[0128] Another type of discrete transcription regulatory sequence element is an enhancer. An enhancer provides specificity of time, location and expression level for a particular encoding region (e.g., gene). A major function of an enhancer is to increase the level of transcription of a coding sequence in a cell that contains one or more transcription factors that bind to that enhancer. Unlike a promoter, an enhancer can function when located at variable distances from transcription start sites so long as a promoter is present.

[0129] As used herein, the phrase “enhancer-promoter” means a composite unit that contains both enhancer and promoter elements. An enhancer-promoter is operatively linked to a coding sequence that encodes at least one gene product. As used herein, the phrase “operatively linked” means that an enhancer-promoter is connected to a coding sequence in such a way that the transcription of that coding sequence is controlled and regulated by that enhancer-promoter. Techniques for operatively linking an enhancer-promoter to a coding sequence are well known in the art. As is also well known in the art, the precise orientation and location relative to a coding sequence whose transcription is controlled, is dependent inter alia upon the specific nature of the enhancer-promoter. Thus, a TATA box minimal promoter is typically located from about 25 to about 30 base pairs upstream of a transcription initiation site and an upstream promoter element is typically located from about 100 to about 200 base pairs upstream of a transcription initiation site. In contrast, an enhancer can be located downstream from the initiation site and can be at a considerable distance from that site.

[0130] An enhancer-promoter used in a vector construct of the present invention can be any enhancer-promoter that drives expression in a cell to be transfected. By employing an enhancer-promoter with well-known properties, the level and pattern of gene product expression can be optimized.

[0131] Commonly used viral promoters for expression vectors are derived from polyoma, cytomegalovirus, Adenovirus 2, and SV40. The early and late promoters of SV40 virus are particularly useful because both are obtained easily from the virus as a fragment which also contains the SV40 viral origin of replication. Smaller or larger SV40 fragments can also be used, provided there is included the approximately 250 bp sequence extending from the Hind III site toward the BglI site located in the viral origin of replication. Further, it is also possible, and often desirable, to utilize promoter or control sequences normally associated with the desired gene sequence, provided such control sequences are compatible with the host cell systems.

[0132] The origin of replication can be provided either by construction of the vector to include an exogenous origin, such as can be derived from SV40 or other viral (e.g., Polyoma, Adeno, VSV, BPV) source, or can be provided by the host cell chromosomal replication mechanism. If the vector is integrated into the host cell chromosome, the latter is often sufficient.

[0133] Where the MT CYP51 gene itself is employed it will be most convenient to simply use the wild type MT CYP51 gene directly. However, it is contemplated that certain regions of the MT CYP51 gene can be employed exclusively without employing the entire isolated wild type MT CYP51 gene. It is proposed that it will ultimately be preferable to employ the smallest region needed to impart CYP450 14α-demethylase metabolic activity so that one is not introducing unnecessary DNA into cells which receive an MT CYP51 gene construct. Techniques well known to those of skill in the art, such as the use of restriction enzymes, will allow for the generation of small regions of the MT CYP51 gene. The ability of these regions to impart CYP450 14α-demethylase metabolic activity can easily be determined by the assays reported in the Examples. In general, techniques for assessing CYP450 14α-demethylase metabolic activity are well known in the art.

[0134] IV. Generation of Antibodies

[0135] In still another embodiment, the present invention provides an antibody immunoreactive with a polypeptide of the present invention. Preferably, an antibody of the invention is a monoclonal antibody. Methodologies for preparing and characterizing antibodies are well known in the art (See, e.g., Howell & Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988).

[0136] Briefly, a polyclonal antibody is prepared by immunizing an animal with an immunogen comprising a polypeptide or polynucleotide of the present invention, and collecting antisera from that immunized animal. A wide range of animal species can be used for the production of antisera. Typically an animal used for production of anti-antisera is a rabbit, a mouse, a rat, a hamster or a guinea pig. Because of the relatively large blood volume of rabbits, a rabbit is a preferred choice for production of polyclonal antibodies.

[0137] As is well known in the art, a given polypeptide or polynucleotide can vary in its immunogenicity. It is often necessary therefore to couple the immunogen (e.g., a polypeptide or polynucleotide) of the present invention) with a carrier. Exemplary and preferred carriers are keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA). Other albumins such as ovalbumin, mouse serum albumin or rabbit serum albumin can also be used as carriers.

[0138] Techniques for conjugating a polypeptide or a polynucleotide to a carrier protein are well known in the art and include glutaraldehyde, m-maleimidobenzoyl-N-hydroxysuccinimide ester, carbodiimide and bis-biazotized benzidine.

[0139] As is also well known in the art, immunogencity to a particular immunogen can be enhanced by the use of non-specific stimulators of the immune response known as adjuvants. Exemplary and preferred adjuvants include complete Freund's adjuvant, incomplete Freund's adjuvants and aluminum hydroxide adjuvant.

[0140] The amount of immunogen used for the production of polyclonal antibodies varies, inter alia, upon the nature of the immunogen as well as the animal used for immunization. A variety of routes can be used to administer the immunogen (subcutaneous, intramuscular, intradermal, intravenous and intraperitoneal. The production of polyclonal antibodies is monitored by sampling blood of the immunized animal at various points following immunization. When a desired level of immunogenicity is obtained, the immunized animal can be bled and the serum isolated and stored.

[0141] In another aspect, the present invention provides a process of producing an antibody immunoreactive with MT CYP51 polypeptide, the process comprising the steps of (a) transfecting recombinant host cells with a polynucleotide that encodes that polypeptide; (b) culturing the host cells under conditions sufficient for expression of the polypeptide; (c) recovering the polypeptide; and (d) preparing antibodies to the polypeptide. Preferably, the MT CYP51 polypeptide possesses CYP450 14α-demethylase biological activity. Even more preferably, the present invention provides antibodies prepared according to the process described above.

[0142] A monoclonal antibody of the present invention can be readily prepared through use of well-known techniques such as those exemplified in U.S. Pat. No 4,196,265, herein incorporated by reference. Typically, a technique involves first immunizing a suitable animal with a selected antigen (e.g., a polypeptide or polynucleotide of the present invention) in a manner sufficient to provide an immune response. Rodents such as mice and rats are preferred animals. Spleen cells from the immunized animal are then fused with cells of an immortal myeloma cell. Where the immunized animal is a mouse, a preferred myeloma cell is a murine NS-1 myeloma cell.

[0143] The fused spleen/myeloma cells are cultured in a selective medium to select fused spleen/myeloma cells from the parental cells. Fused cells are separated from the mixture of non-fused parental cells, for example, by the addition of agents that block the de novo synthesis of nucleotides in the tissue culture media. Exemplary and preferred agents are aminopterin, methotrexate, and azaserine. Aminopterin and methotrexate block de novo synthesis of both purines and pyrimidines, whereas azaserine blocks only purine synthesis. Where aminopterin or methotrexate is used, the media is supplemented with hypoxanthine and thymidine as a source of nucleotides. Where azaserine is used, the media is supplemented with hypoxanthine.

[0144] This culturing provides a population of hybridomas from which specific hybridomas are selected. Typically, selection of hybridomas is performed by culturing the cells by single-clone dilution in microtiter plates, followed by testing the individual clonal supernatants for reactivity with an antigen-polypeptides. The selected clones can then be propagated indefinitely to provide the monoclonal antibody.

[0145] By way of specific example, to produce an antibody of the present invention, mice are injected intraperitoneally with between about 1-200 μg of an antigen comprising a polypeptide of the present invention. B lymphocyte cells are stimulated to grow by injecting the antigen in association with an adjuvant such as complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis). At some time (e.g., at least two weeks) after the first injection, mice are boosted by injection with a second dose of the antigen mixed with incomplete Freund's adjuvant.

[0146] A few weeks after the second injection, mice are tail bled and the sera titered by immunoprecipitation against radiolabeled antigen. Preferably, the process of boosting and titering is repeated until a suitable titer is achieved. The spleen of the mouse with the highest titer is removed and the spleen lymphocytes are obtained by homogenizing the spleen with a syringe. Typically, a spleen from an immunized mouse contains approximately 5×107 to 2×108 lymphocytes.

[0147] Mutant lymphocyte cells known as myeloma cells are obtained from laboratory animals in which such cells have been induced to grow by a variety of well-known methods. Myeloma cells lack the salvage pathway of nucleotide biosynthesis. Because myeloma cells are tumor cells, they can be propagated indefinitely in tissue culture, and are thus denominated immortal. Numerous cultured cell lines of myeloma cells from mice and rats, such as murine NS-1 myeloma cells, have been established.

[0148] Myeloma cells are combined under conditions appropriate to foster fusion with the normal antibody-producing cells from the spleen of the mouse or rat injected with the antigen/polypeptide of the present invention. Fusion conditions include, for example, the presence of polyethylene glycol. The resulting fused cells are hybridoma cells. Like myeloma cells, hybridoma cells grow indefinitely in culture.

[0149] Hybridoma cells are separated from unfused myeloma cells by culturing in a selection medium such as HAT media (hypoxanthine, aminopterin, thymidine). Unfused myeloma cells lack the enzymes necessary to synthesize nucleotides from the salvage pathway because they are killed in the presence of aminopterin, methotrexate, or azaserine. Unfused lymphocytes also do not continue to grow in tissue culture. Thus, only cells that have successfully fused (hybridoma cells) can grow in the selection media.

[0150] Each of the surviving hybridoma cells produces a single antibody. These cells are then screened for the production of the specific antibody immunoreactive with an antigen/polypeptide of the present invention. Single cell hybridomas are isolated by limiting dilutions of the hybridomas. The hybridomas are serially diluted many times and, after the dilutions are allowed to grow, the supernatant is tested for the presence of the monoclonal antibody. The clones producing that antibody are then cultured in large amounts to produce an antibody of the present invention in convenient quantity.

[0151] By use of a monoclonal antibody of the present invention, specific polypeptides and polynucleotide of the invention can be recognized as antigens, and thus identified. Once identified, those polypeptides and polynucleotide can be isolated and purified by techniques such as antibody-affinity chromatography. In antibody-affinity chromatography, a monoclonal antibody is bound to a solid substrate and exposed to a solution containing the desired antigen. The antigen is removed from the solution through an immunospecific reaction with the bound antibody. The polypeptide or polynucleotide is then easily removed from the substrate and purified.

[0152] V. Detecting a Polynucleotide or a Polypeptide of the Present Invention

[0153] Alternatively, the present invention provides a process of detecting a polypeptide of the present invention, wherein the process comprises immunoreacting the polypeptides with antibodies prepared according to the process described above to form antibody-polypeptide conjugates, and detecting the conjugates.

[0154] In yet another embodiment, the present invention provides a process of detecting messenger RNA transcripts that encode a polypeptide of the present invention, wherein the process comprises hybridizing the messenger RNA transcripts with polynucleotide sequences that encode the polypeptide to form duplexes; and detecting the duplex. Alternatively, the present invention provides a process of detecting DNA molecules that encode a polypeptide of the present invention, wherein the process comprises hybridizing DNA molecules with a polynucleotide that encodes that polypeptide to form duplexes; and detecting the duplexes.

[0155] V.A. Detecting a Polypeptide of the Present Invention

[0156] The present invention provides a process of screening a biological sample for the presence of a MT CYP51 polypeptide. Preferably, the MT CYP51 polypeptide possesses CYP450 14α-demethylase biological activity. A biological sample to be screened can be a biological fluid such as extracellular or intracellular fluid or a cell or tissue extract or homogenate. A biological sample can also be an isolated cell (e.g., in culture) or a collection of cells such as in a tissue sample or histology sample. A tissue sample can be suspended in a liquid medium or fixed onto a solid support such as a microscope slide.

[0157] In accordance with a screening assay process, a biological sample is exposed to an antibody immunoreactive with the polypeptide whose presence is being assayed. Typically, exposure is accomplished by forming an admixture in a liquid medium that contains both the antibody and the candidate polypeptide. Either the antibody or the sample with the polypeptide can be affixed to a solid support (e.g., a column or a microtiter plate).

[0158] The biological sample is exposed to the antibody under biological reaction conditions and for a period of time sufficient for antibody-polypeptide conjugate formation. Biological reaction conditions include ionic composition and concentration, temperature, pH and the like.

[0159] Ionic composition and concentration can range from that of distilled water to a 2 molal solution of NaCl. Preferably, osmolality is from about 100 mosmols/l to about 400 mosmols/l and, more preferably from about 200 mosmols/l to about 300 mosmols/l. Temperature preferably is from about 4° C. to about 100° C., more preferably from about 15° C. to about 50° C. and, even more preferably from about 25° C. to about 40° C. pH is preferably from about a value of 4.0 to a value of about 9.0, more preferably from about a value of 6.5 to a value of about 8.5 and, even more preferably from about a value of 7.0 to a value of about 7.5. The only limit on biological reaction conditions is that the conditions selected allow for antibody-polypeptide conjugate formation and that the conditions do not adversely affect either the antibody or the polypeptide.

[0160] Exposure time will vary inter alia with the biological conditions used, the concentration of antibody and polypeptide and the nature of the sample (e.g., fluid or tissue sample). Techniques for determining exposure time are well known to one of ordinary skill in the art. Typically, where the sample is fluid and the concentration of polypeptide in that sample is about 10−10M, exposure time is from about 10 minutes to about 200 minutes.

[0161] The presence of polypeptide in the sample is detected by detecting the formation and presence of antibody-polypeptide conjugates. Methodologies for detecting such antibody-antigen (e.g., ligand-polypeptide) conjugates or complexes are well known in the art and include such procedures as centrifugation, affinity chromatography and the like, binding of a secondary antibody to the antibody-candidate receptor complex.

[0162] In one embodiment, detection is accomplished by detecting an indicator affixed to the antibody. Exemplary and well known such indicators include radioactive labels (e.g., 32p, 125I, 14C), a second antibody or an enzyme such as horse radish peroxidase. Methodologies for affixing indicators to antibodies are well known in the art. Commercial kits are available.

[0163] V.B. Screening Assay for Anti-Polypeptide Antibody

[0164] In another aspect, the present invention provides a process of screening a biological sample for the presence of antibodies immunoreactive with a MT CYP51 polypeptide. Preferably the MT CYP51 polypeptide possesses CYP450 14α-demethylase biological activity. In accordance with such a process, a biological sample is exposed to an MT CYP51 polypeptide under biological conditions and for a period of time sufficient for antibody-polypeptide conjugate formation and the formed conjugates are detected.

[0165] V.C. Screening Assay for Polynucleotide That Encodes a MT CYP51 Polypeptide of the Present Invention

[0166] A DNA molecule and, particularly a probe molecule, can be used for hybridizing as an oligonucleotide probe to a DNA source suspected of encoding an MT CYP51 polypeptide of the present invention. Preferably the MT CYP51 polypeptide possesses CYP450 14α-demethylase biological activity. The probing is usually accomplished by hybridizing the oligonucleotide to a DNA source suspected of possessing an MT CYP51 gene. In some cases, the probes constitute only a single probe, and in others, the probes constitute a collection of probes based on a certain amino acid sequence or sequences of the polypeptide and account in their diversity for the redundancy inherent in the genetic code.

[0167] A suitable source of DNA for probing in this manner is capable of expressing a polypeptide of the present invention and can be a genomic library of a cell line of interest. Alternatively, a source of DNA can include total DNA from the cell line of interest. Once the hybridization process of the invention has identified a candidate DNA segment, one confirms that a positive clone has been obtained by further hybridization, restriction enzyme mapping, sequencing and/or expression and testing.

[0168] Alternatively, such DNA molecules can be used in a number of techniques including their use as: (1) tools to detect normal and abnormal DNA sequences in DNA derived from cells; (2) tools for detecting and isolating other members of the polypeptide family and related polypeptides from a DNA library potentially containing such sequences; (3) primers for hybridizing to related sequences for the purpose of amplifying those sequences; (4) primers for altering native MT CYP51 DNA sequences; as well as other techniques which rely on the similarity of the DNA sequences to those of the DNA segments herein disclosed.

[0169] As set forth above, in certain aspects, DNA sequence information provided by the invention allows for the preparation of relatively short DNA (or RNA) sequences (e.g., probes) that specifically hybridize to encoding sequences of a selected MT CYP51 gene. In these aspects, nucleic acid probes of an appropriate length are prepared based on a consideration of the encoding sequence for a polypeptide of this invention. The ability of such nucleic acid probes to specifically hybridize to other encoding sequences lend them particular utility in a variety of embodiments. Most importantly, the probes can be used in a variety of assays for detecting the presence of complementary sequences in a given sample. However, other uses are envisioned, including the use of the sequence information for the preparation of mutant species primers, or primers for use in preparing other genetic constructions.

[0170] To provide certain of the advantages in accordance with the invention, a preferred nucleic acid sequence employed for hybridization studies or assays includes probe sequences that are complementary to at least a 14 to 40 or so long nucleotide stretch of a nucleic acid sequence of the present invention, such as that shown in any of SEQ ID NO's:1, 3, 5, 7 and 9. A size of at least 14 nucleotides in length helps to ensure that the fragment is of sufficient length to form a duplex molecule that is both stable and selective. Molecules having complementary sequences over stretches greater than 14 bases in length are generally preferred, though, to increase stability and selectivity of the hybrid, and thereby improve the quality and degree of specific hybrid molecules obtained. One will generally prefer to design nucleic acid molecules having gene-complementary stretches of 14 to 20 nucleotides, or even longer where desired. Such fragments can be readily prepared by, for example, directly synthesizing the fragment by chemical reactions, by application of nucleic acid reproduction technology, such as the PCR technology of U.S. Pat. No. 4,683,202, herein incorporated by reference, or by introducing selected sequences into recombinant vectors for recombinant production.

[0171] Accordingly, a nucleotide sequence of the present invention can be used for its ability to selectively form duplex molecules with complementary stretches of the gene. Depending on the application envisioned, one employs varying conditions of hybridization to achieve varying degrees of selectivity of the probe toward the target sequence. For applications requiring a high degree of selectivity, one typically employs relatively stringent conditions to form the hybrids. For example, one selects relatively low salt and/or high temperature conditions, such as provided by 0.02M-0.15M salt at temperatures of about 50° C. to about 70° C. including particularly temperatures of about 55° C., about 60° C. and about 65° C. Such conditions are particularly selective, and tolerate little, if any, mismatch between the probe and the template or target strand.

[0172] Of course, for some applications, for example, where one desires to prepare mutants employing a mutant primer strand hybridized to an underlying template or where one seeks to isolate polypeptide coding sequences from related species, functional equivalents, or the like, less stringent hybridization conditions are typically needed to allow formation of the heteroduplex. Under such circumstances, one employs conditions such as 0.15M-0.9M salt, at temperatures ranging from about 20° C. to about 55° C., including particularly temperatures of about 25° C., about 37° C., about 45° C., and about 50° C. Cross-hybridizing species can thereby be readily identified as positively hybridizing signals with respect to control hybridizations. In any case, it is generally appreciated that conditions can be rendered more stringent by the addition of increasing amounts of formamide, which serves to destabilize the hybrid duplex in the same manner as increased temperature. Thus, hybridization conditions can be readily manipulated, and thus will generally be a method of choice depending on the desired results.

[0173] In certain embodiments, it is advantageous to employ a nucleic acid sequence of the present invention in combination with an appropriate moiety, such as a label, for determining hybridization. A wide variety of appropriate indicators are known in the art, including radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of giving a detectable signal. In preferred embodiments, one likely employs an enzyme tag such a urease, alkaline phosphatase or peroxidase, instead of radioactive or other environmentally undesirable reagents. In the case of enzyme tags, calorimetric indicator substrates are known which can be employed to to permit detection by the human eye or spectrophotometrically, to identify specific hybridization with complementary nucleic acid-containing samples.

[0174] In general, it is envisioned that the hybridization probes described herein are useful both as reagents in solution hybridization as well as in embodiments employing a solid phase. In embodiments involving a solid phase, the sample containing test DNA (or RNA) is adsorbed or otherwise affixed to a selected matrix or surface. This fixed, single-stranded nucleic acid is then subjected to specific hybridization with selected probes under desired conditions. The selected conditions depend inter alia on the particular circumstances based on the particular criteria required (depending, for example, on the G+C contents, type of target nucleic acid, source of nucleic acid, size of hybridization probe, etc.). Following washing of the hybridized surface so as to remove nonspecifically bound probe molecules, specific hybridization is detected, or even quantified, via the label.

[0175] V.D. Assay Kits

[0176] In another aspect, the present invention provides assay kits for detecting the presence of a polypeptide of the present invention in biological samples, where the kits comprise a first container containing a first antibody capable of immunoreacting with the polypeptide, with the first antibody present in an amount sufficient to perform at least one assay. Preferably, the assay kits of the invention further comprise a second container containing a second antibody that immunoreacts with the first antibody. More preferably, the antibodies used in the assay kits of the present invention are monoclonal antibodies. Even more preferably, the first antibody is affixed to a solid support. More preferably still, the first and second antibodies comprise an indicator, and, preferably, the indicator is a radioactive label or an enzyme.

[0177] The present invention also provides a kit for screening agents. Such a kit can contain a polypeptide of the present invention. The kit can contain reagents for detecting an interaction between an agent and an enzyme of the present invention. The provided reagent can be radiolabeled. The kit can contain a known radiolabelled agent capable of binding or interacting with an enzyme of the present invention.

[0178] In an alternative aspect, the present invention provides assay kits for detecting the presence, in biological samples, of a polynucleotide that encodes a polypeptide of the present invention, the kits comprising a first container that contains a second polynucleotide identical or complementary to a segment of at least 10 contiguous nucleotide bases of, as a preferred example, any of SEQ ID NO's:1, 3, 5, 7 and 9.

[0179] In another embodiment, the present invention provides assay kits for detecting the presence, in a biological sample, of antibodies immunoreactive with a polypeptide of the present invention, the kits comprising a first container containing a MT CYP51 polypeptide, that immunoreacts with the antibodies, with the polypeptide present in an amount sufficient to perform at least one assay. Preferably, the MT CYP51 polypeptide possesses CYP450 14α-demethylase biological activity. The reagents of the kit can be provided as a liquid solution, attached to a solid support or as a dried powder. Preferably, when the reagent is provided in a liquid solution, the liquid solution is an aqueous solution. Preferably, when the reagent provided is attached to a solid support, the solid support can be chromatograph media or a microscope slide. When the reagent provided is a dry powder, the powder can be reconstituted by the addition of a suitable solvent. The solvent can be provided.

[0180] VI. Screening Assays

[0181] In yet another aspect, the present invention provides a process of screening substances for their ability to affect or modulate the biological activity of CYP51 enzymes, and preferably, the biological activity of MT CYP51. More preferably, the present invention provides a process of screening substances for their ability to affect or modulate the biological activity of MT CYP51 to thereby affect or modulate MT growth or infection. Utilizing the methods and compositions of the present invention, screening assays for the testing of candidate substances can be derived. A candidate substance is a substance which potentially can promote but preferably inhibits the biological activity of MT CYP51 to thereby affect or modulate the MT growth or infection.

[0182] An exemplary method of screening candidate substances for their ability to modulate CYP51 biological activity comprises the steps of: (a) establishing replicate test and control samples that comprise a biologically active MT CYP51 polypeptide; (b) administering a candidate substance to test sample but not the control sample; (c) measuring the biological activity of the MT CYP51 polypeptide in the test and the control samples; and (d) determining that the candidate substance modulates MT CYP51 biological activity if the biological activity of the MT CYP51 polypeptide measured for the test sample is greater or less than the biological activity of the MT CYP51 polypeptide level measured for the control sample.

[0183] The replicate test and control samples can further comprise a cell that expresses a biologically active CYP51 polypeptide. The present invention thus also provides a recombinant cell line suitable for use in this method.

[0184] A screening assay of the present invention generally involves determining the ability of a candidate substance to modulate CYP51 biological activity in a target cell, such as the screening of candidate substances to identify those that modulate, i.e. inhibit or promote, CYP51 biological activity. Preferably, the CYP51 polypeptide comprises a MT CYP51 polypeptide. Target cells can be either naturally occurring cells known to contain a polypeptide of the present invention (e.g. MT cells) or transformed cell produced in accordance with a process of transformation set forth hereinbefore.

[0185] As is well known in the art, a screening assay provides a cell under conditions suitable for testing the modulation of CYP51 biological activity. These conditions include but are not limited to pH, temperature, tonicity, the presence of relevant metabolic factors (e.g., metal ions such as for example Ca++, growth factor, interleukins, or colony stimulating factors), and relevant modifications to the polypeptide such as glycosylation or prenylation. It is contemplated that a polypeptide of the present invention can be expressed and utilized in a prokaryotic or eukaryotic cell. The host cell can also be fractionated into sub-cellular fractions where CYP45014DM enzymatic substrates can be found. For example, cells expressing the polypeptide can be fractionated into the nuclei, the endoplasmic reticulum, vesicles, or the membrane surfaces of the cell.

[0186] pH is preferably from about a value of 6.0 to a value of about 8.0, more preferably from about a value of about 6.8 to a value of about 7.8 and, most preferably about 7.4. In a preferred embodiment, temperature is from about 20° C. to about 50° C., more preferably from about 30° C. to about 40° C. and, even more preferably about 37° C. Osmolality is preferably from about 5 milliosmols per liter (mosm/L) to about 400 mosm/l and, more preferably from about 200 milliosmols per liter to about 400 mosm/l and, even more preferably from about 290 mosm/L to about 310 mosm/L. The presence of factors can be required for the proper testing of CYP51 biological activity modulation in specific cells. Such factors include, for example, the presence and absence (withdrawal) of growth factor, interleukins, colony stimulating factors and/or reductase systems for CYP450 enzymes. U.S. Pat. No. 5,645,999 also describes exemplary screening assays, and the entire contents of U.S. Pat. No. 5,645,999 are herein incorporated by reference.

[0187] In one embodiment, a screening assay is designed to be capable of discriminating candidate substances having selective ability to interact with one or more of the polypeptides of the present invention but which polypeptides are without a substantially overlapping activity with another of those polypeptides identified herein. Exemplary assays including genetic screening assays and molecular biology screens such as a yeast two-hybrid screen which will effectively identify CYP51-interacting genes important for CYP450 14α-demethylase metabolism modulation or other CYP51-mediated biological activity. One version of the yeast two-hybrid system has been described (Chien et al., (1991) Proc. Natl. Acad. Sci. USA, 88:9578-9582) and is commercially available from Clontech (Palo Alto, Calif.).

[0188] VII. Description of Tables

[0189] Table 1 is a table summarizing the crystal and data statistics obtained from the crystallized MT CYP51 polypeptide in complex with 4-phenylimidazole (4-PI) and fluconazole (FLU). Data on the unit cell are presented, including data on the crystal space group, unit cell dimensions, molecules per asymmetric cell and crystal resolution.

[0190] Table 2 is a table of atomic structure coordinate data obtained from x-ray diffraction from MT CYP51 complexed with 4-phenylimidazole.

[0191] Table 3 is a table of atomic structure coordinate data obtained from x-ray diffraction from mtcyp51 complexed with 4-phenylimidazole and fluconazole.

[0192] Table 4 is a table showing conservation of MT CYP51 active site residues through evolution.

[0193] Table 5 is a table showing MT P45014DM reduction By different electron donors.

[0194] VIII. Formation of MT CYP51 Polypeptide Crystals

[0195] In one embodiment, the present invention provides crystals of an MT CYP51 polypeptide. The crystals were obtained using the methodology disclosed in the Examples. The MT CYP51 crystals, which can be native crystals, derivative crystals or co-crystals, have unit cells wherein a≠b≠c, and wherein α=β=γ=90°) and space group symmetry P212121. Preferably, there is one MT CYP51 molecule in the asymmetric unit. In one embodiment of the MT CYP51 crystalline form, an MT CYP51 polypeptide was co-crystallized with 4-PI, the unit cell has dimensions of a=46.14, b=83.86, c=109.56, and α=β=γ=90°. In another embodiment of the MT CYP51 crystalline form, an MT CYP51 polypeptide was co-crystallized with FLU, and the unit cell has dimensions of a=46.19, b=84.26, c=109.75, α=β=γ=90°. Preferably, there is one molecule of ligand (e.g. a modulator molecule, more preferably an inhibitor such as 4-PI or FLU) per complex.

[0196] The MT CYP51 structure was solved using multiple isomorphous replacement anomalous scattering (MIRAS) techniques. In the MIRAS method of solving protein crystals, a derivative crystal is prepared that contains an atom that is heavier than the other atoms of the sample. One representative heavy atom that can be incorporated into the derivative crystal is mercury. Heavy atom derivative crystals can be prepared by soaking a crystal in a solution containing a selected heavy atom salt. In the present invention, heavy atom derivative crystals were prepared by soaking a crystalline form of the MT CYP51 polypeptide in ethylmercurithiosalicylic acid or gold (I) potassium cyanide over several hours.

[0197] Symmetry-related reflections in the X-ray diffraction pattern, usually identical, are altered by the anomalous scattering contribution of the heavy atoms. The measured differences in symmetry-related reflections are used to determine the position of the heavy atoms, leading to an initial estimation of the diffraction phases, and subsequently, an electron density map is prepared. The prepared electron density map is then used to identify the position of the other atoms in the sample.

[0198] VIII.A. Preparation of MT CYP51 Crystals

[0199] The native and derivative co-crystals, and fragments thereof, disclosed in the present invention can be obtained by a variety of techniques, including batch, liquid bridge, dialysis, vapor diffusion and hanging drop methods (See, e.g., McPherson, (1982) Preparation and Analysis of Protein Crystals, John Wiley, New York.; McPherson, (1990) Eur. J. Biochem. 189:1-23.; Weber, (1991) Adv. Protein Chem. 41:1-36). In a representative embodiment, the vapor diffusion and hanging drop methods are used for the crystallization of MT CYP51 polypeptides and fragments thereof.

[0200] In general, native crystals of the present invention are grown by dissolving substantially pure MT CYP51 polypeptide or a fragment thereof in an aqueous buffer containing a precipitant at a concentration just below that necessary to precipitate the protein. Water is removed by controlled evaporation to produce precipitating conditions, which are maintained until crystal growth ceases.

[0201] In one embodiment of the invention, native crystals are grown by vapor diffusion (See, e.g., McPherson, (1982) Preparation and Analysis of Protein Crystals, John Wiley, New York.; McPherson, (1990) Eur. J. Biochem. 189:1-23). In this method, the polypeptide/precipitant solution is allowed to equilibrate in a closed container with a larger aqueous reservoir having a precipitant concentration optimal for producing crystals. Generally, less than about 2 mL of MT CYP51 polypeptide solution is mixed with an equal volume of reservoir solution, giving a precipitant concentration about half that required for crystallization. This solution is suspended as a droplet underneath a coverslip, which is sealed onto the top of the reservoir. The sealed container is allowed to stand, until crystals grow. Crystals generally form within two to six weeks, and are suitable for data collection within approximately seven to ten weeks. Of course, those of skill in the art will recognize that the above-described crystallization procedures and conditions can be varied.

[0202] VIII.B. Preparation of Derivative Crystals

[0203] Derivative crystals of the present invention, e.g. heavy atom derivative crystals, can be obtained by soaking native crystals in mother liquor containing salts of heavy metal atoms. Such derivative crystals are useful for phase analysis in the solution of crystals of the present invention. In a preferred embodiment of the present invention, for example, soaking a native crystal in a solution comprise mercury or gold atoms provides derivative crystals suitable for use as isomorphous replacements in determining the X-ray crystal structure of an MT CYP51 polypeptide. Additional reagents useful for the preparation of the derivative crystals of the present invention will be apparent to those of skill in the art after review of the disclosure of the present invention presented herein.

[0204] VIII.C. Preparation of Co-crystals

[0205] Co-crystals of the present invention can be obtained by soaking a native crystal in mother liquor containing compounds known or predicted to bind an MT CYP51 polypeptide, or a fragment thereof. Alternatively, co-crystals can be obtained by co-crystallizing an MT CYP51 polypeptide or a fragment thereof in the presence of one or more compounds known or predicted to bind the polypeptide.

[0206] VIII.D. Solving a Crystal Structure of the Present Invention

[0207] Crystal structures of the present invention can be solved using a variety of techniques including, but not limited to, isomorphous replacement anomalous scattering or molecular replacement methods. Computer software packages will also be helpful in solving a crystal structure of the present invention. Applicable software packages include but are not limited to CNS™ program (Brünger et al., (1998) Crystallography and NMR System Version 1.0, A New Software Suite for Macromolecular Structure Determination, Acta Cryst. D54:905-921), Xtal View (McRee, (1992) J. Mol. Graphics 10: 44-47; X-tal View is available from the San Diego Supercomputer Center), SHELXS 97 (Sheldrick (1990) Acta Cryst A46: 467; SHELX 97 is available from the Institute of Inorganic Chemistry, Georg-August-Universität, Göttingen, Germany), HEAVY (Terwilliger, Los Alamos National Laboratory) can be used and SHAKE-AND-BAKE (Hauptman, (1997) Curr. Opin. Struct. Biol. 7: 672-80; Weeks et al., (1993) Acta Cryst. D49: 179; available from the Hauptman-Woodward Medical Research Institute, Buffalo, N.Y.). See also, Ducruix & Geige, (1992) Crystallization of Nucleic Acids and Proteins: A Practical Approach, IRL Press, Oxford, England, and references cited therein.

[0208] IX. Uses of MT CYP51 Crystals and the Three-Dimensional Structure of the MT CYP51 Polypeptide in the Design and Development of MT CYP51 Modulators

[0209] The knowledge of the structure of the MT CYP51 polypeptide, an aspect of the present invention, provides a tool for investigating the mechanism of action of MT CYP51 and other CYP51 polypeptides. For example, various computer models, as described herein, can predict the binding of various substrate molecules to the MT CYP51. Upon discovering that such binding in fact takes place, knowledge of the protein structure then allows design and synthesis of small molecules that mimic the functional binding of the substrate to the MT CYP51, and to other CYP51 polypeptides. This is the method of “rational” drug design, further described herein.

[0210] Use of the isolated and purified MT CYP51 crystalline structure of the present invention in rational drug design is thus provided in accordance with the present invention. Additional rational drug design techniques are described in U.S. Pat. Nos. 5,834,228 and 5,872,011, incorporated herein in their entirety.

[0211] Thus, in addition to the compounds described herein, other sterically similar compounds can be formulated to mimic the key structural regions of an CYP51 in general, or of MT CYP51 in particular. The generation of a structural functional equivalent can be achieved by the techniques of modeling and chemical design known to those of skill in the art and described herein. It will be understood that all such sterically similar constructs fall within the scope of the present invention.

[0212] IX.A. Rational Drug Design

[0213] The three-dimensional structures of the MT CYP51 polypeptide complexed with 4-phenylimidizole and MT CYP51 complexed with fluconazole is unprecedented and will greatly aid in the development of new synthetic ligands for an CYP51 polypeptide, including a MT CYP51 polypeptide, such as a MT CYP51 antagonist, including those that bind exclusively to a MT CYP51 polypeptide. In addition, the MT CYP51 structure is well suited to modern methods, including three-dimensional structure elucidation and combinatorial chemistry, such as those disclosed in U.S. Pat. No. 5,463,564, incorporated herein by reference. Structure determination using X-ray crystallography is possible because of the solubility properties of the MT CYP51s. Computer programs that use crystallography data when practicing the present invention will enable the rational design of substrates to these enzymes. Programs such as RASMOL (Biomolecular Structures Group, Glaxo Wellcome Research & Development Stevenage, Hertfordshire, UK Version 2.6, August 1995, Version 2.6.4, December 1998, Copyright© Roger Sayle 1992-1999) can be used with the atomic structural coordinates from crystals generate by practicing the invention or used to practice the invention by generating three-dimensional models and/or determining the structures involved in substrate binding. Computer programs such as those sold under the registered trademark INSIGHT II® and such as GRASP (Nicholls et al., (1991) Proteins 11: 282) allow for further manipulations and the ability to introduce new structures. In addition, high throughput binding and bioactivity assays can be devised using purified recombinant protein and modern reporter gene transcription assays known to those of skill in the art in order to refine the activity of a designed modulator.

[0214] A method of identifying modulators of the activity of an MT CYP51 polypeptide using rational drug design is thus provided in accordance with the present invention. The method comprises designing a potential modulator for an MT CYP51 polypeptide of the present invention that will form non-covalent bonds with amino acids in the substrate binding site or substrate binding channel, i.e., an “active site” based upon the crystalline structure of the MT CYP51 polypeptide; synthesizing the modulator; and determining whether the potential modulator modulates the activity of the MT CYP51 polypeptide. In a preferred embodiment, the modulator is designed for an MT CYP51 polypeptide. Preferably, the MT CYP51 polypeptide is encoded by a nucleic acid sequence or comprises a polypeptide sequence of any of SEQ ID NOs:1-10. The determination of whether the modulator modulates the biological activity of an MT CYP51 polypeptide is made in accordance with the screening methods disclosed herein, or by other screening methods known to those of skill in the art. Modulators can be synthesized using techniques known to those of ordinary skill in the art.

[0215] In an alternative embodiment, a method of designing a modulator of an MT CYP51 polypeptide in accordance with the present invention is disclosed comprising: (a) selecting a candidate MT CYP51 ligand; (b) determining which amino acid or amino acids of an MT CYP51 polypeptide interact with the ligand using a three-dimensional model of a crystallized MT CYP51 polypeptide; (c) identifying in a biological assay for MT CYP51 activity a degree to which the ligand modulates the activity of the MT CYP51 polypeptide; (d) selecting a chemical modification of the ligand wherein the interaction between the amino acids of the MT CYP51 polypeptide and the ligand is predicted to be modulated by the chemical modification; (e) performing the chemical modification on the ligand to form a modified ligand; (f) contacting the modified ligand with the MT CYP51 polypeptide; (g) identifying in a biological assay for MT CYP51 activity a degree to which the modified ligand modulates the biological activity of the MT CYP51 polypeptide; and (h) comparing the biological activity of the MT CYP51 polypeptide in the presence of modified ligand with the biological activity of the MT CYP51 polypeptide in the presence of the unmodified ligand, whereby a modulator of an MT CYP51 polypeptide is designed.

[0216] IX.B. Methods for Using the MT CYP51 Polypeptide Structural Coordinates For Molecular Design

[0217] For the first time, the present invention permits the use of molecular design techniques to design, select and synthesize chemical entities and compounds, including modulatory compounds, capable of binding to a MT CYP51 polypeptide, in whole or in part. Correspondingly, the present invention also provides for the application of similar techniques in the design of modulators of any CYP51 polypeptide.

[0218] In accordance with a preferred embodiment of the present invention, the structure coordinates of a crystalline MT CYP51 can be used to design compounds that bind to an MT CYP51 polypeptide and alter the properties of an MT CYP51 polypeptide in different ways. One aspect of the present invention provides for the design of compounds that act as competitive inhibitors of an MT CYP51 polypeptide by binding to all, or a portion of, the binding sites on an MT CYP51 polypeptide. The present invention also provides for the design of compounds that can act as non-conpetitive inhibitors of an MT CYP51 polypeptide. These compounds can bind to all, or a portion of, an accessory binding site of an MT CYP51 that is already binding a ligand and can, therefore, be more potent and less non-specific than known competitive inhibitors that compete only for a MT CYP51 substrate binding site. Similarly, non-competitive inhibitors that bind to and inhibit MT CYP51 polypeptide activity, whether or not it is bound to another chemical entity, can be designed using the MT CYP51 polypeptide structure coordinates of this invention.

[0219] A second design approach is to probe an MT CYP51 crystal with molecules comprising a variety of different chemical entities to determine optimal sites for interaction between candidate MT CYP51 modulators and the polypeptide. For example, high resolution X-ray diffraction data collected from crystals saturated with solvent allows the determination of the site where each type of solvent molecule adheres. Small molecules that bind tightly to those sites can then be designed and synthesized and tested for their MT CYP51 modulator activity.

[0220] Once a computationally-designed ligand is synthesized using the methods of the present invention or other methods known to those of skill in the art, assays can be used to establish its efficacy of the ligand as a modulator of CYP51 (preferably MT CYP51) activity. After such assays, the ligands can be further refined by generating intact MT CYP51 crystals with a ligand bound. The structure of the ligand can then be further refined using the chemical modification methods described herein and known to those of skill in the art, in order to improve the modulation activity or the binding affinity of the ligand. This process can lead to second generation ligands with improved properties.

[0221] IX.C. Methods of Designing MT CYP51 Modulator Compounds

[0222] The design of candidate substances, also referred to as “compounds” or “candidate compounds”, that bind to or inhibit MT CYP51-mediated activity according to the present invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with an MT CYP51 polypeptide. Non-covalent molecular interactions important in the association of an MT CYP51 polypeptide with its substrate include hydrogen bonding, van der Waals interactions and hydrophobic interactions.

[0223] Second, the compound must be able to assume a conformation that allows it to associate with an MT CYP51 polypeptide. Although certain portions of the compound will not directly participate in this association with an MT CYP51 polypeptide, those portions can still influence the overall conformation of the molecule. This, in turn, can have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the binding site, e.g., a substrate binding site or an accessory binding site of an MT CYP51 polypeptide, or the spacing between functional groups of a compound comprising several chemical entities that directly interact with an MT CYP51 polypeptide.

[0224] The potential modulatory or binding effect of a chemical compound on an MT CYP51 polypeptide can be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques that employ the coordinates of a crystalline MT CYP51 polypeptide of the present invention. If the theoretical structure of the given compound suggests insufficient interaction and association between it and an MT CYP51 polypeptide, synthesis and testing of the compound is obviated. However, if computer modeling indicates a strong interaction, the molecule can then be synthesized and tested for its ability to bind and modulate the activity of an MT CYP51 polypeptide. In this manner, synthesis of unproductive or inoperative compounds can be avoided.

[0225] A modulatory or other binding compound of an MT CYP51 polypeptide can be computationally evaluated and designed via a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with the individual binding sites or other areas of a crystalline MT CYP51 polypeptide of the present invention.

[0226] One of several methods can be used to screen chemical entities or fragments for their ability to associate with an MT CYP51 polypeptide and, more particularly, with the individual binding sites of an MT CYP51 polypeptide, such as an active site or an accessory binding site. This process can begin by visual inspection of, for example, an active site on a computer screen based on the MT CYP51 atomic coordinates in Tables 2 and 3. Selected fragments or chemical entities can then be positioned in a variety of orientations, or docked, within an individual binding site of an MT CYP51 polypeptide as defined herein above. Docking can be accomplished using software programs such as those available under the tradenames QUANTA™ (Molecular Simulations Inc., San Diego, Calif.) and SYBYL™ (Tripos, Inc., St. Louis, Mo.), followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARM (Brooks et al., (1983) J. Comp. Chem., 8: 132) and AMBER 5 (Case et al., (1997), AMBER 5, University of California, San Francisco; Pearlman et al., (1995) Comput Phys. Commun. 91: 1-41).

[0227] Specialized computer programs can also assist in the process of selecting fragments or chemical entities. These include:

[0228] 1. GRID™ program, version 17 (Goodford, (1985) J. Med. Chem. 28: 849-57), which is available from Molecular Discovery Ltd., Oxford, UK;

[0229] 2. MCSS™ program (Miranker & Karplus, (1991) Proteins 11: 29-34), which is available from Molecular Simulations, Inc., San Diego, Calif.;

[0230] 3. AUTODOCK™ 3.0 program (Goodsell & Olsen, (1990) Proteins 8: 195-202), which is available from the Scripps Research Institute, La Jolla, Calif.;

[0231] 4. DOCK™ 4.0 program (Kuntz et al., (1992) J. Mol. Biol. 161: 269-88), which is available from the University of California, San Francisco, Calif.;

[0232] 5. FLEX-X™ program (See, Rarey et al., (1996) J. Comput. Aid. Mol Des. 10:41-54), which is available from Tripos, Inc., St. Louis, Mo.;

[0233] 6. MVP program (Lambert, (1997) in Practical Application of Computer-Aided Drug Design, (Charifson, ed.) Marcel-Dekker, New York, pp. 243-303); and

[0234] 7. LUDI™ program (Bohm, (1992) J. Comput. Aid. Mol. Des., 6: 61-78), which is available from Molecular Simulations, Inc., San Diego, Calif.

[0235] Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or modulator. Assembly can proceed by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of an MT CYP51 polypeptide. Manual model building using software such as QUANTA™ or SYBYL™ typically follows.

[0236] Useful programs to aid one of ordinary skill in the art in connecting the individual chemical entities or fragments include:

[0237] 1. CAVEAT™ program (Bartlett et al., (1989) Special Pub., Royal Chem. Soc. 78: 182-96), which is available from the University of California, Berkeley, Calif.;

[0238] 2. 3D Database systems, such as MACCS-3D™ system program, which is available from MDL Information Systems, San Leandro, Calif. This area is reviewed in Martin, (1992) J. Med. Chem. 35: 2145-54; and

[0239] 3. HOOK™ program (Eisen et al., (1994). Proteins 19: 199-221), which is available from Molecular Simulations, Inc., San Diego, Calif.

[0240] Instead of proceeding to build an MT CYP51 polypeptide modulator in a step-wise fashion one fragment or chemical entity at a time as described above, modulatory or other binding compounds can be designed as a whole or de novo using the structural coordinates of a crystalline MT CYP51 polypeptide of the present invention and either an empty binding site or optionally including some portion(s) of a known modulator(s). Applicable methods can employ the following software programs:

[0241] 1. LUDI™ program (Bohm, (1992) J. Comput Aid. Mol. Des., 6: 61-78), which is available from Molecular Simulations, Inc., San Diego, Calif.;

[0242] 2. LEGEND™ program (Nishibata & Itai, (1991) Tetrahedron 47: 8985); and

[0243] 3. LEAPFROG™, which is available from Tripos Associates, St. Louis, Mo.

[0244] Other molecular modeling techniques can also be employed in accordance with this invention. See, e.g., Cohen et al., (1990) J. Med. Chem. 33: 883-94. See also, Navia & Murcko, (1992) Curr. Opin. Struc. Biol. 2: 202-10; U.S. Pat. No. 6,008,033, herein incorporated by reference.

[0245] Once a compound has been designed or selected by the above methods, the efficiency with which that compound can bind to an MT CYP51 polypeptide can be tested and optimized by computational evaluation. By way of particular example, a compound that has been designed or selected to function as an MT CYP51 polypeptide modulator should also preferably traverse a volume not overlapping that occupied by the binding site when it is bound to its native ligand. Additionally, an effective MT CYP51 polypeptide modulator should preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient MT CYP51 polypeptide modulators should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole, and preferably, not greater than 7 kcal/mole. It is possible for MT CYP51 polypeptide modulators to interact with the polypeptide in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the modulator binds to the polypeptide.

[0246] A compound designed or selected as binding to an MT CYP51 polypeptide can be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target polypeptide. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the modulator and the polypeptide when the modulator is bound to an MT CYP51 polypeptide preferably make a neutral or favorable contribution to the enthalpy of binding.

[0247] Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include:

[0248] 1. Gaussian 98™, which is available from Gaussian, Inc., Pittsburgh, Pa.;

[0249] 2. AMBER™ program, version 6.0, which is available from the University of California at San Francisco;

[0250] 3. QUANTA™ program, which is available from Molecular Simulations, Inc., San Diego, Calif.;

[0251] 4. CHARMm® program, which is available from Molecular Simulations, Inc., San Diego, Calif.; and

[0252] 5. Insight II® program, which is available from Molecular Simulations, Inc., San Diego, Calif.

[0253] These programs can be implemented using a suitable computer system. Other hardware systems and software packages will be apparent to those skilled in the art after review of the disclosure of the present invention presented herein.

[0254] Once an MT CYP51 polypeptide modulating compound has been optimally selected or designed, as described above, substitutions can then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted chemical compounds can then be analyzed for efficiency of fit to an MT CYP51 polypeptide binding site using the same computer-based approaches described in detail above.

[0255] IX.D. Method of Identifying Compounds Which Inhibit Ligand Binding

[0256] In one aspect of the present invention, an assay method for identifying a compound that inhibits binding of a substrate to an MT CYP51 polypeptide is disclosed. A natural substrate of MT CYP51 can be used in the assay method as the substrate against which the inhibition by a test compound is gauged. The method comprises (a) incubating an MT CYP51 polypeptide with a substrate in the presence of a test inhibitor compound; (b) determining an amount of substrate that is bound to the MT CYP51 polypeptide, wherein decreased binding of substrate to the MT CYP51 polypeptide in the presence of the test inhibitor compound relative to binding in the absence of the test inhibitor compound is indicative of inhibition; and (c) identifying the test compound as an inhibitor of substrate binding if decreased substrate binding is observed. Decreased substrate binding can optionally be detected by detecting amounts of product produced from the substrate.

[0257] In another aspect of the present invention, the disclosed assay method can be used in the structural refinement of candidate MT CYP51 inhibitors. For example, multiple rounds of optimization can be followed by gradual structural changes in a strategy of inhibitor design. A strategy such as this is made possible by the disclosure of the coordinates of the MT CYP51 polypeptide.

[0258] IX.E. Distinguishing Between CYP51 Polypeptides

[0259] The present invention discloses the ability to generate new synthetic ligands to distinguish between CYP51 polypeptides from different species, e.g., fungi, bacteria, plant and animal species. As described herein, computer-designed ligands can be generated that distinguish between such polypeptides, thereby allowing the generation of either species specific or function specific ligands. The atomic structural coordinates disclosed in the present invention reveal structural details unique to MT CYP51. These structural details can be exploited when a novel ligand is designed using the methods of the present invention or other ligand design methods known in the art. The structural features that differentiate an MT CYP51 from another CYP51 can be targeted in ligand design. Thus, for example, a ligand can be designed that will recognize MT CYP51, while not interacting with other CYP51s (e.g. host CYP51s) or even with moieties having similar structural features. Prior to the disclosure of the present invention, the ability to target an MT CYP51 polypeptide was unattainable.

[0260] Moreover, mapping mutations in fungal CYP51 polypeptides to locations in the MT CYP51 crystalline structure of the present invention is provided in the Examples. Use of this information provides for the design of more potent antifungal agents.

[0261] IX.F. Design of CYP51 Isoform Modulators

[0262] The MT CYP51 crystal structure of the present invention can be used to generate modulators of other CYP51 polypeptides from other species including species of plants, animals, or fungi. Analysis of the disclosed crystal structure can provide a guide for designing CYP51 modulators. Absent the crystal structure of the present invention, researches would be required to design CYP51 modulators de novo. The present invention, however, addresses this problem by providing insights into the structure of MT CYP51 which can be extended, due to significant structural similarity, to the structure of another CYP51. The design software and other tools disclosed herein above can also be employed in these efforts.

[0263] Using the discerned structural similarities and differences between CYP51 polypeptides disclosed herein, and as represented and predicted based on the crystal structure of the present invention and homology models, an CYP51 modulator can be designed. Additional modifications can be included, based on the disclosed structure, which are predicted to further define a modulator specific for a CYP51 polypeptide. Thus, the disclosed crystal structure of MT CYP51 can be useful when designing modulators of other CYP 51 polypeptides.

[0264] X. The Role of the Three-Dimensional Structure of the MT CYP51 Polypeptide In Solving Additional CYP51 Crystals

[0265] Because polypeptides can crystallize in more than one crystal form, the structural coordinates of an MT CYP51 polypeptide, or portions thereof, as provided by the present invention, are particularly useful in solving the structure of other crystal forms of MT CYP51 and the crystalline forms of other CYP51s. The coordinates provided in the present invention can also be used to solve the structure of MT CYP51 or other CYP51 polypeptide mutants, MT CYP51 co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of MT CYP51.

[0266] X.A. Determining the Three-Dimensional Structure of a Polypeptide Using the Three-Dimensional Structure of the MT CYP51 Polypeptide As a Template in Molecular Replacement

[0267] One method that can be employed for the purpose of solving additional MT CYP51 crystal structures is molecular replacement. See generally, Rossmann, ed, (1972) The Molecular Replacement Method, Gordon & Breach, New York. In the molecular replacement method, the unknown crystal structure, whether it is another crystal form of an MT CYP51 polypeptide, (i.e. a MT CYP51 polypeptide mutant), an MT CYP51 polypeptide complexed with another compound (a “co-complex”), or the crystal of some other protein (e.g., another CYP51 polypeptide with significant amino acid sequence homology to any functional region of the MT CYP51 polypeptide, can be determined using the MT CYP51 polypeptide structure coordinates provided in Tables 2 and 3. This method provides an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

[0268] In addition, in accordance with this invention and as disclosed in the Examples, MT CYP51 polypeptides, MT CYP51 polypeptide mutants, or other CYP51 polypeptides can be crystallized complexed with known modulators. The crystal structures of a series of such complexes can then be solved by molecular replacement and compared with that of a wild-type MT CYP51 polypeptide. Potential sites for modification within the various binding sites of the enzyme can thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between the CYP51 polypeptide and a chemical entity or compound.

[0269] All of the complexes referred to in the present disclosure can be studied using X-ray diffraction techniques (See, e.g., Blundell & Johnson (1985) Method.Enzymol., 114A & 115B, (Wyckoff et al., eds.), Academic Press) and can be refined using computer software, such as the CNS™ program (Brünger et al., (1998) Crystallography and NMR System Version 1.0, A New Software Suite for Macromolecular Structure Determination, Acta Cryst. D54:905-921). This information can thus be used to optimize known classes of CYP51 polypeptide modulators, and more importantly, to design and synthesize novel classes of CYP51 polypeptide modulators.

[0270] XI. Summary of Drug Design Methods

[0271] The knowledge of the structure of the CYP450 family of proteins, and particularly the MT CYP 51 polypeptide of the present invention, provides a tool for investigating the mechanism of action of these proteins in a subject. For example, binding of these proteins to various substrate molecules can be predicted by various computer models. Upon discovering that such binding in fact takes place, knowledge of the protein structure then allows chemists to design and attempt to synthesize small molecules which mimic the functional binding of the CYP450-family protein to the substrate.

[0272] Thus, a method of designing modulators of CYP450 enzymes is provided in accordance with the present invention. The method comprising the steps of designing a potential modulator for a CYP450 enzyme that will form non-covalent bonds with amino acids in the CYP450 enzyme substrate binding site based upon the crystal structure of a MT CYP51 polypeptide; synthesizing the modulator; and determining whether the potential modulator modulates the activity of a CYP450 enzyme. Modulators are synthesized using techniques disclosed herein and as are known in the art. The determination of whether the modulator modulates the biological activity of a CYP450 enzyme is made in accordance with the screening methods disclosed herein above.

[0273] For example, a representative modulator comprises a peptide modulator, also referred to herein as a subject peptide, and can be synthesized by any of the techniques that are known to those skilled in the polypeptide art, including recombinant DNA techniques. Synthetic chemistry techniques, such as a solid-phase Merrifield-type synthesis, are preferred for reasons of purity, antigenic specificity, freedom from undesired side products, ease of production and the like. An excellent summary of the many techniques available can be found in Steward et al., Solid Phase Peptide Synthesis, W. H. Freeman Co., San Francisco, 1969; Bodanszky, et al., Peptide Synthesis, John Wiley & Sons, Second Edition, 1976; Meienhofer, Hormonal Proteins and Peptides, Vol. 246, Academic Press (New York), 1983; Merrifield, (1969) Adv Enzymol, 32:221-96,; Fields et al., (1990) Int. J. Peptide Protein Res., 35:161-214,; and U.S. Pat. No.4,244,946 for solid phase peptide synthesis, and Schroder et al., The Peptides, Vol. 1, Academic Press (New York), 1965 for classical solution synthesis, each of which is incorporated herein by reference. Appropriate protective groups usable in such synthesis are described in the above texts and in McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973, which is incorporated herein by reference.

[0274] In general, the solid-phase synthesis methods contemplated comprise the sequential addition of one or more amino acid residues or suitably protected amino acid residues to a growing peptide chain. Normally, either the amino or carboxyl group of the first amino acid residue is protected by a suitable, selectively removable protecting group. A different, selectively removable protecting group is utilized for amino acids containing a reactive side group such as lysine.

[0275] Using a solid phase synthesis as exemplary, the protected or derivatized amino acid is attached to an inert solid support through its unprotected carboxyl or amino group. The protecting group of the amino or carboxyl group is then selectively removed and the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected is admixed and reacted under conditions suitable for forming the amide linkage with the residue already attached to the solid support. The protecting group of the amino or carboxyl group is then removed from this newly added amino acid residue, and the next amino acid (suitably protected) is then added, and so forth. After all the desired amino acids have been linked in the proper sequence, any remaining terminal and side group protecting groups (and solid support) are removed sequentially or concurrently, to afford the final linear polypeptide.

[0276] The resultant linear polypeptides prepared for example as described above can be reacted to form their corresponding cyclic peptides. An exemplary method for cyclizing peptides is described by Zimmer et al., Peptides 1992, pp. 393-394, ESCOM Science Publishers, B. V., 1993. Typically, tertbutoxycarbonyl protected peptide methyl ester is dissolved in methanol and sodium hydroxide solution are added and the admixture is reacted at 20° C. to hydrolytically remove the methyl ester protecting group. After evaporating the solvent, the tertbutoxycarbonyl protected peptide is extracted with ethyl acetate from acidified aqueous solvent. The tertbutoxycarbonyl protecting group is then removed under mildly acidic conditions in dioxane cosolvent. The unprotected linear peptide with free amino and carboxy termini so obtained is converted to its corresponding cyclic peptide by reacting a dilute solution of the linear peptide, in a mixture of dichloromethane and dimethylformamide, with dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole and N-methylmorpholine. The resultant cyclic peptide is then purified by chromatography.

[0277] Purification of the resulting peptides is accomplished using conventional procedures, such as preparative HPLC using gel permeation, partition and/or ion exchange chromatography. The choice of appropriate matrices and buffers are well known in the art and so are not described in detail herein.

[0278] XII. Therapeutic Methods

[0279] The candidate drugs and other therapeutic agents screened in accordance with the method of the present invention are contemplated to be useful in the treatment of warm-blooded vertebrates. Therefore, the invention concerns mammals and birds.

[0280] Contemplated is the treatment of mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economical importance (animals raised on farms for consumption by humans) and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses. Also contemplated is the treatment of birds, including the treatment of those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economical importance to humans. Thus, contemplated is the treatment of livestock, including, but not limited to, domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.

[0281] As used herein, the terms “MT CYP51 activity” and “MT CYP51 biological activity” are meant to be synonymous and are meant to refer to any biological activity of MT CYP51. For example, the MT CYP51 gene product is characterized herein as having CYP450 14α-demethylase metabolic activity and this metabolic activity is contemplated by the use of the term “biological activity”. Given that CYP450 14α-demethylase catalyzes an essential step in sterol metabolism (see FIG. 1), modulation of the metabolic activity of the MT CYP51 thus modulates growth and/or infection of MT in a subject.

[0282] In view of the foregoing, a therapeutic method is contemplated according to the present invention. The therapeutic method comprises administering to a subject a substance that modulates MT CYP51 biological activity to thereby modulate growth or infection by MT in the subject. Such a substance can be identified according to the screening assay set forth above. A preferred subject is a vertebrate subject. A preferred example of a vertebrate subject is a mammal. A preferred example of a mammal is a human.

[0283] Thus, the method can comprise treating a patient suffering from a disorder associated with CYP51 biological activity by administering to the patient an effective CYP51 activity-modulating amount of a substance identified according to the screening assay described above. By the term “modulating”, it is contemplated that the substance can optionally promote or inhibit the activity of CYP51, depending on the disorder to be treated.

[0284] Since MT is the major pathogen associated with the disease tuberculosis, a method of treating tuberculosis is contemplated in accordance with the present invention and is described in detail in the Examples below. The contemplated method comprises administering a therapeutically effective amount of a MT CYP51 gene product activity modulator to a subject in need thereof. Preferably, the MT CYP51 activity modulator is in a pharmaceutically acceptable form.

[0285] The CYP51 modulators described herein, including MT CYP51 modulators, are thus adapted for administration as pharmaceutical compositions. Formulation and dose preparation techniques have been described in the art, see for example, those described in U.S. Pat. No. 5,326,902 issued to Seipp et al. on Jul. 5, 1994, U.S. Pat. No. 5,234,933 issued to Marnett et al. on Aug. 10, 1993, and PCT Publication WO 93/25521 of Johnson et al. published Dec. 23, 1993, the entire contents of each of which are herein incorporated by reference.

[0286] For the purposes described above, the identified substances can normally be administered systemically or partially, usually by oral or parenteral administration. The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In a human adult, the doses per person per administration are generally between 1 mg and 500 mg, by oral administration, up to several times per day, and between 1 mg and 100 mg, by parenteral administration up to several times per day. Since the doses to be used depend upon various conditions, as mentioned above, there can be a case in which doses are lower than or greater than the ranges specified above.

[0287] Solid compositions for oral administration include compressed tablets, pills, dispersible powders, capsules, and granules. In such compositions, one or more of the active substance(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate alminate, etc.). The compositions can also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (magnesium stearate, etc.), disintegrating agents (cellulose, calcium glycolate etc.), and assisting agent for dissolving (glutamic acid, aspartic acid, etc.) stabilizing agent (lactose etc.). The tablets or pills can, if desired, be coated with gastric or enteric material (sugar, gelatin, hydroxypropylcellulose or hydroxypropylmethyl cellulose phthalate, etc.). Capsules include soft ones and hard ones.

[0288] Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs. In such compositions, one or more of the active substance(s) is or are admixed with inert diluent(s) commonly used in the art (purified water, ethanol etc.). Besides inert diluents, such compositions can also comprise adjuvants (wetting agents, suspending agents, etc.), sweetening agents, flavoring agents, perfuming agents and preserving agents.

[0289] Other compositions for oral administration include spray compositions which can be prepared by known methods and which comprise one or more of the active substance(s). Spray compositions can comprise additional substances other than inert diluents: e.g. preserving agents (sodium sulfite, etc.), isotonic buffer (sodium chloride, sodium citrate, citric acid, etc.). For preparation of such spray compositions, for example, the method described in U.S. Pat. Nos. 2,868,691 or 3,095,355 can be used.

[0290] Injections for parenteral administration include sterile aqueous or non-aqueous solution, suspensions and emulsions. In such compositions, one or more of active substance(s) is or are admixed with at least one inert aqueous diluent(s) (distilled water for injection, physiological salt solution etc.) or inert non-aqueous diluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol, POLYSOLBATE 80®, etc.). Injections can comprise additional other than inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (lactose, etc.), assisting agents such as for dissolving (glutamic acid, aspartic acid, etc.). They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They also be manufactured in the form of sterile solid compositions, for example, by freeze-drying, and which can be dissolved in sterile water or some other sterile diluents for injection immediately before use.

[0291] Other compositions for administration include liquids for external use, and endermic linaments (ointment, etc.), suppositories and pessaries which comprise one or more of the active substance(s) and can be prepared by known methods.

[0292] A preferred CYP51 modulator has the ability to substantially interact with a CYP51 in solution at modulator concentrations of less than one (1) micro molar (μM), preferably less than 0.1 μM, and more preferably less than 0.01 μM. By “substantially” is meant that at least a 50 percent reduction in CYP51 biological activity is observed by modulation in the presence of the CYP51 modulator, and at 50% reduction is referred to herein as an IC50 value.

[0293] A therapeutically effective amount of a CYP51 modulator of this invention in the form of a monoclonal antibody, or fragment thereof, is typically an amount such that when administered in a physiologically tolerable composition is sufficient to achieve a plasma concentration of from about 0.01 microgram (μg) per milliliter (ml) to about 100 ug/ml, preferably from about 1 ug/ml to about 5 ug/ml, and usually about 5 μg/ml.

[0294] The therapeutic compositions containing a CYP51 activity modulator of this invention are conventionally administered intravenously, as by injection of a unit dose, for example. The term “unit dose” when used in reference to a therapeutic composition of the present invention refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent; i.e., carrier or vehicle.

[0295] The compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual. However, suitable dosage ranges for systemic application are disclosed herein and depend on the route of administration. Suitable regimes for administration are also variable, but are typified by an initial administration followed by repeated doses at one or more hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain concentrations in the blood in the ranges specified for in vivo therapies are contemplated.

[0296] XII.A. Monoclonal Antibodies

[0297] The present invention describes, in one embodiment, MT CYP51 modulators in the form of monoclonal antibodies which immunoreact with MT CYP51 and bind the MT CYP51 to modulate metabolic activity as described herein. The invention also describes above cell lines which produce the antibodies, methods for producing the cell lines, and methods for producing the monoclonal antibodies.

[0298] A monoclonal antibody of this invention comprises antibody molecules that 1) immunoreact with isolated MT CYP51, and 2) bind to the MT CYP51 to modulate its biological function.

[0299] The term “antibody or antibody molecule” in the various grammatical forms is used herein as a collective noun that refers to a population of immunoglobulin molecules and/or immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antibody combining site or paratope. An “antibody combining site” is that structural portion of an antibody molecule comprised of heavy and light chain variable and hypervariable regions that specifically binds antigen.

[0300] Exemplary antibodies for use in the present invention are intact immunoglobulin molecules, substantially intact immunoglobulin molecules, single chain immunoglobulins or antibodies, those portions of an immunoglobulin molecule that contain the paratope, including those portions known in the art as Fab, Fab′, F(ab′)2 and F(v), and also referred to as antibody fragments. Indeed, it is contemplated to be within the scope of the present invention that a monovalent modulator can optionally be is used in the present method. Thus, the terms “modulate”, “modulating”, and “modulator” are meant to be construed to encompass such promotion.

[0301] The phrase “monoclonal antibody” in its various grammatical forms refers to a population of antibody molecules that contain only one species of antibody combining site capable of immunoreacting with a particular epitope. A monoclonal antibody thus typically displays a single binding affinity for any epitope with which it immunoreacts. A monoclonal antibody can therefore contain an antibody molecule having a plurality of antibody combining sites, each immunospecific for a different epitope, e.g., a bispecific monoclonal antibody. Methods of producing a monoclonal antibody, a hybridoma cell, or a hybridoma cell culture are described above.

[0302] It is also possible to determine, without undue experimentation, if a monoclonal antibody has the same (i.e., equivalent) specificity (immunoreaction characteristics) as a monoclonal antibody of this invention by ascertaining whether the former prevents the latter from binding to a preselected target molecule. If the monoclonal antibody being tested competes with the monoclonal antibody of the invention, as shown by a decrease in binding by the monoclonal antibody of the invention in standard competition assays for binding to the target molecule when present in the solid phase, then it is likely that the two monoclonal antibodies bind to the same, or a closely related, epitope.

[0303] Still another way to determine whether a monoclonal antibody has the specificity of a monoclonal antibody of the invention is to pre-incubate the monoclonal antibody of the invention with the target molecule with which it is normally reactive, and then add the monoclonal antibody being tested to determine if the monoclonal antibody being tested is inhibited in its ability to bind the target molecule. If the monoclonal antibody being tested is inhibited then, in all likelihood, it has the same, or functionally equivalent, epitopic specificity as the monoclonal antibody of the invention.

[0304] An additional way to determine whether a monoclonal antibody has the specificity of a monoclonal antibody of the invention is to determine the amino acid residue sequence of the CDR regions of the antibodies in question. Antibody molecules having identical, or functionally equivalent, amino acid residue sequences in their CDR regions have the same binding specificity. “CDRs” (complementarity determining regions) mean the three subregions of the light or heavy chain variable regions which have hypervariable sequences and form loop structures that are primarily responsible for making direct contact with antigen. Antibody molecules having identical, or functionally equivalent, amino acid residue sequences in their CDR regions have the same binding specificity. Methods for sequencing polypeptides are well known in the art.

[0305] The immunospecificity of an antibody, its target molecule binding capacity, and the attendant affinity the antibody exhibits for the epitope, are defined by the epitope with which the antibody immunoreacts. The epitope specificity is defined at least in part by the amino acid residue sequence of the variable region of the heavy chain of the immunoglobulin that comprises the antibody, and in part by the light chain variable region amino acid residue sequence. Use of the terms “having the binding specificity of” or “having the binding preference of” indicates that equivalent monoclonal antibodies exhibit the same or similar immunoreaction (binding) characteristics and compete for binding to a preselected target molecule.

[0306] Humanized monoclonal antibodies offer particular advantages over murine monoclonal antibodies, particularly insofar as they can be used therapeutically in humans. Specifically, human antibodies are not cleared from the circulation as rapidly as “foreign” antigens, and do not activate the immune system in the same manner as foreign antigens and foreign antibodies. Methods of preparing “humanized” antibodies are generally well known in the art, and can readily be applied to the antibodies of the present invention. Thus, the invention provides, in one embodiment, a monoclonal antibody of this invention that is humanized by grafting to introduce components of the human immune system without substantially interfering with the ability of the antibody to bind antigen.

[0307] The use of a molecular cloning approach to generate antibodies, particularly monoclonal antibodies, and more particularly single chain monoclonal antibodies, is also contemplated. The production of single chain antibodies has been described in the art, see e.g., U.S. Pat. No. 5,260,203, the contents of which are herein incorporated by reference. For this, combinatorial immunoglobulin phagemid libraries are prepared from RNA isolated from the spleen of the immunized animal, and phagemids expressing appropriate antibodies are selected by panning on endothelial tissue. The advantages of this approach over conventional hybridoma techniques are that approximately 104 times as many antibodies can be produced and screened in a single round, and that new specificities are generated by H and L chain combination in a single chain, which further increases the chance of finding appropriate antibodies. Thus, an antibody of the present invention, or a “derivative” of an antibody of the present invention pertains to a single polypeptide chain binding molecule which has binding specificity and affinity substantially similar to the binding specificity and affinity of the light and heavy chain aggregate variable region of an antibody described herein.

[0308] XII.B. Other Modulators

[0309] Given the disclosure of the CYP51 biological activity herein, it is also provided that other chemical compounds can be used to modulate CYP51 activity, and particularly MT CYP51 biological activity, in accordance with the methods of the present invention. The identification of such compounds is facilitated by the description of screening assays directed to MT CYP51 activity presented above and in view of the highly conserved nature of biologically active CYP51 polypeptides in plants, animals, fungi and bacteria, as described herein above.

EXAMPLES

[0310] The following Examples have been included to illustrate preferred modes of the invention. Certain aspects of the following Examples are described in terms of techniques and procedures found or contemplated by the present inventors to work well in the practice of the invention. These Examples are exemplified through the use of standard laboratory practices of the inventors. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the invention.

Overview of Examples 1-8

[0311] Sterol 14α-demethylase encoded by CYP51 is a mixed-function oxidase involved in sterol synthesis in eukaryotic organisms. Using genomic DNA from mycobacterial strain H37Rv, applicants have unambiguously established that the MT CYP51-like gene encodes a bacterial sterol 14α-demethylase. Expression of the Mycobacterium tuberculosis CYP51 gene in Escherichia coli yields a P450 which when purified to homogeneity has a molecular weight of about 50 kD on SDS-PAGE, and binds both sterol substrates and azole inhibitors of P450 14α-demethylases. It catalyzes 14α-demethylation of lanosterol, 24,25-dihydrolanosterol (DHL) and obtusifoliol to produce the 8,14-dienes stereoselectively as shown by GC/MS and 1HNMR analysis. Both flavodoxin and ferredoxin redox systems are able to support this enzymatic activity. Structural requirements of a 14α-methyl group and Δ8(9)-bond were established by comparing binding of pairs of sterol substrate that differed in a single molecular feature, e.g., cycloartenol paired with lanosterol. These substrate requirements are similar to those established for plant and animal P450 14α-demethylases.

General Experimental Methods and Materials Used in Examples 1-8

[0312] Absolute spectra of purified MT P45014DM were recorded as described by Sato & Omura, (1964) J. Biol. Chem. 239:2379-85. Protein quantification was performed using the Bradford method. DNA sequencing was carried out using automated (ABI PRISM™ Dye Terminator Cycle Sequencing Ready Reaction kit and ABI PRISM™ 377 DNA sequencer) and manual sequencing (SequiTherm™ Cycle Sequencing, Epicentre Technologies, Madison, Wis.). Sterols were obtained from the Nes collection (Venkatramesh et al., (1996) Biochim. Biophys. Acta 1299:313-24; Nes et al., (1993) Arch. Biochem. Biophys. 300:724-33) and purified by HPLC before assay with P45014DM. The six sterols assayed with MT P45014DM are shown in FIG. 3A.

Example 1

Isolation of MT CYP51 Gene and Gene Product

[0313] A preferred embodiment of the CYP51 gene of the present invention was isolated from Mycobacterium tuberculosis (MT). As such, the experiments disclosed in this Example describe the first characterization of a CYP51 gene encoding the cytochrome P450 enzyme CYP450 14α-demethylase (P45014DM) in bacteria. Indeed, from the combination of results, the interrelationships of substrate functional groups within the active site show that oxidative portions of the sterol biosynthetic pathway are present in procaryotes. The isolated and characterized amino acid sequence possessed about 26-38% amino acid identity with CYP51 in animals, plants and fungi.

[0314] The MT CYP51 gene was cloned from MT DNA using PCR technology and was then inserted into a bacterial expression vector according to standard techniques as are described herein. The cloning protocol also added four histidine residues at the carboxy terminus of the protein (as set forth in SEQ ID NO's:1 and 2) for use in purification of the expressed protein by Ni+2 affinity chromatography. The bacterial expression vector was transfected into bacteria and the bacteria were cultured according to techniques as described herein. The expressed protein was then purified by Ni+2 affinity chromatography.

[0315] The spectral properties of the expressed protein clearly demonstrated that it was a CYP450 enzyme. Optical methods demonstrated that the protein binds lanosterol, dihydrolanosterol and obtusifoliol, which are known to be substrates of different forms of CYP450 14DM. Notably, the isolated recombinant MT CYP51 protein did not bind 24-methylene-dihydrolanosterol, which is a substrate for fungal CYP45014DM.

[0316] Genomic DNA from MT strain H37Rv was provided by the TB Research Materials and Vaccine Testing Contract (NO1 Al-75320) at Colorado State University and the MT CYP51-like gene was cloned by PCR using Vent polymerase (Biolabs, Inc., Bountiful, Utah).

[0317] Primers were designed based on the sequence of cosmid MTCY369 from the MT genome, the upstream primer 5′-cgccatatgagcgctgttgcactaccc-3′ (SEQ ID NO:11) except the first 6 bases being complementary to the sequence between bases 7495-7475 which is predicted to encode the N-terminal sequence of the MT CYP51-like protein. The downstream primer 5′-cgcaagcttcagtgatggtgatgaactcccgttcgccggcggtagc-3′ (SEQ ID NO:12), from bases 24 to 46, is identical to MTCY369 sequence between bases 6143-6165.

[0318] For the Fdx gene, the upstream primer 5′-cgccatatgggctatcgagtcgaagcc-3′ (SEQ ID NO:13) except the first 6 bases, is complementary to MTCY369 sequence between bases 6137-6117, and the downstream primer 5′-cgcaagcttcagtgatggtgatgctctccc gtttctcggatggacagtgcctggg-3′ (SEQ ID NO:14) from bases 24 to 55 is identical to bases 5934-5965. The stop codon was removed in each gene and 4 histidine codons followed by a new stop codon (bold characters) inserted in the 3′-end of the coding sequences. The underlined bases are Ndel cloning sites including the initiator codon in the upstream primers and HindIII cloning sites in the downstream primers.

[0319] Amplification conditions were 94° C. for 5 min then 30 cycles of 94° C. for 30 sec, 50° C. for 30 sec and 72° C. for 45 sec. The PCR program ended using one polymerization step at 72° C. for 10 min and the product was separated by electrophoresis on a 1% agarose gel. Bands of the expected sizes of MT P45014DM (1377 bp) and Fdx (233 bp) were eluted from the gel using Quigen II kit (Quigen, Inc., Chatsworth, Calif.).

[0320] Following digestion by Ndel and HindIII, the cDNAs were cloned into the E. coil expression vector pet17b (Novagen, Madison, Wis.) giving MTP450/pet17b and MTFdx/pet17b. Those vectors were transformed separately into competent HMS174 (Novagen, Madison, Wis.) cells. Single ampicillin-resistant colonies from each transformant were grown overnight at 37° C. in 5 ml of Terrific Broth containing 100 μg/ml of ampicillin. These precultures were used to inoculate (1:100) 500 ml of modified Terrific Broth medium (100 μg/ml of ampicillin) (O'Keefe, et al., (1991) Biochemistry 30:447-455). After 5 hour (h) growth at 37° C. in a shaking incubator at 240 rpm, the culture was induced using 1 mM isopropyl β-D-thiogalactopyranoside (Calbiochem, San Diego, Calif.). At the same time, δ-aminolevulinic acid (Sigma, St. Louis, Mo.) was added to 2 mM final concentration for P450 expression. Growth was continued at 30° C. with shaking at 190 rpm for 20 hours.

[0321] A purine rich region, GAAGAGGGGA, located 10 bp upstream from the start codon is a potential Shine-Dalgarno sequence (FIG. 4A), the length of the spacer between this and the start codon (10 bp) being similar to other mycobacterial genes (Dale & Patki (1990) in Molecular Biology of the Mycobacteria, ed. McFadden, J. (Academic Press, San Diego, Calif.), pp.173-198). MT CYP51 produced in E. coli (2.5 μmol/L) has a typical P450 reduced-CO spectrum (FIG. 4C) as observed by Aoyama et al., (1998) J. Biochem. (Tokyo) 124:694-696. Cell fractionation reveals that MT P45014DM is soluble, no P450 being detected in the membranes as seen upon expression in JM109 E. coli strain in accordance with techniques described by Aoyama et al., (1998) J. Biochem. (Tokyo) 124:694-696.

Example 2

MT P45014DM Purification

[0322] Three liters (L) of MT P450 culture were pelleted and re-suspended in 200 ml of TES buffer in accordance with techniques described by Jenkins, & Waterman, (1994) J. Biol. Chem. 269: 27401-8. Following addition of lysozyme (0.5 mg/ml) and stirring at 4° C. for 15 min, one volume of ice-cold water containing 0.1 mM EDTA was slowly added and stirring continued for 30 min. Spheroplasts were pelleted at 3,000 g for 15 min. The supernatant (fraction A) was centrifuged at 225,000 g for 30 min following addition of DNAase I (1 μg/ml) and stirring at 4° C. for 15 min. Spheroplasts were resuspended in 50 ml of 2 fold diluted TES buffer, sonicated using a Branson sonifier (Model 250) at duty cycle 30-40, 50% maximal output for 30 sec at room temperature followed by 1 min incubation on ice, repeated 10 times.

[0323] Following centrifugation at 225,000 g for 30 min, the supernatant (fraction B) was combined with fraction A and the P450 isolated using a Ni2+ NTA affinity column (Qiagen, Valencia, Calif.) equilibrated with 50 mM potassium phosphate pH 7.4 and 20% glycerol. After washing with the same buffer containing 50 mM glycine and 500 mM NaCl, the P450 was eluted using 40 mM L-histidine in place of glycine. The P450 eluate was dialyzed overnight against 50 mM potassium phosphate pH 7.4 and 20% glycerol.

[0324] One L of MT Fdx culture grown as for MT P450 was pelleted and re-suspended in 50 mL of 50 mM potassium phosphate pH 7.4, 0.1 mM EDTA and 20% glycerol. Following addition of lysozyme (0.5 mg/ml) and stirring at 4° C. for 15 min, cells were sonicated as above. The cytosolic fraction after centrifugation at 225,000 g was loaded on a Ni2+ NTA affinity column. Washing and elution conditions were the same as for MT P450.

[0325] After two consecutive Ni2+ affinity column purification steps, the specific content of the MT P45014DM is about 18 nmol/mg and a single band is observed on SDS-PAGE at about 50 kD, the predicted molecular weight from the sequence being 51.4 kD (FIG. 4D). The oxidized absolute spectrum of the purified enzyme, in the absence of substrate, showed a Soret band at 417 nm and α-, β- and δ-bands at 569, 535 and 369 nm, typical for low spin cytochrome P450 (FIG. 4B). Reduction by sodium hydrosulfite results in a Soret peak at 411 nm.

Example 3

Antibody Production

[0326] Polyclonal antibodies against MT P45014DM purified by two passes over Ni2+NTA were raised in white New Zealand rabbits, injected with 0.5 mg MT P45014DM mixed with either complete Freund's adjuvant (Sigma, St. Louis, Mo.) or TiterMax@Gold (Cytrx Corp., Norcross, Ga.). Two weeks later, the rabbit injected with Freund's adjuvant was boosted using 0.5 mg MT P45014DM in Freund's incomplete adjuvant (Sigma, St. Louis, Mo.) and the antiserum was collected after 4 weeks. From the rabbit injected with TiterMax@Gold™, antiserum was collected after 19 days.

[0327] Immunoblot analysis was carried out on the cytosolic fraction of the MT virulent strain H37Rv (FIG. 7). A band near the expected molecular weight but lower than for purified recombinant MT P45014DM was obtained. Using antiserum depleted with an excess of purified recombinant MT P45014DM, this cytosolic band as well as that for purified P45014DM was dramatically reduced. This indicates that the MT P45014DM is expressed in MT.

[0328] The difference in size between the recombinant and MT proteins might be explained by the presence of four additional histidines at the C-terminus of the recombinant enzyme. Such modification can affect the mobility of proteins during SDS-PAGE. In fact, a single amino acid mutation in P4501 B1 expressed in E. coli results in shift to a greater size on the SDS-PAGE, as described by Shimada et al., (1998) Arch. Biochem. Biophys. 357:111-120.

Example 4

Characterization of Enzymatic Activity of MT CYP 51 Protein

[0329] CYP450 enzymes do not function as independent proteins. Rather, they require a reductase system to support their enzymatic activity. In eukaryotes CYP450 activity in the endoplasmic reticulum (ER), is supported by the ER protein NADPH cytochrome P450 reductase. CYP45014DM is an ER protein in animals, plants and fungi and thus, its activity is supported by CYP450 reductase.

[0330] In most bacterial CYP450s, enzymatic activities are supported by a two-component reductase system, a ferredoxin which interacts with the CYP450 and a ferredoxin reductase. With respect to the MT CYP51 gene product of the present invention, the ability of eukaryotic reductase systems, including rat CYP450 reductase and bovine adrenodoxin and adrenodoxin reductase (a mammalian ferredoxin/ferredixin reductase system), were tested for the ability to reduce MT P45014DM. Neither reduced the enzyme. Applicants then used a two-component system of flavodoxin/flavodoxin reductase, which applicants previously noted in E. coli and other bacteria, to evaluate whether this reductase system would support the activity of the MT P45014DM of the present invention. Jenkins and Waterman, (1994) J. Biol. Chem. 264:27401-27408. This system was observed to readily support 14α-demethylase activity with respect to dihydrolanosterol and obtusifoliol.

[0331] Materials and Methods. Activities of P450 enzymes require support of a reductase, and a functional reductase system for MT P450s was unknown. The capacity of rat microsomal NADPH cytochrome P450 reductase, of bovine adrenodoxinladrenodoxin reductase and E. coli Fld/flavodoxin reductase (Fdr) (Jenkins & Waterman, (1994) J. Biol. Chem. 269:27401-8) to reduce MT P45014DM was determined by formation of the reduced-CO spectrum.

[0332] MT P45014DM (200 pmol) and rat P450 reductase (200 pmol) were incubated in 10 mM potassium phosphate buffer pH 7.4 containing 20% glycerol and 200 μM final concentration of lanosterol with or without 100 μg/ml sonicated dilauroyl-L-a-phosphatidylcholine. After several cycles of degassing and bubbling with carbon monoxide, NADPH (Calbiochem, San Diego, Calif.) was added (final concentration 1 mM) and the reduced-CO spectrum recorded. In the control experiment, 40 μM final concentration of progesterone was added to 200 pmol bovine 17α-hydroxylase P450.

[0333] To study the bovine adrenodoxin/adrenoxin reductase system, 20 mM Tris-HCl pH 7.4 buffer containing 0.2% Tween 20, 4 mM MgCl2 and 200 μM lanosterol (final concentrations) was used with MT P45014DM (100 pmol)/adrenodoxin (1 nmol)/adrenodoxin reductase (100 pmol) with 1 mM NADPH. Bovine cholesterol side chain cleavage P450 (100 pmol) with the substrate 25-hydroxycholesterol (30 μM final concentration) was used as positive control. Using the Fld/Fdr system, 500 pmol of MT P45014DM, 2.5 nmol of Fld and 500 pmol of Fdr were incubated on ice (10 min) in 3-(N-morpholino)propane sulfonic acid buffer containing 200 μM final concentration of lanosterol and 1 mM NADPH with or without 100 μg/ml dilauroyl-L-a-phosphatidylcholine. In the control experiment, 40 mM of progesterone was added to 500 pmol P450 17α-hydroxylase.

[0334] It was observed that despite the fact that lanosterol bound the MT CYP51 protein of the present invention, lanosterol was not a good substrate of the enzyme. No enzymatic activity was initially observed with respect to lanosterol. But, using high performance liquid chromatography (HPLC), mass spectroscopy (MS) and nuclear magnetic resonance (NMR) it was established that the P45014DM protein of the present invention catalyzed 14α-demethylase activity even with lanosterol as substrate (see below).

[0335] To investigate MT P45014DM enzymatic activity, it was first necessary to determine which electron donor can reduce the hemoprotein. In eukaryotes, P450s are localized in either the endoplasmic reticulum and reduced by ubiquitous NADPH cytochrome P450 reductase (Vermilion, J. L. & Coon, M. J. (1978) J. Biol. Chem. 253:8812-9) or in the inner mitochondrial membrane and reduced by a 2 component system of a flavoprotein reductase and a 2Fe-2S protein (Coghlan, V. M. & Vickery L. E. (1991) J. Biol. Chem. 266:18606-12). Neither reducing system was capable of reducing MT P45014DM (Table 5). Nonetheless, applicants found that it can be reduced by a 2 component system, Fld/Fdr from E. coli. Fld/Fdr reduces MT P45014DM at about 20% of the full reduction by sodium hydrosulfite when using the P450: Fld:Fdr ratio of 1:5:1 which reduces bovine P450c17 at 77% (Table 5).

3TABLE 5MT P45014DM Reduction By Different Electron Donorsrat P450Adx/AdrreductaseFld/FdrSCCMTbC17MTbC17MT80%n.r.73%n.r.77%20%CO-based reduction of purified recombinant P450s by adrenodoxin/adrenodoxin reductase, rat P450 reductase and E. coil Fld/Fdr. Reduction is compared to 100% determined by sodium hydrosulfite. Adx/Adr is adrenodoxin/adrenodoxin reductase, Soc is the cholesterol side cleavage P450, bC17 is bovine 17a-hydroxylase and MT is the mycobacterial 14α-demethylase. n.r. = no reduction.

EXAMPLE 5

Reconstituted Catalytic Activity and Sterol Analysis

[0336] MT P45014DM (365 pmol) was incubated on ice (10 min) with 18 nmol Fld and 2 nmol of Fdr or 18 nmol MT Fdx and 2 nmol spinach ferredoxin reductase (Fnr). Since the electron donor to MT Fdx is unknown, Fnr (Sigma, St. Louis, Mo.) shown to reduce ferredoxins from S. griseolus (Bauer & Shiloach, (1974) Biotechnol. Bioeng. 16:933-41), was used. Substrate dispersed in Triton WR 1339 was resuspended in 3-(N-morpholino) propane sulfonic acid buffer (Stromstedt et al., (1996) Arch. Biochem. Biophys. 329:73-81). After mixing, the reaction was initiated (2 mM NADPH) in a final volume of 500 μl. Following catalysis, sterols were extracted twice using 5 volumes of ethyl acetate for small scale reactions or hexane for large scale experiments. In the latter case, 1 volume of methanol containing 10% KOH was used to stop the reaction. One volume of dimethyl sulfoxide was then added and after heating at 90° C. and cooling to room temperature, sterols extracted 3 times using 3 vol of hexane and evaporated to dryness.

[0337] Radiolabeled dihydrolanosterol ([24-3H]DHL) (Fischer et al., (1989) J. Lipid Res. 30:1621-32) and its tritiated 14-desmethyl sterol product were separated by HPLC on a Nova-Pak C18 column (Stromstedt et al., (1996) Arch. Biochem. Biophys. 329:73-81). Nonradioactive sterols were separated by HPLC on a 25 cm Zorbax C18 column (Dupont, Boston, Mass.; 5 mm particle size 4.6 mm i.d.) by elution with 100% methanol at room temperature (flow rate of 1 ml/min). Thin layer chromatography was performed on 250μ silica gel G plates, developed twice with benzene/ether (85/15).

[0338] GLC analysis was performed on a three-foot spiral 3% SE-30 packed column operated isothermally at 245° C. GLC-MS was performed on a Hewlett Packard 5973 Mass Selective Detector interfaced with a 6890 GC system. The capillary column for GLC was a 30-m DB-5 column 250 μM×0.25 μM (from J & W Scientific, Folsom, Calif.). The temperature program was operated at: 170° C. hold for 1 min; ramp at 20° C./min to 280° C.; hold for 15 min. Mass spectroscopy (MS) was performed using MS transfer line at 280° C., with the inlet injector port kept at 250° C. The MS ion source temperature was maintained at 230° C. Helium gas, used as carrier, was maintained at a flow rate of 1.2 ml/min. Proton nuclear magnetic resonance (1HNMR) spectroscopy was performed on samples dissolved in deuterated chloroform at ambient temperature using a AF-300 spectrometer (Billeria, Mass.) with tetramethylsilane as internal standard in accordance with techniques described by Venkatramesh et al., (1996) Biochim. Biophys. Acta 1299:313-24; Nes et al., (1993) Arch. Biochem. Biophys. 300:724-33; Xu et al., (1988) J. Chromatogr. 452:377-98; and Nes et al., (1998) J. Amer. Chem. Soc. 120:5970-5980.

[0339] Preliminary studies on metabolism of [24-3H]DHL by MT P45014DM suggested the reconstituted enzyme using Fld/Fdr catalyzed 14α-demethylation. Cloning Fdx from MT showed that this 3Fe-4S ferredoxin was able to support the MT P45014DM activity to a similar level as E. coli Fld/Fdr when spinach Fnr was used as a Fdx electron donor (FIG. 5). In order to characterize the product, scaled-up batch enzyme experiments using Fld/Fdr as electron donor and three different nonradioactive sterol substrates lanosterol, DHL and obtusifoliol were carried out overnight with 50 μM sterol and 365 pmol enzyme per assay. Total product recovered from the quenched reaction mixtures was 1% for lanosterol, 20% for DHL (FIG. 5C) and 98% for obtusifoliol. From incubation with lanosterol, a single sterol product was detected on TLC at Rf 0.5 (the Rf value distinguishes whether C-demethylation occurs at C4, Rf 0.43, or C14, Rf 0.50), by GC (3% Se-30: retention time relative to cholesterol-RRTc, 1.62) and MS (M+, 410 and related diagnostic ions at m/z, 395, 392, 377, 357, 328) and UV (in ethanol) at λmax 248 nm for a 8,14-diene (Goad & Akhisa, (1997) Analysis of Sterols (Blakie, N.Y.).

[0340] From incubation with DHL, a single sterol product was detected and identified: TLC, Rf 0.5; GLC, RRTc 1.53; MS, M+412 (and related ions at 397, 394, 279, 351, 312, 285, 266, 245, 227,159); UV (in ethanol) λmax 248 nm; 1H NMR analysis of the sample exhibited 4 singlets and 3 doublets in the methyl region of the spectrum between δ0.76 and 1.01 ppm consistent with loss of a methyl group from C14 and a single chemical shift at δ5.34 ppm in the olefinic region corresponding to the Δ14(15)-bond. These structural assignments indicate a 4,4-dimethyl Δ8,14(15)-sterol (Nes et al., (1993) Arch. Biochem. Biophys. 300:724-33). From incubation with obtusifoliol, a single sterol product was detected and identified: TLC, Rf 0.43 (characteristic migration on TLC for a C4-monomethyl sterol), GLC, RRTc 1.55; MS, M+410 (and related ions at m/z 395, 392, 379, 357, 328, 267, 247, 227, 189) UV (in ethanol) λmax 248 nm.

[0341] Substrate binding. In the absence of substrates, most P450 enzymes are low spin (Guengerich, (1983) Biochemistry 22:2811-20). Substrate addition shifts the heme to the high spin state. For MT P45014DM as for most P450s, the change in spin state leads to a peak at 390 nm and a trough at 420 nm in the substrate induced difference spectrum (FIG. 6A). The amplitude of this difference is proportional to the P450-substrate complex. Addition of increasing amounts of substrate permits estimation of a binding constant similar to the Ks value. Binding constants were determined for obtusifoliol, lanosterol and DHL. Obtusifoliol binds to the enzyme with a Ks value of 350±150 nM whereas DHL and lanosterol bind to the enzyme less effectively, ca. 1±0.5 μM each (FIG. 6B). Neither parkeol, cycloartenol, nor zymosterol (FIG. 3A) were found to bind to the enzyme.

[0342] Azole binding spectra. Binding of ketoconazole, clotrimazole and fluconazole, known for their ability to inhibit 14α-demethylase activities (Yoshida & Aoyama, (1987) Biochem. Pharmacol. 36:229-35; Salmon et al., (1992) Arch. Biochem. Biophys. 297:123-31) was examined for MT P45014DM. These molecules produce type II binding spectra due to binding of the azole nitrogen to the 6th coordination position of the heme iron. The type II binding spectrum is characterized by a peak at 434 and a trough at 412 nm (FIG. 6C). Similar to the type I spectra, the P450-inhibitor complex can be titrated leading to an estimation of the inhibitor Ks (FIG. 6D). For ketoconazole and clotrimazole, these values are around 5 μM whereas for fluconazole around 10 μM. Ketoconazole (20 μM) was found to inhibit the 14α-demethylation of DHL by MT P45014DM.

Example 6

Crystalline Structure of MT CYP51 Enzyme

[0343] This example describes the characterization of the three-dimensional (3-D) crystalline structure of the MT CYP51 gene product of the present invention. It is desirable to determine the 3-D structure of this protein at high resolution because of its activity as a 14α-demethylase enzyme. Other known forms of CYP45014DM's are from eukaryotes and are integral membrane proteins in the ER. Efforts to crystalize membrane bound proteins are difficult at best and only a small number of structures of these proteins are known. No crystalline structure is currently available for a eukaryotic CYP45014DM.

[0344] However, bacterial P450s are soluble proteins and are much easier to crystalize. At least six 3-D structures of bacterial CYP450s have been solved at high resolution using x-ray crystallography. Since the MT P45014DM protein of the present invention is a soluble protein, the crystalline structure of this 14α-demethylase is much easier to solve as compared to eukaryotic CYP45014DM's and thus, such a crystalline form is contemplated in accordance with the present invention. Indeed, obtaining crystals of quality sufficient for determining the structure of a CYP45014DM enzyme has not been achievable until the crystallization of MT CYP45014DM as disclosed herein. Thus, the crystalline structure of MT CYP45014DM is used to model the tertiary structure of related proteins in accordance with art-recognized techniques, such as those used in modeling the structure of renin using the tertiary structure of endothiapepsin as a starting point for the derivation (Blundell et al., (1983) Nature 304:273-275). Additional crystallization techniques are described in U.S. Pat. Nos. 5,322,933; 5,834,228; and 5,872,011, the entire contents of which are herein incorporated by reference.

[0345] Furthermore, current methods of tertiary structure determination that do not rely on X-ray diffraction techniques and thus do not require crystallization of the protein, such as NMR techniques, are made much simpler if a model of the structure is available for refinement using the additional data gathered by the alternative technique. The elucidation of the tertiary crystalline structure of MT CYP45014DM in accordance with the present invention thus provides a starting point for investigation into structure of all CYP450 enzymes including particularly, but not limited to, the various species of CYP45014DM's.

[0346] By way of particular example, CYP450 14α-demethylase in fungi (yeast) is targeted by drugs used for the treatment of yeast infections including jock itch and athlete's foot by topical treatment. Inhibitors of P45014DM such as ketoconazole bind tightly to the yeast enzyme in the active site, thereby preventing ergosterol biosynthesis and killing the yeast. Thus, the elucidation of the structure of the P45014DM active site in accordance with this example facilitates the design of even more effective drugs.

[0347] Additionally, the development of very specific drugs for the treatment of Candida albicans infections in immunocompromised (i.e. HIV) individuals is also facilitated. This infection, which can be deadly, requires systemic treatment with azole inhibitors such as ketoconazole. Ketoconazole was formerly used in such treatment, while fluconazole and itracouazole are more commonly used today. One structure of MT CYP51 determined in accordance with the present invention is the complex with fluconazole. But, these inhibitors, when used systemically, will also inhibit the function of endogenous CYP450s in the human host. For example, inhibitors of Candida CYP45014DM will also inhibit human CYP45014DM and probably many other human CYP450s. Therefore systemic use of CYP450 inhibitors is limited to only those patients in dire need of treatment. Accordingly, the resolution of the 3-D structure of MT CYP45014DM in accordance with this example provides a very useful tool in rational drug design for more specific inhibitors of yeast, MT, and other CYP45014DMs.

Example 7

Methods of Treating Tuberculosis

[0348] The characterization of the CYP51 enzyme of the present invention in MT leads to the analysis of the function of this enzyme in the disease tuberculosis and of whether this enzyme represents a new drug target for the treatment of tuberculosis. Particularly, the effects of three azole inhibitors on the growth of MT H37RA, an alternated strain of MTH37R which is the pathogenic strain whose genomic sequence was determined by Cole et al., (1998) Nature 193:537-544 (bacterial strains provided by Dr. Dean Crick at Colorado State University) were examined.

[0349] As contemplated by applicants in accordance with the present invention, it was observed that ketoconazole has a profound effect on the growth of MT, stopping growth at about a 25 μM concentration. This result indicates that the MT P45014DM enzyme isolated in accordance with the present invention plays an essential role in MT growth and that azole inhibitors of CYP450 enzymatic activity provide new candidates for drugs in the treatment of tuberculosis. The targeting of ketoconazole to P45014DM in MT also leads to the identification of additional specific azole inhibitors which have far greater specificity for the MT CYP45014DM enzyme as compared to the human CYP45014DM enzyme. Such inhibitors therefore will have fewer side effects than less specific inhibitors. Thus, as described above, a method of screening for highly specific inhibitors of MT CYP45014DM in accordance with the screening methods described herein above comprises another aspect of the present invention.

Example 8

Modulation of CYP45014DM Biological Activity

[0350] Given the demonstrated biological activity of the isolated MT CYP51 enzyme of the present invention as a 14α-demethylase, and given the characterization of the structure of this enzyme as described herein above, it is contemplated that a method of screening for specific inhibitors of cholesterol synthesis comprises an additional aspect of the present invention. Screening for a modulator of cholesterol synthesis which preferentially modulates CYP45014DM activity is particularly contemplated. By the term “preferentially” it is meant that the contemplated modulator tends to modulate the activity of CYP45014DM enzymes to a greater extent as compared to other CYP450 enzymes. The identification of such modulators is facilitated by the characterization of the crystalline structure of the MT CYP51 polypeptide of the present invention as well as the rational drug design methods disclosed herein above.

[0351] A method of modulating cholesterol synthesis comprising administering an effective amount of a cholesterol synthesis modulating composition to a vertebrate subject in need thereof is also contemplated in accordance with the present invention. Preferably, the cholesterol synthesis modulating composition comprises a therapeutically effective amount of a compound which preferentially modulates the activity of a CYP45014DM enzyme in the vertebrate subject.

[0352] Additionally, given the importance of cholesterol and steroid synthesis during spermatogenesis and given that the highest level of expression of the CYP45014DM enzyme in mammals, and particularly in humans, is found in developing spermatids during spermatogenesis, a screening method for a therapeutic agent useful in the modulation of spermatogenesis is contemplated in accordance with the present invention. Screening for a modulator of spermatogenesis which preferentially modulates CYP45014DM activity is particularly contemplated. By the term “preferentially” it is meant that the contemplated modulator tends to modulate the activity of CYP45014DM enzymes to a greater extent as compared to other CYP450 enzymes. The identification of such modulators is facilitated by the characterization of the crystalline structure of the MT CYP51 polypeptide of the present invention as well as the rational drug design methods disclosed herein above.

[0353] A method of modulating spermatogenesis comprising administering an effective amount of a spermatogenesis modulating composition to a vertebrate subject in which such modulation is desirable is also contemplated in accordance with the present invention. Preferably, the spermatogenesis modulating composition comprises a therapeutically effective amount of a compound which preferentially modulates the activity of a CYP45014DM enzyme in the vertebrate subject.

Discussion of Examples 1-8

[0354] The results of the Examples demonstrate that MT contains a gene encoding an enzyme that catalyzes removal of the sterol 14α-methyl group stereoselectively, producing the 8,14-diene. The influence of substrate structure on MT P45014DM sterol binding has been determined using a series of substrates that differ in a single molecular feature or in a combination of similar features. The tendency for preferential binding of obtusifoliol compared with the five other sterols tested indicates that the active site accommodates sterol side chains with a C24-alkyl group, suggesting the bacterial enzyme is plant/fungal-like in its active site topology. Obtusifoliol was also found to be the best substrate for the MT P45014DM.

[0355] The inability of parkeol or cycloartenol, structural isomers of lanosterol, to bind MT P45014DM indicates that the orientation of the substrate assumed upon binding requires a specific pseudoplanar conformation of the ring system and specific equatorially oriented tilt of the C3-hydroxyl group; analogous structural requirements as observed for the sterol methyl transferase enzyme from fungi and plants (Venkatramesh et al., (1996) Biochim. Biophys. Acta 1299:313-24; Nes et al., (1991) J. Biol. Chem. 266:15202-12). The lack of zymosterol binding (4,4,14-tridesmethyl lanosterol) indicates that one or both of the C4- and C14-methyl groups are important in sterol binding.

[0356] The Δ8-bond is a critical stereoelectronic element of recognition; in each of the three sterols that were found to undergo 14α-demethylation by MT P45014DM the product of the multi-step reaction was a sterol with the conjugated Δ14(15)-bond system, suggesting the bacterial enzyme has evolved to bind and catalyze 14α-methyl sterols in a manner similar to P45014DM enzymes from higher species (Yoshida et al., (1997) J. Biochem. (Tokyo) 122:1122-8). Clearly, there is a conservation in sterol specificity for the P45014DM enzyme from primitive bacteria to advanced fungal and plant systems. The ketoconazole binding constant estimated for maize microsomes is 10 μM (Salmon et al., (1992) Arch. Biochem. Biophys. 297:123-31), about the same as that for MT P45014DM emphasizing similarities between bacterial and eukaryote enzymes.

[0357] A purine rich region located 10 bp upstream the ATG, is associated with the MT CYP51 gene. Similar sequences are associated with other MT genes such as TB dnaj and TB 65 (Dale & Patki, (1990) in Molecular Biology of the Mycobacteria, ed. McFadden, J. (Academic Press, San Diego), pp. 173-198). The structure and the location of this putative MT CYP51 Shine-Dalgarno sequence is also in agreement with what is known in the most studied bacterium, E. coli, where the purine rich region is separated from the ATG by 5 to 12 bases (De Boer & Hui, (1991) in Gene Expression Technology, ed. Goeddel, D. V. (Academic Press, Inc, San Diego, Calif.), Vol. 185, pp. 103-114). No such sequence could be identified upstream the Fdx gene in the P450 open reading frame, suggesting that the 2 genes which are separated by only 2 bp might be expressed as a polycistronic RNA.

[0358] MT P45014DM is the first endogeneous P450 found to accept electrons from both an iron-sulfur protein (Fdx) and a FMN containing protein (Fld). Perhaps this reflects a transition in the P450 evolution between procaryotic electron transfer (iron-sulfur protein) and the eukaryotic type (FMN containing protein for microsomal P450s). The 3Fe-4S ferredoxin is contemplated as a good candidate for the endogeneous MT reductase.

[0359] The formulation of binding topology from studies with sterol substrates and the sensitivity of the P45014DM to azole inhibitors is consistent with MT having a functional sterol pathway, and further refines the general picture of sterol evolution which has emerged from classical natural product chemistry approaches to identify sterol biosynthetic pathways. The identification of P45014DM in MT and its contemplated role in sterol biosynthesis supports the recent demonstration that cholesterol biosynthesis occurs in M. smegmatis via a mevalonic pathway (Lamb et al., (1998) FEBS Lett. 437:142-144). Targeting MT P45014DM provides new options in drug design for new treatments of tuberculosis, a disease infecting one third of the world population (Fenton & Vermeulen, (1996) Infect. Immun. 64:683).

Overview of Examples 9-12

[0360] Cytochrome P450 14α-sterol demethylases (CYP51), are essential enzymes in sterol biosynthesis on eukaryotes. CYP51 removes the 14α-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used on treatment of topical and systemic mycoses. The 2.1 and 2.2 Å crystal structures reported in Examples 9-12 for 4-phenylimidazole (4-PI)- and fluconazole (FLU)-bound Cyp51 from Mycobacterium tuberculosis (MT CYP51) are the first structures of an authentic P450 drug target.

[0361] MT CYP51 exhibits the P450 fold with the exception of two striking differences, bent I-helix and open conformation of BC loop, that define the substrate access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is also evident in MT CYP51, it is not open at the surface. The presence of two different channels one being open to the surface suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51.

[0362] Mapping mutations identified in Candida albicans azole resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.

Materials and Methods for Examples 9-12

[0363] MT CYP51 was expressed and purified as described herein and by Bellamine et al., (1999) Proc. Natl. Acad. Sci. USA 96:8937-8942. Crystals were obtained at 22° C. from 20% PEG 4000, 10% isopropanol, 0.1 M HEPES, pH=7.5, and 4-PI in saturating concentration. Crystals belong in space group P212121, with unit cell dimensions a=46.14, b-83.86, c=109.56, α=β=γ=90°. All data were collected at the laboratory source on R-AXIS IV mounted on RU-200 Rigaku X-ray generator at cryo-temperatures. Data were processed with DENZO and scaled using SCALEPACK (Otwinowski & Minor, (1997) Methods Enzymol. 276:307-26). Data statistics are given in Table 1.

[0364] Two heavy atom derivatives were obtained by soaking 4-PI containing crystals in 1 mM solution of ethylmercurithiosalicylic acid or gold (I) potassium cyanide over several hours. Two heavy atom sites for both derivatives were localized, positions and occupancies being refined using CNS™ (Brünger et al., (1998) Acta Crysta. D54: 905-21). The molecule was traced and the model built in O (Jones et al., (1991) Acta Crystallogr. A47: 110-119). Native 4-PI data were used in refinement. Maximum-likelihood refinement, individual B-factors and bulk solvent corrections were applied as implemented in CNS™. The refined model was used as a search model to find molecular replacement solution for FLU-bound MT CYP51. Phasing and model quality statistics are given in Table 1.

Example 9

Substrate Access Channel

[0365] MT CYP51 exhibits the P450 fold but contains striking differences that define the substrate access channel. Unlike other P450s, the longest helix in the molecule (I-helix, FIG. 8) is disrupted so that the N-terminal portion bends away from the structural core making a 145° angle with the C-terminal part. Three water molecules provide H-bonds to peptide groups that help conpemsate for missing helical H-bonds. Additional stability is provided by H-bonds between the side chains of T260 and Y169 and backbone peptide groups.

[0366] While comparisons of known P450 structures show nearly identical C-terminal portions of the I-helix, the N-terminal halves deviate significantly from one P450 to another (FIGS. 9A and 9B). The MT CYP51 I-helix has the most prominent N-terminal displacement which results in bending of the I-helix away from the heme and enlarging the space available for substrate or inhibitor binding. Bending occurs at positions 253-255 in the 4-PI structure and shifts to positions 256-258 upon FLU binding.

[0367] The middle portion of the I-helix where the different structures start to deviate significantly from each other is well conserved among P450s, including residues A256 and G257 which tend to deviate from α-helical conformation in all known P450 structures, except for P4502c5. This suggests a potential ability of the P450 I-helix to bend in response to certain stimuli, such as substrate or redox partner binding to release the BC loop from close contacts in the binding site. As a consequence of the large repositioning of the I-helix, adjacent regions, namely the H and G helices and loops in between, also exhibit significant topological variations among P450s.

[0368] Another obvious difference is the open position of the BC loop in MT CYP51 (substrate-entry loop) that adopts a closed conformation in other P450 structures (FIG. 10B). Both the bent I-helix and the open BC loop create a large opening leading from the surface of the protein to the heme, which defines the substrate access channel opening approximately 20 Å by 10 Å (FIG. 10A). This channel (channel 1, FIG. 8) runs roughly parallel to the heme in contrast to P450BM3 and P450cam where the substrate access channel runs perpendicular to the heme (channel 2, FIG. 8). Channel 1 converges as an asymmetrical funnel from the surface of the protein along the heme plane. The funnel narrows to a chamber lined by residues from the B′ and I helices, β-sheets 1 and 2, and the loop connecting the K helix and β-sheet 1. The chamber configuration was nicely predicted by probing of S. cerevisiae CYP51 active site with phenyidiazene (Tuck et al., (1992) J. Biol. Chem. 267:13175-79). The dome of this active site chamber is 10-11 Å above the plane of the porphyrin ring. It is most open above the heme iron and pyrrole ring C with ceiling residues F78, M79, F83, and F255 (FIG. 12A). Access to pyrrole rings A, B, and D is limited by residues T260, A256, and L321, respectively. These side chains approach within 4 Å to the porphyrin plane.

[0369] In P450BM3 and open substrate access channel between the β-sheet and helical domains (channel 2, FIGS. 8A and 8B) is oriented about 90° relative to the CYP51 substrate channel 1 (Li & Poulos, (1996) Biochimie 78) (FIGS. 8A and 8B). Although channel 2 is also apparent in MT CYP51 structure, its entrance is closed from the surface by interaction between the A′ helix and FG loop (FIG. 8B). However, rotation of the F and G helices could enable an open/close motion of the FG loop as observed in P450BM3 (Ravichandran et al., (1993) Science 261:731-36; Li & Poulos, (1996) Biochimie 78; Li & Poulos, (1997) Nature Struct. Biol. 4: 140-46). The movement of these two helices in P450BM3 extends through the loop between the H and G helices is a region with very high thermal factors (FIG. 11) (average per residue main chain B-factor=84.2 Å2) that enables it to accommodate a twice between these two helixes. In addition, the substrate-entry BC loop (channel 1) followed by the C helix exhibit large main chain thermal factors (average per residue main chain B-factor=58.7 Å2). Thus, if channel 2 opens up in MT CYP51 as in P450BM3, the required structural changes would necessitate closing of channel 1. Those regions involved, the F, G and H helices and loops in between are known to undergo significant motion in P450BM3 when substrate binds (Li & Poulos, (1996) Biochimie 78; Li & Poulos, (1997) Nature Struct Biol. 4: 140-46). This scenario provides a dynamic and synchronized picture of catalysis where channel 1 is open for substrate entry while channel 2 remains closed. This could provide for substrate to enter one channel and product to depart the other. Given the multiple oxidation steps required of CYP51, such motion is likely necessary in order to position key residues in place for various steps along the catalytic path.

[0370] The BC loop is defined as a site of a substrate entry based exclusively on its open conformation in MT CYP51. The same site has been assumed to be for substrate entry in P4502C5 based on increased values of thermal factors in the BC loop (Williams et al., (2000) Mol. Cell 5: 121-31). It is suggested above that substrate enters the protein interior through the channel 1 and departs as a product through channel 2. However, the passage of substrate in the opposite direction cannot be excluded. Thus, structural data obtained for MT CYP51 strongly indicate the possibility that such substrate passage take place and is accompanied by significant changes in protein conformation.

Example 10

Inhibitor Binding

[0371] 4-PI or FLU are bound in the active site so that the imidazole ring (4-PI) or triazole ring (FLU) are positioned perpendicular to the porphyrin plane with a ring nitrogen atom coordinated to the heme irom (FIGS. 10B and 10C). the 4-PI phenyl group makes several non-bonded contacts with surrounding side chains while the imidazole N3 H-bonds with H259. The larger size of FLU extends the number of contacts in the binding site in comparison with 4-PI. H259 is slightly pulled away from the binding site and does not form a hydrogen bond with FLU while F83 and F255 provide non-bonded contacts. Conformational changes, which occur upon binding of the larger ligand, bring additional residues in close proximity to FLU. The main FLU-induced conformational changes involve a helix-coil transition of the C helix and displacement of the residues in the I-helix. Region 96-100 within the disordered C helix is displaced toward the substrate binding site (FIG. 12C), however the positions of side chains cannot be defined due to poor electron density for region 90-106 reflected in high values of thermal factor.

[0372] The BC loop remains in an open conformation as observed in the 4-PI structure and does not close access to the substrate binding site. However, 4-PI was substituted by FLU in the already formed crystal, and thus, the motion of secondary structure elements might be significantly restricted by crystal packing interactions. Although residues H101, S252, I323, and V434 do not contact either 4-PI or FLU, they line the binding site and are likely to contribute in interaction with substrate. Active site residues can be divided into two groups based on their conservation in different kingdoms, such as bacteria, fungi, higher plants and animals. See Table 4. Variable residues, including F78, M79, K97, M99, H101, F255, S252, I323, and V434, reveal substantial differences from kingdom to kingdom suggesting that these residues contribute to substrate specificity of CYP51 from different species.

Example 11

Mapping of Resistant Variants

[0373] Naturally occurring CYP51 mutations identified in C. Albicans azole resistant isolates and clustered in three hotspots in the primary sequence (Marichal et al., (1999) Microbiology 145: 2701-13), can be divided into four hotspots based on their association with different structural regions observed in the MT CYP51 structure (FIG. 13). The first hotspot, substitutions G464S, G465S and R467K, associate with the N-terminal part of the “cysteine-pocket”, residues G388, A389, and G390 in MT CYP51. Positions 388 and 390 are highly conserved in P450s. These residues lie on the opposite side of the heme from where substrates bind and cannot directly participate in inhibitor binding. However, these residues provide contacts between the β-sheet and α-helical domains and could be involved in interdomain conformational changes upon inhibitor or substrate binding. Changing Gly to other residues would be expected to decrease flexibility required for such changes. Several other C. albicans mutations which are attributed to the same hotspot, including V4371, G448E, F449L, G450E, and V452A, are clustered just N-terminal to the “cysteine-pocket” around the two glycine residues. They lack analogs in MT CYP51 structure due to the large insert occurring at this region in the fungal ortholog.

[0374] A second hotspot is mapped to the C-terminus of the G helix and the H helix, a region too distal to be involved in interaction with the substrate or inhibitor. Mutations here E266D, R267H, D278E, and S279F (A214, N215, D227, V228 in MT CYP51) flank the most dynamic residues of MT CYP51. A third hotspot, substitutions F72L, F105L, S405F, and T229A (M30, F63, S348, and D177 in MT CYP51), associates with the domain interface. Although in FLU-bound MT CYP51 these residues do not interfere with inhibitor bound in the active site, such an interaction might occur during a passage of fluconazole along channel 2, if such a passage exists in MT CYP51.

[0375] The fourth and final hotspot associates with the region between B and C helices that exhibit thermal motion, and for which involvement in inhibitor- or substrate-induced structural changes is envisioned. This hotspot includes mutations D116E, F126L, K128T, G129A, Y132H, K143R, F145L, K147R, A149V, and D153E, which correspond to MT CYP51 positions K74, F83, E85, G86, F89, L100, N102, A103, A104 and E108. Being localized in the region of the mouth of the substrate entry channel these residues could interfere with the entry of the inhibitor or its binding in the active site. Again, mutations flank the most dynamic residues rather than overlap them. The open conformation of the substrate-entry loop observed in MT CYP51 positions some of these residues, including F89 (Y132 in C. albicans), distant to the inhibitor. If upon binding of substrate the BC loop adapts a closed conformation, these residues could come into close proximity with the active site. In P450BM3 the Phe in the corresponding position was shown to block the substrate from approaching close to the heme (Li & Poulos, (1997) Nature Struct. Biol. 4: 140-46). Thus, none of the mutations identified in C. albicans azole resistant isolates are involved in direct interaction with fluconazole when the protein is in the conformation observed in MT CYP51 crystals.

[0376] Some residues from hotspots three and four, however, might encounter the inhibitor upon its passage through the channel 2, or if the BC loop can adapt a closed conformation while fluconazole is bound in the active site. Residues in hotspots one and two lack an opportunity to interfere with fluconazole directly. At the same time, the regions these residues are located in are likely to be involved in conformational changes that accompany substrate binding and product release. It is thus envisioned that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through the different conformational stages along the catalytic cycle.

Example 12

Coordinates

[0377] The coordinates of the structures have been deposited with the Protein Data Bank, (accession codes 1E9X and 1EA1), and are also presented herein in Tables 2 and 3.

References

[0378] The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the foregoing text, and respectively grouped in the list of references presented below.

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4TABLE 1SUMMARY OF CRYSTALLOGRAPHIC DATAData collectionNativeHgAuFluconazoleData set4-PhenylimidazoleEMTS*KAu(CN)2FluconazoleResolution (A)2.12.12.22.2Observed reflections173,919163,256193.495109,615Unique reflections25,10721,75642,18837,242Completeness (%)99.1 (91.3)191.5 (56.0)99.4 (97.1)95.0 (84.9)Redundancy6.9 (4.5)7.5 (4.8)4.6 (3.6)2.9 (2.2)<I/σ>9.8 (3.7)7.1 (3.5)7.1 (2.5)9.7 (2.0)2Rsym (%)11.1 (48.9)11.6 (43.3)12.1 (47.0)10.3 (46.5)Phasing statisticsResolution range40.0-2.840.0-2.8Sites223Phasing power2.03/1.901.85/1.674Rcullis0.46/0.620.46/0.66Quality of modelProtein atoms3,5393,510Heme atoms4343Ligand atoms1122Water molecules2421755Rcrys (Rfree) (%)18.5 (23.0)20.0 (24.9)R.m.s. deviationsBonds (Å)0.0050.007Angles (°)1.21.3Ramachandran689.5%88.9%*Ethylmercurithiosalicylic acid 1Values in parentheses are for the highest resolution shell 2Rsym = Σ| Ii − <I>⊕/Σ<I>, where <I> is the mean intensity of reflection. 3Phasing power = <Fh>/E, where <Fh> is the root mean square heavy atom structure factor and E is the residual lack of closure. 4Rcullis Σ||Fph ± Fp| − Fh,c|/Σ|Fph + Fp|, where Fh,c is the calculated heavy atom structure factor. 5Rcryst = Σ||F0| − |Fc||/Σ|Fo|, calculated with the working reflection set. Rfree is the same as Rcryst but calculated with the reserved reflection set. 6Program PROCHECK (Laskowski et al., (1993) J. Appl. Crystallogr. 26, 283-291.)

[0533]

5

TABLE 4

CONSERVATION OF MTCYP51 ACTIVE SITE RESIDUES

THROUGH EVOLUTION

MTCYP51
Plant
Mammals
Fungi

Y76*
Y
Y
Y

F78
F
R
H(7)**, V(3), K(1), N(1)

M79
N
L
L

F83
F
F
F

F89
F
Y
Y

K97
Q
K
Q(11),H(1)

M99
R
M(2)I(2)
K

H101
F
—
M(4), V(3), A(3), I(2)

S252
A
G
A(6), G(5), T(1)

F255
F
L
M

H259
H
H
H

T260
T
T
T(7), S(5)

L321
L
I
L(6), I(6)

I323
M
T(3), I(1)
S(1), T(1)

M433
M
M
M(7), L(4)

V434
V
I
V(6), F(5)

*Bold letters indicate residues that display significant conservation through evolution.

**Parenthesis shows the numbers of species with indicated substitution.

[0534] Altogether three plant, four animals, and twelve fungi CYP51 sequences were analyzed. Alignment was performed using BCM Search Launcher (Smith et al., (1996) Genome Res. 6, 454-462.).

6TABLE 2ATOMIC STRUCTURE COORDINATE DATA OBTAINED FROM X-RAYDIFFRACTION FROM MT CYP51COMPLEXED WITH 4-PHENYLIMIDAZOLEATOMPROTEINATOMTYPERESIDUE##XYZOCCBATOM 1NMETA1−16.819−14.431105.8691.0066.58N 2CAMETA1−15.674−13.730105.2201.0067.36C 3CMETA1−16.096−13.046103.9181.0067.72C 4OMETA1−17.138−12.388103.8601.0067.97O 5CBMETA1−14.546−14.722104.9501.0067.81C 6NSERA2−15.277−13.202102.8811.0066.32N 7CASERA2−15.551−12.608101.5761.0063.71C 8CSERA2−15.348−13.640100.4681.0061.85C 9OSERA2−15.419−14.845100.7131.0063.34O 10CBSERA2−14.630−11.408101.3411.0064.18C 11OGSERA2−13.266−11.783101.4321.0061.54O 12NALAA3−15.095−13.16899.2511.0058.32N 13CAALAA3−14.886−14.06698.1211.0053.93C 14CALAA3−13.406−14.21397.7881.0051.27C 15OALAA3−12.632−13.26497.9171.0050.01O 16CBALAA3−15.644−13.56096.9041.0054.19C 17NVALA4−13.023−15.41397.3621.0047.69N 18CAVALA4−11.642−15.70596.9981.0044.47C 19CVALA4−11.190−14.77595.8811.0041.72C 20OVALA4−11.950−14.49194.9591.0040.27O 21CBVALA4−11.496−17.16896.5151.0045.43C 22CG1VALA4−10.109−17.39695.9321.0045.41C 23CG2VALA4−11.745−18.12397.6761.0046.08C 24NALAA5−9.954−14.29795.9661.0037.75N 25CAALAA5−9.431−13.41094.9401.0035.61C 26CALAA5−8.999−14.24193.7401.0033.21C 27OALAA5−8.526−15.36393.8901.0033.54O 28CBALAA5−8.251−12.61795.4771.0036.90C 29NLEUA6−9.185−13.69492.5471.0030.23N 30CALEUA6−8.792−14.39191.3301.0028.54C 31CLEUA6−7.325−14.09591.0671.0024.96C 32OLEUA6−6.765−13.15491.6241.0024.10O 33CBLEUA6−9.629−13.90490.1421.0028.67C 34CGLEUA6−11.070−14.41290.0231.0031.11C 35CD1LEUA6−11.045−15.87789.6741.0031.38C 36CD2LEUA6−11.837−14.17991.3241.0030.73C 37NPROA7−6.671−14.90890.2331.0023.80N 38CAPROA7−5.263−14.58489.9941.0023.67C 39CPROA7−5.168−13.18289.3921.0023.77C 40OPROA7−5.958−12.81588.5151.0021.68O 41CBPROA7−4.802−15.69389.0401.0022.92C 42CGPROA7−6.085−16.19188.4141.0025.65C 43CDPROA7−7.062−16.15189.5521.0022.80C 44NARGA8−4.224−12.39789.9011.0023.48N 45CAARGA8−4.010−11.02889.4501.0025.35C 46CARGA8−2.598−10.89088.8941.0024.98C 47OARGA8−1.635−11.32089.5261.0025.20O 48CBARGA8−4.215−10.05990.6221.0026.78C 49CGARGA8−3.882−8.60190.3201.0028.88C 50CDARGA8−4.677−8.06489.1361.0032.40C 51NEARGA8−6.105−7.94589.4171.0036.16N 52CZARGA8−6.633−7.07790.2771.0037.42C 53NH1ARGA8−5.852−6.24190.9511.0036.34N 54NH2ARGA8−7.948−7.03890.4591.0036.93N 55NVALA9−2.479−10.29387.7111.0024.55N 56CAVALA9−1.175−10.11987.0811.0023.45C 57CVALA9−0.356−9.05887.8081.0024.90C 58OVALA9−0.909−8.13988.4121.0025.72O 59CBVALA9−1.313−9.73285.5871.0022.39C 60CG1VALA9−1.851−8.31685.4541.0018.81C 61CG2VALA90.032−9.87284.8841.0020.33C 62NSERA100.965−9.19787.7411.0025.61N 63CASERA101.897−8.27988.3931.0026.04C 64CSERA101.805−6.84887.8651.0026.80C 65OSERA101.197−6.59986.8311.0026.42O 66CBSERA103.325−8.79688.2131.0025.77C 67CGSERA103.637−8.94086.8361.0023.82O 68NGLYA112.425−5.91588.5821.0027.79N 69CAGLYA112.400−4.52188.1701.0026.72C 70CGLYA111.095−3.84988.5451.0027.82C 71OGLYA110.479−4.20089.5531.0026.67O 72NGLYA120.677−2.87887.7381.0027.22N 73CAGLYA12−0.570−2.17887.9931.0027.91C 74CGLYA12−0.570−1.35489.2651.0029.01C 75OGLYA12−1.564−1.29989.9931.0026.93O 76NHISA130.549−0.69889.5301.0030.73N 77CAHISA130.6730.12390.7211.0032.52C 78CHISA130.6201.60890.3791.0032.67C 79OHISA131.0142.45591.1821.0033.80O 80CBHISA131.975−0.23191.4311.0033.73C 81CGHISA132.105−1.69191.7261.0034.78C 82ND1HISA131.261−2.35092.5931.0036.35N 83CD2HISA132.945−2.62991.2321.0034.73C 84CE1HISA131.574−3.63392.6191.0037.09C 85NE2HISA132.592−3.82891.8021.0037.93N 86NASPA140.1321.91589.1801.0031.42N 87CAASPA140.0083.29588.7371.0031.45C 88CASPA14−1.3373.83589.2081.0031.90C 89OASPA14−2.1423.09389.7761.0031.95O 90CBASPA140.1153.38787.2101.0032.61C 91CGASPA141.4832.96786.6921.0033.01C 92OD1ASPA142.5023.36387.2971.0031.71O 93OD2ASPA141.5412.24885.6721.0033.77O 94NGLUA15−1.5855.11888.9661.0030.64N 95CAGLUA15−2.8235.74589.4101.0031.15C 96CGLUA15−4.0774.92189.1791.0026.99C 97OGLUA15−4.8764.73990.0921.0027.88O 98CBGLUA15−3.0067.12088.7601.0032.97C 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224CEMETA30−4.674−7.13174.7091.0017.25C 225NGLNA31−0.569−10.42377.5841.0017.80N 226CAGLNA310.242−11.62377.4521.0019.51C 227CGLNA310.793−12.00878.8161.0019.39C 228OGLNA310.866−13.18979.1421.0021.30O 229CBGLNA311.406−11.40776.4851.0019.75C 230CGGLNA312.245−12.66876.2741.0021.80C 231CDGLNA311.434−13.81175.6851.0023.55C 232OE1GLNA310.885−13.69174.5881.0024.33O 233NE2GLNA311.351−14.92476.4111.0021.57N 234NARGA321.176−11.01579.6131.0017.89N 235CAARGA321.719−11.29380.9371.0020.59C 236CARGA320.650−11.88881.8461.0020.29C 237OARGA320.951−12.69982.7221.0020.98O 238CBARGA322.306−10.02681.5741.0021.92C 239CGARGA323.221−10.34382.7611.0021.27C 240CDARGA324.018−9.13983.2441.0022.61C 241NEARGA323.196−8.14683.9311.0022.66N 242CZARGA322.741−7.03383.3681.0023.52C 243NH1ARGA323.024−6.76682.1021.0022.74N 244NH2ARGA322.018−6.17984.0781.0021.15N 245NVALA33−0.602−11.48881.6361.0022.87N 246CAVALA33−1.702−12.01982.4341.0021.39C 247CVALA33−1.785−13.52782.1931.0021.88C 248OVALA33−1.880−14.31783.1341.0022.53O 249CBVALA33−3.043−11.36682.0421.0022.41C 250CG1VALA33−4.200−12.09182.7251.0023.38C 251CG2VALA33−3.035−9.89882.4351.0020.51C 252NARGA34−1.731−13.92580.9271.0021.46N 253CAARGA34−1.798−15.33880.5861.0021.53C 254CARGA34−0.557−16.09781.0481.0022.11C 255OARGA34−0.662−17.21481.5511.0019.95O 256CBARGA34−1.971−15.51879.0791.0022.16C 257CGARGA34−2.027−16.97978.6511.0025.09C 258CDARGA34−2.166−17.11777.1471.0024.98C 259NEARGA34−2.020−18.50776.7241.0026.45N 260CZARGA34−2.913−19.46476.9481.0024.13C 261NH1ARGA34−4.039−19.19577.5951.0025.53N 262NH2ARGA34−2.667−20.70076.5361.0024.20N 263NASPA350.617−15.49880.8711.0021.24N 264CAASPA351.855−16.15381.2851.0024.50C 265CASPA351.881−16.40482.7901.0024.77C 266OASPA352.179−17.51383.2401.0025.04O 267CBASPA353.071−15.31080.8881.0022.84C 268CCASPA353.263−15.24079.3871.0024.38C 269OD1ASPA352.605−16.02078.6681.0024.05O 270OD2ASPA354.079−14.41678.9281.0024.57O 271NGLUA361.556−15.36983.5591.0024.44N 272CAGLUA361.545−15.45285.0151.0022.18C 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S3290CEMETA4199.252−4.61453.2201.0022.90C3291NALAA4209.1351.90652.0251.0021.44N3292CAALAA42010.0413.04551.9691.0022.13C3293CALAA42010.7273.25553.3221.0023.10C3294OALAA42011.4004.26353.5431.0022.62O3295CBALAA4209.2804.29351.5651.0023.56C3296NGLNA42110.5352.30354.2291.0022.30N3297CAGLNA42111.1552.35755.5461.0023.06C3298CGLNA42111.4170.92355.9961.0023.12C3299OGLNA42110.964−0.02655.3521.0022.86O3300CBGLNA42110.2623.10656.5451.0025.57C3301CGGLNA4218.8642.54856.7101.0027.43C3302CDGLNA4217.9863.42857.5861.0026.80C3303OE1GLNA4217.6494.55757.2211.0024.60O3304NE2GLNA4217.6132.91358.7501.0025.77N3305NPROA42212.1820.74057.0831.0023.83N3306CAPROA42212.468−0.61957.5531.0023.20C3307CPROA42211.209−1.44757.8011.0023.11C3308OPROA42210.243−0.96958.3881.0021.71O3309CBPROA42213.275−0.37658.8281.0024.04C3310CGPROA42214.0100.89558.5051.0024.00C3311CDPROA42212.9291.73757.8711.0023.34C3312NPROA42311.209−2.71057.3561.0024.05N3313CAPROA42310.051−3.58857.5431.0024.90C3314CPROA4239.588−3.65558.9991.0024.90C3315OPROA4238.403−3.83059.2721.0025.54O3316CBPROA42310.560−4.94057.0441.0026.63C3317CGPROA42311.569−4.55856.0081.0026.67C3318CDPROA42312.303−3.42456.6761.0024.79C3319NGLUA42410.528−3.51159.9301.0025.25N3320CAGLUA42410.209−3.58061.3541.0026.45C3321CGLUA4249.629−2.28261.9051.0025.30C3322OGLUA4249.112−2.25863.0211.0027.09O3323CBGLUA42411.457−3.94262.1741.0029.46C3324CGGLUA42412.193−5.19161.7171.0030.82C3325CDGLUA42413.064−4.94360.4971.0033.56C3326OE1GLUA42413.162−3.77660.0611.0032.66O3327OE2GLUA42413.657−5.91659.9821.0036.05O3328NSERA4259.711−1.20861.1261.0023.12N3329CASERA4259.2050.08761.5691.0021.68C3330CSERA4257.6910.23361.4391.0021.52C3331OSERA4257.1171.17361.9761.0019.79O3332CBSERA4259.8911.21660.7981.0020.56C3333OGSERA4259.5881.14959.4181.0019.43O3334NTYRA4267.043−0.67260.7111.0020.52N3335CATYRA4265.594−0.58160.5731.0022.16C3336CTYRA4264.989−1.14161.8421.0022.45C3337OTYRA4265.243−2.28862.2071.0021.33O3338CBTYRA4265.101−1.36559.3541.0020.12C3339CGTYRA4265.647−0.83058.0561.0020.55C3340CD1TYRA4266.880−1.26157.5671.0019.27C3341CD2TYRA4264.9640.15757.3471.0020.04C3342CE1TYRA4267.422−0.71856.4051.0021.67C3343CE2TYRA4265.4960.70856.1831.0020.77C3344CZTYRA4266.7250.26855.7181.0021.03C3345OHTYRA4267.2690.81754.5741.0021.61O3346NARGA4274.194−0.33162.5271.0023.26N3347CAARGA4273.599−0.78263.7781.0023.78C3348CARGA4272.262−0.11964.0171.0022.05C3349OARGA4271.9030.83863.3371.0021.50O3350CBARGA4274.531−0.45064.9411.0026.12C3351CGARGA4274.6851.04665.1451.0030.34C3352CDARGA4275.7021.38966.2171.0033.50C3353NEARGA4275.7392.83166.4451.0037.78N3354CZARGA4274.7623.51767.0331.0039.68C3355NH1ARGA4273.6722.88967.4601.0039.70N3356NH2ARGA4274.8684.83067.1861.0038.65N3357NASNA4281.536−0.64064.9991.0021.40N3358CAASNA4280.230−0.11765.3731.0021.53C3359CASNA4280.3740.81966.5601.0022.80C3360OASNA4281.3630.76667.2951.0020.96O3361CBASNA428−0.696−1.25865.8051.0021.95C3362CGASNA428−1.409−1.91464.6481.0021.57C3363OD1ASNA428−1.662−1.27563.6251.0023.45O3364ND2ASNA428−1.716−3.19764.7881.0017.24N3365NASPA429−0.6211.67766.7371.0021.89N3366CAASPA429−0.6522.56767.8811.0023.16C3367CASPA429−1.7321.91568.7271.0022.44C3368OASPA429−2.8841.83168.3051.0021.20O3369CBASPA429−1.0933.97367.4901.0026.45C3370CGASPA429−1.2234.89168.6941.0027.67C3371OD1ASPA429−1.6514.41269.7661.0027.29O3372OD2ASPA429−0.9126.09068.5671.0030.37O3373NHISA430−1.3581.42469.9021.0022.30N3374CAHISA430−2.3160.76370.7791.0023.30C3375CHISA430−2.6561.62271.9901.0022.97C3376OHISA430−3.0951.10673.0141.0023.76O3377CBHISA430−1.758−0.57571.2751.0024.10C3378CGHISA430−1.513−1.58070.1921.0024.41C3379ND1HISA430−0.248−1.89869.7461.0025.65N3380CD2HISA430−2.367−2.36369.4921.0024.89C3381CE1HISA430−0.333−2.83768.8201.0026.09C3382NE2HISA430−1.608−3.13768.6471.0026.38N3383NSERA431−2.4522.92871.8791.0023.35N3384CASERA431−2.7323.81972.9951.0023.62C3385CSERA431−4.2304.07073.1581.0024.38C3386OSERA431−4.6694.57274.1991.0023.43O3387CBSERA431−1.9925.15072.8111.0022.22C3388OGSERA431−2.5225.89571.7301.0021.34O3389NLYSA432−5.0103.71772.1371.0022.36N3390CALYSA432−6.4603.90972.1791.0022.42C3391CLYSA432−7.1922.56972.0571.0022.30C3392OLYSA432−6.6591.61771.4831.0021.03O3393CBLYSA432−6.9014.84571.0451.0021.17C3394CGLYSA432−6.1996.19771.0281.0022.07C3395CDLYSA432−6.4576.99472.3021.0020.21C3396CELYSA432−5.8498.39772.2151.0021.80C3397NZLYSA432−4.3628.37772.0721.0020.51N3398NMETA433−8.4072.49372.5991.0022.14N3399CAMETA433−9.1841.25672.5291.0021.98C3400CMETA433−9.3530.84671.0701.0022.79C3401OMETA433−9.509−0.33570.7511.0021.12O3402CBMETA433−10.5581.43473.1831.0021.48C3403CGMETA433−10.5061.61874.7001.0024.54C3404SDMETA433−9.4770.37775.5431.0024.96S3405CEMETA433−10.431−1.11975.2831.0021.52C3406NVALA434−9.3321.83670.1841.0022.13N3407CAVALA434−9.4531.57068.7651.0020.48C3408CVALA434−8.0461.61868.2061.0020.18C3409OVALA434−7.4332.68268.1251.0021.08O3410CBVALA434−10.3252.62368.0511.0021.57C3411CG1VALA434−10.2322.43966.5331.0019.72C3412CG2VALA434−11.7742.49068.5121.0019.15C3413NVALA435−7.5350.45267.8351.0019.61N3414CAVALA435−6.1980.34767.2921.0019.65C3415CVALA435−6.1141.01165.9281.0021.46C3416OVALA435−6.9960.85565.0801.0021.49O3417CBVALA435−5.765−1.12867.1741.0019.30C3418CG1VALA435−4.340−1.21766.6361.0016.47C3419CG2VALA435−5.862−1.79968.5351.0020.51C3420NGLNA436−5.0351.75365.7311.0022.68N3421CAGLNA436−4.7912.46364.4871.0023.45C3422CGLNA436−3.3602.19064.0811.0023.02C3423OGLNA436−2.4952.00264.9371.0021.52O3424CBGLNA436−4.9533.96764.7031.0025.05C3425CGGLNA436−6.3434.38365.1241.0030.17C3426CDGLNA436−7.2524.59963.9391.0031.45C3427OE1GLNA436−7.1843.86862.9541.0035.33O3428NE2GLNA436−8.1175.60264.0301.0033.60N3429NLEUA437−3.1112.16262.7791.0021.99N3430CALEUA437−1.7601.96762.2901.0021.67C3431CLEUA437−1.0263.23962.7031.0021.51C3432OLEUA437−1.5824.33062.6281.0021.61O3433CBLEUA437−1.7551.84160.7631.0020.41C3434CGLEUA437−0.3901.64360.0961.0018.38C3435CD1LEUA4370.1720.27860.4741.0018.84C3436CD2LEUA437−0.5351.76358.5881.0014.38C3437NALAA4380.2103.10063.1631.0021.56N3438CAALAA4380.9914.26263.5621.0020.99C3439CALAA4381.7314.80462.3441.0020.49C3440OALAA4381.9554.08261.3731.0018.88O3441CBALAA4381.9913.86964.6481.0022.78C3442NOLNA4392.0946.08262.3871.0021.06N3443CAGLNA4392.8376.69161.2911.0020.80C3444CGLNA4394.2397.03561.7901.0021.17C3445OGLNA4394.4537.21562.9851.0022.54O3446CBGLNA4392.1347.95360.7951.0020.83C3447CGGLNA4390.7637.70460.1921.0022.46C3448CDGLNA4390.0928.98959.7521.0022.24C3449OE1GLNA439−0.0659.91960.5441.0023.41O3450NE2GLNA439−0.3099.05058.4851.0020.50N3451NPROA4405.2167.13160.8771.0021.18N3452CAPROA4405.0736.93959.4311.0019.89C3453CPROA4404.8675.48858.9781.0020.52C3454OPROA4405.2764.53359.6501.0019.75O3455CBPROA4406.3707.53158.8841.0020.41C3456CGPROA4407.3587.16759.9361.0021.04C3457CDPROA4406.6087.46761.2281.0020.19C3458NALAA4414.2205.34357.8291.0018.52N3459CAALAA4413.9714.04357.2201.0021.13C3460CALAA4414.0894.34155.7341.0021.53C3461OALAA4413.1174.24554.9801.0019.47O3462CBALAA4412.5733.54357.5621.0018.03C3463NCYSA4425.2974.72655.3331.0022.57N3464CACYSA4425.5775.09753.9521.0023.43C3465CCYSA4425.8373.93553.0131.0022.43C3466OCYSA4426.6433.04753.2941.0023.97O3467CBCYSA4426.7556.06953.9171.0025.86C3468SGCYSA4426.4417.56254.8831.0033.08S3469NVALA4435.1563.96651.8781.0021.13N3470CAVALA4435.2752.92050.8821.0021.19C3471CVALA4435.4423.50549.4811.0021.86C3472OVALA4434.7824.47749.1291.0022.99O3473CBVALA4434.0202.01550.9201.0019.26C3474CG1VALA4434.0271.04549.7561.0018.29C3475CG2VALA4433.9751.26652.2441.0017.19C3476NARGA4446.3382.91548.6951.0022.91N3477CAARGA4446.5723.36047.3251.0024.75C3478CARGA4445.7372.51046.3771.0024.73C3479OARGA4445.5661.30846.5921.0025.36O3480CBARGA4448.0413.18746.9211.0026.54C3481CGARGA4449.0404.06047.6371.0031.38C3482CDARGA44410.3843.99146.9151.0035.45C3483NEARGA44410.8952.62346.8351.0037.84N3484CZARGA44411.6502.04747.7671.0037.89C3485NH1ARGA44411.9922.72248.8571.0036.60N3486NH2ARGA44412.0550.79047.6131.0037.46N3487NTYRA4455.2283.12845.3191.0023.39N3488CATYRA4454.4482.39144.3341.0023.62C3489CTYRA4454.9732.75342.9541.0024.15C3490OTYRA4455.6343.77742.7871.0021.59O3491CBTYRA4452.9582.74144.4421.0020.58C3492CGTYRA4452.6364.18144.1211.0019.39C3493CD1TYRA4452.5974.63242.7991.0017.80C3494CD2TYRA4452.3935.09945.1391.0016.06C3495CE1TYRA4452.3245.96142.5011.0017.78C3496CE2TYRA4452.1206.42844.8551.0018.77C3497CZTYRA4452.0886.85343.5341.0019.01C3498OHTYRA4451.8388.17343.2541.0017.86O3499NARGA4464.6871.89741.9791.0025.22N3500CAARGA4465.1002.10840.5981.0026.61C3501CARGA4464.1841.28439.7111.0027.09C3502OARGA4463.8600.14440.0421.0025.53O3503CBARGA4466.5541.67040.3931.0028.87C3504CGARGA4466.9871.62838.9331.0034.44C3505CDARGA4468.4881.38338.7941.0039.72C3506NEARGA4469.2702.59039.0551.0043.04N3507CZARGA4469.3063.64538.2461.0044.92C3508NH1ARGA4468.6073.64537.1171.0047.79N3509NH2ARGA44610.0334.70638.5671.0046.87N3510NARGA4473.7531.85638.5921.0028.93N3511CAARGA4472.8711.12537.6931.0031.84C3512CARGA4473.509−0.18437.2771.0033.54C3513OARGA4474.714−0.24337.0371.0033.99O3514CBARGA4472.5491.94136.4391.0031.92C3515CCARGA4471.3862.89136.5961.0030.46C3516CDARGA4470.9613.46435.2521.0029.32C3517NEARGA447−0.0244.52935.4061.0026.78N3518CZARGA447−1.2584.35435.8661.0028.65C3519NH1ARGA447−1.6723.14736.2211.0027.68N3520NH2ARGA447−2.0825.39135.9731.0029.90N3521NARGA4482.699−1.23637.2071.0035.45N3522CAARGA4483.195−2.53836.7931.0038.60C3523CARGA4483.394−2.51235.2851.0041.71C3524OARGA4482.788−1.69634.5911.0041.82O3525CBARGA4482.200−3.63537.1581.0036.35C3526CGARGA4482.046−3.87138.6471.0035.61C3527CDARGA4481.193−5.09838.8761.0035.48C3528NEARGA4481.754−6.25638.1881.0032.11N3529CZARGA4481.068−7.35237.8901.0031.52C3530NH1ARGA448−0.212−7.44438.2201.0033.83N3531NH2ARGA4481.662−8.35637.2611.0030.31N3532NTHRA4494.240−3.40734.7871.0046.19N3533CATHRA4494.531−3.49533.3591.0049.73C3534CTHRA4495.338−2.27832.9171.0051.56C3535OTHRA4496.557−2.43232.6911.0052.96O3536CBTHRA4493.231−3.55932.5301.0050.52C3537OG1THRA4492.472−4.71132.9201.0051.81O3538CG2THRA4493.545−3.63031.0421.0051.92C3539OXTTHRA4494.747−1.18232.8181.0052.35O

[0535]

7

TABLE 3

ATOMIC STRUCTURE COORDINATE DATA OBTAINED FROM X-RAY

DIFFRACTION FROM MT CYP51 COMPLEXED WITH

FLUCONAZOLE

ATOM

PROTEIN

ATOM
TYPE
RESIDUE
#
#
X
Y
Z
OCC
B
ATOM

1
N
ALA
A
3
−14.763
−13.683
100.347
1.00
49.82
N

2
CA
ALA
A
3
−14.759
−13.806
98.856
1.00
50.45
C

3
C
ALA
A
3
−13.343
−14.025
98.327
1.00
49.54
C

4
O
ALA
A
3
−12.509
−13.118
98.350
1.00
48.65
O

5
CB
ALA
A
3
−15.371
−12.553
98.227
1.00
51.16
C

6
N
VAL
A
4
−13.088
−15.237
97.845
1.00
49.20
N

7
CA
VAL
A
4
−11.781
−15.620
97.314
1.00
48.77
C

8
C
VAL
A
4
−11.248
−14.700
96.215
1.00
46.92
C

9
O
VAL
A
4
−11.986
−14.274
95.325
1.00
46.78
O

10
CB
VAL
A
4
−11.816
−17.070
96.758
1.00
49.91
C

11
CG1
VAL
A
4
−10.486
−17.417
96.092
1.00
49.37
C

12
CG2
VAL
A
4
−12.108
−18.048
97.886
1.00
51.16
C

13
N
ALA
A
5
−9.955
−14.403
96.285
1.00
44.76
N

14
CA
ALA
A
5
−9.313
−13.557
95.287
1.00
42.96
C

15
C
ALA
A
5
−8.981
−14.395
94.059
1.00
41.01
C

16
O
ALA
A
5
−8.600
−15.564
94.172
1.00
40.79
O

17
CB
ALA
A
5
−8.033
−12.946
95.852
1.00
42.74
C

18
N
LEU
A
6
−9.143
−13.801
92.885
1.00
38.16
N

19
CA
LEU
A
6
−8.828
−14.493
91.647
1.00
36.43
C

20
C
LEU
A
6
−7.376
−14.164
91.347
1.00
32.97
C

21
O
LEU
A
6
−6.843
−13.186
91.864
1.00
32.34
O

22
CB
LEU
A
6
−9.727
−14.000
90.508
1.00
37.43
C

23
CG
LEU
A
6
−11.203
−14.412
90.550
1.00
40.26
C

24
CD1
LEU
A
6
−11.321
−15.922
90.462
1.00
40.27
C

25
CD2
LEU
A
6
−11.849
−13.910
91.831
1.00
40.69
C

26
N
PRO
A
7
−6.703
−14.990
90.537
1.00
31.19
N

27
CA
PRO
A
7
−5.302
−14.664
90.245
1.00
30.87
C

28
C
PRO
A
7
−5.204
−13.229
89.715
1.00
30.06
C

29
O
PRO
A
7
−6.056
−12.795
88.938
1.00
28.45
O

30
CB
PRO
A
7
−4.920
−15.708
89.199
1.00
30.14
C

31
CG
PRO
A
7
−5.736
−16.895
89.613
1.00
29.76
C

32
CD
PRO
A
7
−7.087
−16.276
89.934
1.00
29.11 C

33
N
ARG
A
8
−4.174
−12.505
90.151
1.00
30.08
N

34
CA
ARG
A
8
−3.947
−11.116
89.750
1.00
29.96
C

35
C
ARG
A
8
−2.532
−10.957
89.209
1.00
28.71 C

36
O
ARG
A
8
−1.568
−11.398
89.839
1.00
28.60
O

37
CB
ARG
A
8
−4.155
−10.184
90.958
1.00
32.82
C

38
CG
ARC
A
8
−3.777
−8.709
90.740
1.00
35.99
C

39
CD
ARC
A
8
−4.488
−8.104
89.535
1.00
39.84
C

40
NE
ARC
A
8
−5.942
−8.151
89.661
1.00
43.72
N

41
CZ
ARG
A
8
−6.657
−7.347
90.441
1.00
45.49
C

42
NH1
ARG
A
8
−6.057
−6.415
91.172
1.00
46.06
N

43
NH2
ARG
A
8
−7.976
−7.488
90.503
1.00
47.11
N

44
N
VAL
A
9
−2.407
−10.330
88.041
1.00
27.10
N

45
CA
VAL
A
9
−1.101
−10.131
87.420
1.00
25.67
C

46
C
VAL
A
9
−0.294
−9.067
88.161
1.00
27.18
C

47
O
VAL
A
9
−0.857
−8.189
88.820
1.00
28.32
O

48
CB
VAL
A
9
−1.250
−9.732
85.924
1.00
24.18
C

49
CG1
VAL
A
9
−1.989
−8.411
85.809
1.00
21.98
C

50
CG2
VAL
A
9
0.122
−9.647
85.252
1.00
21.33
C

51
N
SER
A
10
1.030
−9.153
88.050
1.00
29.73
N

52
CA
SER
A
10
1.942
−8.217
88.708
1.00
28.03
C

53
C
SER
A
10
1.818
−6.779
88.198
1.00
27.68
C

54
O
SER
A
10
1.163
−6.520
87.191
1.00
26.32
O

55
CB
SER
A
10
3.386
−8.703
88.537
1.00
29.33
C

56
OG
SER
A
10
3.711
−8.897
87.168
1.00
30.58
O

57
N
GLY
A
11
2.453
−5.845
88.902
1.00
27.26
N

58
CA
GLY
A
11
2.399
−4.449
88.502
1.00
26.68
C

59
C
GLY
A
11
1.054
−3.842
88.840
1.00
26.65
C

60
O
GLY
A
11
0.363
−4.321
89.735
1.00
26.69
O

61
N
GLY
A
12
0.678
−2.785
88.127
1.00
27.21
N

62
CA
GLY
A
12
−0.606
−2.149
88.380
1.00
28.89
C

63
C
GLY
A
12
−0.628
−1.249
89.605
1.00
30.60
C

64
O
GLY
A
12
−1.659
−1.113
90.271
1.00
28.07
O

65
N
HIS
A
13
0.508
−0.621
89.895
1.00
31.76
N

66
CA
HIS
A
13
0.617
0.260
91.044
1.00
34.70
C

67
C
HIS
A
13
0.519
1.739
90.663
1.00
35.43
C

68
O
HIS
A
13
0.784
2.612
91.494
1.00
35.90
O

69
CB
HIS
A
13
1.939
−0.003
91.764
1.00
38.90
C

70
OG
HIS
A
13
2.220
−1.457
91.990
1.00
43.60
C

71
ND1
HIS
A
13
1.354
−2.285
92.674
1.00
45.67
N

72
CD2
HIS
A
13
3.263
−2.234
91.610
1.00
44.08
C

73
CE1
HIS
A
13
1.851
−3.510
92.703
1.00
46.26
C

74
NE2
HIS
A
13
3.008
−3.505
92.064
1.00
46.21
N

75
N
ASP
A
14
0.156
2.025
89.412
1.00
35.02
N

76
CA
ASP
A
14
0.016
3.412
88.971
1.00
36.28
C

77
C
ASP
A
14
−1.315
3.959
89.481
1.00
37.25
C

78
O
ASP
A
14
−2.096
3.222
90.085
1.00
38.76
O

79
CB
ASP
A
14
0.076
3.511
87.447
1.00
36.77
C

80
CG
ASP
A
14
1.435
3.116
86.888
1.00
38.08
C

81
OD1
ASP
A
14
2.465
3.600
87.409
1.00
36.86
O

82
OD2
ASP
A
14
1.472
2.326
85.919
1.00
38.73
O

83
N
GLU
A
15
−1.586
5.238
89.233
1.00
36.94
N

84
CA
GLU
A
15
−2.823
5.849
89.728
1.00
37.59
C

85
C
GLU
A
15
−4.109
5.077
89.452
1.00
34.84
C

86
O
GLU
A
15
−4.969
4.976
90.316
1.00
34.65
O

87
CB
GLU
A
15
−2.973
7.281
89.205
1.00
38.44
C

88
CG
GLU
A
15
−4.259
7.942
89.672
1.00
41.49
C

89
CD
GLU
A
15
−4.186
9.454
89.665
1.00
43.71
C

90
OE1
GLU
A
15
−3.381
10.012
90.440
1.00
46.13
O

91
OE2
GLU
A
15
−4.935
10.084
88.891
1.00
45.48
O

92
N
HIS
A
16
−4.247
4.536
88.252
1.00
33.17
N

93
CA
HIS
A
16
−5.444
3.786
87.916
1.00
31.36
C

94
C
HIS
A
16
−5.143
2.296
87.774
1.00
31.14
C

95
O
HIS
A
16
−5.682
1.619
86.893
1.00
31.38
O

96
CB
HIS
A
16
−6.059
4.338
86.630
1.00
31.37
C

97
CG
HIS
A
16
−6.533
5.755
86.751
1.00
31.85
C

98
ND1
HIS
A
16
−7.628
6.113
87.510
1.00
31.44
N

99
CD2
HIS
A
16
−6.054
6.904
86.218
1.00
30.01
C

100
CE1
HIS
A
16
−7.805
7.420
87.437
1.00
30.57
C

101
NE2
HIS
A
16
−6.862
7.924
86.659
1.00
32.18
N

102
N
GLY
A
17
−4.282
1.793
88.654
1.00
29.27
N

103
CA
GLY
A
17
−3.940
0.381
88.627
1.00
27.41
C

104
C
GLY
A
17
−3.128
−0.013
87.413
1.00
27.09
C

105
O
GLY
A
17
−2.016
0.480
87.215
1.00
25.12
O

106
N
HIS
A
18
−3.689
−0.904
86.599
1.00
26.01
N

107
CA
HIS
A
18
−3.027
−1.371
85.390
1.00
26.38
C

108
C
HIS
A
18
−3.420
−0.547
84.178
1.00
27.63
C

109
O
HIS
A
18
−2.888
−0.758
83.078
1.00
26.96
O

110
CB
HIS
A
18
−3.391
−2.824
85.107
1.00
23.49
C

111
CG
HIS
A
18
−2.648
−3.813
85.948
1.00
24.04
C

112
ND1
HIS
A
18
−3.225
−4.467
87.015
1.00
22.78
N

113
CD2
HIS
A
18
−1.379
−4.278
85.863
1.00
22.49
C

i14
CEI
HIS
A
18
−2.345
−5.294
87.549
1.00
23.50
C

115
NE2
HIS
A
18
−1.217
−5.199
86.868
1.00
20.74
N

116
N
LEU
A
19
−4.349
0.385
84.367
1.00
27.22
N

117
CA
LEU
A
i9
−4.813
1.192
83.249
1.00
26.97
C

118
C
LEU
A
19
−3.675
1.853
82.496
1.00
27.97
C

119
O
LEU
A
19
−3.622
1.772
81.268
1.00
27.85
O

120
CB
LEU
A
19
−5.811
2.249
83.713
1.00
27.65
C

121
CG
LEU
A
19
−6.522
2.961
82.558
1.00
28.05
C

122
CD1
LEU
A
19
−7.912
3.351
82.988
1.00
29.42
C

123
CD2
LEU
A
19
−5.729
4.168
82.111
1.00
27.86
C

124
N
GLU
A
20
−2.761
2.494
83.220
1.00
26.69
N

125
CA
GLU
A
20
−1.637
3.169
82.579
1.00
28.78
C

126
C
GLU
A
20
−0.843
2.235
81.678
1.00
28.51
C

127
O
GLU
A
20
−0.498
2.591
80.556
1.00
28.99
O

128
CB
GLU
A
20
−0.696
3.785
83.622
1.00
28.78
C

129
CG
GLU
A
20
−1.186
5.090
84.225
1.00
31.37
C

130
CD
GLU
A
20
−2.365
4.908
85.164
1.00
33.31
C

131
CE1
GLU
A
20
−2.693
3.751
85.506
1.00
31.79
O

132
OE2
GLU
A
20
−2.957
5.933
85.569
1.00
34.92
O

133
N
GLU
A
21
−0.539
1.043
82.171
1.00
29.59
N

134
CA
GLU
A
21
0.213
0.089
81.371
1.00
30.40
C

135
C
GLU
A
21
−0.641
−0.404
80.207
1.00
31.08
C

136
O
GLU
A
21
−0.125
−0.732
79.136
1.00
32.36
O

137
CB
GLU
A
21
0.661
−1.101
82.231
1.00
29.37
C

138
CG
GLU
A
21
1.275
−2.237
81.425
1.00
28.43
C

139
CD
GLU
A
21
1.838
−3.350
82.290
1.00
30.42
C

140
OE1
GLU
A
21
1.315
−3.572
83.407
1.00
28.90
O

141
OE2
GLU
A
21
2.796
−4.014
81.839
1.00
27.92
O

142
N
PHE
A
22
−1.951
−0.460
80.412
1.00
31.42
N

143
CA
PHE
A
22
−2.831
−0.923
79.349
1.00
32.26
C

144
C
PHE
A
22
−2.805
0.068
78.194
1.00
32.45
C

145
O
PHE
A
22
−3.014
−0.302
77.036
1.00
32.99
O

146
CB
PHE
A
22
−4.270
−1.076
79.843
1.00
31.87
C

147
CG
PHE
A
22
−5.138
−1.847
78.893
1.00
34.50
C

148
CD1
PHE
A
22
−5.167
−3.240
78.934
1.00
33.49
C

149
CD2
PHE
A
22
−5.852
−1.192
77.893
1.00
35.56
C

150
CE1
PHE
A
22
−5.885
−3.966
77.991
1.00
32.44
C

151
CE2
PHE
A
22
−6.574
−1.913
76.944
1.00
34.79
C

152
CZ
PHE
A
22
−6.588
−3.302
76.995
1.00
33.74
C

153
N
ARG
A
23
−2.545
1.331
78.515
1.00
32.27
N

154
CA
ARG
A
23
−2.496
2.364
77.498
1.00
32.54
C

155
C
ARG
A
23
−1.185
2.321
76.722
1.00
32.50
C

156
O
ARG
A
23
−1.173
2.503
75.506
1.00
32.79
O

157
CB
ARG
A
23
−2.664
3.751
78.124
1.00
32.84
C

158
CC
ARG
A
23
−2.541
4.871
77.099
1.00
36.21
C

159
CD
ARG
A
23
−2.531
6.260
77.721
1.00
37.78
C

160
NE
ARG
A
23
−3.760
6.567
78.444
1.00
37.93
N

161
CZ
ARG
A
23
−3.838
6.679
79.765
1.00
39.02
C

162
NH1
ARG
A
23
−2.754
6.505
80.512
1.00
37.02
N

163
NH2
ARG
A
23
−4.998
6.975
80.337
1.00
39.11
N

164
N
THR
A
24
−0.079
2.073
77.415
1.00
31.21
N

165
CA
THR
A
24
1.213
2.049
76.744
1.00
31.22
C

166
C
THR
A
24
1.582
0.706
76.105
1.00
31.11
C

167
O
THR
A
24
2.268
0.673
75.081
1.00
31.03
O

168
CB
THR
A
24
2.340
2.509
77.709
1.00
31.80
C

169
OG1
THR
A
24
2.422
1.619
78.827
1.00
33.63
O

170
CG2
THR
A
24
2.042
3.906
78.232
1.00
31.43
C

171
N
ASP
A
25
1.114
−0.397
76.685
1.00
30.51
N

172
CA
ASP
A
25
1.426
−1.722
76.145
1.00
29.11
C

173
C
ASP
A
25
0.386
−2.762
76.571
1.00
27.36
C

174
O
ASP
A
25
0.689
−3.671
77.341
1.00
28.36
O

175
CB
ASP
A
25
2.813
−2.152
76.631
1.00
31.30
C

176
CG
ASP
A
25
3.228
−3.503
76.090
1.00
34.32
C

177
OD1
ASP
A
25
2.517
−4.038
75.214
1.00
37.30
O

178
OD2
ASP
A
25
4.269
−4.029
76.535
1.00
34.61
O

179
N
PRO
A
26
−0.851
−2.653
76.056
1.00
26.20
N

180
CA
PRO
A
26
−1.928
−3.589
76.399
1.00
23.79
C

181
C
PRO
A
26
−1.636
−5.060
76.096
1.00
24.23
C

182
O
PRO
A
26
−2.037
−5.946
76.855
1.00
23.28
O

183
CB
PRO
A
26
−3.117
−3.057
75.592
1.00
24.86
C

184
CC
PRO
A
26
−2.457
−2.467
74.382
1.00
25.21
C

185
CD
PRO
A
26
−1.285
−1.724
74.994
1.00
24.03
C

186
N
WE
A
27
−0.948
−5.317
74.985
1.00
23.69
N

187
CA
ILE
A
27
−0.620
−6.684
74.577
1.00
22.71
C

188
C
ILE
A
27
0.400
−7.305
75.528
1.00
22.96
C

189
O
ILE
A
27
0.217
−8.432
75.997
1.00
21.41
O

190
CB
ILE
A
27
−0.088
−6.707
73.109
1.00
21.77
C

191
CG1
ILE
A
27
−1.213
−6.289
72.155
1.00
19.10
C

192
CG2
ILE
A
27
0.421
−8.103
72.742
1.00
21.15
C

193
CD1
ILE
A
27
−0.804
−6.220
70.698
1.00
18.79
C

194
N
CLY
A
28
1.466
−6.563
75.821
1.00
23.13
N

195
CA
CLY
A
28
2.471
−7.059
76.739
1.00
22.71
C

196
C
CLY
A
28
1.823
−7.343
78.084
1.00
22.95
C

197
O
CLY
A
28
2.102
−8.360
78.719
1.00
22.36
O

198
N
LEU
A
29
0.945
−6.444
78.516
1.00
23.26
N

199
CA
LEU
A
29
0.249
−6.603
79.790
1.00
24.19
C

200
C
LEU
A
29
−0.622
−7.861
79.808
1.00
24.95
C

201
O
LEU
A
29
−0.569
−8.651
80.758
1.00
24.56
O

202
CB
LEU
A
29
−0.621
−5.369
80.075
1.00
23.39
C

203
CC
LEU
A
29
−1.726
−5.517
81.132
1.00
25.25
C

204
CD1
LEU
A
29
−1.123
−5.824
82.509
1.00
25.17
C

205
CD2
LEU
A
29
−2.537
−4.238
81.183
1.00
23.97
C

206
N
MET
A
30
−1.427
−8.038
78.763
1.00
24.77
N

207
CA
MET
A
30
−2.310
−9.197
78.672
1.00
25.61
C

208
C
MET
A
30
−1.523
−10.507
78.570
1.00
25.56
C

209
O
MET
A
30
−1.968
−11.550
79.070
1.00
24.34
O

210
OB
MET
A
30
−3.260
−9.048
77.477
1.00
23.98
C

211
CG
MET
A
30
−4.301
−7.941
77.671
1.00
26.49
C

212
SD
MET
A
30
−5.602
−7.894
76.409
1.00
24.65
S

213
CE
MET
A
30
−4.659
−7.271
75.011
1.00
21.88
C

214
N
GLN
A
31
−0.356
−10.455
77.931
1.00
24.43
N

215
CA
GLN
A
31
0.467
−11.649
77.807
1.00
24.99
C

216
C
GLN
A
31
1.016
−12.016
79.168
1.00
25.40
C

217
O
GLN
A
31
1.090
−13.191
79.503
1.00
28.36
O

218
CB
GLN
A
31
1.635
−11.437
76.840
1.00
24.55
C

219
CG
GLN
A
31
2.448
−12.717
76.591
1.00
23.10
C

220
CD
GLN
A
31
1.597
−13.836
76.016
1.00
25.85
C

221
OE1
GLN
A
31
1.040
−13.698
74.928
1.00
27.38
O

222
NE2
GLN
A
31
1.477
−14.947
76.749
1.00
24.52
N

223
N
ARG
A
32
1.407
−11.015
79.957
1.00
24.93
N

224
CA
ARG
A
32
1.940
−11.293
81.283
1.00
24.69
C

225
C
ARG
A
32
0.843
−11.878
82.171
1.00
25.56
C

226
O
ARG
A
32
1.122
−12.665
83.073
1.00
24.92
O

227
CB
ARG
A
32
2.531
−10.030
81.930
1.00
24.56
C

228
CG
ARG
A
32
3.322
−10.361
83.186
1.00
23.56
C

229
CD
ARG
A
32
4.162
−9.218
83.711
1.00
22.54
C

230
NE
ARG
A
32
3.372
−8.178
84.363
1.00
22.79
N

231
CZ
ARG
A
32
2.984
−7.058
83.767
1.00
20.83
C

232
NH1
ARG
A
32
3.315
−6.830
82.498
1.00
20.87
N

233
NH2
ARG
A
32
2.272
−6.165
84.441
1.00
17.74
N

234
N
VAL
A
33
−0.407
−11.498
81.910
1.00
25.79
N

235
CA
VAL
A
33
−1.521
−12.025
82.684
1.00
26.24
C

236
C
VAL
A
33
−1.570
−13.544
82.515
1.00
26.35
C

237
O
VAL
A
33
−1.583
−14.286
83.498
1.00
27.14
O

238
CD
VAL
A
33
−2.869
−11.417
82.227
1.00
26.55
C

239
CG1
VAL
A
33
−4.031
−12.248
82.767
1.00
25.53
C

240
CG2
VAL
A
33
−2.988
−9.979
82.729
1.00
25.34
C

241
N
ARG
A
34
−1.576
−14.004
81.266
1.00
25.80
N

242
CA
ARG
A
34
−1.623
−15.432
80.984
1.00
23.78
C

243
C
ARG
A
34
−0.376
−16.160
81.485
1.00
23.67
C

244
O
ARG
A
34
−0.481
−17.223
82.090
1.00
21.83
O

245
CB
ARG
A
34
−1.798
−15.668
79.481
1.00
25.08
C

246
CG
ARG
A
34
−1.805
−17.144
79.067
1.00
23.93
C

247
CD
ARG
A
34
−2.107
−17.293
77.585
1.00
27.78
C

248
NE
ARG
A
34
−1.889
−18.653
77.092
1.00
28.14
N

249
CZ
ARO
A
34
−2.675
−19.688
77.361
1.00
28.23
C

250
NH1
ARG
A
34
−3.750
−19.528
78.120
1.00
29.65
N

251
NH2
ARG
A
34
−2.377
−20.893
76.883
1.00
29.78
N

252
N
ASP
A
35
0.802
−15.595
81.234
1.00
23.87
N

253
CA
ASP
A
35
2.040
−16.231
81.682
1.00
24.82
C

254
C
ASP
A
35
2.030
−16.443
83.198
1.00
25.86
C

255
O
ASP
A
35
2.296
−17.541
83.682
1.00
26.84
O

256
CB
ASP
A
35
3.267
−15.385
81.314
1.00
22.78
C

257
CC
ASP
A
35
3.502
−15.293
79.815
1.00
23.72
C

258
OD1
ASP
A
35
3.000
−16.155
79.051
1.00
23.53
O

259
OD2
ASP
A
35
4.215
−14.354
79.405
1.00
20.66
O

260
N
GLU
A
36
1.721
−15.388
83.943
1.00
25.39
N

261
CA
GLU
A
36
1.691
−15.472
85.398
1.00
25.29
C

262
C
GLU
A
36
0.448
−16.167
85.972
1.00
27.79
C

263
O
GLU
A
36
0.552
−16.954
86.922
1.00
29.24
O

264
CB
GLU
A
36
1.784
−14.067
86.011
1.00
24.35
C

265
CG
GLU
A
36
3.032
−13.269
85.649
1.00
24.58
C

266
CD
GLU
A
36
3.092
−11.915
86.357
1.00
25.55
C

267
OE1
GLU
A
36
2.119
−11.557
87.060
1.00
26.00
O

268
OE2
GLU
A
36
4.113
−11.204
86.213
1.00
25.26
O

269
N
CYS
A
37
−0.723
−15.885
85.401
1.00
26.50
N

270
CA
CYS
A
37
−1.968
−16.443
85.920
1.00
25.69
C

271
C
CYS
A
37
−2.544
−17.674
85.250
1.00
26.21
C

272
O
CYS
A
37
−3.211
−18.480
85.902
1.00
26.09
O

273
CB
CYS
A
37
−3.046
−15.360
85.935
1.00
24.93
C

274
SG
CYS
A
37
−2.557
−13.871
86.820
1.00
27.45
S

275
N
GLY
A
38
−2.315
−17.817
83.950
1.00
27.99
N

276
CA
GLY
A
38
−2.864
−18.961
83.247
1.00
27.79
C

277
C
GLY
A
38
−4.151
−18.576
82.541
1.00
28.12
C

278
O
GLY
A
38
−4.384
−17.394
82.292
1.00
28.92
O

279
N
ASP
A
39
−4.988
−19.568
82.239
1.00
27.50
N

280
CA
ASP
A
39
−6.252
−19.358
81.5333
1.00
27.22
C

281
C
ASP
A
39
−7.186
−18.322
82.146
1.00
28.44
C

282
O
ASP
A
39
−8.017
−17.743
81.441
1.00
27.81
O

283
CB
ASP
A
39
−7.008
−20.678
81.420
1.00
28.97
C

284
CG
ASP
A
39
−6.257
−21.718
80.614
1.00
30.19
C

285
OD1
ASP
A
39
−5.294
−21.352
79.906
1.00
29.11
O

286
OD2
ASP
A
39
−6.642
−22.907
80.690
1.00
32.77
O

287
N
VAL
A
40
−7.064
−18.101
83.454
1.00
28.10
N

288
CA
VAL
A
40
−7.914
−17.138
84.153
1.00
27.45
C

289
C
VAL
A
40
−7.099
−16.215
85.052
1.00
27.27
C

290
O
VAL
A
40
−6.677
−16.617
86.132
1.00
29.11
O

291
CB
VAL
A
40
−8.954
−17.845
85.045
1.00
26.94
C

292
CG1
VAL
A
40
−9.933
−16.818
85.624
1.00
25.86
C

293
CG2
VAL
A
40
−9.685
−18.912
84.252
1.00
27.02
C

294
N
GLY
A
41
−6.886
−14.983
84.602
1.00
26.50
N

295
CA
GLY
A
41
−6.133
−14.022
85.385
1.00
25.68
C

296
C
GLY
A
41
−6.863
−12.695
85.384
1.00
26.16
C

297
O
GLY
A
41
−7.835
−12.527
84.652
1.00
26.38
O

298
N
THR
A
42
−6.417
−11.744
86.197
1.00
24.40
N

299
CA
THR
A
42
−7.088
−10.447
86.230
1.00
23.31
C

300
C
THR
A
42
−6.119
−9.289
86.282
1.00
23.83
C

301
O
THR
A
42
−4.947
−9.450
86.626
1.00
24.79
O

302
CB
THR
A
42
−8.008
−10.297
87.459
1.00
21.89
C

303
OG1
THR
A
42
−7.207
−10.240
88.652
1.00
20.56
O

304
CG2
THR
A
42
−8.980
−11.467
87.549
1.00
20.31
C

305
N
PHE
A
43
−6.623
−8.121
85.908
1.00
24.73
N

306
CA
PHE
A
43
−5.852
−6.893
85.967
1.00
26.19
C

307
C
PHE
A
43
−6.855
−5.786
86.269
1.00
27.55
C

308
O
PHE
A
43
−8.034
−5.894
85.935
1.00
27.36
O

309
CB
PHE
A
43
−5.034
−6.654
84.676
1.00
23.36
C

310
CG
PHE
A
43
−5.848
−6.378
83.436
1.00
21.73
C

311
CD1
PHE
A
43
−6.234
−5.076
83.113
1.00
20.44
C

312
CD2
PHE
A
43
−6.136
−7.406
82.537
1.00
19.77
C

313
CE1
PHE
A
43
−6.888
−4.799
81.902
1.00
22.37
C

314
CE2
PHE
A
43
−6.790
−7.146
81.321
1.00
22.12
C

315
CZ
PHE
A
43
−7.166
−5.838
81.000
1.00
20.48
C

316
N
GLN
A
44
−6.387
−4.753
86.955
1.00
29.63
N

317
CA
GLN
A
44
−7.236
−3.648
87.365
1.00
31.34
C

318
C
GLN
A
44
−7.253
−2.531
86.327
1.00
30.64
C

319
O
GLN
A
44
−6.211
−2.006
85.948
1.00
31.39
O

320
CB
GLN
A
44
−6.730
−3.119
88.708
1.00
33.72
C

321
CG
GLN
A
44
−7.683
−2.224
89.472
1.00
38.67
C

322
CD
GLN
A
44
−8.927
−2.953
89.941
1.00
41.28
C

323
OE1
GLN
A
44
−8.898
−4.161
90.190
1.00
42.74
O

324
NE2
GLN
A
44
−10.028
−2.215
90.086
1.00
41.02
N

325
N
LEU
A
45
−8.447
−2.181
85.863
1.00
29.37
N

326
CA
LEU
A
45
−8.600
−1.111
84.888
1.00
28.43
C

327
C
LEU
A
45
−9.329
0.023
85.599
1.00
27.93
C

328
O
LEU
A
45
−10.553
0.147
85.510
1.00
27.80
O

329
CB
LEU
A
45
−9.416
−1.603
83.694
1.00
28.85
C

330
OG
LEU
A
45
−9.191
−0.860
82.378
1.00
28.85
C

331
CD1
LEU
A
45
−7.734
−1.009
81.947
1.00
26.85
C

332
CD2
LEU
A
45
−10.118
−1.431
81.319
1.00
27.72
C

333
N
ALA
A
46
−8.562
0.847
86.306
1.00
28.89
N

334
CA
ALA
A
46
−9.109
1.957
87.081
1.00
29.25
C

335
C
ALA
A
46
−9.912
1.358
88.234
1.00
29.24
C

336
O
ALA
A
46
−9.356
0.653
89.073
1.00
30.26
O

337
CB
ALA
A
46
−9.988
2.842
86.213
1.00
27.01
C

338
N
GLY
A
47
−11.214
1.612
88.270
1.00
30.34
N

339
CA
GLY
A
47
−12.026
1.069
89.347
1.00
30.77
C

340
C
GLY
A
47
−12.752
−0.227
89.021
1.00
31.12
C

341
O
GLY
A
47
−13.575
−0.698
89.814
1.00
33.33
O

342
N
LYS
A
48
−12.460
−0.806
87.859
1.00
29.86
N

343
CA
LYS
A
48
−13.092
−2.053
87.436
1.00
29.46
C

344
C
LYS
A
48
−12.080
−3.186
87.291
1.00
27.66
C

345
O
LYS
A
48
−10.999
−2.993
86.738
1.00
27.25
O

346
CB
LYS
A
48
−13.807
−1.859
86.095
1.00
31.84
C

347
CG
LYS
A
48
−15.134
−1.106
86.166
1.00
37.06
C

348
CD
LYS
A
48
−16.236
−1.957
86.811
1.00
39.98
C

349
CE
LYS
A
48
−17.615
−1.308
86.654
1.00
43.31
C

350
NZ
LYS
A
48
−17.663
0.091
87.183
1.00
43.08
N

351
N
GLN
A
49
−12.429
−4.366
87.791
1.00
25.67
N

352
CA
GLN
A
49
−11.548
−5.518
87.668
1.00
27.16
C

353
C
GLN
A
49
−11.851
−6.220
86.350
1.00
27.89
C

354
O
GLN
A
49
−13.018
−6.440
86.009
1.00
29.43
O

355
CB
GLN
A
49
−11.766
−6.505
88.817
1.00
26.79
C

356
CG
GLN
A
49
−11.294
−7.917
88.474
1.00
27.99
C

357
CD
GLN
A
49
−11.470
−8.901
89.611
1.00
26.27
C

358
OE1
GLN
A
49
−10.545
−9.143
90.388
1.00
25.40
O

359
NE2
GLN
A
49
−12.663
−9.469
89.718
1.00
25.93
N

360
N
VAL
A
50
−10.810
−6.576
85.604
1.00
26.01
N

361
CA
VAL
A
50
−11.016
−7.266
84.332
1.00
23.33
C

362
C
VAL
A
50
−10.561
−8.715
84.436
1.00
22.80
C

363
O
VAL
A
50
−9.381
−8.979
84.689
1.00
21.69
O

364
CB
VAL
A
50
−10.226
−6.590
83.181
1.00
21.59
C

365
CG1
VAL
A
50
−10.414
−7.388
81.873
1.00
21.62
C

366
CG2
VAL
A
50
−10.700
−5.160
82.996
1.00
21.80
C

367
N
VAL
A
51
−11.494
−9.647
84.258
1.00
22.15
N

368
CA
VAL
A
51
−11.175
−11.072
84.299
1.00
22.20
C

369
C
VAL
A
51
−10.865
−11.472
82.862
1.00
23.41
C

370
O
VAL
A
51
−11.774
−11.625
82.046
1.00
23.23
O

371
CB
VAL
A
51
−12.364
−11.917
84.808
1.00
24.12
C

372
CG1
VAL
A
51
−11.971
−13.393
84.863
1.00
22.66
C

373
CG2
VAL
A
51
−12.790
−11.437
86.191
1.00
25.71
C

374
N
LEU
A
52
−9.576
−11.623
82.562
1.00
23.35
N

375
CA
LEU
A
52
−9.108
−11.969
81.223
1.00
24.58
C

376
C
LEU
A
52
−8.959
−13.476
81.032
1.00
24.69
C

377
O
LEU
A
52
−8.154
−14.132
81.698
1.00
23.24
O

378
CB
LEU
A
52
−7.770
−11.268
80.941
1.00
21.25
C

379
CG
LEU
A
52
−7.072
−11.509
79.598
1.00
22.68
C

380
CD1
LEU
A
52
−7.939
−11.016
78.431
1.00
20.12
C

381
CD2
LEU
A
52
−5.743
−10.780
79.598
1.00
22.20
C

382
N
LEU
A
53
−9.744
−14.004
80.100
1.00
24.93
N

383
CA
LEU
A
53
−9.750
−15.428
79.789
1.00
23.37
C

384
C
LEU
A
53
−8.930
−15.730
78.545
1.00
23.27
C

385
O
LEU
A
53
−9.070
−15.060
77.517
1.00
23.43
O

386
CB
LEU
A
53
−11.188
−15.898
79.563
1.00
22.06
C

387
CG
LEU
A
53
−12.158
−15.603
80.712
1.00
22.29
C

388
CD1
LEU
A
53
−13.564
−16.046
80.351
1.00
22.13
C

389
CD2
LEU
A
53
−11.687
−16.318
81.953
1.00
22.73
C

390
N
SER
A
54
−8.081
−16.748
78.639
1.00
21.03
N

391
CA
SER
A
54
−7.258
−17.166
77.514
1.00
22.40
C

392
C
SER
A
54
−7.327
−18.688
77.440
1.00
23.57
C

393
O
SER
A
54
−7.744
−19.338
78.397
1.00
22.91
O

394
CB
SER
A
54
−5.807
−16.691
77.702
1.00
22.58
C

395
OG
SER
A
54
−5.323
−16.987
79.003
1.00
22.25
O

396
N
GLY
A
55
−6.925
−19.259
76.311
1.00
24.70
N

397
CA
GLY
A
55
−6.985
−20.703
76.182
1.00
26.05
C

398
C
GLY
A
55
−8.318
−21.123
75.595
1.00
26.59
C

399
O
GLY
A
55
−9.311
−20.404
75.704
1.00
25.80
O

400
N
SER
A
56
−8.338
−22.295
74.970
1.00
27.92
N

401
CA
SER
A
56
−9.537
−22.821
74.326
1.00
26.51
C

402
C
SER
A
56
−10.763
−22.988
75.223
1.00
26.48
C

403
O
SER
A
56
−11.869
−22.589
74.861
1.00
25.17
O

404
CB
SER
A
56
−9.219
−24.163
73.682
1.00
25.34
C

405
OG
SER
A
56
−10.349
−24.643
72.978
1.00
31.64
O

406
N
HIS
A
57
−10.568
−23.587
76.390
1.00
28.67
N

407
CA
HIS
A
57
−11.671
−23.834
77.314
1.00
29.77
C

408
C
HIS
A
57
−12.358
−22.565
77.824
1.00
28.83
C

409
O
HIS
A
57
−13.586
−22.455
77.757
1.00
28.34
O

410
CB
HIS
A
57
−11.176
−24.661
78.503
1.00
33.57
C

411
CG
HIS
A
57
−12.273
−25.147
79.396
1.00
38.66
C

412
ND1
HIS
A
57
−12.088
−25.378
80.743
1.00
42.27
N

413
CD2
HIS
A
57
−13.568
−25.447
79.137
1.00
42.27
C

414
CE1
HIS
A
57
−13.223
−25.797
81.275
1.00
43.98
C

415
NE2
HIS
A
57
−14.137
−25.848
80.323
1.00
43.32
N

416
N
ALA
A
58
−11.571
−21.620
78.339
1.00
27.53
N

417
CA
ALA
A
58
−12.107
−20.358
78.868
1.00
25.72
C

418
C
ALA
A
58
−12.724
−19.504
77.760
1.00
24.36
C

419
O
ALA
A
58
−13.765
−18.876
77.949
1.00

23.43
O

420
CB
ALA
A
58
−11.009
−19.580
79.577
1.00
23.22
C

421
N
ASN
A
59
−12.070
−19.480
76.605
1.00
24.39
N

422
CA
ASN
A
59
−12.580
−18.729
75.470
1.00
23.12
C

423
C
ASN
A
59
−13.952
−19.279
75.066
1.00
24.90
C

424
O
ASN
A
59
−14.885
−18.513
74.799
1.00
21.12
O

425
CB
ASN
A
59
−11.606
−18.835
74.292
1.00
20.68
C

426
CG
ASN
A
59
−10.508
−17.789
74.347
1.00
22.68
C

427
CD1
ASN
A
59
−10.291
−17.153
75.382
1.00
19.37
O

428
ND2
ASN
A
59
−9.802
−17.608
73.226
1.00
20.59
N

429
N
GLU
A
60
−14.075
−20.607
75.015
1.00
26.27
N

430
CA
GLU
A
60
−15.348
−21.219
74.635
1.00
27.32
C

431
C
GLU
A
60
−16.467
−20.712
75.534
1.00
26.74
C

432
O
GLU
A
60
−17.519
−20.285
75.053
1.00
27.15
O

433
CB
GLU
A
60
−15.284
−22.744
74.733
1.00
26.47
C

434
OG
GLU
A
60
−16.520
−23.411
74.154
1.00
27.57
C

435
CD
GLU
A
60
−16.479
−24.927
74.227
1.00
31.10
C

436
OE1
GLU
A
60
−15.371
−25.511
74.168
1.00
31.55
O

437
OE2
GLU
A
60
−17.565
−25.537
74.322
1.00
33.37
O

438
N
PHE
A
61
−16.236
−20.764
76.843
1.00
26.89
N

439
CA
PHE
A
61
−17.232
−20.294
77.799
1.00
27.44
C

440
C
PHE
A
61
−17.558
−18.844
77.503
1.00
27.44
C

441
O
PHE
A
61
−18.706
−18.423
77.604
1.00
27.95
O

442
CB
PHE
A
61
−16.706
−20.398
79.234
1.00
28.00
C

443
CG
PHE
A
61
−17.456
−19.532
80.213
1.00
30.35
C

444
CD1
PHE
A
61
−18.726
−19.893
80.656
1.00
32.93
C

445
CD2
PHE
A
61
−16.911
−18.326
80.652
1.00
29.85
C

446
CE1
PHE
A
61
−19.448
−19.062
81.527
1.00
33.50
C

447
CE2
PHE
A
61
−17.621
−17.491
81.516
1.00
30.88
C

448
CZ
PHE
A
61
−18.889
−17.859
81.954
1.00
32.95
C

449
N
PHE
A
62
−16.530
−18.083
77.142
1.00
28.01
N

450
CA
PHE
A
62
−16.682
−16.666
76.844
1.00
26.56
C

451
C
PHE
A
62
−17.530
−16.365
75.616
1.00
26.51
C

452
O
PHE
A
62
−18.376
−15.468
75.646
1.00
26.29
O

453
CB
PHE
A
62
−15.312
−16.018
76.652
1.00
25.13
C

454
CG
PHE
A
62
−15.378
−14.549
76.361
1.00
25.15
C

455
CD1
PHE
A
62
−15.397
−13.622
77.400
1.00
24.10
C

456
CD2
PHE
A
62
−15.442
−14.089
75.045
1.00
25.51
C

457
CEI
PHE
A
62
−15.478
−12.255
77.133
1.00
23.53
C

458
CE2
PHE
A
62
−15.522
−12.725
74.764
1.00
24.92
C

459
CZ
PHE
A
62
−15.540
−11.806
75.811
1.00
24.83
C

460
N
PHE
A
63
−17.307
−17.099
74.531
1.00
26.40
N

461
CA
PHE
A
63
−18.051
−16.841
73.304
1.00
26.90
C

462
C
PHE
A
63
−19.404
−17.512
73.200
1.00
27.73
C

463
O
PHE
A
63
−20.263
−17.069
72.434
1.00
27.02
O

464
CB
PHE
A
63
−17.214
−17.223
72.090
1.00
24.66
C

465
CG
PHE
A
63
−15.954
−16.428
71.956
1.00
24.42
C

466
CD1
PHE
A
63
−15.990
−15.127
71.471
1.00
21.50
C

467
CD2
PHE
A
63
−14.723
−16.980
72.311
1.00
24.17
C

468
CE1
PHE
A
63
−14.826
−14.389
71.338
1.00
20.03
C

469
CE2
PHE
A
63
−13.549
−16.247
72.180
1.00
20.88
C

470
CZ
PHE
A
63
−13.603
−14.948
71.691
1.00
21.44
C

471
N
ARG
A
64
−19.598
−18.580
73.962
1.00
30.72
N

472
CA
ARG
A
64
−20.867
−19.303
73.918
1.00
33.22
C

473
C
ARG
A
64
−21.864
−18.805
74.955
1.00
34.09
C

474
O
ARG
A
64
−23.033
−19.182
74.926
1.00
35.09
O

475
CB
ARG
A
64
−20.629
−20.804
74.113
1.00
32.39
C

476
OG
ARG
A
64
−19.781
−21.446
73.017
1.00
30.64
C

477
CD
ARG
A
64
−19.793
−22.957
73.159
1.00
30.33
C

478
NE
ARG
A
64
−21.121
−23.502
72.893
1.00
28.25
N

479
CZ
ARG
A
64
−21.514
−24.723
73.235
1.00
28.03
C

480
NH1
ARG
A
64
−20.680
−25.538
73.866
1.00
27.34
N

481
NH2
ARG
A
64
−22.742
−25.129
72.937
1.00
30.09
N

482
N
ALA
A
65
−21.399
−17.954
75.865
1.00
34.56
N

483
CA
ALA
A
65
−22.258
−17.415
76.911
1.00
35.80
C

484
C
ALA
A
65
−23.453
−16.670
76.327
1.00
36.85
C

485
O
ALA
A
65
−23.336
−15.970
75.319
1.00
36.91
O

486
CB
ALA
A
65
−21.461
−16.485
77.819
1.00
33.49
C

487
N
GLY
A
66
−24.608
−16.835
76.962
1.00
38.37
N

488
CA
GLY
A
66
−25.796
−16.149
76.502
1.00
40.15
C

489
C
GLY
A
66
−25.729
−14.682
76.883
1.00
41.23
C

490
O
GLY
A
66
−24.916
−14.279
77.718
1.00
39.52
O

491
N
ASP
A
67
−26.582
−13.878
76.262
1.00
43.81
N

492
CA
ASP
A
67
−26.638
−12.451
76.538
1.00
45.64
C

493
C
ASP
A
67
−27.099
−12.216
77.979
1.00
45.54
C

494
O
ASP
A
67
−26.792
−11.186
78.581
1.00
44.75
O

495
CB
ASP
A
67
−27.599
−11.781
75.560
1.00
48.29
C

496
CG
ASP
A
67
−27.164
−11.940
74.116
1.00
50.25
C

497
OD1
ASP
A
67
−26.170
−11.293
73.724
1.00
51.88
O

498
OD2
ASP
A
67
−27.811
−12.714
73.374
1.00
52.62
O

499
N
ASP
A
68
−27.834
−13.180
78.525
1.00
45.65
N

500
CA
ASP
A
68
−28.324
−13.079
79.894
1.00
47.03
C

501
C
ASP
A
68
−27.197
−13.327
80.896
1.00
46.58
C

502
O
ASP
A
68
−27.342
−13.048
82.088
1.00
46.36
O

503
CB
ASP
A
68
−29.449
−14.093
80.145
1.00
50.18
C

504
CG
ASP
A
68
−30.662
−13.861
79.258
1.00
53.72
C

505
OD1
ASP
A
68
−31.001
−12.681
79.005
1.00
55.13
O

506
OD2
ASP
A
68
−31.287
−14.859
78.830
1.00
55.03
O

507
N
ASP
A
69
−26.075
−13.848
80.408
1.00
44.59
N

508
CA
ASP
A
69
−24.936
−14.142
81.269
1.00
42.77
C

509
C
ASP
A
69
−23.788
−13.146
81.112
1.00
40.88
C

510
O
ASP
A
69
−23.352
−12.529
82.083
1.00
39.21
O

511
CB
ASP
A
69
−24.446
−15.564
80.994
1.00
44.32
C

512
CG
ASP
A
69
−25.553
−16.596
81.146
1.00
44.89
C

513
OD1
ASP
A
69
−26.404
−16.427
82.046
1.00
44.10
O

514
OD2
ASP
A
69
−25.566
−17.576
80.373
1.00
45.78
O

515
N
LEU
A
70
−23.282
−13.008
79.891
1.00
39.40
N

516
CA
LEU
A
70
−22.205
−12.066
79.618
1.00
37.12
C

517
C
LEU
A
70
−22.774
−11.017
78.670
1.00
38.49
C

518
O
LEU
A
70
−23.082
−11.308
77.515
1.00
38.02
O

519
CB
LEU
A
70
−21.002
−12.781
78.990
1.00
33.37
C

520
CG
LEU
A
70
−20.215
−13.758
79.882
1.00
31.35
C

521
CD1
LEU
A
70
−18.987
−14.257
79.117
1.00
27.23
C

522
CD2
LEU
A
70
−19.783
−13.077
81.187
1.00
25.32
C

523
N
ASP
A
71
−22.927
−9.796
79.174
1.00
40.17
N

524
CA
ASP
A
71
−23.497
−8.711
78.384
1.00
40.99
C

525
C
ASP
A
71
−22.442
−7.870
77.676
1.00
40.58
C

526
O
ASP
A
71
−21.441
−7.471
78.267
1.00
38.85
O

527
CB
ASP
A
71
−24.352
−7.810
79.276
1.00
42.28
C

528
CG
ASP
A
71
−25.538
−7.224
78.540
1.00
44.07
C

529
OD1
ASP
A
71
−25.359
−6.761
77.395
1.00
45.50
O

530
OD2
ASP
A
71
−26.648
−7.226
79.108
1.00
44.73
O

531
N
GLN
A
72
−22.690
−7.599
76.402
1.00
41.65
N

532
CA
GLN
A
72
−21.787
−6.813
75.571
1.00
43.31
C

533
C
GLN
A
72
−22.230
−5.348
75.517
1.00
43.15
C

534
O
GLN
A
72
−21.459
−4.463
75.135
1.00
42.94
O

535
CB
GLN
A
72
−21.776
−7.411
74.161
1.00
45.04
C

536
OG
GLN
A
72
−21.097
−6.565
73.105
1.00
49.16
C

537
CD
GLN
A
72
−21.330
−7.104
71.705
1.00
52.55
C

538
OE1
GLN
A
72
−20.945
−8.233
71.391
1.00
53.01
O

539
NE2
GLN
A
72
−21.971
−6.299
70.856
1.00
53.53
N

540
N
ALA
A
73
−23.470
−5.108
75.928
1.00
42.94
N

541
CA
ALA
A
73
−24.081
−3.783
75.903
1.00
43.98
C

542
C
ALA
A
73
−23.316
−2.633
76.552
1.00
43.94
C

543
O
ALA
A
73
−23.237
−1.544
75.977
1.00
45.86
O

544
CB
ALA
A
73
−25.483
−3.862
76.495
1.00
44.39
C

545
N
LYS
A
74
−22.763
−2.854
77.741
1.00
41.72
N

546
CA
LYS
A
74
−22.030
−1.793
78.429
1.00
40.07
C

547
C
LYS
A
74
−20.539
−2.096
78.604
1.00
38.40
C

548
O
LYS
A
74
−19.871
−1.498
79.449
1.00
38.43
O

549
CB
LYS
A
74
−22.664
−1.538
79.801
1.00
39.68
C

550
N
ALA
A
75
−20.022
−3.013
77.793
1.00
35.60
N

551
CA
ALA
A
75
−18.625
−3.417
77.875
1.00
34.13
C

552
C
ALA
A
75
−17.679
−2.465
77.161
1.00
33.74
C

553
O
ALA
A
75
−16.458
−2.553
77.320
1.00
33.04
O

554
CB
ALA
A
75
−18.470
−4.814
77.306
1.00
33.00
C

555
N
TYR
A
76
−18.243
−1.562
76.367
1.00
34.09
N

556
CA
TYR
A
76
−17.435
−0.609
75.618
1.00
34.79
C

557
C
TYR
A
76
−17.926
0.816
75.818
1.00
35.22
C

558
O
TYR
A
76
−18.393
1.461
74.880
1.00
35.02
O

559
CB
TYR
A
76
−17.461
−0.946
74.123
1.00
32.21
C

560
CG
TYR
A
76
−17.078
−2.367
73.799
1.00
30.71
C

561
CD1
TYR
A
76
−15.758
−2.790
73.902
1.00
30.69
C

562
CD2
TYR
A
76
−18.034
−3.286
73.366
1.00
30.50
C

563
CE1
TYR
A
76
−15.392
−4.095
73.576
1.00
30.62
C

564
CE2
TYR
A
76
−17.684
−4.593
73.036
1.00
29.17
C

565
CZ
TYR
A
76
−16.358
−4.989
73.140
1.00
30.89
C

566
OH
TYR
A
76
−15.984
−6.262
72.773
1.00
29.07
O

567
N
PRO
A
77
−17.823
1.332
77.048
1.00
37.03
N

568
CA
PRO
A
77
−18.277
2.702
77.306
1.00
37.39
C

569
C
PRO
A
77
−17.649
3.745
76.373
1.00
37.15
C

570
O
PRO
A
77
−18.231
4.804
76.143
1.00
38.76
O

571
CB
PRO
A
77
−17.897
2.919
78.774
1.00
37.42
C

572
CG
PRO
A
77
−16.704
1.998
78.960
1.00
37.86
C

573
CD
PRO
A
77
−17.168
0.758
78.237
1.00
37.69
C

574
N
PHE
A
78
−16.475
3.445
75.822
1.00
35.91
N

575
CA
PHE
A
78
−15.810
4.392
74.931
1.00
36.40
C

576
C
PHE
A
78
−16.543
4.594
73.605
1.00
36.86
C

577
O
PHE
A
78
−16.215
5.502
72.837
1.00
36.12
O

578
CB
PHE
A
78
−14.355
3.964
74.682
1.00
36.71
C

579
CG
PHE
A
78
−14.204
2.617
74.022
1.00
37.54
C

580
CD1
PHE
A
78
−14.216
2.497
72.636
1.00
36.10
C

581
CD2
PHE
A
78
−14.012
1.467
74.791
1.00
38.01
C

582
CE1
PHE
A
78
−14.034
1.254
72.021
1.00
34.99
C

583
CE2
PHE
A
78
−13.831
0.220
74.186
1.00
35.91
C

584
CZ
PHE
A
78
−13.841
0.116
72.800
1.00
36.31
C

585
N
MET
A
79
−17.546
3.756
73.355
1.00
36.41
N

586
CA
MET
A
79
−18.342
3.825
72.133
1.00
35.58
C

587
C
MET
A
79
−19.558
4.736
72.275
1.00
34.91
C

588
O
MET
A
79
−20.167
5.131
71.277
1.00
34.34
O

589
CB
MET
A
79
−18.822
2.422
71.740
1.00
33.58
C

590
CG
MET
A
79
−17.736
1.508
71.209
1.00
33.69
C

591
SD
MET
A
79
−16.846
2.260
69.826
1.00
34.84
S

592
CE
MET
A
79
−18.180
2.398
68.603
1.00
33.42
C

593
N
THR
A
80
−19.901
5.062
73.516
1.00
33.93
N

594
CA
THR
A
80
−21.063
5.889
73.822
1.00
34.14
C

595
C
THR
A
80
−21.046
7.304
73.254
1.00
34.33
C

596
O
THR
A
80
−22.035
7.756
72.676
1.00
33.66
O

597
CB
THR
A
80
−21.272
5.985
75.347
1.00
34.49
C

598
OG1
THR
A
80
−21.415
4.666
75.887
1.00
32.28
O

599
CG2
THR
A
80
−22.519
6.809
75.671
1.00
31.46
C

600
N
PRO
A
81
−19.933
8.030
73.429
1.00
35.47
N

601
CA
PRO
A
81
−19.854
9.400
72.909
1.00
35.73
C

602
C
PRO
A
81
−19.782
9.463
71.386
1.00
36.34
C

603
O
PRO
A
81
−20.133
10.480
70.788
1.00
36.73
O

604
CB
PRO
A
81
−18.589
9.950
73.571
1.00
36.84
C

605
CG
PRO
A
81
−18.475
9.138
74.837
1.00
36.59
C

606
CD
PRO
A
81
−18.809
7.756
74.341
1.00
36.01
C

607
N
ILE
A
82
−19.310
8.384
70.765
1.00
38.12
N

608
CA
ILE
A
82
−19.199
8.318
69.307
1.00
39.03
C

609
C
ILE
A
82
−20.584
8.105
68.710
1.00
41.16
C

610
O
ILE
A
82
−21.018
8.869
67.847
1.00
40.47
O

611
CB
ILE
A
82
−18.257
7.163
68.851
1.00
38.07
C

612
CG1
ILE
A
82
−16.788
7.594
68.958
1.00
37.53
C

613
CG2
ILE
A
82
−18.550
6.776
67.406
1.00
37.30
C

614
CD1
ILE
A
82
−16.316
7.870
70.366
1.00
39.09
C

615
N
PHE
A
83
−21.270
7.067
69.184
1.00
43.73
N

616
CA
PHE
A
83
−22.614
6.733
68.724
1.00
47.73
C

617
C
PHE
A
83
−23.577
7.891
68.965
1.00
51.78
C

618
O
PHE
A
83
−24.326
8.290
68.073
1.00
51.87
O

619
CB
PHE
A
83
−23.127
5.490
69.459
1.00
47.24
C

620
CG
PHE
A
83
−22.495
4.201
69.003
1.00
47.19
C

621
CD1
PHE
A
83
−21.875
4.108
67.759
1.00
46.90
C

622
CD2
PHE
A
83
−22.554
3.066
69.806
1.00
48.23
C

623
CE1
PHE
A
83
−21.325
2.905
67.322
1.00
45.74
C

624
CE2
PHE
A
83
−22.005
1.855
69.378
1.00
47.22
C

625
CZ
PHE
A
83
−21.390
1.776
68.132
1.00
47.17
C

626
N
GLY
A
84
−23.556
8.424
70.181
1.00
56.40
N

627
CA
GLY
A
84
−24.433
9.530
70.515
1.00
60.93
C

628
C
GLY
A
84
−25.841
9.066
70.820
1.00
64.29
C

629
O
GLY
A
84
−26.075
7.882
71.064
1.00
63.22
O

630
N
GLU
A
85
−26.783
10.002
70.809
1.00
69.25
N

631
CA
GLU
A
85
−28.168
9.667
71.093
1.00
74.62
C

632
C
GLU
A
85
−28.581
8.513
70.192
1.00
77.42
C

633
O
GLU
A
85
−28.421
8.588
68.973
1.00
77.19
O

634
CB
GLU
A
85
−29.080
10.868
70.841
1.00
75.22
C

635
CG
GLU
A
85
−30.165
11.025
71.896
1.00
77.83
C

636
CD
GLU
A
85
−30.868
9.715
72.215
1.00
78.75
C

637
OE1
GLU
A
85
−31.562
9.179
71.327
1.00
79.96
O

638
OE2
GLU
A
85
−30.720
9.219
73.354
1.00
79.32
O

639
N
GLY
A
86
−29.099
7.451
70.807
1.00
80.67
N

640
CA
GLY
A
86
−29.536
6.273
70.074
1.00
83.43
C

641
C
GLY
A
86
−29.961
6.536
68.642
1.00
85.00
C

642
O
GLY
A
86
−30.595
7.550
68.348
1.00
85.55
O

643
N
VAL
A
87
−29.606
5.612
67.753
1.00
86.38
N

644
CA
VAL
A
87
−29.927
5.712
66.331
1.00
87.61
C

645
C
VAL
A
87
−31.281
6.365
66.042
1.00
87.91
C

646
O
VAL
A
87
−32.212
6.296
66.847
1.00
87.93
O

647
CB
VAL
A
87
−29.879
4.311
65.668
1.00
88.27
C

648
CG1
VAL
A
87
−30.307
4.391
64.207
1.00
88.10
C

649
CG2
VAL
A
87
−28.471
3.748
65.773
1.00
88.03
C

650
N
VAL
A
88
−31.364
7.002
64.878
1.00
88.01
N

651
CA
VAL
A
88
−32.562
7.695
64.412
1.00
88.13
C

652
C
VAL
A
88
−33.893
7.002
64.720
1.00
87.78
C

653
O
VAL
A
88
−34.889
7.668
65.007
1.00
87.82
O

654
CB
VAL
A
88
−32.464
7.945
62.883
1.00
88.22
C

655
CG1
VAL
A
88
−33.810
8.340
62.320
1.00
88.54
C

656
CG2
VAL
A
88
−31.440
9.035
62.605
1.00
88.15
C

657
N
PHE
A
89
−33.912
5.674
64.666
1.00
87.47
N

658
CA
PHE
A
89
−35.140
4.929
64.927
1.00
87.26
C

659
C
PHE
A
89
−35.199
4.342
66.336
1.00
87.74
C

660
O
PHE
A
89
−34.400
3.474
66.694
1.00
88.06
O

661
CB
PHE
A
89
−35.298
3.804
63.902
1.00
86.59
C

662
CG
PHE
A
89
−34.945
4.210
62.502
1.00
85.68
C

663
CD1
PHE
A
89
−33.623
4.182
62.071
1.00
85.11
C

664
CD2
PHE
A
89
−35.929
4.647
61.621
1.00
85.40
C

665
CE1
PHE
A
89
−33.285
4.585
60.780
1.00
84.61
C

666
CE2
PHE
A
89
−35.602
5.054
60.328
1.00
84.69
C

667
CZ
PHE
A
89
−34.277
5.022
59.907
1.00
84.30
C

668
N
ASP
A
90
−36.156
4.820
67.129
1.00
87.92
N

669
CA
ASP
A
90
−36.340
4.346
68.499
1.00
87.80
C

670
C
ASP
A
90
−37.263
3.130
68.509
1.00
87.79
C

671
O
ASP
A
90
−38.478
3.261
68.656
1.00
87.58
O

672
CB
ASP
A
90
−36.942
5.458
69.366
1.00
87.67
C

673
N
ALA
A
91
−36.678
1.948
68.353
1.00
88.09
N

674
CA
ALA
A
91
−37.447
0.711
68.334
1.00
88.79
C

675
C
ALA
A
91
−36.735
−0.393
69.107
1.00
89.28
C

676
O
ALA
A
91
−36.186
−1.320
68.508
1.00
89.39
O

677
CB
ALA
A
91
−37.675
0.269
66.893
1.00
89.24
C

678
N
SER
A
92
−36.746
−0.299
70.434
1.00
89.35
N

679
CA
SER
A
92
−36.091
−1.305
71.261
1.00
89.63
C

680
C
SER
A
92
−34.608
−1.328
70.890
1.00
90.30
C

681
O
SER
A
92
−34.135
−0.450
70.168
1.00
90.34
O

682
CB
SER
A
92
−36.729
−2.676
71.010
1.00
88.72
C

683
N
PRO
A
93
−33.848
−2.320
71.386
1.00
91.49
N

684
CA
PRO
A
93
−32.425
−2.358
71.036
1.00
91.36
C

685
C
PRO
A
93
−32.175
−2.416
69.531
1.00
91.63
C

686
O
PRO
A
93
−32.344
−3.467
68.910
1.00
91.85
O

687
CB
PRO
A
93
−31.934
−3.614
71.746
1.00
91.76
C

688
CG
PRO
A
93
−32.772
−3.632
72.982
1.00
91.91
C

689
CD
PRO
A
93
−34.148
−3.304
72.444
1.00
91.78
C

690
N
GLU
A
94
−31.784
−1.284
68.950
1.00
92.11
N

691
CA
GLU
A
94
−31.489
−1.221
67.520
1.00
92.04
C

692
C
GLU
A
94
−30.097
−1.817
67.359
1.00
92.76
C

693
O
GLU
A
94
−29.586
−1.962
66.249
1.00
92.14
O

694
CB
GLU
A
94
−31.481
0.228
67.024
1.00
91.50
C

695
CG
GLU
A
94
−32.523
1.125
67.667
1.00
90.92
C

696
CD
GLU
A
94
−31.968
1.910
68.841
1.00
90.83
C

697
OE1
GLU
A
94
−31.312
1.297
69.709
1.00
90.79
O

698
OE2
GLU
A
94
−32.188
3.139
68.898
1.00
90.02
O

699
N
ARG
A
95
−29.496
−2.147
68.499
1.00
93.86
N

700
CA
ARG
A
95
−28.164
−2.733
68.571
1.00
94.72
C

701
C
ARG
A
95
−27.887
−3.714
67.440
1.00
94.93
C

702
O
ARG
A
95
−28.555
−4.742
67.324
1.00
95.34
O

703
CB
ARG
A
95
−27.987
−3.421
69.934
1.00
95.11
C

704
CG
ARO
A
95
−26.824
−4.405
70.033
1.00
96.34
C

705
CD
ARG
A
95
−27.256
−5.827
69.664
1.00
97.32
C

706
NE
ARG
A
95
−26.162
−6.793
69.776
1.00
98.20
N

707
CZ
ARG
A
95
−26.295
−8.104
69.591
1.00
97.68
C

708
NH1
ARG
A
95
−27.478
−8.621
69.283
1.00
97.56
N

709
NH2
ARO
A
95
−25.241
−8.901
69.711
1.00
97.50
N

710
N
ARG
A
96
−26.900
−3.377
66.608
1.00
94.87
N

711 CA
ARG
A
96
−26.488
−4.204
65.474
1.00
94.77
C

712
C
ARG
A
96
−27.629
−4.476
64.491
1.00
95.84
C

713
O
ARG
A
96
−27.389
−4.778
63.319
1.00
96.17
O

714
CB
ARG
A
96
−25.890
−5.530
65.977
1.00
93.45
C

715
CG
ARG
A
96
−24.493
−5.415
66.605
1.00
91.19
C

716
CD
ARG
A
96
−24.431
−4.334
67.682
1.00
90.24
C

717
NE
ARG
A
96
−23.129
−4.251
68.345
1.00
89.35
N

718
CZ
ARG
A
96
−22.782
−3.284
69.194
1.00
88.17
C

719
NH1
ARG
A
96
−23.639
−2.313
69.483
1.00
87.34
N

720
NH2
ARG
A
96
−21.581
−3.287
69.758
1.00
87.36
N

721
N
LYS
A
97
−28.866
−4.366
64.971
1.00
96.62
N

722
CA
LYS
A
97
−30.041
−4.587
64.138
1.00
96.97
C

723
C
LYS
A
97
−30.170
−3.401
63.197
1.00
97.16
C

724
O
LYS
A
97
−30.374
−3.566
61.998
1.00
97.53
O

725
CD
LYS
A
97
−31.297
−4.704
65.006
1.00
97.00
C

726
N
GLU
A
98
−30.045
−2.203
63.759
1.00
97.60
N

727
CA
GLU
A
98
−30.125
−0.974
62.984
1.00
97.87
C

728
C
GLU
A
98
−28.728
−0.366
62.865
1.00
97.87
C

729
O
GLU
A
98
−28.284
−0.030
61.765
1.00
97.56
O

730
CB
GLU
A
98
−31.074
0.023
63.658
1.00
97.80
C

731
N
MET
A
99
−28.038
−0.235
63.999
1.00
97.93
N

732
CA
MET
A
99
−26.690
0.331
64.014
1.00
97.93
C

733
C
MET
A
99
−25.809
−0.312
62.949
1.00
97.90
C

734
O
MET
A
99
−25.058
0.377
62.261
1.00
98.20
O

735
CD
MET
A
99
−26.038
0.163
65.397
1.00
97.83
C

736
CO
MET
A
99
−26.558
1.135
66.462
1.00
98.20
C

737
SD
MET
A
99
−25.607
1.154
68.019
1.00
98.20
S

738
CE
MET
A
99
−26.817
0.496
69.195
1.00
97.72
C

739
N
LEU
A
100
−25.911
−1.632
62.812
1.00
97.41
N

740
CA
LEU
A
100
−25.124
−2.365
61.824
1.00
96.59
C

741
C
LEU
A
100
−26.008
−3.342
61.057
1.00
96.21
C

742
O
LEU
A
100
−25.611
−4.477
60.783
1.00
96.04
O

743
CB
LEU
A
100
−23.991
−3.128
62.510
1.00
97.00
C

744
N
HIS
A
101
−27.210
−2.887
60.716
1.00
95.42
N

745
CA
HIS
A
101
−28.169
−3.702
59.984
1.00
94.13
C

746
C
HIS
A
101
−27.476
−4.537
58.922
1.00
93.43
C

747
O
HIS
A
101
−26.742
−4.005
58.086
1.00
92.55
O

748
CB
HIS
A
101
−29.220
−2.809
59.319
1.00
94.04
C

749
N
ASN
A
102
−27.703
−5.847
58.964
1.00
92.95
N

750
CA
ASN
A
102
−27.106
−6.741
57.981
1.00
92.50
C

751
C
ASN
A
102
−27.722
−6.381
56.633
1.00
92.17
C

752
O
ASN
A
102
−27.298
−6.879
55.587
1.00
92.32
O

753
CB
ASN
A
102
−27.407
−8.208
58.313
1.00
92.27
C

754
CG
ASN
A
102
−28.696
−8.705
57.673
1.00
91.28
C

755
OD1
ASN
A
102
−29.792
−8.259
58.017
1.00
91.01
O

756
ND2
ASN
A
102
−28.566
−9.631
56.728
1.00
90.36
N

757
N
ALA
A
103
−28.735
−5.516
56.678
1.00
91.58
N

758
CA
ALA
A
103
−29.420
−5.057
55.476
1.00
90.44
C

759
C
ALA
A
103
−28.369
−4.457
54.552
1.00
89.65
C

760
O
ALA
A
103
−28.404
−4.653
53.335
1.00
89.40
O

761
CB
ALA
A
103
−30.467
−4.009
55.838
1.00
90.80
C

762
N
ALA
A
104
−27.430
−3.729
55.150
1.00
88.06
N

763
CA
ALA
A
104
−26.348
−3.101
54.407
1.00
86.32
C

764
C
ALA
A
104
−25.491
−4.175
53.743
1.00
85.48
C

765
O
ALA
A
104
−25.247
−4.130
52.540
1.00
84.88
O

766
CB
ALA
A
104
−25.499
−2.258
55.346
1.00
85.97
C

767
N
LEU
A
105
−25.049
−5.146
54.537
1.00
84.76
N

768
CA
LEU
A
105
−24.217
−6.236
54.039
1.00
83.95
C

769
C
LEU
A
105
−25.028
−7.397
53.461
1.00
83.71
C

770
O
LEU
A
105
−24.515
−8.509
53.318
1.00
83.56
O

771
CB
LEU
A
105
−23.311
−6.745
55.165
1.00
83.98
C

772
CG
LEU
A
105
−23.968
−7.203
56.475
1.00
84.31
C

773
CD1
LEU
A
105
−24.741
−8.499
56.261
1.00
84.30
C

774
CD2
LEU
A
105
−22.891
−7.411
57.530
1.00
84.02
C

775
N
ARG
A
106
−26.289
−7.138
53.125
1.00
83.48
N

776
CA
ARG
A
106
−27.162
−8.169
52.570
1.00
82.84
C

777
C
ARG
A
106
−26.539
−8.849
51.352
1.00
81.56
C

778
O
ARG
A
106
−25.873
−8.206
50.539
1.00
81.70
O

779
CB
ARG
A
106
−28.521
−7.573
52.192
1.00
84.23
C

780
CG
ARG
A
106
−29.536
−8.618
51.758
1.00
86.06
C

781
CD
ARO
A
106
−30.923
−8.028
51.546
1.00
88.06
C

782
NE
ARG
A
106
−30.963
−7.060
50.453
1.00
89.73
N

783
CZ
ARG
A
106
−32.082
−6.535
49.962
1.00
90.04
C

784
NH1
ARG
A
106
−33.260
−6.884
50.467
1.00
89.25
N

785
NH2
ARG
A
106
−32.025
−5.662
48.965
1.00
90.08
N

786
N
GLY
A
107
−26.768
−10.155
51.236
1.00
79.82
N

787
CA
GLY
A
107
−26.218
−10.928
50.135
1.00
77.13
C

788
C
GLY
A
107
−26.671
−10.541
48.740
1.00
75.07
C

789
O
GLY
A
107
−25.963
−10.803
47.766
1.00
75.14
O

790
N
GLU
A
108
−27.847
−9.929
48.631
1.00
72.66
N

791
CA
GLU
A
108
−28.367
−9.512
47.329
1.00
69.63
C

792
C
GLU
A
108
−27.535
−8.351
46.790
1.00
65.82
C

793
O
GLU
A
108
−27.324
−8.226
45.584
1.00
64.77
O

794
CB
GLU
A
108
−29.831
−9.057
47.444
1.00
71.84
C

795
CG
GLU
A
108
−30.762
−10.023
48.170
1.00
75.44
C

796
CD
GLU
A
108
−32.236
−9.680
47.978
1.00
77.42
C

797
CE1
GLU
A
108
−32.539
−8.768
47.178
1.00
79.74
O

798
OE2
GLU
A
108
−33.094
−10.328
48.620
1.00
78.86
O

799
N
GLN
A
109
−27.059
−7.511
47.704
1.00
61.03
N

800
CA
GLN
A
109
−26.274
−6.337
47.352
1.00
56.45
C

801
C
GLN
A
109
−24.763
−6.562
47.366
1.00
52.38
C

802
O
GLN
A
109
−23.999
−5.668
47.000
1.00
52.09
O

803
CB
GLN
A
109
−26.622
−5.196
48.313
1.00
57.60
C

804
CG
GLN
A
109
−28.090
−4.787
48.288
1.00
60.13
C

805
CD
GLN
A
109
−28.491
−3.931
49.482
1.00
62.08
C

806
OE1
GLN
A
109
−29.612
−3.425
49.547
1.00
63.44
O

807
NE2
GLN
A
109
−27.579
−3.776
50.438
1.00
62.71
N

808
N
MET
A
110
−24.330
−7.750
47.773
1.00
46.94
N

809
CA
MET
A
110
−22.905
−8.045
47.859
1.00
41.97
C

810
C
MET
A
110
−22.129
−7.762
46.574
1.00
38.00
C

811
O
MET
A
110
−21.100
−7.082
46.603
1.00
35.32
O

812
CB
MET
A
110
−22.689
−9.500
48.274
1.00
44.17
C

813
CG
MET
A
110
−21.340
−9.735
48.921
1.00
46.26
C

814
SD
MET
A
110
−21.189
−8.834
50.487
1.00
50.36
S

815
CE
MET
A
110
−20.399
−10.079
51.506
1.00
49.93
C

816
N
LYS
A
111
−22.616
−8.295
45.456
1.00
33.13
N

817
CA
LYS
A
111
−21.969
−8.100
44.165
1.00
29.43
C

818
C
LYS
A
111
−21.861
−6.602
43.917
1.00
26.54
C

819
O
LYS
A
111
−20.835
−6.105
43.453
1.00
23.82
O

820
CB
LYS
A
111
−22.802
−8.766
43.057
1.00
30.87
C

821 CG
LYS
A
111
−22.276
−8.588
41.637
1.00
30.79
C

822
CD
LYS
A
111
−23.244
−9.222
40.633
1.00
33.88
C

823
CE
LYS
A
111
−22.772
−9.093
39.187
1.00
33.61
C

824
NZ
LYS
A
111
−21.438
−9.723
38.954
1.00
35.96
N

825
N
GLY
A
112
−22.933
−5.888
44.245
1.00
26.62
N

826
CA
GLY
A
112
−22.953
−4.450
44.060
1.00
23.72
C

827
C
GLY
A
112
−21.871
−3.776
44.873
1.00
23.52
C

828
O
GLY
A
112
−21.143
−2.927
44.363
1.00
24.73
O

829
N
HIS
A
113
−21.750
−4.161
46.139
1.00
21.34
N

830
CA
HIS
A
113
−20.740
−3.572
47.010
1.00
22.30
C

831
C
HIS
A
113
−19.319
−3.735
46.485
1.00
21.05
C

832
O
HIS
A
113
−18.500
−2.806
46.580
1.00
17.98
O

833
CB
HIS
A
113
−20.835
−4.176
48.411
1.00
23.57
C

834
CG
HIS
A
113
−22.057
−3.754
49.154
1.00
24.00
C

835
ND1
HIS
A
113
−22.533
−2.462
49.113
1.00
24.95
N

836
CD2
HIS
A
113
−22.882
−4.436
49.982
1.00
26.03
C

837
CE1
HIS
A
113
−23.600
−2.365
49.887
1.00
26.74
C

838
NE2
HIS
A
113
−23.833
−3.548
50.427
1.00
24.25
N

839
N
ALA
A
114
−19.030
−4.919
45.946
1.00
19.01
N

840
CA
ALA
A
114
−17.710
−5.212
45.403
1.00
20.75
C

841
C
ALA
A
114
−17.391
−4.213
44.299
1.00
21.21
C

842
O
ALA
A
114
−16.280
−3.694
44.232
1.00
21.22
O

843
CB
ALA
A
114
−17.671
−6.634
44.855
1.00
20.33
C

844
N
ALA
A
115
−18.374
−3.951
43.438
1.00
22.65
N

845
CA
ALA
A
115
−18.207
−3.000
42.336
1.00
23.32
C

846
C
ALA
A
115
−18.036
−1.594
42.910
1.00
22.60
C

847
O
ALA
A
115
−17.250
−0.801
42.406
1.00
24.37
O

848
CB
ALA
A
115
−19.426
−3.051
41.390
1.00
19.81
C

849
N
THR
A
116
−18.775
−1.284
43.966
1.00
22.89
N

850
CA
THR
A
116
−18.655
0.028
44.591
1.00
23.40
C

851
C
THR
A
116
−17.234
0.168
45.124
1.00
−23.53
C

852
O
THR
A
116
−16.559
1.172
44.902
1.00
22.96
O

853
CB
THR
A
116
−19.635
0.176
45.767
1.00
23.88
C

854
OG1
THR
A
116
−20.979
0.068
45.280
1.00
23.74
O

855
OG2
THR
A
116
−19.445
1.523
46.464
1.00
21.91
C

856
N
ILE
A
117
−16.780
−0.861
45.823
1.00
24.62
N

857
CA
ILE
A
117
−15.445
−0.844
46.400
1.00
23.62
C

858
C
ILE
A
117
−14.373
−0.696
45.330
1.00
23.22
C

859
O
ILE
A
117
−13.406
0.044
45.520
1.00
23.25
O

860
CB
ILE
A
1i7
−15.222
−2.102
47.252
1.00
22.25
C

861
CG1
ILE
A
117
−16.186
−2.054
48.445
1.00
20.81
C

862
CG2
ILE
A
117
−13.770
−2.178
47.720
1.00
19.36
C

863
OD1
ILE
A
117
−16.258
−3.333
49.267
1.00
16.26
C

864
N
GLU
A
118
−14.543
−1.387
44.205
1.00
24.07
N

865
CA
GLU
A
118
−13.588
−1.280
43.105
1.00
22.48
C

866
C
GLU
A
118
−13.495
0.180
42.673
1.00
22.67
C

867
O
GLU
A
118
−12.408
0.733
42.544
1.00
23.68
O

868
CB
GLU
A
118
−14.026
−2.111
41.888
1.00
20.70
C

869
CG
GLU
A
118
−13.132
−1.848
40.658
1.00
22.64
C

870
CD
GLU
A
118
−13.488
−2.670
39.427
1.00
25.59
C

871
OE1
GLU
A
118
−14.623
−3.185
39.338
1.00
26.19
O

872
OE2
GLU
A
118
−12.620
−2.790
38.534
1.00
27.42
O

873
N
ASP
A
119
−14.649
0.795
42.446
1.00
23.31
N

874
CA
ASP
A
119
−14.714
2.184
42.014
1.00
24.25
C

875
C
ASP
A
119
−14.027
3.146
42.995
1.00
23.73
C

876
O
ASP
A
119
−13.337
4.077
42.581
1.00
25.13
O

877
CB
ASP
A
119
−16.176
2.584
41.824
1.00
27.30
C

878
CG
ASP
A
119
−16.334
3.906
41.100
1.00
29.63
C

879
OD1
ASP
A
119
−15.737
4.067
40.014
1.00
33.07
O

880
OD2
ASP
A
119
−17.061
4.780
41.613
1.00
31.78
O

881
N
GLN
A
120
−14.215
2.922
44.293
1.00
23.63
N

882
CA
GLN
A
120
−13.605
3.777
45.311
1.00
22.41
C

883
C
GLN
A
120
−12.080
3.689
45.294
1.00
21.94
C

884
O
GLN
A
120
−11.387
4.691
45.499
1.00
21.52
O

885
CB
GLN
A
120
−14.111
3.403
46.710
1.00
21.76
C

886
CG
GLN
A
120
−15.610
3.592
46.918
1.00
25.54
C

887
CD
GLN
A
120
−16.128
4.900
46.351
1.00
25.07
C

888
OE1
GLN
A
120
−15.588
5.972
46.626
1.00
27.21
O

889
NE2
GLN
A
120
−17.183
4.817
45.555
1.00
26.42
N

890
N
VAL
A
121
−11.554
2.487
45.073
1.00
21.03
N

891
CA
VAL
A
121
−10.110
2.304
45.019
1.00
20.68
C

892
C
VAL
A
121
−9.546
3.046
43.804
1.00
21.51
C

893
O
VAL
A
121
−8.542
3.758
43.901
1.00
20.87
O

894
CB
VAL
A
121
−9.746
0.804
44.921
1.00
21.23
C

895
CG1
VAL
A
121
−8.246
0.629
44.865
1.00
21.42
C

896
CG2
VAL
A
121
−10.307
0.062
46.113
1.00
21.74
C

897
N
ARG
A
122
−10.199
2.897
42.659
1.00
20.78
N

898
CA
ARG
A
122
−9.728
3.564
41.450
1.00
23.30
C

899
C
ARG
A
122
−9.756
5.091
41.560
1.00
23.50
C

900
O
ARG
A
122
−8.875
5.771
41.033
1.00
22.31
O

901
CB
ARG
A
122
−10.551
3.109
40.243
1.00
21.69
C

902
CG
ARG
A
122
−10.345
1.640
39.888
1.00
22.06
C

903
CD
ARG
A
122
−11.001
1.300
38.563
1.00
21.91
C

904
NE
ARG
A
122
−10.978
−0.135
38.291
1.00
24.92
N

905
CZ
ARG
A
122
−9.895
−0.827
37.940
1.00
25.62
C

906
NH1
ARG
A
122
−8.716
−0.224
37.804
1.00
23.04
N

907
NH2
ARG
A
122
−9.993
−2.135
37.747
1.00
24.91
N

908
N
ARG
A
123
−10.766
5.632
42.237
1.00
24.09
N

909
CA
ARG
A
123
−10.858
7.080
42.402
1.00
25.46
C

910
C
ARG
A
123
−9.732
7.541
43.311
1.00
24.81
C

911
O
ARG
A
123
−9.198
8.639
43.163
1.00
24.25
O

912
CB
ARG
A
123
−12.190
7.472
43.045
1.00
27.61
C

913
CG
ARG
A
123
−13.421
7.188
42.208
1.00
31.95
C

914
CD
ARG
A
123
−14.669
7.785
42.867
1.00
36.00
C

915
NE
ARG
A
123
−14.465
9.190
43.229
1.00
38.13
N

916
CZ
ARG
A
123
−15.428
10.000
43.664
1.00
39.18
C

917
NH1
ARG
A
123
−16.671
9.547
43.791
1.00
36.13
N

918
NH2
ARG
A
123
−15.145
11.264
43.975
1.00
38.18
N

919
N
MET
A
124
−9.377
6.677
44.253
1.00
24.68
N

920
CA
MET
A
124
−8.340
6.956
45.237
1.00
24.42
C

921
C
MET
A
124
−6.917
6.911
44.653
1.00
25.19
C

922
O
MET
A
124
−6.041
7.638
45.117
1.00
27.11
O

923
CB
MET
A
124
−8.483
5.953
46.382
1.00
25.15
C

924
CG
MET
A
124
−7.970
6.408
47.726
1.00
29.69
C

925
SD
MET
A
124
−8.763
7.879
48.426
1.00
23.76
S

926
CE
MET
A
124
−7.393
8.450
49.423
1.00
27.49
C

927
N
ILE
A
125
−6.679
6.069
43.647
1.00
21.55
N

928
CA
ILE
A
125
−5.345
5.988
43.040
1.00
21.82
C

929
C
ILE
A
125
−5.323
6.714
41.701
1.00
20.31
C

930
O
WE
A
125
−4.329
6.675
40.984
1.00
21.26
O

931
CB
ILE
A
125
−4.900
4.514
42.796
1.00
19.77
C

932
CG1
ILE
A
125
−5.773
3.872
41.711
1.00
20.91
C

933
CG2
ILE
A
125
−5.030
3.712
44.082
1.00
19.32
C

934
CD1
ILE
A
125
−5.399
2.435
41.376
1.00
20.58
C

935
N
ALA
A
126
−6.426
7.378
41.375
1.00
21.86
N

936
CA
ALA
A
126
−6.563
8.104
40.114
1.00
22.09
C

937
C
ALA
A
126
−5.449
9.099
39.801
1.00
23.30
C

938
O
ALA
A
126
−5.100
9.296
38.635
1.00
22.16
O

939
CB
ALA
A
126
−7.904
8.823
40.084
1.00
23.46
C

940
N
ASP
A
127
−4.895
9.733
40.829
1.00
24.43
N

941
CA
ASP
A
127
−3.836
10.714
40.612
1.00
25.94
C

942
C
ASP
A
127
−2.450
10.233
41.021
1.00
26.93
C

943
O
ASP
A
127
−1.555
11.050
41.254
1.00
27.51
O

944
CB
ASP
A
127
−4.160
12.006
41.366
1.00
26.73
C

945
CG
ASP
A
127
−4.327
11.788
42.860
1.00
28.04
C

946
OD1
ASP
A
127
−4.152
10.644
43.327
1.00
29.96
O

947
OD2
ASP
A
127
−4.638
12.767
43.572
1.00
29.71
O

948
N
TRP
A
128
−2.260
8.917
41.092
1.00
25.93
N

949
CA
TRP
A
128
−0.969
8.358
41.498
1.00
25.26
C

950
C
TRP
A
128
0.140
8.493
40.472
1.00
25.08
C

951
O
TRP
A
128
1.313
8.590
40.833
1.00
25.76
O

952
CB
TRP
A
128
−1.122
6.883
41.875
1.00
22.91
C

953
CG
TRP
A
128
−1.545
6.668
43.297
1.00
22.96
C

954
CD1
TRP
A
128
−2.107
7.593
44.147
1.00
20.70
C

955
CD2
TRP
A
128
−1.468
5.442
44.033
1.00
22.22
C

956
NE1
TRP
A
128
−2.383
7.010
45.364
1.00
20.60
N

957
CE2
TRP
A
128
−2.003
5.693
45.323
1.00
22.19
C

958
CE3
TRP
A
128
−1.003
4.152
43.729
1.00
22.14
C

959
CZ2
TRP
A
128
−2.084
4.696
46.311
1.00
20.81
C

960
CZ3
TRP
A
128
−1.086
3.159
44.712
1.00
21.65
C

961
CH2
TRP
A
128
−1.624
3.443
45.988
1.00
20.74
C

962
N
GLY
A
129
−0.217
8.499
39.196
1.00
25.00
N

963
CA
GLY
A
129
0.806
8.617
38.177
1.00
26.71
C

964
C
GLY
A
129
1.629
7.346
38.083
1.00
26.94
C

965
O
GLY
A
129
1.183
6.285
38.525
1.00
28.41
O

966
N
GLU
A
130
2.833
7.446
37.527
1.00
26.89
N

967
CA
GLU
A
130
3.696
6.280
37.365
1.00
27.34
C

968
C
GLU
A
130
4.453
5.861
38.623
1.00
26.59
C

969
O
GLU
A
130
4.817
4.694
38.769
1.00
26.33
O

970
CB
GLU
A
130
4.706
6.526
36.236
1.00
28.00
C

971
N
ALA
A
131
4.687
6.803
39.530
1.00
24.86
N

972
CA
ALA
A
131
5.437
6.497
40.741
1.00
25.70
C

973
C
ALA
A
131
5.196
7.534
41.823
1.00
25.38
C

974
O
ALA
A
131
4.729
8.635
41.539
1.00
27.22
O

975
CB
ALA
A
131
6.932
6.421
40.417
1.00
25.22
C

976
N
GLY
A
132
5.526
7.175
43.061
1.00
25.38
N

977
CA
GLY
A
132
5.340
8.083
44.180
1.00
24.28
C

978
C
GLY
A
132
5.338
7.343
45.504
1.00
23.91
C

979
O
GLY
A
132
5.772
6.196
45.586
1.00
23.32
O

980
N
GLU
A
133
4.846
7.998
46.546
1.00
25.12
N

981
CA
GLU
A
133
4.784
7.387
47.866
1.00
25.20
C

982
C
GLU
A
133
3.455
7.693
48.526
1.00
22.44
C

983
O
GLU
A
133
2.763
8.623
48.135
1.00
21.91
O

984
CB
GLU
A
133
5.899
7.930
48.756
1.00
28.74
C

985
CG
GLU
A
133
7.293
7.610
48.285
1.00
35.37
C

986
CD
GLU
A
133
8.217
8.800
48.411
1.00
40.22
C

987
OE1
GLU
A
133
8.217
9.457
49.478
1.00
45.86
O

988
OE2
GLU
A
133
8.946
9.080
47.441
1.00
44.31
O

989
N
ILE
A
134
3.109
6.899
49.531
1.00
21.71
N

990
CA
ILE
A
134
1.883
7.096
50.294
1.00
21.96
C

991
C
ILE
A
134
2.122
6.676
51.730
1.00
22.31
C

992
O
ILE
A
134
3.105
6.003
52.043
1.00
23.63
O

993
CB
ILE
A
134
0.713
6.228
49.782
1.00
21.05
C

994
CG1
ILE
A
134
1.131
4.755
49.803
1.00
22.62
C

995
CG2
ILE
A
134
0.275
6.693
48.402
1.00
22.16
C

996
CD1
ILE
A
134
0.004
3.777
49.577
1.00
25.01
C

997
N
ASP
A
135
1.226
7.097
52.609
1.00
22.76
N

998
CA
ASP
A
135
1.294
6.690
53.993
1.00
23.90
C

999
C
ASP
A
135
0.055
5.818
54.133
1.00
24.44
C

1000
O
ASP
A
135
−1.063
6.271
53.883
1.00
23.77
O

1001
CB
ASP
A
135
1.222
7.886
54.940
1.00
24.14
C

1002
CG
ASP
A
135
1.320
7.467
56.387
1.00
22.50
C

1003
OD1
ASP
A
135
0.286
7.064
56.961
1.00
23.49
O

1004
OD2
ASP
A
135
2.435
7.510
56.943
1.00
21.93
O

1005
N
LEU
A
136
0.265
4.561
54.504
1.00
24.90
N

1006
CA
LEU
A
136
−0.822
3.600
54.646
1.00
24.75
C

1007
C
LEU
A
136
−2.013
4.039
55.496
1.00
24.52
C

1008
O
LEU
A
136
−3.160
3.746
55.149
1.00
23.95
O

1009
CB
LEU
A
136
−0.270
2.274
55.180
1.00
23.12
C

1010
CG
LEU
A
136
0.682
1.547
54.227
1.00
20.26
C

1011
CD1
LEU
A
136
0.948
0.160
54.760
1.00
21.40
C

1012
CD2
LEU
A
136
0.073
1.452
52.834
1.00
21.22
C

1013
N
LEU
A
137
−1.752
4.731
56.602
1.00
24.23
N

1014
CA
LEU
A
137
−2.829
5.187
57.469
1.00
23.92
C

1015
C
LEU
A
137
−3.684
6.230
56.755
1.00
24.15
C

1016
O
LEU
A
137
−4.907
6.117
56.727
1.00
25.03
O

1017
CB
LEU
A
137
−2.266
5.766
58.778
1.00
23.87
C

1018
OG
LEU
A
137
−3.291
6.356
59.759
1.00
23.15
C

1019
CD1
LEU
A
137
−4.429
5.371
60.020
1.00
22.66
C

1020
CD2
LEU
A
137
−2.589
6.710
61.041
1.00
22.42
C

1021
N
ASP
A
138
−3.041
7.244
56.182
1.00
23.59
N

1022
CA
ASP
A
138
−3.753
8.292
55.455
1.00
22.85
C

1023
C
ASP
A
138
−4.551
7.711
54.292
1.00
21.81
C

1024
O
ASP
A
138
−5.717
8.046
54.091
1.00
21.47
O

1025
CB
ASP
A
138
−2.766
9.304
54.894
1.00
21.47
C

1026
CG
ASP
A
138
−2.138
10.151
55.959
1.00
24.70
C

1027
OD1
ASP
A
138
−2.761
10.333
57.030
1.00
24.78
O

1028
OD2
ASP
A
138
−1.015
10.649
55.712
1.00
28.04
O

1029
N
PHE
A
139
−3.908
6.840
53.526
1.00
19.70
N

1030
CA
PHE
A
139
−4.540
6.224
52.370
1.00
20.23
C

1031
C
PHE
A
139
−5.696
5.296
52.731
1.00
22.01
C

1032
O
PHE
A
139
−6.837
5.509
52.308
1.00
22.42
O

1033
CB
PHE
A
139
−3.509
5.430
51.576
1.00
19.32
C

1034
CG
PHE
A
139
−4.067
4.794
50.345
1.00
18.50
C

1035
CD1
PHE
A
139
−4.324
5.560
49.212
1.00
16.87
C

1036
CD2
PHE
A
139
−4.379
3.436
50.332
1.00
17.80
C

1037
CE1
PHE
A
139
−4.894
4.984
48.066
1.00
19.79
C

1038
CE2
PHE
A
139
−4.944
2.841
49.207
1.00
19.44
C

1039
CZ
PHE
A
139
−5.205
3.620
48.062
1.00
22.11
C

1040
N
PHE
A
140
−5.413
4.265
53.519
1.00
21.18
N

1041
CA
PHE
A
140
−6.467
3.323
53.874
1.00
22.12
C

1042
C
PHE
A
140
−7.569
3.866
54.773
1.00
22.23
C

1043
O
PHE
A
140
−8.720
3.433
54.676
1.00
20.73
O

1044
CB
PHE
A
140
−5.844
2.051
54.446
1.00
19.23
C

1045
CG
PHE
A
140
−5.244
1.162
53.384
1.00
17.32
C

1046
CD1
PHE
A
140
−6.058
0.579
52.415
1.00
17.84
C

1047
CD2
PHE
A
140
−3.874
0.927
53.335
1.00
17.48
C

1048
CE1
PHE
A
140
−5.522
−0.230
51.408
1.00
18.31
C

1049
CE2
PHE
A
140
−3.315
0.119
52.330
1.00
18.07
C

1050
CZ
PHE
A
140
−4.142
−0.463
51.364
1.00
17.92
C

1051
N
ALA
A
141
−7.233
4.826
55.630
1.00
23.34
N

1052
CA
ALA
A
141
−8.235
5.431
56.510
1.00
22.80
C

1053
C
ALA
A
141
−9.207
6.258
55.679
1.00
23.14
C

1054
O
ALA
A
141
−10.386
6.331
56.000
1.00
24.44
O

1055
CB
ALA
A
141
−7.570
6.320
57.539
1.00
21.25
C

1056
N
GLU
A
142
−8.700
6.894
54.624
1.00
21.94
N

1057
CA
GLU
A
142
−9.532
7.719
53.762
1.00
21.19
C

1058
C
GLU
A
142
−10.342
6.818
52.841
1.00
21.90
C

1059
O
GLU
A
142
−11.551
6.993
52.693
1.00
19.72
O

1060
CB
GLU
A
142
−8.677
8.682
52.930
1.00
20.84
C

1061
CG
GLU
A
142
−9.500
9.496
51.934
1.00
23.49
C

1062
CD
GLU
A
142
−8.721
10.623
51.266
1.00
26.51
C

1063
OE1
GLU
A
142
−7.470
10.616
51.322
1.00
28.69
O

1064
OE2
GLU
A
142
−9.368
11.511
50.665
1.00
27.01
O

1065
N
LEU
A
143
−9.672
5.849
52.226
1.00
21.86
N

1066
CA
LEU
A
143
−10.344
4.912
51.335
1.00
22.54
C

1067
C
LEU
A
143
−11.531
4.239
52.025
1.00
21.61
C

1068
O
LEU
A
143
−12.620
4.154
51.455
1.00
22.31
O

1069
CB
LEU
A
143
−9.362
3.835
50.851
1.00
21.06
C

1070
CG
LEU
A
143
−9.957
2.723
49.978
1.00
20.23
C

1071
CD1
LEU
A
143
−10.530
3.315
48.692
1.00
21.96
C

1072
CD2
LEU
A
143
−8.882
1.716
49.642
1.00
18.98
C

1073
N
THR
A
144
−11.332
3.776
53.258
1.00
20.14
N

1074
CA
THR
A
144
−12.405
3.086
53.963
1.00
19.90
C

1075
C
THR
A
144
−13.546
3.990
54.411
1.00
20.33
C

1076
O
THR
A
144
−14.619
3.510
54.773
1.00
20.64
O

1077
CB
THR
A
144
−11.853
2.271
55.153
1.00
20.33
C

1078
OG1
THR
A
144
−11.053
3.108
55.995
1.00
18.07
O

1079
CG2
THR
A
144
−10.998
1.118
54.633
1.00
20.26
C

1080
N
ILE
A
145
−13.319
5.298
54.394
1.00
19.67
N

1081
CA
ILE
A
145
−14.371
6.240
54.741
1.00
17.07
C

1082
C
ILE
A
145
−15.287
6.293
53.519
1.00
18.75
C

1083
O
ILE
A
145
−16.504
6.448
53.635
1.00
18.06
O

1084
CB
ILE
A
145
−13.804
7.660
54.995
1.00
17.66
C

1085
CG1
ILE
A
145
−13.229
7.752
56.411
1.00
16.26
C

1086
CG2
ILE
A
145
−14.911
8.705
54.832
1.00
16.07
C

1087
CD1
ILE
A
145
−14.272
7.571
57.501
1.00
12.45
C

1088
N
TYR
A
146
−14.681
6.152
52.345
1.00
17.43
N

1089
CA
TYR
A
146
−15.417
6.191
51.091
1.00
21.86
C

1090
C
TYR
A
146
−16.150
4.881
50.826
1.00
21.61
C

1091
O
TYR
A
146
−17.322
4.886
50.441
1.00
23.32
O

1092
CB
TYR
A
146
−14.457
6.522
49.944
1.00
19.99
C

1093
CG
TYR
A
146
−13.852
7.902
50.071
1.00
20.98
C

9094
CD1
TYR
A
146
−14.582
8.959
50.621
1.00
20.51
C

1095
CD2
TYR
A
146
−12.549
8.155
49.642
1.00
22.93
C

1096
CE1
TYR
A
146
−14.025
10.237
50.742
1.00
21.41
C

1097
CE2
TYR
A
146
−11.980
9.431
49.761
1.00
21.69
C

1098
CZ
TYR
A
146
−12.720
10.460
50.311
1.00
21.97
C

1099
OH
TYR
A
146
−12.142
11.702
50.447
1.00
22.41
O

1100
N
THR
A
147
−15.474
3.759
51.049
1.00
21.98
N

1101
CA
THR
A
147
−16.115
2.474
50.840
1.00
22.14
C

1102
C
THR
A
147
−17.280
2.317
51.817
1.00
24.67
C

1103
O
THR
A
147
−18.404
1.999
51.409
1.00
25.74
O

1104
CB
THR
A
147
−15.115
1.296
51.026
1.00
22.16
C

1105
OG1
THR
A
147
−14.470
1.389
52.305
1.00
21.72
O

1106
CG2
THR
A
147
−14.061
1.323
49.934
1.00
20.99
C

1107
N
SER
A
148
−17.028
2.559
53.102
1.00
24.18
N

1108
CA
SER
A
148
−18.083
2.413
54.100
1.00
25.31
C

1109
C
SER
A
148
−19.273
3.346
53.876
1.00
24.62
C

1110
O
SER
A
148
−20.420
2.935
54.053
1.00
22.98
O

1111
CB
SER
A
148
−17.526
2.623
55.513
1.00
27.02
C

1112
OG
SER
A
148
−17.046
3.943
55.685
1.00
34.43
O

1113
N
SER
A
149
−19.017
4.592
53.480
1.00
23.26
N

1114
CA
SER
A
149
−20.117
5.530
53.263
1.00
20.29
C

1115
C
SER
A
149
−20.899
5.207
51.999
1.00
20.93
C

1116
O
SER
A
149
−22.131
5.261
51.984
1.00
20.94
O

1117
CB
SER
A
149
−19.599
6.966
53.200
1.00
16.97
C

1118
OG
SER
A
149
−18.580
7.104
52.227
1.00
15.48
O

1119
N
ALA
A
150
−20.181
4.859
50.940
1.00
22.23
N

1120
CA
ALA
A
150
−20.814
4.536
49.674
1.00
22.77
C

1121
C
ALA
A
150
−21.611
3.236
49.761
1.00
24.28
C

1122
O
ALA
A
150
−22.692
3.125
49.178
1.00
24.74
O

1123
CB
ALA
A
150
−19.762
4.442
48.583
1.00
19.97
C

1124
N
CYS
A
151
−21.091
2.256
50.494
1.00
25.78
N

1125
CA
CYS
A
151
−21.789
0.977
50.637
1.00
27.79
C

1126
C
CYS
A
151
−22.893
0.999
51.694
1.00
29.74
C

1127
O
CYS
A
151
−23.999
0.509
51.453
1.00
29.40
O

1128
CB
CYS
A
151
−20.799
−0.140
50.979
1.00
27.02
C

1129
SG
CYS
A
151
−19.710
−0.604
49.625
1.00
25.46
S

1130
N
LEU
A
152
−22.593
1.571
52.859
1.00
30.86
N

1131
CA
LEU
A
152
−23.552
1.628
53.963
1.00
32.21
C

1132
C
LEU
A
152
−24.528
2.795
53.965
1.00
32.89
C

1133
O
LEU
A
152
−25.480
2.801
54.736
1.00
32.98
O

1134
CB
LEU
A
152
−22.809
1.614
55.299
1.00
31.29
C

1135
CG
LEU
A
152
−22.367
0.262
55.848
1.00
29.16
C

1136
CD1
LEU
A
152
−21.818
−0.608
54.740
1.00
31.06
C

1137
CD2
LEU
A
152
−21.315
0.493
56.924
1.00
29.70
C

1138
N
ILE
A
153
−24.300
3.793
53.124
1.00
34.91
N

1139
CA
ILE
A
153
−25.219
4.922
53.098
1.00
35.59
C

1140
C
ILE
A
153
−25.689
5.259
51.689
1.00
34.88
C

1141
O
ILE
A
153
−26.887
5.395
51.451
1.00
36.83
O

1142
CB
ILE
A
153
−24.583
6.165
53.767
1.00
34.64
C

1143
CG1
ILE
A
153
−24.282
5.846
55.237
1.00
35.99
C

1144
CG2
ILE
A
153
−25.527
7.352
53.683
1.00
32.47
C

1145
CD1
ILE
A
153
−23.534
6.926
55.976
1.00
35.13
C

1146
N
GLY
A
154
−24.752
5.382
50.756
1.00
34.08
N

1147
CA
GLY
A
154
−25.122
5.698
49.388
1.00
33.03
C

1148
C
GLY
A
154
−23.998
6.385
48.645
1.00
32.49
C

1149
O
GLY
A
154
−23.287
7.214
49.213
1.00
32.42
O

1150
N
LYS
A
155
−23.837
6.044
47.373
1.00
32.50
N

1151
CA
LYS
A
155
−22.784
6.626
46.544
1.00
33.46
C

1152
C
LYS
A
155
−22.982
8.131
46.447
1.00
32.83
C

1153
O
LYS
A
155
−22.022
8.905
46.439
1.00
32.58
O

1154
CB
LYS
A
155
−22.826
6.017
45.139
1.00
34.43
C

1155
CG
LYS
A
155
−22.872
4.490
45.111
1.00
38.45
C

1156
CD
LYS
A
155
−22.963
3.981
43.673
1.00
42.73
C

1157
CE
LYS
A
155
−23.180
2.478
43.615
1.00
44.54
C

1158
NZ
LYS
A
155
−23.376
2.012
42.210
1.00
45.88
N

1159
N
LYS
A
156
−24.245
8.533
46.367
1.00
33.01
N

1160
CA
LYS
A
156
−24.607
9.937
46.264
1.00
31.99
C

1161
C
LYS
A
156
−24.035
10.692
47.457
1.00
31.02
C

1162
O
LYS
A
156
−23.415
11.746
47.298
1.00
31.36
O

1163
CB
LYS
A
156
−26.132
10.069
46.217
1.00
34.16
C

1164
CG
LYS
A
156
−26.635
11.478
45.967
1.00
37.02
C

1165
CD
LYS
A
156
−28.151
11.498
45.875
1.00
39.20
C

1166
CE
LYS
A
156
−28.665
12.910
45.674
1.00
40.11
C

1167
NZ
LYS
A
156
−30.129
12.912
45.459
1.00
40.58
N

1168
N
PHE
A
157
−24.233
10.142
48.651
1.00
29.53
N

1169
CA
PHE
A
157
−23.721
10.767
49.862
1.00
28.73
C

1170
C
PHE
A
157
−22.197
10.765
49.874
1.00
28.15
C

1171
O
PHE
A
157
−21.575
11.787
50.169
1.00
27.07
O

1172
CB
PHE
A
157
−24.232
10.041
51.107
1.00
27.21
C

1173
CG
PHE
A
157
−23.733
10.631
52.399
1.00
27.52
C

1174
CD1
PHE
A
157
−24.102
11.917
52.781
1.00
26.14
C

1175
CD2
PHE
A
157
−22.887
9.904
53.233
1.00
26.20
C

1176
CE1
PHE
A
157
−23.639
12.470
53.967
1.00
25.48
C

1177
CE2
PHE
A
157
−22.416
10.449
54.424
1.00
23.58
C

1178
CZ
PHE
A
157
−22.792
11.734
54.791
1.00
24.38
C

1179
N
ARG
A
158
−21.595
9.620
49.556
1.00
27.58
N

1180
CA
ARG
A
158
−20.134
9.516
49.545
1.00
25.84
C

1181
C
ARG
A
158
−19.525
10.533
48.601
1.00
25.31
C

1182
O
ARG
A
158
−18.506
11.145
48.919
1.00
23.82
O

1183
CB
ARG
A
158
−19.681
8.109
49.127
1.00
24.79
C

1184
CG
ARG
A
158
−18.171
7.987
48.870
1.00
23.16
C

1185
CD
ARG
A
158
−17.803
8.467
47.472
1.00
21.71
C

1186
NE
ARG
A
158
−16.366
8.433
47.201
1.00
21.15
N

1187
CZ
ARG
A
158
−15.550
9.482
47.300
1.00
24.39
C

1188
NH1
ARG
A
158
−16.021
10.667
47.670
1.00
23.95
N

1189
NH2
ARG
A
158
−14.257
9.351
47.008
1.00
24.29
N

1190
N
ASP
A
159
−20.150
10.694
47.436
1.00
26.13
N

1191
CA
ASP
A
159
−19.683
11.627
46.413
1.00
25.70
C

1192
C
ASP
A
159
−19.588
13.060
46.899
1.00
24.81
C

1193
O
ASP
A
159
−18.940
13.893
46.263
1.00
25.51
O

1194
CB
ASP
A
159
−20.611
11.589
45.197
1.00
28.50
C

1195
CG
ASP
A
159
−20.373
10.382
44.325
1.00
30.82
C

1196
OD1
ASP
A
159
−19.453
9.600
44.649
1.00
32.20
O

1197
OD2
ASP
A
159
−21.100
10.220
43.316
1.00
29.86
O

1198
N
GLN
A
160
−20.243
13.358
48.013
1.00
26.01
N

1199
CA
GLN
A
160
−20.218
14.712
48.559
1.00
28.05
C

1200
C
GLN
A
160
−19.255
14.817
49.734
1.00
28.19
C

1201
O
GLN
A
160
−19.231
15.817
50.457
1.00
28.93
O

1202
CB
GLN
A
160
−21.629
15.124
48.989
1.00
29.31
C

1203
CG
GLN
A
160
−22.556
15.375
47.808
1.00
34.46
C

1204
CD
GLN
A
160
−23.954
15.750
48.238
1.00
35.05
C

1205
OE1
GLN
A
160
−24.755
14.889
48.598
1.00
35.42
O

1206
NE2
GLN
A
160
−24.251
17.047
48.217
1.00
35.96
N

1207
N
LEU
A
161
−18.461
13.773
49.920
1.00
27.06
N

1208
CA
LEU
A
161
−17.494
13.751
51.001
1.00
27.60
C

1209
C
LEU
A
161
−16.112
13.913
50.402
1.00
27.20
C

1210
O
LEU
A
161
−15.923
13.683
49.216
1.00
28.92
O

1211
CB
LEU
A
161
−17.571
12.423
51.757
1.00
27.31
C

1212
CG
LEU
A
161
−18.880
12.099
52.485
1.00
26.26
C

1213
CD1
LEU
A
161
−18.731
10.783
53.221
1.00
25.01
C

1214
CD2
LEU
A
161
−19.223
13.215
53.457
1.00
24.59
C

1215
N
ASP
A
162
−15.157
14.329
51.221
1.00
26.14
N

1216
CA
ASP
A
162
−13.787
14.479
50.768
1.00
27.09
C

1217
C
ASP
A
162
−12.867
14.123
51.934
1.00
26.64
C

1218
O
ASP
A
162
−13.288
13.451
52.880
1.00
26.41
O

1219
CB
ASP
A
162
−13.527
15.910
50.261
1.00
29.81
C

1220
CG
ASP
A
162
−13.789
16.980
51.320
1.00
32.11
C

1221
OD1
ASP
A
162
−14.118
16.632
52.474
1.00
32.85
O

1222
OD2
ASP
A
162
−13.661
18.179
50.989
1.00
32.21
O

1223
N
GLY
A
163
−11.615
14.559
51.873
1.00
26.42
N

1224
CA
GLY
A
163
−10.685
14.242
52.942
1.00
25.60
C

1225
C
GLY
A
163
−11.034
14.780
54.320
1.00
26.77
C

1226
O
GLY
A
163
−10.627
14.201
55.338
1.00
26.97
O

1227
N
ARG
A
164
−11.789
15.874
54.375
1.00
25.69
N

1228
CA
ARG
A
164
−12.141
16.466
55.662
1.00
27.49
C

1229
C
ARG
A
164
−12.951
15.527
56.543
1.00
27.12
C

1230
O
ARG
A
164
−12.772
15.493
57.763
1.00
26.61
O

1231
CB
ARG
A
164
−12.890
17.784
55.453
1.00
28.87
C

1232
CG
ARG
A
164
−12.104
18.778
54.592
1.00
34.31
C

1233
CD
ARG
A
164
−12.686
20.200
54.594
1.00
35.68
C

1234
NE
ARG
A
164
−11.926
21.063
53.687
1.00
39.51
N

1235
CZ
ARG
A
164
−12.061
22.387
53.589
1.00
40.29
C

1236
NH1
ARG
A
164
−12.933
23.038
54.352
1.00
40.02
N

1237
NH2
ARG
A
164
−11.324
23.061
52.713
1.00
37.55
N

1238
N
PHE
A
165
−13.831
14.747
55.929
1.00
27.61
N

1239
CA
PHE
A
165
−14.653
13.819
56.689
1.00
25.97
C

1240
C
PHE
A
165
−13.780
12.765
57.362
1.00
25.01
C

1241
O
PHE
A
165
−14.023
12.385
58.512
1.00
26.58
O

1242
CB
PHE
A
165
−15.666
13.132
55.775
1.00
27.60
C

1243
CG
PHE
A
165
−16.844
12.544
56.509
1.00
28.12
C

1244
CD1
PHE
A
165
−16.775
11.265
57.053
1.00
27.19
C

1245
CD2
PHE
A
165
−18.013
13.281
56.676
1.00
27.86
C

1246
CE1
PHE
A
165
−17.853
10.728
57.755
1.00
28.75
C

1247
CE2
PHE
A
165
−19.101
12.752
57.377
1.00
29.10
C

1248
CZ
PHE
A
165
−19.018
11.474
57.917
1.00
27.55
C

1249
N
ALA
A
166
−12.764
12.295
56.646
1.00
23.99
N

1250
CA
ALA
A
166
−11.856
11.275
57.175
1.00
24.93
C

1251
C
ALA
A
166
−11.056
11.831
58.346
1.00
25.42
C

1252
O
ALA
A
166
−10.954
11.196
59.397
1.00
25.72
O

1253
CB
ALA
A
166
−10.908
10.785
56.069
1.00
24.95
C

1254
N
LYS
A
167
−10.489
13.019
58.159
1.00
26.89
N

1255
CA
LYS
A
167
−9.713
13.672
59.208
1.00
28.19
C

1256
C
LYS
A
167
−10.494
13.734
60.512
1.00
28.34
C

1257
O
LYS
A
167
−10.015
13.278
61.551
1.00
28.75
O

1258
CB
LYS
A
167
−9.323
15.089
58.779
1.00
31.26
C

1259
CG
LYS
A
167
−8.025
15.150
57.992
1.00
36.50
C

1260
CD
LYS
A
167
−6.869
14.633
58.844
1.00
38.79
C

1261
CE
LYS
A
167
−5.548
14.651
58.090
1.00
41.42
C

1262
NZ
LYS
A
167
−4.424
14.169
58.957
1.00
43.92
N

1263
N
LEU
A
168
−11.702
14.290
60.454
1.00
27.43
N

1264
CA
LEU
A
168
−12.546
14.411
61.641
1.00
26.43
C

1265
C
LEU
A
168
−12.956
13.059
62.211
1.00
26.72
C

1266
O
LEU
A
168
−12.928
12.859
63.428
1.00
27.66
O

1267
CB
LEU
A
168
−13.798
15.226
61.314
1.00
24.76
C

1268
CG
LEU
A
168
−13.529
16.670
60.884
1.00
23.96
C

1269
CD1
LEU
A
168
−14.809
17.258
60.309
1.00
24.30
C

1270
CD2
LEU
A
168
−13.025
17.502
62.081
1.00
22.71
C

1271
N
TYR
A
169
−13.337
12.129
61.339
1.00
28.06
N

1272
CA
TYR
A
169
−13.749
10.805
61.793
1.00
28.20
C

1273
C
TYR
A
169
−12.600
10.155
62.546
1.00
28.50
C

1274
O
TYR
A
169
−12.816
9.459
63.531
1.00
28.61
O

1275
CB
TYR
A
169
−14.142
9.920
60.613
1.00
28.11
C

1276
CG
TYR
A
169
−15.071
8.790
60.997
1.00
27.44
C

1277
CD1
TYR
A
169
−14.590
7.649
61.638
1.00
27.35
C

1278
CD2
TYR
A
169
−16.440
8.869
60.733
1.00
28.87
C

1279
CE1
TYR
A
169
−15.451
6.610
62.009
1.00
26.94
C

1280
CE2
TYR
A
169
−17.313
7.835
61.098
1.00
27.43
C

1281
CZ
TYR
A
169
−16.808
6.710
61.735
1.00
27.23
C

1282
OH
TYR
A
169
−17.662
5.686
62.079
1.00
27.32
O

1283
N
HIS
A
170
−11.378
10.385
62.070
1.00
30.29
N

1284
CA
HIS
A
170
−10.183
9.840
62.709
1.00
29.65
C

1285
C
HIS
A
170
−10.094
10.382
64.141
1.00
30.06
C

1286
O
HIS
A
170
−9.854
9.632
65.086
1.00
31.02
O

1287
CB
HIS
A
170
−8.935
10.248
61.918
1.00
29.71
C

1288
CG
HIS
A
170
−7.659
9.703
62.480
1.00
29.66
C

1289
ND1
HIS
A
170
−7.370
8.354
62.498
1.00
30.87
N

1290
CD2
HIS
A
170
−6.601
10.323
63.054
1.00
29.16
C

1291
CE1
HIS
A
170
−6.188
8.167
63.058
1.00
30.02
C

1292
NE2
HIS
A
170
−5.700
9.346
63.403
1.00
30.71
N

1293
N
GLU
A
171
−10.291
11.692
64.287
1.00
29.07
N

1294
CA
GLU
A
171
−10.253
12.353
65.591
1.00
27.64
C

1295
C
GLU
A
171
−11.302
11.747
66.503
1.00
27.41
C

1296
O
GLU
A
171
−11.097
11.629
67.711
1.00
27.21
O

1297
CB
GLU
A
171
−10.510
13.852
65.433
1.00
27.02
C

1298
CG
GLU
A
171
−9.380
14.594
64.748
1.00
28.38
C

1299
CD
GLU
A
171
−8.092
14.473
65.519
1.00
31.02
C

1300
OE1
GLU
A
171
−8.122
14.733
66.740
1.00
32.85
O

1301
OE2
GLU
A
171
−7.057
14.119
64.914
1.00
31.72
O

1302
N
LEU
A
172
−12.431
11.368
65.912
1.00
28.55
N

1303
CA
LEU
A
172
−13.523
10.738
66.651
1.00
28.96
C

1304
C
LEU
A
172
−12.952
9.439
67.226
1.00
28.68
C

1305
O
LEU
A
172
−12.953
9.220
68.442
1.00
28.36
O

1306
CB
LEU
A
172
−14.675
10.399
65.700
1.00
28.70
C

1307
CG
LEU
A
172
−16.134
10.782
65.970
1.00
31.30
C

1308
OD1
LEU
A
172
−17.006
9.892
65.081
1.00
31.11
C

1309
CD2
LEU
A
172
−16.518
10.592
67.424
1.00
29.62
C

1310
N
GLU
A
173
−12.446
8.593
66.332
1.00
27.93
N

1311
CA
GLU
A
173
−11.872
7.307
66.716
1.00
29.85
C

1312
C
GLU
A
173
−10.770
7.423
67.770
1.00
30.31
C

1313
O
GLU
A
173
−10.611
6.525
68.601
1.00
31.15
O

1314
CB
GLU
A
173
−11.335
6.576
65.472
1.00
29.11
C

1315
CG
GLU
A
173
−12.411
6.278
64.429
1.00
27.60
C

1316
CD
GLU
A
173
−11.873
5.588
63.183
1.00
26.80
C

1317
OE1
GLU
A
173
−10.737
5.891
62.780
1.00
27.62
O

1318
OE2
GLU
A
173
−12.597
4.757
62.594
1.00
25.20
O

1319
N
ARG
A
174
−10.019
8.523
67.748
1.00
30.97
N

1320
CA
ARG
A
174
−8.935
8.715
68.714
1.00
30.78
C

1321
C
ARG
A
174
−9.394
9.197
70.088
1.00
28.14
C

1322
O
ARG
A
174
−8.582
9.381
70.984
1.00
29.50
O

1323
CB
ARG
A
174
−7.881
9.671
68.153
1.00
33.65
C

1324
OG
ARG
A
174
−7.285
9.187
66.838
1.00
37.03
C

1325
CD
ARG
A
174
−5.773
9.368
66.777
1.00
41.12
C

1326
NE
ARG
A
174
−5.350
10.767
66.832
1.00
42.17
N

1327
CZ
ARG
A
174
−4.767
11.335
67.883
1.00
43.14
C

1328
NH1
ARG
A
174
−4.533
10.628
68.982
1.00
42.67
N

1329
NH2
ARG
A
174
−4.401
12.610
67.830
1.00
43.85
N

1330
N
GLY
A
175
−10.694
9.396
70.254
1.00
27.27
N

1331
CA
GLY
A
175
−11.210
9.822
71.543
1.00
28.21
C

1332
C
GLY
A
I~
−11.697
8.595
72.292
1.00
29.17
C

1333
O
GLY
A
175
−12.765
8.605
72.917
1.00
27.86
O

1334
N
THR
A
176
−10.910
7.523
72.216
1.00
28.81
N

1335
CA
THR
A
176
−11.256
6.269
72.868
1.00
29.48
C

1336
C
THR
A
176
−10.175
5.776
73.831
1.00
29.99
C

1337
O
THR
A
176
−9.942
4.573
73.949
1.00
29.59
O

1338
CB
THR
A
176
−11.551
5.152
71.823
1.00
29.92
C

1339
OG1
THR
A
176
−10.407
4.958
70.976
1.00
29.17
O

1340
CG2
THR
A
176
−12.758
5.530
70.966
1.00
29.00
C

1341
N
ASP
A
177
−9.514
6.713
74.508
1.00
29.85
N

1342
CA
ASP
A
177
−8.482
6.373
75.482
1.00
29.05
C

1343
C
ASP
A
177
−9.127
5.503
76.559
1.00
28.22
C

1344
O
ASP
A
177
−10.292
5.698
76.899
1.00
28.61
O

1345
CB
ASP
A
177
−7.911
7.652
76.106
1.00
30.47
C

1346
CG
ASP
A
177
−6.890
7.374
77.209
1.00
31.45
C

1347
OD1
ASP
A
177
−7.280
6.891
78.294
1.00
31.89
O

1348
OD2
ASP
A
177
−5.690
7.643
76.992
1.00
33.83
O

1349
N
PRO
A
178
−8.376
4.530
77.108
1.00
27.37
N

1350
CA
PRO
A
178
−8.870
3.617
78.152
1.00
27.67
C

1351
C
PRO
A
178
−9.523
4.314
79.355
1.00
29.38
C

1352
O
PRO
A
178
−10.288
3.695
80.102
1.00
27.50
O

1353
CB
PRO
A
178
−7.619
2.837
78.553
1.00
27.67
C

1354
CG
PRO
A
178
−6.800
2.826
77.276
1.00
28.64
C

1355
CD
PRO
A
178
−6.972
4.238
76.767
1.00
25.94
C

1356
N
LEU
A
179
−9.217
5.593
79.561
1.00
30.15
N

1357
CA
LEU
A
179
−9.816
6.311
80.681
1.00
31.66
C

1358
C
LEU
A
179
−11.345
6.306
80.546
1.00
32.07
C

1359
O
LEU
A
179
−12.068
6.609
81.502
1.00
31.66
O

1360
CB
LEU
A
179
−9.281
7.750
80.751
1.00
32.31
C

1361
CG
LEU
A
179
−7.945
7.943
81.485
1.00
32.46
C

1362
CD1
LEU
A
179
−7.478
9.381
81.362
1.00
32.36
C

1363
CD2
LEU
A
179
−8.114
7.567
82.955
1.00
33.84
C

1364
N
ALA
A
180
−11.829
5.944
79.358
1.00
30.78
N

1365
CA
ALA
A
180
−13.265
5.880
79.097
1.00
30.82
C

1366
C
ALA
A
180
−13.932
4.900
80.059
1.00
31.31
C

1367
O
ALA
A
180
−15.156
4.912
80.238
1.00
30.28
O

1368
CB
ALA
A
180
−13.520
5.451
77.653
1.00
29.19
C

1369
N
TYR
A
181
−13.129
4.037
80.671
1.00
33.28
N

1370
CA
TYR
A
181
−13.675
3.080
81.621
1.00
32.91
C

1371
C
TYR
A
181
−13.857
3.739
82.979
1.00
32.62
C

1372
O
TYR
A
181
−14.497
3.187
83.874
1.00
30.37
O

1373
CB
TYR
A
181
−12.794
1.834
81.701
1.00
33.90
C

1374
CG
TYR
A
181
−13.061
0.882
80.551
1.00
34.13
C

1375
CD1
TYR
A
181
−14.097
−0.053
80.630
1.00
32.91
C

1376
CD2
TYR
A
181
−12.319
0.946
79.364
1.00
33.33
C

1377
CE1
TYR
A
181
−14.394
−0.904
79.559
1.00
33.98
C

1378
CE2
tYR
A
181
−12.610
0.095
78.282
1.00
34.07
C

1379
CZ
TYR
A
181
−13.649
−0.825
78.392
1.00
34.01
C

1380
OH
TYR
A
181
−13.954
−1.669
77.349
1.00
34.54
O

1381
N
VAL
A
182
−13.279
4.928
83.128
1.00
33.88
N

1382
CA
VAL
A
182
−13.460
5.707
84.347
1.00
35.31
C

1383
C
VAL
A
182
−14.749
6.448
83.982
1.00
35.25
C

1384
O
VAL
A
182
−15.809
6.207
84.560
1.00
35.34
O

1385
CB
VAL
A
182
−12.306
6.726
84.567
1.00
36.65
C

1386
CG1
VAL
A
182
−12.551
7.544
85.840
1.00
35.76
C

1387
CG2
VAL
A
182
−10.983
5.996
84.661
1.00
36.14
C

1388
N
ASP
A
183
−14.650
7.314
82.978
1.00
35.79
N

1389
CA
ASP
A
183
−15.798
8.068
82.480
1.00
36.45
C

1390
C
ASP
A
183
−15.482
8.557
81.066
1.00
36.10
C

1391
O
ASP
A
183
−14.494
9.264
80.851
1.00
35.24
O

1392
CB
ASP
A
183
−16.104
9.257
83.405
1.00
37.32
C

1393
CG
ASP
A
183
−17.369
10.008
83.005
1.00
39.05
C

1394
OD1
ASP
A
183
−17.810
9.885
81.844
1.00
39.32
O

1395
OD2
ASP
A
183
−17.922
10.734
83.858
1.00
42.36
O

1396
N
PRO
A
184
−16.312
8.172
80.080
1.00
35.78
N

1397
CA
PRO
A
184
−16.100
8.585
78.687
1.00
36.63
C

1398
C
PRO
A
184
−16.280
10.083
78.459
1.00
36.54
C

1399
O
PRO
A
184
−16.094
10.565
77.347
1.00
37.47
O

1400
CB
PRO
A
184
−17.129
7.758
77.919
1.00
36.03
C

1401
CG
PRO
A
184
−18.247
7.614
78.917
1.00
36.86
C

1402
CD
PRO
A
184
−17.496
7.301
80.192
1.00
36.13
C

1403
N
TYR
A
185
−16.629
10.819
79.512
1.00
36.81
N

1404
CA
TYR
A
185
−16.829
12.260
79.389
1.00
35.91
C

1405
C
TYR
A
185
−15.910
13.111
80.276
1.00
35.98
C

1406
O
TYR
A
185
−16.193
14.286
80.524
1.00
35.53
O

1407
CB
TYR
A
185
−18.298
12.608
79.663
1.00
34.96
C

1408
CG
TYR
A
185
−19.263
11.955
78.690
1.00
34.85
C

1409
CD1
TYR
A
185
−19.490
12.508
77.428
1.00
33.08
C

1410
CD2
TYR
A
185
−19.925
10.767
79.018
1.00
34.87
C

1411
CE1
TYR
A
185
−20.347
11.899
76.517
1.00
33.26
C

1412
CE2
TYR
A
185
−20.792
10.147
78.112
1.00
33.43
C

1413
CZ
TYR
A
185
−20.996
10.719
76.864
1.00
34.94
C

1414
OH
TYR
A
185
−21.851
10.114
75.959
1.00
35.85
O

1415
N
LEU
A
186
−14.810
12.520
80.742
1.00
35.03
N

1416
CA
LEU
A
186
−13.849
13.238
81.577
1.00
36.08
C

1417
C
LEU
A
186
−13.265
14.409
80.789
1.00
37.79
C

1418
O
LEU
A
186
−13.318
14.425
79.563
1.00
37.39
O

1419
CB
LEU
A
186
−12.713
12.306
82.016
1.00
33.37
C

1420
CG
LEU
A
186
−13.053
11.109
82.910
1.00
31.97
C

1421
CD1
LEU
A
186
−11.804
10.261
83.101
1.00
30.15
C

1422
CD2
LEU
A
186
−13.594
11.588
84.256
1.00
28.93
C

1423
N
PRO
A
187
−12.709
15.412
81.491
1.00
40.56
N

1424
CA
PRO
A
187
−12.112
16.597
80.859
1.00
42.28
C

1425
C
PRO
A
187
−10.764
16.344
80.185
1.00
44.41
C

1426
O
PRO
A
187
−9.851
17.162
80.300
1.00
44.99
O

1427
CB
PRO
A
187
−11.981
17.583
82.025
1.00
41.28
C

1428
CG
PRO
A
187
−13.060
17.153
82.967
1.00
40.27
C

1429
CD
PRO
A
187
−12.926
15.655
82.928
1.00
39.80
C

1430
N
ILE
A
188
−10.641
15.214
79.492
1.00
46.21
N

1431
CA
ILE
A
188
−9.404
14.858
78.789
1.00
47.48
C

1432
C
ILE
A
188
−9.274
15.671
77.494
1.00
47.31
C

1433
O
ILE
A
188
−10.276
16.075
76.899
1.00
46.77
O

1434
CB
ILE
A
188
−9.388
13.348
78.391
1.00
49.85
C

1435
CG1
ILE
A
188
−9.582
12.470
79.624
1.00
51.37
C

1436
CG2
ILE
A
188
−8.069
12.992
77.702
1.00
50.10
C

1437
CD1
ILE
A
188
−9.636
10.989
79.302
1.00
52.12
C

1438
N
GLU
A
189
−8.040
15.895
77.054
1.00
47.35
N

1439
CA
GLU
A
189
−7.802
16.636
75.821
1.00
46.96
C

1440
C
GLU
A
189
−8.347
15.858
74.622
1.00
45.12
C

1441
O
GLU
A
189
−8.974
16.433
73.735
1.00
44.65
O

1442
CB
GLU
A
189
−6.305
16.884
75.631
1.00
49.04
C

1443
CG
GLU
A
189
−5.935
18.356
75.509
1.00
53.40
C

1444
CD
GLU
A
189
−6.529
19.014
74.275
1.00
55.03
C

1445
OE1
GLU
A
189
−6.066
18.721
73.149
1.00
55.73
O

1446
OE2
GLU
A
189
−7.464
19.826
74.433
1.00
56.97
O

1447
N
SER
A
190
−8.111
14.548
74.599
1.00
43.62
N

1448
CA
SER
A
190
−8.585
13.716
73.495
1.00
42.50
C

1449
C
SER
A
190
−10.110
13.591
73.475
1.00
40.84
C

1450
O
SER
A
190
−10.708
13.413
72.414
1.00
40.62
O

1451
CB
SER
A
190
−7.945
12.321
73.555
1.00
42.19
C

1452
OG
SER
A
190
−8.338
11.619
74.720
1.00
43.54
O

1453
N
PHE
A
191
−10.737
13.677
74.644
1.00
38.92
N

1454
CA
PHE
A
191
−12.193
13.594
74.720
1.00
37.81
C

1455
C
PHE
A
191
−12.810
14.904
74.245
1.00
37.45
C

1456
O
PHE
A
191
−13.932
14.925
73.742
1.00
38.11
O

1457
CB
PHE
A
191
−12.648
13.280
76.153
1.00
34.81
C

1458
CG
PHE
A
191
−12.437
11.843
76.557
1.00
34.90
C

1459
CD1
PHE
A
191
−11.841
10.935
75.682
1.00
33.69
C

1460
CD2
PHE
A
191
−12.836
11.394
77.810
1.00
33.75
C

1461
CE1
PHE
A
191
−11.648
9.610
76.051
1.00
33.10
C

1462
CE2
PHE
A
191
−12.646
10.066
78.187
1.00
34.44
C

1463
CZ
PHE
A
191
−12.051
9.174
77.306
1.00
33.37
C

1464
N
ARG
A
192
−12.069
15.995
74.414
1.00
37.61
N

1465
CA
ARG
A
192
−12.516
17.310
73.979
1.00
38.21
C

1466
C
ARG
A
192
−12.379
17.348
72.458
1.00
37.61
C

1467
O
ARG
A
192
−13.288
17.785
71.752
1.00
36.20
O

1468
CB
ARG
A
192
−11.646
18.415
74.598
1.00
40.44
C

1469
CG
ARG
A
192
−12.053
19.841
74.184
1.00
45.15
C

1470
CD
ARG
A
192
−10.972
20.876
74.517
1.00
47.79
C

1471
NE
ARG
A
192
−9.830
20.809
73.604
1.00
49.51
N

1472
CZ
ARG
A
192
−9.822
21.310
72.370
1.00
51.18
C

1473
NH1
ARG
A
192
−10.901
21.925
71.898
1.00
52.13
N

1474
NH2
ARG
A
192
−8.739
21.193
71.604
1.00
50.05
N

1475
N
ARG
A
193
−11.233
16.884
71.961
1.00
37.84
N

1476
CA
ARG
A
193
−10.976
16.861
70.525
1.00
37.47
C

1477
C
ARG
A
193
−11.922
15.895
69.823
1.00
34.74
C

1478
O
ARG
A
193
−12.164
16.012
68.626
1.00
34.78
O

1479
CB
ARG
A
193
−9.518
16.478
70.244
1.00
40.02
C

1480
CG
ARG
A
193
−8.512
17.560
70.627
1.00
44.48
C

1481
CD
ARG
A
193
−7.083
17.157
70.279
1.00
47.58
C

1482
NE
ARG
A
193
−6.858
17.076
68.837
1.00
50.36
N

1483
CZ
ARG
A
193
−5.691
16.760
68.284
1.00
51.50
C

1484
NH1
ARG
A
193
−4.644
16.493
69.054
1.00
52.49
N

1487
CA
ARG
A
194
−13.400
13.974
70.048
1.00
30.32
C

1488
C
ARG
A
194
−14.745
14.686
69.849
1.00
31.15
C

1489
O
ARG
A
194
−15.336
14.642
68.763
1.00
29.49
O

1490
CB
ARG
A
194
−13.570
12.821
71.035
1.00
28.99
C

1491
CG
ARG
A
194
−14.687
11.850
70.686
1.00
30.44
C

1492
CD
ARG
A
194
−15.091
11.050
71.910
1.00
31.84
C

1493
NE
ARG
A
194
−15.741
11.899
72.906
1.00
33.16
N

1494
CZ
ARG
A
194
−15.881
11.583
74.190
1.00
33.95
C

1495
NH1
ARG
A
194
−15.410
10.428
74.651
1.00
32.09
N

1496
NH2
ARG
A
194
−16.501
12.420
75.013
1.00
33.36
N

1497
N
ASP
A
195
−15.221
15.345
70.905
1.00
32.25
N

1498
CA
ASP
A
195
−16.490
16.064
70.851
1.00
32.80
C

1499
C
ASP
A
195
−16.452
17.174
69.801
1.00
32.06
C

1500
O
ASP
A
195
−17.449
17.444
69.128
1.00
31.84
O

1501
CB
ASP
A
195
−16.836
16.652
72.227
1.00
33.44
C

1502
CG
ASP
A
195
−16.920
15.590
73.317
1.00
36.10
C

1503
OD1
ASP
A
195
−17.318
14.444
73.016
1.00
36.09
O

1504
OD2
ASP
A
195
−16.600
15.905
74.485
1.00
36.61
O

1505
N
GLU
A
196
−15.299
17.816
69.662
1.00
32.35
N

1506
CA
GLU
A
196
−15.140
18.881
68.683
1.00
33.54
C

1507
C
GLU
A
196
−15.163
18.262
67.277
1.00
33.60
C

1508
O
GLU
A
196
−15.686
18.855
66.328
1.00
33.17
O

1509
CB
GLU
A
196
−13.817
19.613
68.942
1.00
37.97
C

1510
CG
GLU
A
196
−13.544
20.828
68.070
1.00
44.62
C

1511
CD
GLU
A
196
−12.253
21.557
68.470
1.00
50.93
C

1512
OE1
GLU
A
196
−11.177
20.903
68.505
1.00
52.13
O

1513
OE2
GLU
A
196
−12.317
22.784
68.745
1.00
51.94
O

1514
N
ALA
A
197
−14.609
17.058
67.147
1.00
31.62
N

1515
CA
ALA
A
197
−14.582
16.374
65.858
1.00
31.36
C

1516
C
ALA
A
197
−16.001
15.984
65.440
1.00
30.44
C

1517
O
ALA
A
197
−16.409
16.203
64.297
1.00
28.71
O

1518
CB
ALA
A
197
−13.699
15.133
65.940
1.00
29.14
C

1519
N
ARG
A
198
−16.752
15.408
66.375
1.00
31.47
N

1520
CA
ARG
A
198
−18.124
14.986
66.099
1.00
30.99
C

1521
C
ARO
A
198
−18.922
16.207
65.646
1.00
30.79
C

1522
O
ARG
A
198
−19.734
16.133
64.719
1.00
27.83
O

1523
CB
ARG
A
198
−18.748
14.380
67.354
1.00
30.42
C

1524
CG
ARG
A
198
−19.993
13.550
67.083
1.00
32.73
C

1525
CD
ARG
A
198
−20.487
12.874
68.349
1.00
33.95
C

1526
NE
ARG
A
198
−21.510
11.859
68.089
1.00
38.49
N

1527
CZ
ARG
A
198
−22.736
12.116
67.640
1.00
38.45
C

1528
NH1
ARG
A
198
−23.111
13.363
67.390
1.00
38.97
N

1529
NH2
ARG
A
198
−23.593
11.121
67.457
1.00
38.91
N

1530
N
ASN
A
199
−18.672
17.333
66.310
1.00
30.81
N

1531
CA
ASN
A
199
−19.329
18.593
65.979
1.00
29.43
C

1532
C
ASN
A
199
−18.984
18.992
64.557
1.00
25.92
C

1533
O
ASN
A
199
−19.830
19.494
63.822
1.00
24.63
O

1534
CB
ASN
A
199
−18.879
19.688
66.943
1.00
33.06
C

1535
CG
ASN
A
199
−19.753
19.770
68.174
1.00
36.23
C

1536
OD1
ASN
A
199
−20.220
18.753
68.693
1.00
38.56
O

1537
ND2
ASN
A
199
−19.972
20.985
68.658
1.00
38.62
N

1538
N
GLY
A
200
−17.732
18.771
64.172
1.00
24.69
N

1539
CA
GLY
A
200
−17.321
19.099
62.821
1.00
22.56
C

1540
C
GLY
A
200
−18.038
18.207
61.825
1.00
22.34
C

1541
O
GLY
A
200
−18.410
18.648
60.738
1.00
21.04
O

1542
N
LEU
A
201
−18.236
16.943
62.192
1.00
22.58
N

1543
CA
LEU
A
201
−18.928
16.013
61.306
1.00
23.66
C

1544
C
LEU
A
201
−20.369
16.467
61.098
1.00
24.58
C

1545
O
LEU
A
201
−20.861
16.490
59.969
1.00
24.38
O

1546
CB
LEU
A
201
−18.904
14.595
61.883
1.00
21.02
C

1547
CG
LEU
A
201
−17.552
13.874
61.834
1.00
22.73
C

1548
CD1
LEU
A
201
−17.620
12.600
62.660
1.00
23.61
C

1549
CD2
LEU
A
201
−17.176
13.566
60.385
1.00
18.67
C

1550
N
VAL
A
202
−21.042
16.841
62.184
1.00
25.84
N

1551
CA
VAL
A
202
−22.429
17.295
62.090
1.00
26.34
C

1552
C
VAL
A
202
−22.524
18.489
61.151
1.00
26.17
C

1553
O
VAL
A
202
−23.469
18.597
60.375
1.00
26.31
O

1554
CB
VAL
A
202
−22.997
17.679
63.485
1.00
26.46
C

1555
CG1
VAL
A
202
−24.445
18.148
63.364
1.00
25.68
C

1556
CG2
VAL
A
202
−22.924
16.482
64.407
1.00
26.43
C

1557
N
ALA
A
203
−21.535
19.378
61.206
1.00
27.42
N

1558
CA
ALA
A
203
−21.538
20.559
60.340
1.00
26.01
C

1559
C
ALA
A
203
−21.405
20.170
58.871
1.00
24.46
C

1560
O
ALA
A
203
−22.113
20.699
58.022
1.00
22.15
O

1561
CB
ALA
A
203
−20.416
21.522
60.744
1.00
25.80
C

1562
N
LEU
A
204
−20.502
19.243
58.565
1.00
24.24
N

1563
CA
LEU
A
204
−20.337
18.810
57.184
1.00
24.69
C

1564
C
LEU
A
204
−21.642
18.228
56.634
1.00
27.06
C

1565
O
LEU
A
204
−22.005
18.451
55.471
1.00
27.84
O

1566
CB
LEU
A
204
−19.227
17.757
57.077
1.00
25.42
C

1567
CG
LEU
A
204
−17.780
18.232
57.233
1.00
24.57
C

1568
CD1
LEU
A
204
−16.825
17.068
56.964
1.00
20.29
C

1569
CD2
LEU
A
204
−17.517
19.382
56.258
1.00
22.84
C

1570
N
VAL
A
205
−22.338
17.467
57.470
1.00
26.81
N

1571
CA
VAL
A
205
−23.593
16.852
57.065
1.00
27.58
C

1572
C
VAL
A
205
−24.668
17.923
56.908
1.00
28.08
C

1573
O
VAL
A
205
−25.437
17.899
55.944
1.00
29.21
O

1574
CB
VAL
A
205
−24.043
15.783
58.100
1.00
27.06
C

1575
CG1
VAL
A
205
−25.390
15.182
57.698
1.00
26.21
C

1576
CG2
VAL
A
205
−22.983
14.685
58.190
1.00
22.88
C

1577
N
ALA
A
206
−24.723
18.867
57.845
1.00
27.99
N

1578
CA
ALA
A
206
−25.711
19.943
57.757
1.00
27.03
C

1579
C
ALA
A
206
−25.473
20.698
56.450
1.00
26.01
C

1580
O
ALA
A
206
−26.419
21.107
55.778
1.00
26.17
O

1581
CB
ALA
A
206
−25.588
20.889
58.953
1.00
23.80
C

1582
N
ASP
A
207
−24.208
20.877
56.086
1.00
26.43
N

1583
CA
ASP
A
207
−23.885
21.563
54.838
1.00
27.81
C

1584
C
ASP
A
207
−24.457
20.800
53.653
1.00
26.32
C

1585
O
ASP
A
207
−25.025
21.391
52.742
1.00
26.46
O

1586
CB
ASP
A
207
−22.372
21.703
54.658
1.00
30.53
C

1587
CG
ASP
A
207
−21.782
22.809
55.512
1.00
33.12
C

1588
OD1
ASP
A
207
−22.394
23.896
55.578
1.00
34.08
O

1589
OD2
ASP
A
207
−20.702
22.598
56.103
1.00
34.20
O

1590
N
ILE
A
208
−24.299
19.482
53.661
1.00
25.49
N

1591
CA
ILE
A
208
−24.822
18.667
52.572
1.00
25.80
C

1592
C
ILE
A
208
−26.350
18.719
52.520
1.00
25.33
C

1593
O
ILE
A
208
−26.937
18.811
51.447
1.00
25.95
O

1594
CB
ILE
A
208
−24.365
17.196
52.707
1.00
26.61
C

1595
CG1
ILE
A
208
−22.841
17.120
52.572
1.00
26.73
C

1596
CG2
ILE
A
208
−25.046
16.336
51.651
1.00
21.81
C

1597
CD1
ILE
A
208
−22.274
15.759
52.842
1.00
28.32
C

1598
N
MET
A
209
−26.996
18.656
53.678
1.00
26.33
N

1599
CA
MET
A
209
−28.447
18.707
53.720
1.00
27.44
C

1600
C
MET
A
209
−28.944
19.972
53.033
1.00
28.71
C

1601
O
MET
A
209
−29.844
19.917
52.198
1.00
27.87
O

1602
CB
MET
A
209
−28.929
18.650
55.171
1.00
27.37
C

1603
CG
MET
A
209
−28.713
17.286
55.821
1.00
28.09
C

1604
SD
MET
A
209
−28.926
17.246
57.610
1.00
30.68
S

1605
CE
MET
A
209
−30.691
17.509
57.784
1.00
26.37
C

1606
N
ASN
A
210
−28.346
21.110
53.373
1.00
32.20
N

1607
CA
ASN
A
210
−28.738
22.382
52.769
1.00
35.81
C

1608
C
ASN
A
210
−28.578
22.338
51.259
1.00
35.85
C

1609
O
ASN
A
210
−29.515
22.627
50.518
1.00
35.95
O

1610
CB
ASN
A
210
−27.896
23.533
53.329
1.00
38.56
C

1611
CG
ASN
A
210
−28.281
23.909
54.753
1.00
41.84
C

1612
OD1
ASN
A
210
−27.688
24.813
55.344
1.00
46.06
O

1613
ND2
ASN
A
210
−29.277
23.223
55.309
1.00
41.03
N

1614
N
GLY
A
211
−27.380
21.979
50.809
1.00
36.59
N

1615
CA
GLY
A
211
−27.125
21.910
49.384
1.00
37.66
C

1616
C
GLY
A
211
−28.194
21.121
48.657
1.00
39.40
C

1617
O
GLY
A
211
−28.680
21.546
47.611
1.00
39.14
O

1618
N
ARG
A
212
−28.565
19.973
49.220
1.00
41.03
N

1619
CA
ARG
A
212
−29.577
19.106
48.623
1.00
42.19
C

1620
C
ARG
A
212
−30.986
19.672
48.665
1.00
44.20
C

1621
O
ARG
A
212
−31.866
19.217
47.931
1.00
43.70
O

1622
CB
ARG
A
212
−29.578
17.745
49.306
1.00
41.08
C

1623
CG
ARG
A
212
−28.346
16.927
49.022
1.00
40.49
C

1624
CD
ARO
A
212
−28.552
15.525
49.526
1.00
40.77
C

1625
NE
ARG
A
212
−27.435
14.650
49.200
1.00
37.94
N

1626
CZ
ARG
A
212
−27.499
13.328
49.280
1.00
36.92
C

1627
NH1
ARG
A
212
−28.630
12.748
49.670
1.00
37.46
N

1628
NH2
ARG
A
212
−26.443
12.591
48.973
1.00
33.80
N

1629
N
ILE
A
213
−31.210
20.648
49.535
1.00
45.69
N

1630
CA
ILE
A
213
−32.522
21.257
49.639
1.00
48.52
C

1631
C
ILE
A
213
−32.645
22.390
48.631
1.00
50.55
C

1632
O
ILE
A
213
−33.730
22.673
48.132
1.00
50.62
O

1633
CB
ILE
A
213
−32.763
21.766
51.066
1.00
48.66
C

1634
OG1
ILE
A
213
−33.005
20.563
51.984
1.00
49.48
C

1635
CG2
ILE
A
213
−33.933
22.733
51.091
1.00
50.48
C

1636
CD1
ILE
A
213
−33.021
20.884
53.458
1.00
49.01
C

1637
N
ALA
A
214
−31.514
23.012
48.315
1.00
54.31
N

1638
CA
ALA
A
214
−31.472
24.115
47.361
1.00
57.77
C

1639
C
ALA
A
214
−31.542
23.619
45.919
1.00
60.68
C

1640
O
ALA
A
214
−31.992
24.340
45.031
1.00
61.79
O

1641
CB
ALA
A
214
−30.202
24.929
47.573
1.00
56.41
C

1642
N
ASN
A
215
−31.092
22.389
45.690
1.00
65.32
N

1643
CA
ASN
A
215
−31.105
21.798
44.353
1.00
69.29
C

1644
C
ASN
A
215
−31.332
20.282
44.403
1.00
71.88
C

1645
O
ASN
A
215
−30.392
19.496
44.258
1.00
71.74
O

1646
CB
ASN
A
215
−29.786
22.098
43.632
1.00
69.76
C

1647
N
PRO
A
216
−32.592
19.855
44.609
1.00
74.99
N

1648
CA
PRO
A
216
−32.937
18.430
44.678
1.00
76.66
C

1649
C
PRO
A
216
−32.608
17.667
43.392
1.00
78.59
C

1650
O
PRO
A
216
−32.244
18.270
42.378
1.00
78.69
O

1651
CB
PRO
A
216
−34.436
18.453
44.992
1.00
76.35
C

1652
CG
PRO
A
216
−34.897
19.734
44.376
1.00
75.83
C

1653
CD
PRO
A
216
−33.797
20.690
44.767
1.00
75.63
C

1654
N
PRO
A
217
−32.731
16.326
43.419
1.00
80.27
N

1655
CA
PRO
A
217
−32.444
15.472
42.260
1.00
81.80
C

1656
C
PRO
A
217
−33.416
15.610
41.085
1.00
82.59
C

1657
O
PRO
A
217
−34.629
15.701
41.269
1.00
83.05
O

1658
CB
PRO
A
217
−32.461
14.068
42.860
1.00
81.59
C

1659
CG
PRO
A
217
−33.496
14.187
43.929
1.00
81.32
C

1660
CD
PRO
A
217
−33.130
15.505
44.578
1.00
81.13
C

1661
N
THR
A
218
−32.866
15.622
39.876
1.00
84.11
N

1662
CA
THR
A
218
−33.672
15.732
38.667
1.00
85.61
C

1663
C
THR
A
218
−34.207
14.348
38.298
1.00
86.22
C

1664
O
THR
A
218
−34.617
14.107
37.160
1.00
86.47
O

1665
CB
THR
A
218
−32.840
16.278
37.490
1.00
86.70
C

1666
N
ASP
A
219
−34.192
13.443
39.274
1.00
85.35
N

1667
CA
ASP
A
219
−34.671
12.079
39.083
1.00
84.23
C

1668
C
ASP
A
219
−35.127
11.505
40.419
1.00
83.48
C

1669
O
ASP
A
219
−34.302
11.199
41.281
1.00
83.34
O

1670
CB
ASP
A
219
−33.558
11.203
38.501
1.00
83.84
C

1671
N
LYS
A
220
−36.442
11.364
40.585
1.00
82.92
N

1672
CA
LYS
A
220
−37.025
10.826
41.817
1.00
81.89
C

1673
C
LYS
A
220
−36.599
9.378
42.037
1.00
80.50
C

1674
O
LYS
A
220
−37.194
8.651
42.838
1.00
80.43
O

1675
CB
LYS
A
220
−38.556
10.909
41.764
1.00
82.38
C

1676
N
SER
A
221
−35.562
8.973
41.313
1.00
78.61
N

1677
CA
SER
A
221
−35.018
7.627
41.401
1.00
76.18
C

1678
C
SER
A
221
−33.667
7.637
42.122
1.00
74.20
C

1679
O
SER
A
221
−33.373
6.748
42.927
1.00
74.16
O

1680
CB
SER
A
221
−34.863
7.047
39.991
1.00
76.04
C

1681
OG
SER
A
221
−34.216
7.968
39.125
1.00
74.12
O

1682
N
ASP
A
222
−32.855
8.654
41.840
1.00
71.30
N

1683
CA
ASP
A
222
−31.537
8.768
42.455
1.00
68.71
C

1684
C
ASP
A
222
−31.535
9.520
43.789
1.00
65.62
C

1685
O
ASP
A
222
−30.782
10.478
43.973
1.00
66.54
O

1686
CB
ASP
A
222
−30.558
9.449
41.492
1.00
69.27
C

1687
CG
ASP
A
222
−29.123
9.407
41.995
1.00
69.54
C

1688
OD1
ASP
A
222
−28.859
8.697
42.994
1.00
69.51
O

1689
OD2
ASP
A
222
−28.258
10.077
41.389
1.00
69.41
O

1690
N
ARG
A
223
−32.384
9.091
44.716
1.00
61.09
N

1691
CA
ARG
A
223
−32.444
9.712
46.033
1.00
55.60
C

1692
C
ARG
A
223
−31.877
8.672
46.983
1.00
53.19
C

1693
O
ARG
A
223
−32.310
7.518
46.959
1.00
53.89
O

1694
CB
ARG
A
223
−33.893
10.035
46.416
1.00
54.10
C

1695
CG
ARG
A
223
−34.674
10.735
45.321
1.00
53.03
C

1696
CD
ARG
A
223
−36.052
11.200
45.776
1.00
53.03
C

1697
NE
ARG
A
223
−36.001
12.477
46.484
1.00
53.17
N

1698
CZ
ARG
A
223
−36.062
12.609
47.803
1.00
53.27
C

1699
NH1
ARG
A
223
−36.183
11.538
48.572
1.00
53.16
N

1700
NH2
ARG
A
223
−35.993
13.813
48.354
1.00
55.17
N

1701
N
ASP
A
224
−30.900
9.054
47.801
1.00
48.87
N

1702
CA
ASP
A
224
−30.317
8.096
48.735
1.00
44.79
C

1703
C
ASP
A
224
−30.957
8.162
50.117
1.00
41.93
C

1704
O
ASP
A
224
−32.022
8.758
50.297
1.00
39.24
O

1705
CB
ASP
A
224
−28.792
8.280
48.858
1.00
43.65
C

1706
CG
ASP
A
224
−28.396
9.619
49.459
1.00
43.18
C

1707
OD1
ASP
A
224
−29.121
10.128
50.340
1.00
40.93
O

1708
OD2
ASP
A
224
−27.336
10.150
49.061
1.00
42.62
O

1709
N
MET
A
225
−30.299
7.540
51.088
1.00
40.11
N

1710
CA
MET
A
225
−30.798
7.513
52.451
1.00
38.70
C

1711
C
MET
A
225
−30.968
8.911
53.042
1.00
38.01
C

1712
O
MET
A
225
−31.959
9.184
53.727
1.00
38.53
O

1713
CB
MET
A
225
−29.853
6.710
53.335
1.00
39.34
C

1714
CG
MET
A
225
−30.386
6.493
54.737
1.00
40.09
C

1715
SD
MET
A
225
−29.193
5.640
55.754
1.00
41.11
S

1716
CE
MET
A
225
−29.265
4.003
55.027
1.00
40.39
C

1717
N
LEU
A
226
−30.003
9.791
52.785
1.00
34.31
N

1718
CA
LEU
A
226
−30.068
11.150
53.317
1.00
31.64
C

1719
C
LEU
A
226
−31.299
11.889
52.800
1.00
30.37
C

1720
O
LEU
A
226
−31.999
12.542
53.566
1.00
29.78
O

1721
CB
LEU
A
226
−28.802
11.929
52.950
1.00
28.99
C

1722
CG
LEU
A
226
−28.758
13.370
53.467
1.00
26.52
C

1723
OD1
LEU
A
226
−28.866
13.381
54.987
1.00
26.11
C

1724
CD2
LEU
A
226
−27.469
14.025
53.011
1.00
27.27
C

1725
N
ASP
A
227
−31.547
11.789
51.496
1.00
30.92
N

1726
CA
ASP
A
227
−32.698
12.430
50.861
1.00
29.97
C

1727
C
ASP
A
227
−33.974
12.033
51.579
1.00
30.27
C

1728
O
ASP
A
227
−34.877
12.856
51.778
1.00
29.96
O

1729
CB
ASP
A
227
−32.807
11.992
49.406
1.00
30.39
C

1730
CG
ASP
A
227
−31.764
12.630
48.528
1.00
31.82
C

1731
OD1
ASP
A
227
−31.268
13.722
48.882
1.00
33.91
O

1732
OD2
ASP
A
227
−31.452
12.044
47.475
1.00
30.38
O

1733
N
VAL
A
228
−34.035
10.760
51.961
1.00
30.19
N

1734
CA
VAL
A
228
−35.185
10.200
52.655
1.00
30.00
C

1735
C
VAL
A
228
−35.373
10.809
54.039
1.00
29.39
C

1736
O
VAL
A
228
−36.458
11.282
54.368
1.00
29.77
O

1737
CB
VAL
A
228
−35.042
8.668
52.793
1.00
31.01
C

1738
CG1
VAL
A
228
−36.263
8.080
53.502
1.00
31.55
C

1739
CG2
VAL
A
228
−34.879
8.043
51.411
1.00
32.93
C

1740
N
LEU
A
229
−34.312
10.798
54.842
1.00
30.30
N

1741
CA
LEU
A
229
−34.367
11.333
56.202
1.00
30.15
C

1742
C
LEU
A
229
−34.630
12.837
56.227
1.00
29.44
C

1743
O
LEU
A
229
−35.234
13.358
57.161
1.00
29.17
O

1744
CB
LEU
A
229
−33.067
10.997
56.946
1.00
29.30
C

1745
CG
LEU
A
229
−32.807
9.489
57.126
1.00
30.40
C

1746
CD1
LEU
A
229
−31.452
9.253
57.771
1.00
31.06
C

1747
CD2
LEU
A
229
−33.902
8.875
57.990
1.00
26.71
C

1748
N
ILE
A
230
−34.182
13.530
55.190
1.00
28.84
N

1749
CA
ILE
A
230
−34.383
14.968
55.090
1.00
30.65
C

1750
C
ILE
A
230
−35.867
15.301
54.870
1.00
31.90
C

1751
O
ILE
A
230
−36.373
16.310
55.366
1.00
28.46
O

1752
CB
ILE
A
230
−33.563
15.552
53.909
1.00
30.68
C

1753
CG1
ILE
A
230
−32.078
15.575
54.272
1.00
29.06
C

1754
CG2
ILE
A
230
−34.077
16.949
53.542
1.00
30.56
C

1755
CD1
ILE
A
230
−31.195
16.116
53.177
1.00
28.96
C

1756
N
ALA
A
231
−36.555
14.435
54.130
1.00
33.07
N

1757
CA
ALA
A
231
−37.962
14.639
53.816
1.00
33.39
C

1758
C
ALA
A
231
−38.924
14.209
54.911
1.00
33.63
C

1759
O
ALA
A
231
−40.087
14.613
54.891
1.00
34.47
O

1760
CB
ALA
A
231
−38.309
13.928
52.511
1.00
33.70
C

1761
N
VAL
A
232
−38.461
13.397
55.860
1.00
32.63
N

1762
CA
VAL
A
232
−39.339
12.946
56.940
1.00
32.16
C

1763
C
VAL
A
232
−39.855
14.133
57.747
1.00
35.12
C

1764
O
VAL
A
232
−39.082
14.907
58.317
1.00
34.91
O

1765
CB
VAL
A
232
−38.626
11.959
57.895
1.00
30.61
C

1766
CG1
VAL
A
232
−39.550
11.598
59.061
1.00
24.92
C

1767
CG2
VAL
A
232
−38.231
10.704
57.138
1.00
28.62
C

1768
N
LYS
A
233
−41.172
14.270
57.798
1.00
37.18
N

1769
CA
LYS
A
233
−41.779
15.375
58.520
1.00
40.68
C

1770
C
LYS
A
233
−42.375
14.973
59.856
1.00
42.48
C

1771
O
LYS
A
233
−42.896
13.872
60.016
1.00
42.63
O

1772
CB
LYS
A
233
−42.857
16.029
57.650
1.00
40.54
C

1773
CG
LYS
A
233
−42.308
16.632
56.367
1.00
41.07
C

1774
CD
LYS
A
233
−41.234
17.664
56.676
1.00
42.46
C

1775
CE
LYS
A
233
−40.519
18.125
55.416
1.00
44.86
C

1776
NZ
LYS
A
233
−39.411
19.074
55.741
1.00
46.96
N

1777
N
ALA
A
234
−42.286
15.879
60.821
1.00
45.45
N

1778
CA
ALA
A
234
−42.842
15.637
62.141
1.00
47.43
C

1779
C
ALA
A
234
−44.359
15.810
62.052
1.00
49.65
C

1780
O
ALA
A
234
−44.936
15.831
60.958
1.00
49.45
O

1781
CB
ALA
A
234
−42.251
16.617
63.153
1.00
46.96
C

1782
N
GLU
A
235
−44.994
15.955
63.208
1.00
51.35
N

1783
CA
GLU
A
235
−46.438
16.098
63.291
1.00
52.19
C

1784
C
GLU
A
235
−47.008
17.384
62.694
1.00
51.97
C

1785
O
GLU
A
235
−48.092
17.373
62.107
1.00
52.61
O

1786
CB
GLU
A
235
−46.862
15.987
64.752
1.00
53.83
C

1787
CG
GLU
A
235
−48.352
16.081
64.986
1.00
57.80
C

1788
CD
GLU
A
235
−48.695
16.021
66.461
1.00
60.32
C

1789
OE1
GLU
A
235
−48.250
16.922
67.207
1.00
60.18
O

1790
OE2
GLU
A
235
−49.402
15.072
66.873
1.00
62.03
O

1791
N
THR
A
236
−46.288
18.490
62.835
1.00
50.84
N

1792
CA
THR
A
236
−46.788
19.756
62.317
1.00
49.69
C

1793
C
THR
A
236
−46.156
20.204
60.993
1.00
48.86
C

1794
O
THR
A
236
−46.293
21.359
60.599
1.00
48.44
O

1795
CB
THR
A
236
−46.619
20.874
63.372
1.00
49.86
C

1796
OG1
THR
A
236
−47.408
22.013
62.997
1.00
50.23
O

1797
CG2
THR
A
236
−45.157
21.278
63.495
1.00
49.58
C

1798
N
GLY
A
237
−45.477
19.288
60.309
1.00
47.53
N

1799
CA
GLY
A
237
−44.854
19.620
59.038
1.00
45.82
C

1800
C
GLY
A
237
−43.369
19.913
59.144
1.00
45.01
C

1801
O
GLY
A
237
−42.672
20.015
58.135
1.00
44.87
O

1802
N
THR
A
238
−42.884
20.041
60.374
1.00
44.35
N

1803
CA
THR
A
238
−41.477
20.332
60.642
1.00
43.16
C

1804
C
THR
A
238
−40.564
19.138
60.399
1.00
41.82
C

1805
O
THR
A
238
−40.926
18.000
60.700
1.00
41.60
O

1806
CB
THR
A
238
−41.286
20.790
62.108
1.00
43.56
C

1807
OG1
THR
A
238
−41.828
22.104
62.268
1.00
44.90
O

1808
CG2
THR
A
238
−39.806
20.797
62.496
1.00
43.85
C

1809
N
PRO
A
239
−39.364
19.382
59.843
1.00
39.95
N

1810
CA
PRO
A
239
−38.436
18.277
59.596
1.00
38.44
C

1811
C
PRO
A
239
−38.305
17.487
60.893
1.00
36.18
C

1812
O
PRO
A
239
−38.119
18.070
61.961
1.00
35.37
O

1813
CB
PRO
A
239
−37.143
18.996
59.225
1.00
38.11
C

1814
CG
PRO
A
239
−37.643
20.210
58.510
1.00
38.28
C

1815
CD
PRO
A
239
−38.787
20.662
59.392
1.00
39.74
C

1816
N
ARG
A
240
−38.415
16.168
60.813
1.00
34.91
N

1817
CA
ARG
A
240
−38.319
15.357
62.014
1.00
33.91
C

1818
C
ARG
A
240
−36.907
15.150
62.549
1.00
31.69
C

1819
O
ARG
A
240
−36.709
15.033
63.759
1.00
31.32
O

1820
CB
ARG
A
240
−38.970
13.992
61.785
1.00
36.42
C

1821
CG
ARG
A
240
−38.874
13.090
63.002
1.00
39.66
C

1822
CD
ARG
A
240
−39.736
11.847
62.873
1.00
45.16
C

1823
NE
ARG
A
240
−41.160
12.161
62.948
1.00
49.40
N

1824
CZ
ARG
A
240
−42.127
11.249
62.972
1.00
49.40
C

1825
NH1
ARG
A
240
−41.824
9.959
62.925
1.00
49.20
N

1826
NH2
ARG
A
240
−43.397
11.631
63.048
1.00
49.95
N

1827
N
PHE
A
241
−35.922
15.102
61.663
1.00
29.38
N

1828
CA
PHE
A
241
−34.555
14.860
62.105
1.00
29.66
C

1829
C
PHE
A
241
−33.573
15.998
61.878
1.00
28.98
C

1830
O
PHE
A
241
−33.509
16.588
60.800
1.00
27.63
O

1831
CB
PHE
A
241
−34.020
13.594
61.439
1.00
29.23
C

1832
CG
PHE
A
241
−34.865
12.377
61.690
1.00
29.60
C

1833
CD1
PHE
A
241
−35.059
11.906
62.982
1.00
28.11
C

1834
CD2
PHE
A
241
−35.471
11.703
60.632
1.00
31.04
C

1835
CE1
PHE
A
241
−35.843
10.783
63.220
1.00
29.17
C

1836
CE2
PHE
A
241
−36.259
10.576
60.858
1.00
29.49
C

1837
CZ
PHE
A
241
−36.446
10.116
62.153
1.00
30.24
C

1838
N
SER
A
242
−32.797
16.286
62.915
1.00
29.50
N

1839
CA
SER
A
242
−31.793
17.337
62.872
1.00
29.00
C

1840
C
SER
A
242
−30.524
16.798
62.220
1.00
30.46
C

1841
O
SER
A
242
−30.423
15.605
61.926
1.00
30.01
O

1842
CB
SER
A
242
−31.472
17.783
64.290
1.00
27.14
C

1843
OG
SER
A
242
−31.087
16.662
65.066
1.00
26.00
O

1844
N
ALA
A
243
−29.553
17.679
62.007
1.00
30.61
N

1845
CA
ALA
A
243
−28.291
17.275
61.414
1.00
31.66
C

1846
C
ALA
A
243
−27.523
16.410
62.406
1.00
31.21
C

1847
O
ALA
A
243
−26.813
15.492
62.009
1.00
31.96
O

1848
CB
ALA
A
243
−27.463
18.507
61.032
1.00
32.35
C

1849
N
ASP
A
244
−27.668
16.694
63.696
1.00
31.52
N

1850
CA
ASP
A
244
−26.966
15.917
64.713
1.00
32.81
C

1851
C
ASP
A
244
−27.504
14.492
64.784
1.00
32.68
C

1852
O
ASP
A
244
−26.736
13.534
64.891
1.00
30.58
O

1853
CB
ASP
A
244
−27.092
16.577
66.091
1.00
35.24
C

1854
CG
ASP
A
244
−26.352
15.800
67.180
1.00
40.31
C

1855
OD1
ASP
A
244
−25.115
15.653
67.078
1.00
44.22
O

1856
OD2
ASP
A
244
−27.001
15.329
68.141
1.00
44.02
O

1857
N
GLU
A
245
−28.828
14.359
64.727
1.00
32.46
N

1858
CA
GLU
A
245
−29.471
13.054
64.784
1.00
30.78
C

1859
C
GLU
A
245
−29.057
12.209
63.590
1.00
30.06
C

1860
O
GLU
A
245
−28.641
11.057
63.746
1.00
28.32
O

1861
CB
GLU
A
245
−30.991
13.219
64.806
1.00
32.67
C

1862
CG
GLU
A
245
−31.527
13.764
66.121
1.00
34.01
C

1863
CD
GLU
A
245
−32.995
14.110
66.049
1.00
34.19
C

1864
CE1
GLU
A
245
−33.359
14.960
65.212
1.00
37.55
O

1865
OE2
GLU
A
245
−33.785
13.536
66.827
1.00
36.69
O

1866
N
ILE
A
246
−29.168
12.785
62.396
1.00
28.73
N

1867
CA
ILE
A
246
−28.797
12.071
61.182
1.00
28.60
C

1868
C
ILE
A
246
−27.314
11.709
61.173
1.00
27.07
C

1869
O
ILE
A
246
−26.956
10.575
60.849
1.00
27.98
O

1870
CB
ILE
A
246
−29.124
12.892
59.916
1.00
26.41
C

1871
CG1
ILE
A
246
−30.639
13.049
59.775
1.00
26.14
C

1872
CG2
ILE
A
246
−28.587
12.176
58.692
1.00
27.76
C

1873
CD1
ILE
A
246
−31.059
13.996
58.681
1.00
22.86
C

1874
N
THR
A
247
−26.458
12.666
61.532
1.00
26.23
N

1875
CA
THR
A
247
−25.011
12.434
61.564
1.00
25.07
C

1876
C
THR
A
247
−24.656
11.316
62.555
1.00
25.76
C

1877
O
THR
A
247
−23.858
10.428
62.243
1.00
26.39
O

1878
CB
THR
A
247
−24.240
13.727
61.953
1.00
24.20
C

1879
OG1
THR
A
247
−24.569
14.780
61.037
1.00
22.10
O

1880
CG2
THR
A
247
−22.723
13.490
61.913
1.00
22.37
C

1881
N
GLY
A
248
−25.249
11.362
63.743
1.00
24.37
N

1882
CA
GLY
A
248
−24.988
10.341
64.741
1.00
27.71
C

1883
C
GLY
A
248
−25.295
8.938
64.237
1.00
28.41
C

1884
O
GLY
A
248
−24.584
7.983
64.554
1.00
26.64
O

1885
N
MET
A
249
−26.361
8.808
63.454
1.00
29.78
N

1886
CA
MET
A
249
−26.720
7.512
62.901
1.00
30.48
C

1887
C
MET
A
249
−25.712
7.122
61.818
1.00
28.52
C

1888
O
MET
A
249
−25.267
5.981
61.771
1.00
28.91
O

1889
CB
MET
A
249
−28.128
7.543
62.305
1.00
32.98
C

1890
CG
MET
A
249
−28.618
6.176
61.852
1.00
36.59
C

1891
SD
MET
A
249
−30.217
6.251
61.034
1.00
41.53
S

1892
CE
MET
A
249
−29.691
6.384
59.338
1.00
38.75
C

1893
N
PHE
A
250
−25.347
8.065
60.954
1.00
27.48
N

1894
CA
PHE
A
250
−24.376
7.773
59.896
1.00
26.90
C

1895
C
PHE
A
250
−23.023
7.361
60.479
1.00
26.97
C

1896
O
PHE
A
250
−22.382
6.436
59.974
1.00
26.26
O

1897
CB
PHE
A
250
−24.192
8.981
58.972
1.00
24.57
C

1898
OG
PHE
A
250
−25.323
9.190
58.006
1.00
23.08
C

1899
CD1
PHE
A
250
−26.418
8.327
57.985
1.00
24.03
C

1900
CD2
PHE
A
250
−25.287
10.247
57.102
1.00
21.69
C

1901
CE1
PHE
A
250
−27.466
8.510
57.074
1.00
21.97
C

1902
CE2
PHE
A
250
−26.326
10.445
56.189
1.00
22.49
C

1903
CZ
PHE
A
250
−27.421
9.570
56.175
1.00
23.05
C

9904
N
ILE
A
251
−22.595
8.051
61.536
1.00
25.44
N

1905
CA
ILE
A
251
−21.332
7.743
62.204
1.00
25.67
C

1906
C
ILE
A
251
−21.391
6.325
62.785
1.00
26.42
C

1907
O
ILE
A
251
−20.431
5.552
62.688
1.00
26.86
O

1908
CB
ILE
A
251
−21.063
8.708
63.386
1.00
23.39
C

1909
CG1
ILE
A
251
−20.712
10.101
62.885
1.00
21.84
C

1910
CG2
ILE
A
251
−19.943
8.168
64.256
1.00
24.02
C

1911
CD1
ILE
A
251
−20.503
11.090
64.038
1.00
18.88
C

1912
N
SER
A
252
−22.520
6.005
63.409
1.00
26.76
N

1913
CA
SER
A
252
−22.715
4.701
64.022
1.00
29.57
C

1914
C
SER
A
252
−22.599
3.574
63.005
1.00
30.56
C

1915
O
SER
A
252
−21.911
2.585
63.250
1.00
30.56
O

1916
CB
SER
A
252
−24.082
4.636
64.701
1.00
29.30
C

1917
OG
SER
A
252
−24.181
5.612
65.721
1.00
32.00
O

1918
N
MET
A
253
−23.270
3.729
61.869
1.00
29.47
N

1919
CA
MET
A
253
−23.246
2.718
60.814
1.00
31.92
C

1920
C
MET
A
253
−21.871
2.531
60.181
1.00
31.71
C

1921
O
MET
A
253
−21.421
1.400
59.969
1.00
31.52
O

1922
CB
MET
A
253
−24.251
3.080
59.720
1.00
34.07
C

1923
CG
MET
A
253
−25.707
3.019
60.161
1.00
36.64
C

1924
SD
MET
A
253
−26.763
3.875
58.979
1.00
42.08
S

1925
CE
MET
A
253
−26.682
2.755
57.564
1.00
43.33
C

1926
N
MET
A
254
−21.204
3.637
59.878
1.00
30.94
N

1927
CA
MET
A
254
−19.890
3.568
59.250
1.00
32.81
C

1928
C
MET
A
254
−18.785
2.989
60.137
1.00
32.18
C

1929
O
MET
A
254
−17.832
2.400
59.630
1.00
33.20
O

1930
CB
MET
A
254
−19.457
4.960
58.777
1.00
31.88
C

1931
CG
MET
A
254
−20.338
5.569
57.704
1.00
32.71
C

1932
SD
MET
A
254
−19.705
7.166
57.139
1.00
30.76
S

1933
CE
MET
A
254
−20.187
8.200
58.499
1.00
35.90
C

1934
N
PHE
A
255
−18.904
3.156
61.451
1.00
31.87
N

1935
CA
PHE
A
255
−17.860
2.668
62.347
1.00
32.40
C

1936
C
PHE
A
255
−17.496
1.216
62.062
1.00
33.23
C

1937
O
PHE
A
255
−16.319
0.877
61.916
1.00
33.88
O

1938
CB
PHE
A
255
−18.274
2.809
63.812
1.00
28.19
C

1939
CG
PHE
A
255
−17.108
2.907
64.750
1.00
29.91
C

1940
CD1
PHE
A
255
−16.496
1.758
65.246
1.00
29.08
C

1941
CD2
PHE
A
255
−16.576
4.146
65.088
1.00
28.74
C

1942
CE1
PHE
A
255
−15.367
1.835
66.063
1.00
31.00
C

1943
CE2
PHE
A
255
−15.448
4.240
65.903
1.00
30.94
C

1944
CZ
PHE
A
255
−14.838
3.079
66.394
1.00
30.02
C

1945
N
ALA
A
256
−18.515
0.367
61.974
1.00
34.22
N

1946
CA
ALA
A
256
−18.322
−1.052
61.706
1.00
33.73
C

1947
C
ALA
A
256
−17.523
−1.299
60.425
1.00
33.31
C

1948
O
ALA
A
256
−16.752
−2.252
60.335
1.00
32.46
O

1949
CB
ALA
A
256
−19.676
−1.743
61.620
1.00
32.93
C

1950
N
GLY
A
257
−17.697
−0.437
59.430
1.00
34.21
N

1951
CA
GLY
A
257
−16.974
−0.634
58.186
1.00
31.69
C

1952
C
GLY
A
257
−15.750
0.241
58.036
1.00
30.87
C

1953
O
GLY
A
257
−15.307
0.481
56.912
1.00
32.71
O

1954
N
HIS
A
258
−15.179
0.714
59.142
1.00
28.04
N

1955
CA
HIS
A
258
−14.021
1.584
59.014
1.00
26.65
C

1956
C
HIS
A
258
−12.671
1.171
59.593
1.00
24.72
C

1957
O
HIS
A
258
−11.870
0.560
58.898
1.00
23.49
O

1958
CB
HIS
A
258
−14.351
3.000
59.514
1.00
26.16
C

1959
CG
HIS
A
258
−13.273
3.996
59.211
1.00
24.36
C

1960
ND1
HIS
A
258
−12.382
4.445
60.161
1.00
22.48
N

1961
CD2
HIS
A
258
−12.873
4.538
58.037
1.00
24.27
C

1962
CE1
HIS
A
258
−11.478
5.216
59.586
1.00
22.80
C

1963
NE2
HIS
A
258
−11.752
5.287
58.296
1.00
22.81
N

1964
N
HIS
A
259
−12.408
1.491
60.857
1.00
24.40
N

1965
CA
HIS
A
259
−11.093
1.182
61.416
1.00
22.84
C

1966
C
HIS
A
259
−10.622
−0.278
61.408
1.00
22.09
C

1967
O
HIS
A
259
−9.411
−0.528
61.380
1.00
22.77
O

1968
CB
HIS
A
259
−10.952
1.775
62.826
1.00
23.14
C

1969
CG
HIS
A
259
−11.246
0.810
63.933
1.00
24.47
C

1970
ND1
HIS
A
259
−12.526
0.537
64.366
1.00
26.20
N

1971
CD2
HIS
A
259
−10.420
0.065
64.704
1.00
25.01
C

1972
CE1
HIS
A
259
−12.475
−0.333
65.360
1.00
27.38
C

1973
NE2
HIS
A
259
−11.208
−0.635
65.584
1.00
26.08
N

1974
N
THR
A
260
−11.538
−1.244
61.432
1.00
19.98
N

1975
CA
THR
A
260
−11.105
−2.638
61.409
1.00
19.73
C

1976
C
THR
A
260
−10.642
−3.005
60.005
1.00
19.29
C

1977
O
THR
A
260
−9.669
−3.733
59.844
1.00
20.76
O

1978
CB
THR
A
260
−12.217
−3.621
61.833
1.00
20.06
C

1979
OG1
THR
A
260
−13.419
−3.339
61.102
1.00
21.85
O

1980
CG2
THR
A
260
−12.472
−3.534
63.322
1.00
20.05
C

1981
N
SER
A
261
−11.341
−2.496
58.994
1.00
18.70
N

1982
CA
SER
A
261
−10.989
−2.757
57.602
1.00
17.39
C

1983
C
SER
A
261
−9.761
−1.945
57.226
1.00
19.46
C

1984
O
SER
A
261
−8.872
−2.424
56.499
1.00
20.28
O

1985
CB
SER
A
261
−12.145
−2.368
56.672
1.00
14.94
C

1986
OG
SER
A
261
−13.276
−3.202
56.866
1.00
14.57
O

1987
N
SER
A
262
−9.729
−0.706
57.717
1.00
19.39
N

1988
CA
SER
A
262
−8.628
0.224
57.465
1.00
20.19
C

1989
C
SER
A
262
−7.293
−0.377
57.883
1.00
20.97
C

1990
O
SER
A
262
−6.397
−0.550
57.059
1.00
22.95
O

1991
CB
SER
A
262
−8.865
1.531
58.229
1.00
19.96
C

1992
OG
SER
A
262
−7.753
2.404
58.105
1.00
22.66
O

1993
N
GLY
A
263
−7.156
−0.686
59.167
1.00
18.81
N

1994
CA
GLY
A
263
−5.921
−1.285
59.638
1.00
18.77
C

1995
C
GLY
A
263
−5.642
−2.633
58.989
1.00
19.16
C

1996
O
GLY
A
263
−4.490
−2.964
58.670
1.00
18.87
O

1997
N
THR
A
264
−6.687
−3.425
58.771
1.00
18.20
N

1998
CA
THR
A
264
−6.483
−4.734
58.163
1.00
16.00
C

1999
C
THR
A
264
−5.969
−4.633
56.737
1.00
18.01
C

2000
O
THR
A
264
−5.234
−5.518
56.267
1.00
17.85
O

2001
CB
THR
A
264
−7.752
−5.555
58.167
1.00
14.11
C

2002
OG1
THR
A
264
−8.219
−5.685
59.513
1.00
11.59
O

2003
CG2
THR
A
264
−7.474
−6.950
57.605
1.00
12.92
C

2004
N
ALA
A
265
−6.353
−3.570
56.035
1.00
18.33
N

2005
CA
ALA
A
265
−5.871
−3.384
54.670
1.00
18.28
C

2006
C
ALA
A
265
−4.402
−2.964
54.737
1.00
17.36
C

2007
O
ALA
A
265
−3.572
−3.430
53.958
1.00
17.15
O

2008
CB
ALA
A
265
−6.688
−2.315
53.954
1.00
20.26
C

2009
N
SER
A
266
−4.082
−2.088
55.680
1.00
17.14
N

2010
CA
SER
A
266
−2.709
−1.618
55.831
1.00
18.78
C

2011
C
SER
A
266
−1.755
−2.784
56.114
1.00
19.15
C

2012
O
SER
A
266
−0.731
−2.938
55.446
1.00
16.71
O

2013
CB
SER
A
266
−2.620
−0.592
56.974
1.00
20.48
C

2014
OG
SER
A
266
−3.309
0.614
56.671
1.00
19.11
O

2015
N
TRP
A
267
−2.102
−3.602
57.107
1.00
19.96
N

2016
CA
TRP
A
267
−1.273
−4.735
57.494
1.00
21.79
C

2017
C
TRP
A
267
−1.163
−5.808
56.424
1.00
21.83
C

2018
O
TRP
A
267
−0.114
−6.430
56.273
1.00
21.74
O

2019
CB
TRP
A
267
−1.781
−5.348
58.804
1.00
21.77
C

2020
CG
TRP
A
267
−1.401
−4.541 59.997
1.00
23.86
C

2021
CD1
TRP
A
267
−2.222
−3.754
60.753
1.00
23.39
C

2022
CD2
TRP
A
267
−0.083
−4.388
60.540
1.00
23.58
C

2023
NE1
TRP
A
267
−1.494
−3.118
61.734
1.00
24.71
N

2024
CE2
TRP
A
267
−0.178
−3.489
61.623
1.00
24.11
C

2025
CE3
TRP
A
267
1.171
−4.923
60.214
1.00
24.48
C

2026
CZ2
TRP
A
267
0.935
−3.110
62.384
1.00
24.36
C

2027
CZ3
TRP
A
267
2.281
−4.546
60.974
1.00
25.11
C

2028
CH2
TRP
A
267
2.152
−3.647
62.044
1.00
25.04
C

2029
N
THR
A
268
−2.236
−6.027
55.675
1.00
22.52
N

2030
CA
THR
A
268
−2.191
−7.030
54.623
1.00
22.89
C

2031
C
THR
A
268
−1.078
−6.678
53.637
1.00
24.36
C

2032
O
THR
A
268
−0.260
−7.530
53.277
1.00
26.33
O

2033
CB
THR
A
268
−3.521
−7.109
53.873
1.00
22.34
C

2034
OG1
THR
A
268
−4.558
−7.502
54.784
1.00
24.03
O

2035
CG2
THR
A
268
−3.433
−8.121
52.747
1.00
20.49
C

2036
N
LEU
A
269
−1.042
−5.416
53.212
1.00
22.37
N

2037
CA
LEU
A
269
−0.024
−4.955
52.270
1.00
18.95
C

2038
C
LEU
A
269
1.349
−5.046
52.938
1.00
18.79
C

2039
O
LEU
A
269
2.323
−5.498
52.329
1.00
15.79
O

2040
CB
LEU
A
269
−0.301
−3.503
51.871
1.00
17.84
C

2041
CG
LEU
A
269
0.057
−3.014
50.466
1.00
21.14
C

2042
CD1
LEU
A
269
0.626
−1.609
50.567
1.00
20.10
C

2043
CD2
LEU
A
269
1.052
−3.947
49.793
1.00
20.48
C

2044
N
ILE
A
270
1.422
−4.607
54.192
1.00
17.59
N

2045
CA
ILE
A
270
2.682
−4.643
54.939
1.00
20.79
C

2046
C
ILE
A
270
3.281
−6.050
54.996
1.00
19.12
C

2047
O
ILE
A
270
4.472
−6.227
54.781
1.00
18.27
O

2048
CB
ILE
A
270
2.498
−4.129
56.386
1.00
19.44
C

2049
CG1
ILE
A
270
2.405
−2.603
56.388
1.00
19.46
C

2050
CG2
ILE
A
270
3.670
−4.574
57.259
1.00
20.14
C

2051
CD1
ILE
A
270
2.069
−2.015
57.759
1.00
20.41
C

2052
N
GLU
A
271
2.449
−7.044
55.285
1.00
20.97
N

2053
CA
GLU
A
271
2.925
−8.415
55.357
1.00
20.70
C

2054
C
GLU
A
271
3.314
−8.929
53.977
1.00
20.80
C

2055
O
OLU
A
271
4.209
−9.770
53.862
1.00
19.06
O

2056
CB
GLU
A
271
1.864
−9.317
55.991
1.00
19.27
C

2057
CG
GLU
A
271
1.675
−9.065
57.480
1.00
21.55
C

2058
CD
GLU
A
271
2.919
−9.386
58.313
1.00
24.77
C

2059
OE1
GLU
A
271
3.900
−9.948
57.769
1.00
24.56
O

2060
OE2
GLU
A
271
2.911
−9.082
59.525
1.00
25.27
O

2061
N
LEU
A
272
2.653
−8.427
52.932
1.00
20.18
N

2062
CA
LEU
A
272
2.984
−8.852
51.573
1.00
20.72
C

2063
C
LEU
A
272
4.345
−8.330
51.194
1.00
22.35
C

2064
O
LEU
A
272
5.131
−9.028
50.551
1.00
22.24
O

2065
CB
LEU
A
272
1.970
−8.339
50.560
1.00
19.20
C

2066
CG
LEU
A
272
0.627
−9.063
50.542
1.00
19.39
C

2067
CD1
LEU
A
272
−0.336
−8.283
49.657
1.00
17.88
C

2068
CD2
LEU
A
272
0.812
−10.499
50.040
1.00
15.88
C

2069
N
MET
A
273
4.629
−7.091
51.579
1.00
24.26
N

2070
CA
MET
A
273
5.925
−6.514
51.259
1.00
25.23
C

2071
C
MET
A
273
7.017
−7.185
52.084
1.00
24.84
C

2072
O
MEt
A
273
8.116
−7.409
51.593
1.00
27.42
O

2073
CB
MET
A
273
5.901
−5.006
51.497
1.00
23.88
C

2074
CG
MET
A
273
4.899
−4.292
50.610
1.00
22.37
C

2075
SD
MET
A
273
4.902
−2.505
50.821
1.00
25.58
S

2076
CE
MET
A
273
4.123
−2.356
52.433
1.00
22.55
C

2077
N
ARG
A
274
6.698
−7.525
53.330
1.00
24.92
N

2078
CA
ARG
A
274
7.644
−8.192
54.229
1.00
23.96
C

2079
C
ARG
A
274
7.962
−9.608
53.773
1.00
24.49
C

2080
O
ARO
A
274
8.953
−10.193
54.188
1.00
23.28
O

2081
CB
ARG
A
274
7.068
−8.294
55.642
1.00
23.71
C

2082
CG
ARG
A
274
7.146
−7.041
56.483
1.00
23.31
C

2083
CD
ARG
A
274
6.430
−7.269
57.795
1.00
21.79
C

2084
NE
ARG
A
274
6.664
−6.178
58.731
1.00
23.13
N

2085
CZ
ARO
A
274
6.090
−6.084
59.921
1.00
22.08
C

2086
NH1
ARG
A
274
5.241
−7.028
60.323
1.00
20.48
N

2087
NH2
ARG
A
274
6.364
−5.045
60.703
1.00
23.28
N

2088
N
HIS
A
275
7.097
−10.170
52.943
1.00
26.80
N

2089
CA
HIS
A
275
7.294
−11.533
52.470
1.00
28.09
C

2090
C
HIS
A
275
7.062
−11.598
50.970
1.00
28.52
C

2091
O
HIS
A
275
6.033
−12.081
50.510
1.00
28.57
O

2092
CB
HIS
A
275
6.338
−12.454
53.224
1.00
26.41
C

2093
CG
HIS
A
275
6.470
−12.348
54.711
1.00
25.44
C

2094
ND1
HIS
A
275
7.493
−12.950
55.411
1.00
25.81
N

2095
CD2
HIS
A
275
5.756
−11.644
55.622
1.00
23.86
C

2096
CE1
HIS
A
275
7.404
−12.621
56.687
1.00
25.77
C

2097
NE2
HIS
A
275
6.358
−11.829
56.841
1.00
24.29
N

2098
N
ARG
A
276
8.050
−11.113
50.222
1.00
31.09
N

2099
CA
ARG
A
276
7.992
−11.047
48.767
1.00
33.66
C

2100
C
ARG
A
276
7.574
−12.332
48.060
1.00
31.55
C

2101
O
ARG
A
276
7.038
−12.280
46.951
1.00
31.17
O

2102
CB
ARG
A
276
9.338
−10.548
48.231
1.00
39.65
C

2103
CO
ARO
A
276
9.228
−9.255
47.424
1.00
49.10
C

2104
CD
ARG
A
276
8.637
−9.532
46.034
1.00
55.75
C

2105
NE
ARG
A
276
8.094
−8.335
45.391
1.00
58.55
N

2106
CZ
ARG
A
276
7.569
−8.323
44.169
1.00
60.08
C

2107
NH1
ARG
A
276
7.522
−9.442
43.456
1.00
60.39
N

2108
NH2
ARG
A
276
7.073
−7.198
43.668
1.00
60.33
N

2109
N
ASP
A
277
7.801
−13.479
48.696
1.00
29.42
N

2110
CA
ASP
A
277
7.423
−14.755
48.096
1.00
28.03
C

2111
C
ASP
A
277
5.907
−14.908
48.105
1.00
24.10
C

2112
O
ASP
A
277
5.312
−15.311
47.115
1.00
23.38
O

2113
CB
ASP
A
277
8.107
−15.932
48.821
1.00
29.98
C

2114
CG
ASP
A
277
7.793
−15.989
50.312
1.00
35.27
C

2115
OD1
ASP
A
277
8.088
−15.011
51.037
1.00
37.93
O

2116
OD2
ASP
A
277
7.259
−17.028
50.765
1.00
37.40
O

2117
N
ALA
A
278
5.281
−14.570
49.225
1.00
22.80
N

2118
CA
ALA
A
278
3.828
−14.645
49.326
1.00
21.76
C

2119
C
ALA
A
278
3.237
−13.614
48.365
1.00
20.09
C

2120
O
ALA
A
278
2.223
−13.853
47.705
1.00
20.62
O

2121
CB
ALA
A
278
3.390
−14.342
50.757
1.00
18.78
C

2122
N
TYR
A
279
3.890
−12.463
48.300
1.00
19.28
N

2123
CA
TYR
A
279
3.471
−11.366
47.442
1.00
21.75
C

2124
C
TYR
A
279
3.494
−11.829
45.985
1.00
23.43
C

2125
O
TYR
A
279
2.566
−11.545
45.217
1.00
23.09
O

2126
CB
TYR
A
279
4.421
−10.176
47.662
1.00
24.37
C

2127
CG
TYR
A
279
4.010
−8.855
47.037
1.00
26.37
C

2128
CD1
TYR
A
279
2.912
−8.766
46.182
1.00
28.24
C

2129
CD2
TYR
A
279
4.752
−7.699
47.273
1.00
26.94
C

2130
CE1
TYR
A
279
2.570
−7.561
45.573
1.00
29.32
C

2131
CE2
TYR
A
279
4.417
−6.489
46.667
1.00
28.78
C

2132
CZ
TYR
A
279
3.329
−6.432
45.816
1.00
28.48
C

2133
OH
TYR
A
279
3.007
−5.257
45.187
1.00
31.85
O

2134
N
ALA
A
280
4.544
−12.560
45.612
1.00
23.56
N

2135
CA
ALA
A
280
4.684
−13.067
44.246
1.00
24.76
C

2136
C
ALA
A
280
3.595
−14.088
43.907
1.00
24.23
C

2137
O
ALA
A
280
3.080
−14.117
42.789
1.00
24.41
O

2138
CB
ALA
A
280
6.069
−13.690
44.069
1.00
23.66
C

2139
N
ALA
A
281
3.249
−14.928
44.877
1.00
25.59
N

2140
CA
ALA
A
281
2.213
−15.945
44.682
1.00
26.26
C

2141
C
ALA
A
281
0.855
−15.269
44.468
1.00
27.24
C

2142
O
ALA
A
281
0.057
−15.704
43.634
1.00
28.66
O

2143
CB
ALA
A
281
2.154
−16.873
45.901
1.00
24.65
C

2144
N
VAL
A
282
0.593
−14.210
45.231
1.00
26.13
N

2145
CA
VAL
A
282
−0.662
−13.480
45.103
1.00
26.01
C

2146
C
VAL
A
282
−0.775
−12.821
43.726
1.00
26.05
C

2147
O
VAL
A
282
−1.823
−12.921
43.089
1.00
26.24
O

2148
CB
VAL
A
282
−0.806
−12.389
46.200
1.00
26.16
C

2149
CG1
VAL
A
282
−2.086
−11.593
45.970
1.00
25.59
C

2150
CG2
VAL
A
282
−0.846
−13.038
47.588
1.00
23.98
C

2151
N
ILE
A
283
0.293
−12.153
43.274
1.00
25.09
N

2152
CA
ILE
A
283
0.309
−11.491
41.958
1.00
25.01
C

2153
C
ILE
A
283
−0.040
−12.496
40.864
1.00
22.60
C

2154
O
ILE
A
283
−0.979
−12.292
40.101
1.00
22.69
O

2155
CB
ILE
A
283
1.707
−10.890
41.616
1.00
27.70
C

2156
CG1
ILE
A
283
2.070
−9.772
42.588
1.00
30.28
C

2157
CG2
ILE
A
283
1.692
−10.309
40.211
1.00
28.19
C

2158
CD1
ILE
A
283
1.166
−8.574
42.495
1.00
33.50
C

2159
N
ASP
A
284
0.732
−13.577
40.789
1.00
23.30
N

2160
CA
ASP
A
284
0.510
−14.642
39.809
1.00
23.90
C

2161
C
ASP
A
284
−0.946
−15.136
39.808
1.00
23.79
C

2162
O
ASP
A
284
−1.572
−15.260
38.758
1.00
25.94
O

2163
CB
ASP
A
284
1.446
−15.823
40.104
1.00
22.65
C

2164
OG
ASP
A
284
2.890
−15.544
39.717
1.00
23.09
C

2165
OD1
ASP
A
284
3.160
−14.470
39.139
1.00
22.70
O

2166
OD2
ASP
A
284
3.759
−16.405
39.984
1.00
20.91
O

2167
N
GLU
A
285
−1.466
−15.429
40.992
1.00
24.75
N

2168
CA
GLU
A
285
−2.834
−15.908
41.171
1.00
25.07
C

2169
C
GLU
A
285
−3.864
−14.913
40.632
1.00
25.58
C

2170
O
GLU
A
285
−4.815
−15.298
39.952
1.00
24.45
O

2171
CB
GLU
A
285
−3.086
−16.150
42.658
1.00
26.28
C

2172
CG
GLU
A
285
−4.495
−16.590
43.013
1.00
29.41
C

2173
CD
GLU
A
285
−4.673
−16.769
44.505
1.00
30.44
C

2174
OE1
GLU
A
285
−4.541
−15.773
45.253
1.00
33.09
O

2175
OE2
GLU
A
285
−4.935
−17.905
44.936
1.00
32.41
O

2176
N
LEU
A
286
−3.671
−13.634
40.940
1.00
26.12
N

2177
CA
LEU
A
286
−4.579
−12.589
40.481
1.00
26.55
C

2178
C
LEU
A
286
−4.519
−12.426
38.962
1.00
28.12
C

2179
O
LEU
A
286
−5.560
−12.363
38.299
1.00
29.90
O

2180
CB
LEU
A
286
−4.248
−11.261
41.172
1.00
24.17
C

2181
CG
LEU
A
286
−4.529
−11.251
42.680
1.00
24.94
C

2182
CD1
LEU
A
286
−3.906
−10.011
43.310
1.00
22.10
C

2183
CD2
LEU
A
286
−6.049
−11.312
42.937
1.00
20.14
C

2184
N
ASP
A
287
−3.312
−12.360
38.405
1.00
27.78
N

2185
CA
ASP
A
287
−3.178
−12.215
36.957
1.00
28.42
C

2186
C
ASP
A
287
−3.885
−13.358
36.244
1.00
28.12
C

2187
O
ASP
A
287
−4.674
−13.142
35.321
1.00
29.11
O

2188
CB
ASP
A
287
−1.705
−12.199
36.538
1.00
28.84
C

2189
CG
ASP
A
287
−1.000
−10.922
36.930
1.00
31.55
C

2190
OD1
ASP
A
287
−1.686
−9.906
37.178
1.00
35.86
O

2191
OD2
ASP
A
287
0.243
−10.925
36.975
1.00
32.54
O

2192
N
GLU
A
288
−3.592
−14.578
36.678
1.00
26.83
N

2193
CA
GLU
A
288
−4.190
−15.765
36.091
1.00
27.36
C

2194
C
GLU
A
288
−5.701
−15.808
36.322
1.00
27.32
C

2195
O
GLU
A
288
−6.467
−16.163
35.427
1.00
25.98
O

2196
CB
GLU
A
288
−3.518
−17.004
36.681
1.00
29.46
C

2197
CG
GLU
A
288
−4.209
−18.319
36.381
1.00
33.56
C

2198
CD
GLU
A
288
−3.401
−19.509
36.878
1.00
37.40
C

2199
OE1
GLU
A
288
−2.204
−19.321
37.199
1.00
38.69
O

2200
OE2
GLU
A
288
−3.959
−20.628
36.941
1.00
39.23
O

2201
N
LEU
A
289
−6.130
−15.427
37.521
1.00
28.16
N

2202
CA
LEU
A
289
−7.548
−15.441
37.861
1.00
27.05
C

2203
C
LEU
A
289
−8.357
−14.427
37.053
1.00
26.89
C

2204
O
LEU
A
289
−9.431
−14.746
36.550
1.00
25.16
O

2205
CB
LEU
A
289
−7.728
−15.164
39.348
1.00
30.64
C

2206
CG
LEU
A
289
−9.034
−15.657
39.953
1.00
32.53
C

2207
CD1
LEU
A
289
−9.100
−17.175
39.855
1.00
32.53
C

2208
CD2
LEU
A
289
−9.110
−15.209
41.398
1.00
35.29
C

2209
N
TYR
A
290
−7.850
−1 3.205
36.928
1.00
25.56
N

2210
CA
TYR
A
290
−8.571
−12.192
36.173
1.00
24.14
C

2211
C
TYR
A
290
−8.384
−12.358
34.672
1.00
24.92
C

2212
O
TYR
A
290
−8.858
−11.544
33.879
1.00
24.51
O

2213
CB
TYR
A
290
−8.157
−10.787
36.623
1.00
21.61
C

2214
CG
TYR
A
290
−8.846
−10.367
37.902
1.00
19.35
C

2215
CD1
TYR
A
290
−8.345
−10.742
39.150
1.00
19.56
C

2216
CD2
TYR
A
290
−10.030
−9.633
37.862
1.00
16.68
C

2217
CE1
TYR
A
290
−9.013
−10.391
40.327
1.00
19.49
C

2218
CE2
TYR
A
290
−10.703
−9.282
39.027
1.00
15.70
C

2219
CZ
TYR
A
290
−10.197
−9.661
40.250
1.00
16.30
C

2220
OH
TYR
A
290
−10.885
−9.324
41.396
1.00
17.71
O

2221
N
GLY
A
291
−7.697
−13.434
34.298
1.00
25.89
N

2222
CA
GLY
A
291
−7.469
−13.726
32.900
1.00
22.99
C

2223
C
GLY
A
291
−8.731
−14.278
32.274
1.00
24.59
C

2224
O
GLY
A
291
−8.766
−14.511
31.067
1.00
24.58
O

2225
N
ASP
A
292
−9.772
−14.510
33.075
1.00
24.12
N

2226
CA
ASP
A
292
−11.016
−15.021
32.502
1.00
25.10
C

2227
C
ASP
A
292
−11.865
−13.866
31.963
1.00
25.10
C

2228
O
ASP
A
292
−12.847
−14.082
31.244
1.00
24.76
O

2229
CB
ASP
A
292
−11.813
−15.857
33.521
1.00
24.75
C

2230
CG
ASP
A
292
−12.263
−15.056
34.735
1.00
27.12
C

2231
OD1
ASP
A
292
−12.067
−13.823
34.755
1.00
26.57
O

2232
OD2
ASP
A
292
−12.827
−15.671
35.673
1.00
28.96
O

2233
N
GLY
A
293
−11.473
−12.639
32.300
1.00
24.10
N

2234
CA
GLY
A
293
−12.197
−11.475
31.811
1.00
23.78
C

2235
C
GLY
A
293
−13.337
−10.987
32.684
1.00
22.82
C

2236
O
GLY
A
293
−13.946
−9.951
32.399
1.00
23.58
O

2237
N
ARG
A
294
−13.629
−11.719
33.752
1.00
21.79
N

2238
CA
ARG
A
294
−14.704
−11.334
34.646
1.00
20.13
C

2239
C
ARG
A
294
−14.254
−10.173
35.521
1.00
20.96
C

2240
O
ARG
A
294
−13.057
−9.974
35.757
1.00
20.90
O

2241
CB
ARG
A
294
−15.132
−12.529
35.494
1.00
19.99
C

2242
CG
ARG
A
294
−15.594
−13.732
34.687
1.00
20.18
C

2243
CD
ARG
A
294
−16.603
−13.338
33.601
1.00
21.86
C

2244
NE
ARG
A
294
−17.808
−12.712
34.147
1.00
24.55
N

2245
CZ
ARG
A
294
−18.813
−13.382
34.705
1.00
26.99
C

2246
NH1
ARG
A
294
−18.761
−14.707
34.788
1.00
29.40
N

2247
NH2
ARG
A
294
−19.866
−12.730
35.185
1.00
25.53
N

2248
N
SER
A
295
−15.226
−9.408
35.998
1.00
22.37
N

2249
CA
SER
A
295
−14.974
−8.228
36.816
1.00
22.42
C

2250
C
SER
A
295
−14.523
−8.512
38.250
1.00
23.35
C

2251
O
SER
A
295
−14.533
−9.659
38.720
1.00
23.39
O

2252
CB
SER
A
295
−16.243
−7.377
36.873
1.00
20.93
C

2253
OG
SER
A
295
−17.216
−8.002
37.699
1.00
20.14
O

2254
N
VAL
A
296
−14.132
−7.446
38.941
1.00
21.93
N

2255
CA
VAL
A
296
−13.731
−7.552
40.332
1.00
21.23
C

2256
C
VAL
A
296
−14.981
−7.925
41.144
1.00
21.79
C

2257
O
VAL
A
296
−14.896
−8.692
42.107
1.00
22.30
O

2258
CB
VAL
A
296
−13.152
−6.208
40.851
1.00
21.71
C

2259
CG1
VAL
A
296
−13.041
−6.229
42.375
1.00
19.79
C

2260
CG2
VAL
A
296
−11.782
−5.960
40.222
1.00
19.19
C

2261
N
SER
A
297
−16.141
−7.397
40.757
1.00
20.97
N

2262
CA
SER
A
297
−17.375
−7.710
41.480
1.00
22.18
C

2263
C
SER
A
297
−17.673
−9.201
41.383
1.00
23.10
C

2264
O
SER
A
297
−18.365
−9.766
42.237
1.00
24.64
O

2265
CB
SER
A
297
−18.555
−6.909
40.929
1.00
19.71
C

2266
OG
SER
A
297
−18.706
−7.129
39.540
1.00
25.23
O

2267
N
PHE
A
298
−17.149
−9.836
40.339
1.00
22.92
N

2268
CA
PHE
A
298
−17.330
−11.270
40.156
1.00
23.27
C

2269
C
PHE
A
298
−16.354
−12.043
41.053
1.00
23.71
C

2270
O
PHE
A
298
−16.762
−12.876
41.859
1.00
23.60
O

2271
CB
PHE
A
298
−17.069
−11.661
38.702
1.00
24.59
C

2272
CG
PHE
A
298
−17.158
−13.144
38.442
1.00
26.67
C

2273
CD1
PHE
A
298
−18.395
−13.761
38.255
1.00
28.41
C

2274
CD2
PHE
A
298
−16.005
−13.922
38.382
1.00
27.06
C

2275
CE1
PHE
A
298
−18.484
−15.133
38.008
1.00
28.62
C

2276
CE2
PHE
A
298
−16.078
−15.295
38.137
1.00
28.00
C

2277
CZ
PHE
A
298
−17.321
−15.904
37.949
1.00
29.56
C

2278
N
HIS
A
299
−15.063
−11.746
40.913
1.00
23.16
N

2279
CA
HIS
A
299
−14.016
−12.432
41.663
1.00
23.35
C

2280
C
HIS
A
299
−13.884
−12.136
43.147
1.00
24.79
C

2281
O
HIS
A
299
−13.396
−12.976
43.910
1.00
24.89
O

2282
CB
HIS
A
299
−12.668
−12.197
40.987
1.00
21.74
C

2283
CG
HIS
A
299
−12.517
−12.918
39.685
1.00
22.63
C

2284
ND1
HIS
A
299
−12.381
−14.288
39.608
1.00
23.00
N

2285
CD2
HIS
A
299
−12.496
−12.464
38.409
1.00
20.47
C

2286
CE1
HIS
A
299
−12.282
−14.648
38.341
1.00
19.54
C

2287
NE2
HIS
A
299
−12.350
−13.561
37.593
1.00
22.87
N

2288
N
ALA
A
300
−14.293
−10.950
43.574
1.00
25.00
N

2289
CA
ALA
A
300
−14.176
−10.632
44.988
1.00
25.38
C

2290
C
ALA
A
300
−15.095
−11.551
45.805
1.00
25.88
C

2291
O
ALA
A
300
−14.807
−11.858
46.966
1.00
27.32
O

2292
CB
ALA
A
300
−14.528
−9.162
45.228
1.00
23.29
C

2293
N
LEU
A
301
−16.191
−11.992
45.191
1.00
22.59
N

2294
CA
LEU
A
301
−17.158
−12.863
45.855
1.00
22.20
C

2295
C
LEU
A
301
−16.799
−14.331
45.703
1.00
22.87
C

2296
O
LEU
A
301
−17.554
−15.209
46.130
1.00
22.12
O

2297
CB
LEU
A
301
−18.562
−12.634
45.287
1.00
20.76
C

2298
CG
LEU
A
301
−19.402
−11.479
45.851
1.00
19.43
C

2299
CD1
LEU
A
301
−18.615
−10.187
45.827
1.00
19.96
C

2300
CD2
LEU
A
301
−20.681
−11.351
45.036
1.00
19.49
C

2301
N
ARG
A
302
−15.643
−14.597
45.103
1.00
21.49
N

2302
CA
ARG
A
302
−15.213
−15.967
44.891
1.00
20.79
C

2303
C
ARG
A
302
−13.814
−16.236
45.415
1.00
22.89
C

2304
O
ARG
A
302
−13.155
−15.338
45.941
1.00
24.38
O

2305
CB
ARG
A
302
−15.325
−16.303
43.402
1.00
20.72
C

2306
CG
ARG
A
302
−16.782
−16.290
42.945
1.00
19.87
C

2307
CD
ARG
A
302
−16.994
−16.340
41.444
1.00
16.79
C

2308
NE
ARG
A
302
−18.421
−16.481
41.164
1.00
17.39
N

2309
CZ
ARG
A
302
−19.321
−15.508
41.301
1.00
18.29
C

2310
NH1
ARG
A
302
−18.947
−14.296
41.701
1.00
15.00
N

2311
NH2
ARG
A
302
−20.609
−15.756
41.070
1.00
16.21
N

2312
N
GLN
A
303
−13.372
−17.482
45.285
1.00
22.63
N

2313
CA
GLN
A
303
−12.059
−17.892
45.758
1.00
23.76
C

2314
C
GLN
A
303
−10.854
−17.185
45.141
1.00
23.28
C

2315
O
GLN
A
303
−10.759
−17.023
43.928
1.00
22.69
O

2316
CB
GLN
A
303
−11.878
−19.395
45.555
1.00
27.17
C

2317
CG
GLN
A
303
−12.599
−20.250
46.560
1.00
36.21
C

2318
CD
GLN
A
303
−11.841
−20.357
47.867
1.00
41.74
C

2319
OE1
GLN
A
303
−12.338
−20.924
48.843
1.00
45.43
O

2320
NE2
GLN
A
303
−10.625
−19.817
47.892
1.00
43.22
N

2321
N
ILE
A
304
−9.939
−16.778
46.015
1.00
23.71
N

2322
CA
ILE
A
304
−8.668
−16.145
45.663
1.00
23.40
C

2323
C
ILE
A
304
−7.812
−16.646
46.829
1.00
24.26
C

2324
O
ILE
A
304
−7.277
−15.856
47.610
1.00
25.14
O

2325
CB
ILE
A
304
−8.740
−14.599
45.700
1.00
21.99
C

2326
CG1
ILE
A
304
−9.917
−14.096
44.855
1.00
23.20
C

2327
CG2
ILE
A
304
−7.449
−14.003
45.125
1.00
21.53
C

2328
CD1
ILE
A
304
−10.041
−12.573
44.817
1.00
17.76
C

2329
N
PRO
A
305
−7.680
−17.986
46.949
1.00
24.59
N

2330
CA
PRO
A
305
−6.939
−18.730
47.980
1.00
23.71
C

2331
C
PRO
A
305
−5.663
−18.140
48.578
1.00
23.54
C

2332
O
PRO
A
305
−5.594
−17.924
49.784
1.00
21.56
O

2333
CB
PRO
A
305
−6.718
−20.109
47.338
1.00
24.05
C

2334
CG
PRO
A
305
−6.872
−19.853
45.863
1.00
26.65
C

2335
CD
PRO
A
305
−8.000
−18.874
45.815
1.00
23.77
C

2336
N
GLN
A
306
−4.658
−17.885
47.752
1.00
23.72
N

2337
CA
GLN
A
306
−3.397
−17.332
48.239
1.00
22.04
C

2338
C
GLN
A
306
−3.595
−16.016
48.982
1.00
20.62
C

2339
O
GLN
A
306
−3.059
−15.806
50.067
1.00
20.21
O

2340
CB
GLN
A
306
−2.450
−17.098
47.066
1.00
25.73
C

2341
CG
GLN
A
306
−2.115
−18.343
46.284
1.00
32.32
C

2342
CD
GLN
A
306
−1.407
−19.374
47.130
1.00
35.14
C

2343
OE1
GLN
A
306
−0.411
−19.075
47.790
1.00
38.23
O

2344
NE2
GLN
A
306
−1.916
−20.600
47.116
1.00
39.11
N

2345
N
LEU
A
307
−4.363
−15.121
48.381
1.00
20.58
N

2346
CA
LEU
A
307
−4.616
−13.819
48.977
1.00
20.22
C

2347
C
LEU
A
307
−5.415
−14.012
50.267
1.00
20.67
C

2348
O
LEU
A
307
−5.190
−13.329
51.268
1.00
18.90
O

2349
CB
LEU
A
307
−5.392
−12.954
47.981
1.00
18.73
C

2350
CG
LEU
A
307
−5.342
−11.434
48.090
1.00
20.28
C

2351
CD1
LEU
A
307
−6.747
−10.887
47.949
1.00
18.68
C

2352
CD2
LEU
A
307
−4.711
−11.007
49.414
1.00
18.64
C

2353
N
GLU
A
308
−6.343
−14.961
50.251
1.00
20.74
N

2354
CA
GLU
A
308
−7.144
−15.216
51.438
1.00
22.90
C

2355
C
GLU
A
308
−6.339
−15.763
52.596
1.00
20.86
C

2356
O
GLU
A
308
−6.622
−15.428
53.743
1.00
21.97
O

2357
CB
GLU
A
308
−8.294
−16.164
51.119
1.00
23.11
C

2358
CG
GLU
A
308
−9.318
−15.527
50.218
1.00
27.15
C

2359
CD
GLU
A
308
−10.536
−16.389
50.042
1.00
28.19
C

2360
OE1
GLU
A
308
−11.243
−16.599
51.050
1.00
30.06
O

2361
OE2
GLU
A
308
−10.775
−16.853
48.907
1.00
25.95
O

2362
N
ASN
A
309
−5.346
−16.606
52.312
1.00
20.76
N

2363
CA
ASN
A
309
−4.522
−17.156
53.387
1.00
21.94
C

2364
C
ASN
A
309
−3.574
−16.077
53.919
1.00
21.40
−C

2365
O
ASN
A
309
−3.230
−16.070
55.103
1.00
21.53
O

2366
CB
ASN
A
309
−3.746
−18.391
52.908
1.00
21.55
−C

2367
CG
ASN
A
309
−4.668
−19.562
52.593
1.00
24.92
−C

2368
OD1
ASN
A
309
−5.747
−19.691
53.187
1.00
24.74
−O

2369
ND2
ASN
A
309
−4.249
−20.422
51.666
1.00
21.78
N

2370
N
VAL
A
310
−3.160
−15.162
53.043
1.00
20.71
N

2371
CA
VAL
A
310
−2.300
−14.059
53.458
1.00
18.85
C

2372
C
VAL
A
310
−3.152
−13.153
54.358
1.00
19.96
C

2373
O
VAL
A
310
−2.660
−12.595
55.343
1.00
20.13
O

2374
CB
VAL
A
310
−1.777
−13.260
52.241
1.00
16.64
C

2375
CG1
VAL
A
310
−1.162
−11.949
52.699
1.00
17.06
C

2376
CG2
VAL
A
310
−0.726
−14.078
51.496
1.00
14.14
C

2377
N
LEU
A
311
−4.440
−13.033
54.032
1.00
19.72
N

2378
CA
LEU
A
311
−5.360
−12.215
54.825
1.00
19.18
C

2379
C
LEU
A
311
−5.592
−12.844
56.183
1.00
19.50
C

2380
O
LEU
A
311
−5.499
−12.170
57.209
1.00
22.93
O

2381
CB
LEU
A
311
−6.716
−12.041
54.118
1.00
17.05
C

2382
CG
LEU
A
311
−7.810
−11.366
54.964
1.00
18.01
C

2383
CD1
LEU
A
311
−7.320
−10.014
55.450
1.00
13.09
C

2384
CD2
LEU
A
311
−9.099
−11.209
54.148
1.00
15.78
C

2385
N
LYS
A
312
−5.897
−14.137
56.199
1.00
18.61
N

2386
CA
LYS
A
312
−6.134
−14.829
57.461
1.00
19.03
C

2387
C
LYS
A
312
−4.926
−14.741
58.377
1.00
18.34
C

2388
O
LYS
A
312
−5.074
−14.626
59.594
1.00
18.54
O

2389
CB
LYS
A
312
−6.457
−16.310
57.227
1.00
19.53
C

2390
CG
LYS
A
312
−7.806
−16.589
56.596
1.00
17.38
C

2391
CD
LYS
A
312
−8.005
−18.091
56.426
1.00
18.90
C

2392
CE
LYS
A
312
−9.398
−18.416
55.914
1.00
19.35
C

2393
NZ
LYS
A
312
−9.576
−19.882
55.709
1.00
18.07
N

2394
N
GLU
A
313
−3.733
−14.828
57.797
1.00
18.53
N

2395
CA
GLU
A
313
−2.499
−14.765
58.579
1.00
19.06
C

2396
C
GLU
A
313
−2.244
−13.335
59.054
1.00
18.52
C

2397
O
GLU
A
313
−1.699
−13.116
60.140
1.00
17.36
O

2398
CB
GLU
A
313
−1.311
−15.273
57.750
1.00
19.46
C

2399
CG
GLU
A
313
−0.005
−15.402
58.527
1.00
18.65
C

2400
CD
GLU
A
313
−0.065
−16.412
59.676
1.00
24.09
C

2401
OE1
GLU
A
313
−1.180
−16.764
60.128
1.00
24.29
O

2402
OE2
GLU
A
313
1.012
−16.849
60.143
1.00
22.12
O

2403
N
THR
A
314
−2.635
−12.359
58.243
1.00
18.37
N

2404
CA
THR
A
314
−2.471
−10.960
58.634
1.00
20.35
C

2405
C
THR
A
314
−3.382
−10.718
59.841
1.00
19.23
C

2406
O
THR
A
314
−2.990
−10.075
60.822
1.00
20.83
O

2407
CB
THR
A
314
−2.894
−9.985
57.502
1.00
19.17
C

2408
OG1
THR
A
314
−2.161
−10.281
56.310
1.00
18.95
O

2409
CG2
THR
A
314
−2.607
−8.542
57.906
1.00
19.15
C

2410
N
LEU
A
315
−4.598
−11.246
59.758
1.00
18.55
N

2411
CA
LEU
A
315
−5.574
−11.111
60.829
1.00
18.99
C

2412
C
LEU
A
315
−5.181
−11.846
62.114
1.00
19.31
C

2413
O
LEU
A
315
−5.567
−11.433
63.203
1.00
21.35
O

2414
CB
LEU
A
315
−6.949
−11.589
60.352
1.00
19.43
C

2415
CG
LEU
A
315
−7.693
−10.634
59.406
1.00
20.80
C

2416
CD1
LEU
A
315
−8.914
−11.328
58.820
1.00
21.71
C

2417
CD2
LEU
A
315
−8.123
−9.375
60.162
1.00
23.34
C

2418
N
ARG
A
316
−4.412
−12.923
62.013
1.00
17.96
N

2419
CA
ARG
A
316
−4.010
−13.639
63.225
1.00
16.82
C

2420
C
ARG
A
316
−2.982
−12.819
64.016
1.00
18.63
C

2421
O
ARG
A
316
−3.087
−12.664
65.241
1.00
19.90
O

2422
CB
ARG
A
316
−3.397
−14.996
62.863
1.00
17.95
C

2423
CG
ARG
A
316
−3.056
−15.877
64.074
1.00
16.88
C

2424
CD
ARG
A
316
−2.442
−17.213
63.645
1.00
18.54
C

2425
NE
ARG
A
316
−1.133
−17.049
63.030
1.00
16.50
N

2426
CZ
ARG
A
316
−0.033
−16.719
63.700
1.00
19.92
C

2427
NH1
ARG
A
316
−0.086
−16.532
65.013
1.00
18.92
N

2428
NH2
ARG
A
316
1.114
−16.536
63.052
1.00
17.92
N

2429
N
LEU
A
317
−1.993
−12.301
63.296
1.00
16.46
N

2430
CA
LEU
A
317
−0.911
−11.516
63.870
1.00
18.27
C

2431
C
LEU
A
317
−1.288
−10.088
64.211
1.00
19.51
C

2432
O
LEU
A
317
−0.712
−9.497
65.129
1.00
19.39
O

2433
CB
LEU
A
317
0.263
−11.461
62.891
1.00
17.21
C

2434
CG
LEU
A
317
0.967
−12.773
62.543
1.00
17.34
C

2435
CD1
LEU
A
317
1.819
−12.571
61.297
1.00
15.00
C

2436
CD2
LEU
A
317
1.807
−13.239
63.726
1.00
15.34
C

2437
N
HIS
A
318
−2.240
−9.532
63.466
1.00
20.21
N

2438
CA
HIS
A
318
−2.642
−8.147
63.671
1.00
20.19
C

2439
C
HIS
A
318
−4.145
−7.956
63.801
1.00
22.72
C

2440
O
HIS
A
318
−4.748
−7.197
63.036
1.00
22.62
O

2441
CB
HIS
A
318
−2.136
−7.297
62.507
1.00
16.11
C

2442
CG
HIS
A
318
−0.709
−7.554
62.150
1.00
14.54
C

2443
ND1
HIS
A
318
0.337
−7.225
62.985
1.00
16.86
N

2444
CD2
HIS
A
318
−0.151
−8.129
61.056
1.00
15.44
C

2445
CE1
HIS
A
318
1.479
−7.584
62.421
1.00
16.71
C

2446
NE2
HIS
A
318
1.211
−8.137
61.250
1.00
14.60
N

2447
N
PRO
A
319
−4.781
−8.643
64.761
1.00
22.68
N

2448
CA
PRO
A
319
−6.227
−8.441
64.874
1.00
23.02
C

2449
C
PRO
A
319
−6.498
−6.993
65.293
1.00
23.28
C

2450
O
PRO
A
319
−5.889
−6.507
66.239
1.00
22.71
O

2451
CB
PRO
A
319
−6.636
−9.468
65.931
1.00
22.10
C

2452
CG
PRO
A
319
−5.404
−9.605
66.765
1.00
21.54
C

2453
CD
PRO
A
319
−4.294
−9.612
65.756
1.00
20.64
C

2454
N
PRO
A
320
−7.400
−6.290
64.574
1.00
22.99
N

2455
CA
PRO
A
320
−7.819
−4.892
64.782
1.00
22.33
C

2456
C
PRO
A
320
−8.310
−4.638
66.205
1.00
21.76
C

2457
O
PRO
A
320
−7.991
−3.615
66.808
1.00
21.13
O

2458
CB
PRO
A
320
−8.945
−4.707
63.763
1.00
20.32
C

2459
CG
PRO
A
320
−8.624
−5.683
62.709
1.00
23.90
C

2460
CD
PRO
A
320
−8.184
−6.898
63.487
1.00
22.34
C

2461
N
LEU
A
321
−9.115
−5.573
66.706
1.00
20.34
N

2462
CA
LEU
A
321
−9.654
−5.525
68.059
1.00
21.44
C

2463
C
LEU
A
321
−8.810
−6.517
68.861
1.00
22.69
C

2464
O
LEU
A
321
−8.981
−7.731
68.711
1.00
22.86
O

2465
CB
LEU
A
321
−11.122
−5.972
68.077
1.00
21.11
C

2466
CG
LEU
A
321
−12.236
−4.923
67.909
1.00
22.67
C

2467
CD1
LEU
A
321
−12.132
−4.247
66.575
1.00
16.59
C

2468
CD2
LEU
A
321
−13.597
−5.590
68.045
1.00
20.92
C

2469
N
ILE
A
322
−7.897
−6.002
69.692
1.00
22.64
N

2470
CA
ILE
A
322
−7.010
−6.842
70.501
1.00
21.34
C

2471
C
ILE
A
322
−7.660
−7.338
71.775
1.00
23.03
C

2472
O
ILE
A
322
−7.130
−8.224
72.450
1.00
23.98
O

2473
CB
ILE
A
322
−5.708
−6.098
70.888
1.00
19.54
C

2474
OG1
ILE
A
322
−6.022
−4.957
71.860
1.00
19.76
C

2475
CG2
ILE
A
322
−5.028
−5.561
69.640
1.00
15.60
C

2476
OD1
ILE
A
322
−4.800
−4.172
72.313
1.00
17.98
C

2477
N
ILE
A
323
−8.805
−6.759
72.121
1.00
25.70
N

2478
CA
ILE
A
323
−9.517
−7.190
73.315
1.00
25.21
C

2479
C
WE
A
323
−11.028
−7.117
73.089
1.00
26.09
C

2480
O
1LE
A
323
−11.524
−6.206
72.427
1.00
26.00
O

2481
CB
ILE
A
323
−9.109
−6.346
74.546
1.00
23.89
C

2482
OG1
ILE
A
323
−9.564
−7.056
75.825
1.00
23.20
C

2483
CG2
ILE
A
323
−9.715
−4.947
74.461
1.00
23.71
C

2484
OD1
WE
A
323
−9.166
−6.329
77.088
1.00
22.75
C

2485
N
LEU
A
324
−11.742
−8.106
73.618
1.00
26.29
N

2486
CA
LEU
A
324
−13.195
−8.187
73.497
1.00
26.18
C

2487
C
LEU
A
324
−13.729
−8.177
74.921
1.00
28.22
C

2488
O
LEU
A
324
−13.172
−8.849
75.793
1.00
29.89
O

2489
CB
LEU
A
324
−13.585
−9.476
72.775
1.00
24.21
C

2490
CG
LEU
A
324
−12.999
−9.577
71.366
1.00
24.84
C

2491
OD1
LEU
A
324
−13.480
−10.843
70.670
1.00
25.31
C

2492
CD2
LEU
A
324
−13.417
−8.348
70.579
1.00
23.78
C

2493
N
MET
A
325
−14.800
−7.424
75.158
1.00
28.23
N

2494
CA
MET
A
325
−15.344
−7.282
76.507
1.00
28.19
C

2495
C
MET
A
325
−16.816
−7.620
76.705
1.00
26.84
C

2496
O
MET
A
325
−17.624
−7.524
75.784
1.00
23.28
O

2497
CB
MET
A
325
−15.108
−5.846
76.983
1.00
30.46
C

2498
CG
MET
A
325
−13.645
−5.476
77.116
1.00
35.90
C

2499
SD
MET
A
325
−13.000
−5.887
78.751
1.00
41.22
S

2500
CE
MET
A
325
−12.488
−4.276
79.314
1.00
39.46
C

2501
N
ARG
A
326
−17.139
−7.998
77.939
1.00
28.45
N

2502
CA
ARG
A
326
−18.496
−8.334
78.358
1.00
28.18
C

2503
C
ARG
A
326
−18.641
−7.906
79.814
1.00
30.14
C

2504
O
ARG
A
326
−17.648
−7.645
80.502
1.00
32.15
O

2505
CB
ARG
A
326
−18.736
−9.844
78.293
1.00
27.24
C

2506
CG
ARG
A
326
−18.491
−10.490
76.941
1.00
27.83
C

2507
CD
ARG
A
326
−19.701
−10.413
76.032
1.00
26.95
C

2508
NE
ARG
A
326
−19.458
−11.131
74.777
1.00
29.15
N

2509
CZ
ARG
A
326
−18.638
−10.712
73.814
1.00
29.23
C

2510
NH1
ARG
A
326
−17.977
−9.567
73.953
1.00
29.74
N

2511
NH2
ARG
A
326
−18.464
−11.444
72.716
1.00
28.12
N

2512
N
VAL
A
327
−19.880
−7.830
80.281
1.00
30.01
N

2513
CA
VAL
A
327
−20.151
−7.491
81.670
1.00
28.04
C

2514
C
VAL
A
327
−20.843
−8.730
82.195
1.00
27.47
C

2515
O
VAL
A
327
−21.832
−9.167
81.618
1.00
26.08
O

2516
CB
VAL
A
327
−21.129
−6.301
81.815
1.00
27.79
C

2517
CG1
VAL
A
327
−21.445
−6.084
83.287
1.00
25.93
C

2518
CG2
VAL
A
327
−20.533
−5.049
81.219
1.00
25.62
C

2519
N
ALA
A
328
−20.318
−9.310
83.266
1.00
30.10
N

2520
CA
ALA
A
328
−20.925
−10.505
83.843
1.00
31.84
C

2521
C
ALA
A
328
−22.262
−10.139
84.496
1.00
33.02
C

2522
O
ALA
A
328
−22.318
−9.252
85.346
1.00
32.86
O

2523
CB
ALA
A
328
−19.983
−11.120
84.867
1.00
28.00
C

2524
N
LYS
A
329
−23.336
−10.814
84.094
1.00
34.87
N

2525
CA
LYS
A
329
−24.659
−10.540
84.660
1.00
38.45
C

2526
C
LYS
A
329
−25.071
−11.588
85.694
1.00
39.30
C

2527
O
LYS
A
329
−26.241
−11.687
86.066
1.00
40.50
O

2528
CB
LYS
A
329
−25.726
−10.471
83.553
1.00
39.13
C

2529
CG
LYS
A
329
−25.472
−9.415
82.477
1.00
39.80
C

2530
CD
LYS
A
329
−24.953
−8.101
83.058
1.00
41.23
C

2531
CE
LYS
A
329
−25.922
−7.464
84.045
1.00
43.87
C

2532
NZ
LYS
A
329
−25.274
−6.329
84.781
1.00
44.31
N

2533
N
GLY
A
330
−24.100
−12.370
86.150
1.00
40.14
N

2534
CA
GLY
A
330
−24.362
−13.394
87.141
1.00
39.63
C

2535
C
GLY
A
330
−23.043
−14.005
87.558
1.00
40.25
C

2536
O
GLY
A
330
−21.989
−13.543
87.123
1.00
39.53
O

2537
N
GLU
A
331
−23.088
−15.033
88.399
1.00
40.44
N

2538
CA
GLU
A
331
−21.872
−15.699
88.841
1.00
41.21
C

2539
C
GLU
A
331
−21.652
−16.995
88.067
1.00
41.16
C

2540
O
GLU
A
331
−22.583
−17.776
87.867
1.00
40.39
O

2541
CB
GLU
A
331
−21.945
−16.002
90.334
1.00
43.25
C

2542
CG
GLU
A
331
−21.978
−14.765
91.206
1.00
46.62
C

2543
CD
GLU
A
331
−21.430
−15.031
92.594
1.00
49.31
C

2544
OE1
GLU
A
331
−21.054
−16.194
92.876
1.00
48.59
O

2545
OE2
GLU
A
331
−21.372
−14.075
93.401
1.00
52.59
O

2546
N
PHE
A
332
−20.419
−17.224
87.630
1.00
40.80
N

2547
CA
PHE
A
332
−20.107
−18.433
86.882
1.00
40.95
C

2548
C
PHE
A
332
−18.758
−18.990
87.305
1.00
41.40
C

2549
O
PHE
A
332
−17.905
−18.262
87.816
1.00
40.77
O

2550
CB
PHE
A
332
−20.089
−18.147
85.375
1.00
39.63
C

2551
CG
PHE
A
332
−21.240
−17.305
84.902
1.00
39.62
C

2552
CD1
PHE
A
332
−21.172
−15.916
84.962
1.00
38.34
C

2553
CD2
PHE
A
332
−22.403
−17.898
84.416
1.00
40.49
C

2554
CE1
PHE
A
332
−22.244
−15.127
84.545
1.00
39.10
C

2555
CE2
PHE
A
332
−23.485
−17.115
83.996
1.00
40.73
C

2556
CZ
PHE
A
332
−23.403
−15.726
84.062
1.00
39.16
C

2557
N
GLU
A
333
−18.575
−20.287
87.099
1.00
40.52
N

2558
CA
GLU
A
333
−17.322
−20.926
87.449
1.00
41.70
C

2559
C
GLU
A
333
−16.605
−21.323
86.167
1.00
40.17
C

2560
O
GLU
A
333
−17.194
−21.934
85.276
1.00
38.06
O

2561
CB
GLU
A
333
−17.573
−22.158
88.327
1.00
44.57
C

2562
CG
GLU
A
333
−16.306
−22.764
88.925
1.00
48.87
C

2563
CD
GLU
A
333
−16.598
−23.785
90.017
1.00
51.50
C

2564
OE1
GLU
A
333
−17.363
−23.455
90.952
1.00
53.78
O

2565
OE2
GLU
A
333
−16.058
−24.911
89.947
1.00
53.46
O

2566
N
VAL
A
334
−15.334
−20.952
86.084
1.00
39.28
N

2567
CA
VAL
A
334
−14.507
−21.251
84.925
1.00
39.91
C

2568
C
VAL
A
334
−13.164
−21.768
85.416
1.00
40.89
C

2569
O
VAL
A
334
−12.365
−21.020
85.971
1.00
40.90
O

2570
CB
VAL
A
334
−14.274
−19.986
84.062
1.00
39.34
C

2571
CG1
VAL
A
334
−13.389
−20.316
82.867
1.00
38.65
C

2572
CG2
VAL
A
334
−15.604
−19.422
83.599
1.00
36.77
C

2573
N
GLN
A
335
−12.928
−23.057
85.220
1.00
43.12
N

2574
CA
GLN
A
335
−11.683
−23.677
85.644
1.00
44.42
C

2575
C
GLN
A
335
−11.374
−23.476
87.122
1.00
43.95
C

2576
O
GLN
A
335
−10.223
−23.280
87.500
1.00
44.26
O

2577
CB
GLN
A
335
−10.525
−23.155
84.799
1.00
45.90
C

2578
CG
GLN
A
335
−10.426
−23.817
83.444
1.00
49.66
C

2579
CD
GLN
A
335
−9.258
−23.301
82.639
1.00
51.44
C

2580
OE1
GLN
A
335
−8.148
−23.155
83.158
1.00
54.81
O

2581
NE2
GLN
A
335
−9.493
−23.027
81.362
1.00
52.38
N

2582
N
GLY
A
336
−12.407
−23.533
87.955
1.00
44.23
N

2583
CA
GLY
A
336
−12.208
−23.376
89.382
1.00
44.50
C

2584
C
GLY
A
336
−12.109
−21.942
89.860
1.00
45.21
C

2585
O
GLY
A
336
−11.841
−21.705
91.034
1.00
46.62
O

2586
N
HIS
A
337
−12.320
−20.985
88.961
1.00
44.61
N

2587
CA
HIS
A
337
−12.260
−19.572
89.326
1.00
43.44
C

2588
C
HIS
A
337
−13.648
−18.940
89.211
1.00
43.39
C

2589
O
HIS
A
337
−14.350
−19.120
88.214
1.00
43.17
O

2590
CB
HIS
A
337
−11.255
−18.848
88.430
1.00
42.32
C

2591
CG
HIS
A
337
−9.853
−19.354
88.574
1.00
42.03
C

2592
ND1
HIS
A
337
−9.133
−19.230
89.744
1.00
42.31
N

2593
CD2
HIS
A
337
−9.045
−20.004
87.703
1.00
40.98
C

2594
CE1
HIS
A
337
−7.943
−19.781
89.587
1.00
41.99
C

2595
NE2
HIS
A
337
−7.864
−20.258
88.357
1.00
41.14
N

2596
N
ARO
A
338
−14.042
−18.200
90.240
1.00
43.42
N

2597
CA
ARG
A
338
−15.362
−17.577
90.270
1.00
43.12
C

2598
C
ARG
A
338
−15.443
−16.181
89.656
1.00
40.77
C

2599
O
ARG
A
338
−14.653
−15.295
89.980
1.00
42.38
O

2600
CB
ARG
A
338
−15.870
−17.522
91.721
1.00
46.17
C

2601
CG
ARG
A
338
−17.285
−16.979
91.888
1.00
49.43
C

2602
CD
ARG
A
338
−18.312
−17.918
91.267
1.00
55.40
C

2603
NE
ARG
A
338
−18.332
−19.227
91.918
1.00
57.40
N

2604
CZ
ARG
A
338
−18.731
−19.432
93.170
1.00
59.19
C

2605
NH1
ARG
A
338
−19.146
−18.413
93.913
1.00
59.67
N

2606
NH2
ARG
A
338
−18.718
−20.656
93.681
1.00
59.44
N

2607
N
ILE
A
339
−16.410
−16.007
88.761
1.00
36.96
N

2608
CA
ILE
A
339
−16.672
−14.733
88.110
1.00
33.79
C

2609
C
ILE
A
339
−17.916
−14.189
88.803
1.00
33.88
C

2610
O
ILE
A
339
−18.862
−14.937
89.044
1.00
34.15
O

2611
CB
ILE
A
339
−16.961
−14.929
86.601
1.00
33.45
C

2612
CG1
ILE
A
339
−15.646
−15.128
85.843
1.00
29.98
C

2613
CG2
ILE
A
339
−17.742
−13.744
86.052
1.00
32.33
C

2614
CD1
ILE
A
339
−15.820
−15.370
84.370
1.00
30.67
C

2615
N
HIS
A
340
−17.924
−12.901
89.133
1.00
33.69
N

2616
CA
HIS
A
340
−19.076
−12.319
89.822
1.00
33.55
C

2617
C
HIS
A
340
−19.834
−11.269
89.013
1.00
33.57
C

2618
O
HIS
A
340
−19.276
−10.648
88.105
1.00
33.00
O

2619
CB
HIS
A
340
−18.634
−11.698
91.157
1.00
33.13
C

2620
CG
HIS
A
340
−17.924
−12.656
92.064
1.00
33.64
C

2621
ND1
HIS
A
340
−16.578
−12.931
91.949
1.00
33.55
N

2622
CD2
HIS
A
340
−18.380
−13.424
93.082
1.00
32.29
C

2623
CE1
HIS
A
340
−16.234
−13.826
92.859
1.00
34.10
C

2624
NE2
HIS
A
340
−17.310
−14.143
93.558
1.00
34.64
N

2625
N
GLU
A
341
−21.105
−11.068
89.362
1.00
34.15
N

2626
CA
GLU
A
341
−21.946
−10.085
88.683
1.00
34.80
C

2627
C
GLU
A
341
−21.218
−8.746
88.737
1.00
34.32
C

2628
O
GLU
A
341
−20.624
−8.395
89.761
1.00
35.38
O

2629
CB
GLU
A
341
−23.310
−9.987
89.384
1.00
36.93
C

2630
CG
GLU
A
341
−24.344
−9.086
88.696
1.00
39.47
C

2631
CD
GLU
A
341
−24.190
−7.607
89.040
1.00
41.17
C

2632
OE1
GLU
A
341
−23.306
−7.263
89.851
1.00
40.59
O

2633
OE2
GLU
A
341
−24.962
−6.784
88.498
1.00
43.58
O

2634
N
GLY
A
342
−21.240
−8.013
87.630
1.00
32.35
N

2635
CA
GLY
A
342
−20.569
−6.728
87.594
1.00
32.09
C

2636
C
GLY
A
342
−19.144
−6.798
87.074
1.00
32.19
C

2637
O
GLY
A
342
−18.623
−5.804
86.551
1.00
32.53
O

2638
N
ASP
A
343
−18.506
−7.959
87.230
1.00
31.53
N

2639
CA
ASP
A
343
−17.138
−8.161
86.753
1.00
29.63
C

2640
C
ASP
A
343
−17.057
−7.933
85.249
1.00
29.10
C

2641
O
ASP
A
343
−18.005
−8.227
84.514
1.00
26.30
O

2642
CB
ASP
A
343
−16.672
−9.597
87.003
1.00
32.25
C

2643
CG
ASP
A
343
−15.949
−9.778
88.326
1.00
35.66
C

2644
OD1
ASP
A
343
−15.357
−8.807
88.852
1.00
38.02
O

2645
OD2
ASP
A
343
−15.952
−10.922
88.827
1.00
36.00
O

2646
N
LEU
A
344
−15.925
−7.404
84.797
1.00
28.61
N

2647
CA
LEU
A
344
−15.695
−7.215
83.375
1.00
27.60
C

2648
C
LEU
A
344
−15.024
−8.515
82.969
1.00
26.48
C

2649
O
LEU
A
344
−14.157
−9.018
83.684
1.00
24.94
O

2650
CB
LEU
A
344
−14.746
−6.046
83.094
1.00
28.02
C

2651
CG
LEU
A
344
−15.324
−4.635
83.201
1.00
31.29
C

2652
CD1
LEU
A
344
−14.332
−3.642
82.607
1.00
30.71
C

2653
CD2
LEU
A
344
−16.651
−4.552
82.457
1.00
32.34
C

2654
N
VAL
A
345
−15.437
−9.074
81.838
1.00
25.52
N

2655
CA
VAL
A
345
−14.859
−10.329
81.374
1.00
22.55
C

2656
C
VAL
A
345
−14.323
−10.100
79.965
1.00
20.85
C

2657
O
VAL
A
345
−15.012
−9.538
79.102
1.00
18.20
O

2658
CB
VAL
A
345
−15.923
−11.461
81.411
1.00
22.16
C

2659
CG1
VAL
A
345
−15.267
−12.822
81.165
1.00
21.54
C

2660
CG2
VAL
A
345
−16.618
−11.457
82.777
1.00
19.93
C

2661
N
ALA
A
346
−13.085
−10.525
79.739
1.00
19.11
N

2662
CA
ALA
A
346
−12.459
−10.311
78.449
1.00
19.30
C

2663
C
ALA
A
346
−11.733
−11.497
77.846
1.00
19.24
C

2664
O
ALA
A
346
−11.252
−12.394
78.550
1.00
18.86
O

2665
CB
ALA
A
346
−11.482
−9.124
78.548
1.00
18.27
C

2666
N
ALA
A
347
−11.657
−11.465
76.520
1.00
19.27
N

2667
CA
ALA
A
347
−10.950
−12.462
75.740
1.00
19.14
C

2668
C
ALA
A
347
−10.044
−11.607
74.872
1.00
19.88
C

2669
O
ALA
A
347
−10.385
−10.468
74.545
1.00
19.42
O

2670
CB
ALA
A
347
−11.916
−13.259
74.882
1.00
19.93
C

2671
N
SER
A
348
−8.891
−12.136
74.487
1.00
20.95
N

2672
CA
SER
A
348
−7.979
−11.344
73.682
1.00
20.39
C

2673
C
SER
A
348
−7.512
−12.000
72.400
1.00
20.09
C

2674
O
SER
A
348
−6.734
−12.953
72.435
1.00
23.05
O

2675
CB
SER
A
348
−6.757
−10.960
74.518
1.00
18.71
C

2676
OG
SER
A
348
−5.809
−10.268
73.725
1.00
19.99
O

2677
N
PRO
A
349
−7.985
−11.502
71.243
1.00
20.46
N

2678
CA
PRO
A
349
−7.562
−12.079
69.963
1.00
17.68
C

2679
C
PRO
A
349
−6.051
−11.920
69.791
1.00
18.79
C

2680
O
PRO
A
349
−5.367
−12.807
69.260
1.00
18.94
O

2681
CR
PRO
A
349
−8.340
−11.254
68.945
1.00
15.01
C

2682
CG
PRO
A
349
−9.620
−10.966
69.676
1.00
15.48
C

2683
CD
PRO
A
349
−9.106
−10.560
71.043
1.00
17.53
C

2684
N
ALA
A
350
−5.536
−10.778
70.241
1.00
16.84
N

2685
CA
ALA
A
350
−4.112
−10.492
70.137
1.00
17.20
C

2686
C
ALA
A
350
−3.291
−11.590
70.788
1.00
15.86
C

2687
O
ALA
A
350
−2.339
−12.106
70.199
1.00
15.79
O

2688
CB
ALA
A
350
−3.795
−9.148
70.799
1.00
19.59
C

2689
N
ILE
A
351
−3.672
−11.946
72.005
1.00
15.66
N

2690
CA
ILE
A
351
−2.970
−12.970
72.762
1.00
17.70
C

2691
C
ILE
A
351
−3.313
−14.393
72.324
1.00
19.92
C

2692
O
ILE
A
351
−2.412
−15.221
72.135
1.00
21.02
O

2693
CB
ILE
A
351
−3.265
−12.834
74.280
1.00
16.35
C

2694
CG1
ILE
A
351
−2.787
−11.469
74.785
1.00
16.39
C

2695
CG2
ILE
A
351
−2.580
−13.947
75.051
1.00
16.40
C

2696
CD1
ILE
A
351
−1.340
−11.144
74.443
1.00
13.75
C

2697
N
SER
A
352
−4.604
−14.683
72.172
1.00
20.18
N

2698
CA
SER
A
352
−5.032
−16.023
71.771
1.00
23.02
C

2699
C
SER
A
352
−4.513
−16.445
70.404
1.00
22.75
C

2700
O
SER
A
352
−4.120
−17.595
70.215
1.00
22.68
O

2701
CB
SER
A
352
−6.563
−16.129
71.770
1.00
24.41
C

2702
OG
SER
A
352
−7.058
−16.280
73.092
1.00
33.41
O

2703
N
ASN
A
353
−4.538
−15.518
69.450
1.00
22.36
N

2704
CA
ASN
A
353
−4.079
−15.792
68.094
1.00
21.11
C

2705
C
ASN
A
353
−2.627
−16.245
68.053
1.00
20.21
C

2706
O
ASN
A
353
−2.151
−16.689
67.009
1.00
20.46
O

2707
CB
ASN
A
353
−4.235
−14.548
67.212
1.00
19.12
C

2708
CG
ASN
A
353
−5.682
−14.218
66.917
1.00
21.62
C

2709
OD1
ASN
A
353
−6.597
−14.916
67.360
1.00
20.66
O

2710
ND2
ASN
A
353
−5.899
−13.147
66.161
1.00
19.89
N

2711
N
ARG
A
354
−1.923
−16.151
69.179
1.00
19.63
N

2712
CA
ARO
A
354
−0.515
−16.543
69.201
1.00
19.34
C

2713
C
ARG
A
354
−0.159
−17.590
70.249
1.00
20.15
C

2714
O
ARO
A
354
0.998
−17.705
70.642
1.00
19.99
O

2715
CB
ARG
A
354
0.375
−15.308
69.399
1.00
17.61
C

2716
CG
ARG
A
354
0.126
−14.187
68.399
1.00
17.11
C

2717
CD
ARG
A
354
1.331
−13.272
68.294
1.00
16.16
C

2718
NE
ARG
A
354
1.107
−12.140
67.391
1.00
17.35
N

2719
CZ
ARG
A
354
2.085
−11.423
66.839
1.00
18.34
C

2720
NH1
ARO
A
354
3.351
−11.723
67.090
1.00
19.25
N

2721
NH2
ARG
A
354
1.804
−10.398
66.041
1.00
19.78
N

2722
N
ILE
A
355
−1.145
−18.345
70.719
1.00
21.36
N

2723
CA
ILE
A
355
−0.862
−19.384
71.700
1.00
23.37
C

2724
C
WE
A
355
0.031
−20.416
71.017
1.00
24.66
C

2725
O
WE
A
355
−0.391
−21.089
70.071
1.00
23.83
O

2726
CB
WE
A
355
−2.153
−20.048
72.196
1.00
24.06
C

2727
CG1
ILE
A
355
−2.923
−19.053
73.072
1.00
24.23
C

2728
CG2
ILE
A
355
−1.818
−21.334
72.953
1.00
22.97
C

2729
CD1
ILE
A
355
−4.237
−19.579
73.618
1.00
24.30
C

2730
N
PRO
A
356
1.285
−20.550
71.490
1.00
25.73
N

2731
CA
PRO
A
356
2.291
−21.476
70.960
1.00
26.09
C

2732
C
PRO
A
356
1.802
−22.901
70.698
1.00
27.91
C

2733
O
PRO
A
356
2.146
−23.498
69.677
1.00
27.37
O

2734
CB
PRO
A
356
3.390
−21.436
72.019
1.00
23.09
C

2735
CG
PRO
A
356
3.271
−20.085
72.584
1.00
23.57
C

2736
CD
PRO
A
356
1.784
−19.902
72.715
1.00
24.98
C

2737
N
GLU
A
357
1.010
−23.446
71.617
1.00
27.67
N

2738
CA
GLU
A
357
0.508
−24.805
71.461
1.00
28.63
C

2739
C
GLU
A
357
−0.542
−24.934
70.372
1.00
27.70
C

2740
O
GLU
A
357
−0.726
−26.011
69.805
1.00
28.67
O

2741
CB
GLU
A
357
−0.046
−25.318
72.794
1.00
32.56
C

2742
CG
GLU
A
357
0.832
−26.380
73.444
1.00
37.77
C

2743
CD
GLU
A
357
0.603
−27.776
72.864
1.00
40.53
C

2744
OE1
GLU
A
357
0.395
−27.907
71.635
1.00
44.43
O

2745
OE2
GLU
A
357
0.639
−28.750
73.641
1.00
42.96
O

2746
N
ASP
A
358
−1.228
−23.839
70.061
1.00
27.21
N

2747
CA
ASP
A
358
−2.249
−23.893
69.023
1.00
24.66
C

2748
C
ASP
A
358
−1.730
−23.454
67.660
1.00
24.78
C

2749
O
ASP
A
358
−2.218
−23.916
66.626
1.00
25.70
O

2750
CB
ASP
A
358
−3.456
−23.039
69.410
1.00
23.99
C

2751
CG
ASP
A
358
−4.105
−23.499
70.702
1.00
23.99
C

2752
OD1
ASP
A
358
−3.786
−24.616
71.164
1.00
24.63
O

2753
OD2
ASP
A
358
−4.937
−22.747
71.254
1.00
25.46
O

2754
N
PHE
A
359
−0.736
−22.574
67.641
1.00
23.92
N

2755
CA
PHE
A
359
−0.212
−22.114
66.362
1.00
22.86
C

2756
C
PHE
A
359
1.305
−22.208
66.269
1.00
22.69
C

2757
O
PHE
A
359
2.021
−21.318
66.723
1.00
23.00
O

2758
CB
PHE
A
359
−0.665
−20.669
66.096
1.00
21.20
C

2759
CG
PHE
A
359
−2.140
−20.444
66.327
1.00
19.93
C

2760
CD1
PHE
A
359
−3.065
−20.696
65.315
1.00
19.12
C

2761
CD2
PHE
A
359
−2.606
−20.037
67.571
1.00
18.07
C

2762
CE1
PHE
A
359
−4.441
−20.550
65.541
1.00
20.65
C

2763
CE2
PHE
A
359
−3.978
−19.887
67.814
1.00
18.91
C

2764
CZ
PHE
A
359
−4.900
−20.145
66.793
1.00
18.89
C

2765
N
PRO
A
360
1.817
−23.305
65.690
1.00
22.93
N

2766
CA
PRO
A
360
3.261
−23.495
65.541
1.00
22.66
C

2767
C
PRO
A
360
3.937
−22.217
65.036
1.00
23.45
C

2768
O
PRO
A
360
3.521
−21.656
64.014
1.00
21.44
O

2769
CB
PRO
A
360
3.336
−24.637
64.540
1.00
20.94
C

2770
CG
PRO
A
360
2.207
−25.501
64.990
1.00
23.01
C

2771
CD
PRO
A
360
1.085
−24.499
65.226
1.00
23.13
C

2772
N
ASP
A
361
4.974
−21.774
65.756
1.00
22.64
N

2773
CA
ASP
A
361
5.715
−20.552
65.428
1.00
21.48
C

2774
C
ASP
A
361
4.691
−19.417
65.283
1.00
21.89
C

2775
O
ASP
A
361
4.494
−18.867
64.194
1.00
19.90
O

2776
CB
ASP
A
361
6.498
−20.738
64.122
1.00
21.70
C

2777
CG
ASP
A
361
7.296
−22.038
64.096
1.00
26.19
C

2778
OD1
ASP
A
361
8.027
−22.321
65.072
1.00
26.11
O

2779
OD2
ASP
A
361
7.196
−22.781
63.092
1.00
26.36
O

2780
N
PRO
A
362
4.028
−19.051
66.392
1.00
21.74
N

2781
CA
PRO
A
362
3.008
−17.998
66.446
1.00
22.09
C

2782
C
PRO
A
362
3.400
−16.595
66.007
1.00
23.01
C

2783
O
PRO
A
362
2.527
−15.798
65.655
1.00
24.30
O

2784
CB
PRO
A
362
2.554
−18.034
67.907
1.00
22.45
C

2785
CG
PRO
A
362
3.793
−18.452
68.632
1.00
22.02
C

2786
CD
PRO
A
362
4.291
−19.580
67.746
1.00
22.29
C

2787
N
HIS
A
363
4.694
−16.284
66.025
1.00
22.05
N

2788
CA
HIS
A
363
5.150
−14.954
65.637
1.00
23.14
C

2789
C
HIS
A
363
5.656
−14.892
64.205
1.00
24.35
C

2790
O
HIS
A
363
6.161
−13.857
63.765
1.00
25.28
O

2791
CB
HIS
A
363
6.242
−14.471
66.596
1.00
24.04
C

2792
CG
HIS
A
363
5.852
−14.554
68.039
1.00
23.91
C

2793
ND1
HIS
A
363
4.691
−13.994
68.528
1.00
24.48
N

2794
CD2
HIS
A
363
6.453
−15.157
69.093
1.00
24.27
C

2795
CE1
HIS
A
363
4.592
−14.251
69.821
1.00
25.63
C

2796
NE2
HIS
A
363
5.648
−14.957
70.189
1.00
23.31
N

2797
N
ASP
A
364
5.520
−15.999
63.477
1.00
25.24
N

2798
CA
ASP
A
364
5.947
−16.054
62.080
1.00
25.53
C

2799
C
ASP
A
364
4.753
−15.914
61.140
1.00
23.98
C

2800
O
ASP
A
364
3.618
−16.265
61.492
1.00
22.46
O

2801
CB
ASP
A
364
6.654
−17.380
61.786
1.00
29.95
C

2802
CG
ASP
A
364
7.976
−17.514
62.517
1.00
35.09
C

2803
OD1
ASP
A
364
8.472
−16.502
63.052
1.00
38.16
O

2804
OD2
ASP
A
364
8.527
−18.637
62.552
1.00
39.50
O

2805
N
PHE
A
365
5.018
−15.389
59.950
1.00
20.45
N

2806
CA
PHE
A
365
3.989
−15.218
58.930
1.00
21.15
C

2807
C
PHE
A
365
4.002
−16.513
58.124
1.00
20.95
C

2808
O
PHE
A
365
4.927
−16.748
57.352
1.00
22.82
O

2809
CB
PHE
A
365
4.352
−14.047
58.015
1.00
18.12
C

2810
CG
PHE
A
365
3.336
−13.769
56.936
1.00
17.17
C

2811
CD1
PHE
A
365
2.103
−13.192
57.248
1.00
17.73
C

2812
CD2
PHE
A
365
3.633
−14.031
55.604
1.00
15.77
C

2813
CE1
PHE
A
365
1.185
−12.875
56.247
1.00
14.66
C

2814
CE2
PHE
A
365
2.729
−13.717
54.598
1.00
17.11
C

2815
CZ
PHE
A
365
1.497
−13.133
54.920
1.00
15.51
C

2816
N
VAL
A
366
2.984
−17.347
58.299
1.00
20.95
N

2817
CA
VAL
A
366
2.920
−18.627
57.598
1.00
20.87
C

2818
C
VAL
A
366
1.520
−18.881
57.031
1.00
22.97
C

2819
O
VAL
A
366
0.741
−19.653
57.593
1.00
24.60
O

2820
CB
VAL
A
366
3.297
−19.779
58.568
1.00
19.85
C

2821
CG1
VAL
A
366
3.423
−21.100
57.811
1.00
18.58
C

2822
CG2
VAL
A
366
4.605
−19.444
59.289
1.00
14.47
C

2823
N
PRO
A
367
1.181
−18.231
55.907
1.00
23.40
N

2824
CA
PRO
A
367
−0.137
−18.408
55.290
1.00
23.45
C

2825
C
PRO
A
367
−0.509
−19.856
55.016
1.00
24.16
C

2826
O
PRO
A
367
−1.690
−20.198
54.954
1.00
23.95
O

2827
CB
PRO
A
367
−0.049
−17.567
54.011
1.00
24.93
C

2828
CG
PRO
A
367
1.424
−17.455
53.742
1.00
25.49
C

2829
CD
PRO
A
367
2.015
−17.307
55.117
1.00
25.13
C

2830
N
ALA
A
368
0.497
−20.711
54.864
1.00
24.93
N

2831
CA
ALA
A
368
0.249
−22.126
54.609
1.00
26.23
C

2832
C
ALA
A
368
−0.583
−22.786
55.718
1.00
26.81
C

2833
O
ALA
A
368
−1.184
−23.838
55.496
1.00
28.34
O

2834
CB
ALA
A
368
1.577
−22.864
54.437
1.00
25.08
C

2835
N
ARO
A
369
−0.625
−22.167
56.898
1.00
27.19
N

2836
CA
ARG
A
369
−1.385
−22.691
58.046
1.00
27.63
C

2837
C
ARG
A
369
−2.816
−23.003
57.687
1.00
28.92
C

2838
O
ARG
A
369
−3.443
−23.890
58.265
1.00
28.69
O

2839
CB
ARG
A
369
−1.506
−21.660
59.161
1.00
25.54
C

2840
CG
ARG
A
369
−0.288
−21.338
59.919
1.00
25.90
C

2841
CD
ARG
A
369
−0.595
−20.168
60.835
1.00
22.77
C

2842
NE
ARG
A
369
0.655
−19.544
61.214
1.00
19.13
N

2843
CZ
ARG
A
369
1.484
−20.056
62.103
1.00
17.63
C

2844
NH1
ARG
A
369
1.176
−21.193
62.717
1.00
17.25
N

2845
NH2
ARG
A
369
2.636
−19.452
62.339
1.00
18.61
N

2846
N
TYR
A
370
−3.339
−22.220
56.757
1.00
28.92
N

2847
CA
TYR
A
370
−4.724
−22.334
56.366
1.00
30.51
C

2848
C
TYR
A
370
−4.983
−23.157
55.111
1.00
35.27
C

2849
O
TYR
A
370
−6.104
−23.165
54.598
1.00
36.30
O

2850
CB
TYR
A
370
−5.285
−20.915
56.243
1.00
25.07
C

2851
CG
TYR
A
370
−4.898
−20.048
57.438
1.00
20.00
C

2852
CD1
TYR
A
370
−5.531
−20.212
58.665
1.00
17.88
C

2853
CD2
TYR
A
370
−3.871
−19.094
57.350
1.00
18.51
C

2854
CE1
TYR
A
370
−5.164
−19.457
59.782
1.00
17.66
C

2855
CE2
TYR
A
370
−3.490
−18.326
58.473
1.00
15.96
C

2856
CZ
TYR
A
370
−4.146
−18.521
59.683
1.00
15.76
C

2857
OH
TYR
A
370
−3.786
−17.815
60.811
1.00
16.76
O

2858
N
GLU
A
371
−3.951
−23.857
54.635
1.00
39.66
N

2859
CA
GLU
A
371
−4.061
−24.706
53.446
1.00
44.10
C

2860
C
GLU
A
371
−4.526
−26.117
53.783
1.00
48.00
C

2861
O
GLU
A
371
−4.495
−26.530
54.945
1.00
48.75
O

2862
CB
GLU
A
371
−2.718
−24.792
52.716
1.00
42.84
C

2863
CG
GLU
A
371
−2.400
−23.580
51.864
1.00
41.97
C

2864
CD
GLU
A
371
−1.009
−23.633
51.267
1.00
40.85
C

2865
OE1
GLU
A
371
−0.294
−24.633
51.482
1.00
39.81
O

2866
OE2
GLU
A
371
−0.630
−22.666
50.582
1.00
41.73
O

2867
N
GLN
A
372
−4.933
−26.851
52.746
1.00
52.29
N

2868
CA
GLN
A
372
−5.428
−28.226
52.864
1.00
54.73
C

2869
C
GLN
A
372
−5.026
−28.988
54.125
1.00
54.44
C

2870
O
GLN
A
372
−5.890
−29.453
54.873
1.00
54.00
O

2871
CB
GLN
A
372
−5.009
−29.054
51.641
1.00
58.43
C

2872
CG
GLN
A
372
−5.771
−28.755
50.357
1.00
63.71
C

2873
CD
GLN
A
372
−5.464
−29.758
49.253
1.00
66.56
C

2874
OE1
GLN
A
372
−4.325
−29.858
48.785
1.00
68.36
O

2875
NE2
GLN
A
372
−6.481
−30.512
48.836
1.00
68.29
N

2876
N
PRO
A
373
−3.711
−29.135
54.373
1.00
54.84
N

2877
CA
PRO
A
373
−3.270
−29.862
55.566
1.00
54.09
C

2878
C
PRO
A
373
−3.785
−29.259
56.869
1.00
52.91
C

2879
O
PRO
A
373
−4.950
−29.434
57.241
1.00
54.27
O

2880
CB
PRO
A
373
−1.739
−29.796
55.475
1.00
53.87
C

2881
CG
PRO
A
373
−1.482
−29.670
54.008
1.00
55.55
C

2882
CD
PRO
A
373
−2.549
−28.681
53.587
1.00
55.74
C

2883
N
ARG
A
374
−2.895
−28.537
57.540
1.00
49.09
N

2884
CA
ARG
A
374
−3.158
−27.899
58.823
1.00
46.12
C

2885
C
ARG
A
374
−4.482
−27.147
59.057
1.00
42.73
C

2886
O
ARG
A
374
−5.161
−27.422
60.045
1.00
41.82
O

2887
CB
ARG
A
374
−1.950
−27.012
59.176
1.00
46.46
C

2888
CG
ARG
A
374
−1.214
−26.454
57.959
1.00
47.68
C

2889
CD
ARG
A
374
0.280
−26.293
58.215
1.00
46.84
C

2890
NE
ARG
A
374
0.560
−25.472
59.389
1.00
48.84
N

2891
CZ
ARG
A
374
1.768
−25.017
59.719
1.00
49.40
C

2892
NH1
ARG
A
374
2.817
−25.301
58.955
1.00
50.36
N

2893
NH2
ARG
A
374
1.931
−24.285
60.817
1.00
47.37
N

2894
N
GLN
A
375
−4.857
−26.221
58.174
1.00
39.15
N

2895
CA
GLN
A
375
−6.097
−25.453
58.354
1.00
36.01
C

2896
C
GLN
A
375
−6.270
−25.022
59.816
1.00
32.52
C

2897
O
GLN
A
375
−7.306
−25.283
60.432
1.00
31.16
O

2898
CB
GLN
A
375
−7.307
−26.289
57.935
1.00
37.33
C

2899
CG
GLN
A
375
−7.565
−26.336
56.440
1.00
41.30
C

2900
CD
GLN
A
375
−8.738
−27.235
56.092
1.00
43.54
C

2901
OE1
GLN
A
375
−8.692
−28.448
56.317
1.00
45.12
O

2902
NE2
GLN
A
375
−9.800
−26.646
55.552
1.00
43.17
N

2903
N
GLU
A
376
−5.263
−24.343
60.355
1.00
28.23
N

2904
CA
GLU
A
376
−5.272
−23.923
61.748
1.00
25.06
C

2905
C
GLU
A
376
−6.376
−22.994
62.219
1.00
24.02
C

2906
O
GLU
A
376
−6.632
−22.892
63.422
1.00
22.94
O

2907
CB
GLU
A
376
−3.897
−23.366
62.111
1.00
25.50
C

2908
CG
GLU
A
376
−2.887
−24.496
62.277
1.00
26.70
C

2909
CD
GLU
A
376
−1.450
−24.041
62.293
1.00
26.21
C

2910
OE1
GLU
A
376
−1.169
−22.936
62.802
1.00
25.73
O

2911
OE2
GLU
A
376
−0.595
−24.811
61.810
1.00
26.56
O

2912
N
ASP
A
377
−7.042
−22.315
61.297
1.00
23.59
N

2913
CA
ASP
A
377
−8.130
−21.449
61.710
1.00
23.81
C

2914
C
ASP
A
377
−9.348
−22.296
62.090
1.00
25.73
C

2915
O
ASP
A
377
−9.997
−22.046
63.108
1.00
25.48
O

2916
CB
ASP
A
377
−8.510
−20.461
60.596
1.00
22.88
C

2917
CG
ASP
A
377
−8.763
−21.137
59.264
1.00
22.10
C

2918
OD1
ASP
A
377
−8.288
−22.272
59.064
1.00
25.96
O

2919
OD2
ASP
A
377
−9.429
−20.523
58.404
1.00
21.83
O

2920
N
LEU
A
378
−9.643
−23.312
61.284
1.00
26.06
N

2921
CA
LEU
A
378
−10.808
−24.163
61.531
1.00
28.52
C

2922
C
LEU
A
378
−10.656
−25.190
62.648
1.00
29.57
C

2923
O
LEU
A
378
−11.657
−25.634
63.219
1.00
30.10
O

2924
CB
LEU
A
378
−11.215
−24.875
60.238
1.00
28.81
C

2925
CG
LEU
A
378
−11.481
−23.939
59.060
1.00
28.96
C

2926
CD1
LEU
A
378
−12.053
−24.742
57.892
1.00
31.56
C

2927
CD2
LEU
A
378
−12.443
−22.830
59.489
1.00
28.83
C

2928
N
LEU
A
379
−9.416
−25.568
62.954
1.00
30.17
N

2929
CA
LEU
A
379
−9.143
−26.538
64.014
1.00
32.04
C

2930
C
LEU
A
379
−9.048
−25.857
65.389
1.00
31.27
C

2931
O
LEU
A
379
−9.244
−26.491
66.424
1.00
33.19
O

2932
CB
LEU
A
379
−7.845
−27.302
63.711
1.00
34.35
C

2933
CG
LEU
A
379
−7.834
−28.067
62.376
1.00
39.04
C

2934
CD1
LEU
A
379
−6.542
−28.868
62.242
1.00
40.32
C

2935
CD2
LEU
A
379
−9.046
−29.000
62.301
1.00
38.65
C

2936
N
ASN
A
380
−8.746
−24.566
65.398
1.00
28.84
N

2937
CA
ASN
A
380
−8.654
−23.830
66.648
1.00
27.77
C

2938
C
ASN
A
380
−9.805
−22.852
66.642
1.00
27.46
C

2939
O
ASN
A
380
−9.621
−21.635
66.647
1.00
28.40
O

2940
CB
ASN
A
380
−7.304
−23.122
66.734
1.00
26.10
C

2941
CG
ASN
A
380
−6.150
−24.107
66.808
1.00
25.55
C

2942
OD1
ASN
A
380
−6.023
−24.851
67.783
1.00
26.03
O

2943
ND2
ASN
A
380
−5.319
−24.136
65.773
1.00
20.28
N

2944
N
ARG
A
381
−11.004
−23.420
66.629
1.00
27.59
N

2945
CA
ARG
A
381
−12.236
−22.655
66.573
1.00
27.33
C

2946
C
ARG
A
381
−12.479
−21.717
67.745
1.00
26.29
C

2947
O
ARG
A
381
−13.289
−20.797
67.635
1.00
26.16
O

2948
CB
ARG
A
381
−13.423
−23.610
66.393
1.00
29.58
C

2949
CG
ARG
A
381
−13.555
−24.686
67.460
1.00
32.60
C

2950
CD
ARG
A
381
−14.572
−25.753
67.034
1.00
34.13
C

2951
NE
ARG
A
381
−15.818
−25.158
66.544
1.00
34.24
N

2952
CZ
ARG
A
381
−16.989
−25.231
67.167
1.00
32.06
C

2953
NH1
ARG
A
381
−17.097
−25.880
68.320
1.00
32.21
N

2954
NH2
ARG
A
381
−18.056
−24.646
66.636
1.00
31.42
N

2955
N
TRP
A
382
−11.782
−21.931
68.859
1.00
24.27
N

2956
CA
TRP
A
382
−11.952
−21.055
70.008
1.00
23.61
C

2957
C
TRP
A
382
−10.733
−20.183
70.281
1.00
23.39
C

2958
O
TRP
A
382
−10.800
−19.299
71.134
1.00
24.14
O

2959
CB
TRP
A
382
−12.305
−21.864
71.257
1.00
24.51
C

2960
CG
TRP
A
382
−13.598
−22.611
71.108
1.00
27.04
C

2961
CD1
TRP
A
382
−13.782
−23.966
71.205
1.00
27.65
C

2962
CD2
TRP
A
382
−14.873
−22.058
70.764
1.00
26.96
C

2963
NE1
TRP
A
382
−15.090
−24.285
70.934
1.00
27.68
N

2964
CE2
TRP
A
382
−15.782
−23.134
70.660
1.00
26.63
C

2965
CE3
TRP
A
382
−15.336
−20.755
70.529
1.00
27.63
C

2966
CZ2
TRP
A
382
−17.125
−22.951
70.332
1.00
26.39
C

2967
CZ3
TRP
A
382
−16.668
−20.571
70.203
1.00
28.27
C

2968
CH2
TRP
A
382
−17.550
−21.668
70.107
1.00
29.91
C

2969
N
THR
A
383
−9.626
−20.419
69.570
1.00
20.79
N

2970
CA
THR
A
383
−8.426
−19.601
69.772
1.00
21.82
C

2971
C
THR
A
383
−8.000
−18.755
68.559
1.00
22.51
C

2972
O
THR
A
383
−7.276
−17.768
68.722
1.00
20.04
O

2973
CB
THR
A
383
−7.229
−20.444
70.268
1.00
20.62
C

2974
OG1
THR
A
383
−7.057
−21.586
69.423
1.00
22.89
O

2975
CG2
THR
A
383
−7.469
−20.904
71.711
1.00
21.21
C

2976
N
TRP
A
384
−8.418
−19.142
67.349
1.00
21.51
N

2977
CA
TRP
A
384
−8.115
−18.328
66.171
1.00
20.63
C

2978
C
TRP
A
384
−9.340
−17.417
66.173
1.00
21.11
C

2979
O
TRP
A
384
−10.403
−17.811
65.691
1.00
20.50
O

2980
CB
TRP
A
384
−8.086
−19.167
64.885
1.00
19.54
C

2981
CG
TRP
A
384
−7.622
−18.373
63.669
1.00
18.63
C

2982
OD1
TRP
A
384
−6.329
−18.062
63.333
1.00
20.48
C

2983
CD2
TRP
A
384
−8.453
−17.734
62.681
1.00
19.11
C

2984
NE1
TRP
A
384
−6.304
−17.269
62.202
1.00
19.46
N

2985
CE2
TRP
A
384
−7.591
−17.052
61.783
1.00
16.39
C

2986
CE3
TRP
A
384
−9.841
−17.670
62.468
1.00
16.64
C

2987
CZ2
TRP
A
384
−8.071
−16.318
60.698
1.00
17.11
C

2988
CZ3
TRP
A
384
−10.317
−16.937
61.384
1.00
17.59
C

2989
CH2
TRP
A
384
−9.432
−16.270
60.512
1.00
18.40
C

2990
N
ILE
A
385
−9.194
−16.208
66.719
1.00
20.98
N

2991
CA
ILE
A
385
−10.329
−15.300
66.855
1.00
19.97
C

2992
C
ILE
A
385
−10.225
−13.849
66.378
1.00
23.26
C

2993
O
ILE
A
385
−10.624
−12.934
67.104
1.00
22.91
O

2994
CB
ILE
A
385
−10.770
−15.258
68.321
1.00
18.38
C

2995
CG1
ILE
A
385
−9.563
−14.924
69.213
1.00
17.76
C

2996
CG2
ILE
A
385
−11.359
−16.610
68.716
1.00
17.47
C

2997
CD1
ILE
A
385
−9.904
−14.706
70.699
1.00
12.81
C

2998
N
PRO
A
386
−9.711
−13.614
65.154
1.00
23.16
N

2999
CA
PRO
A
386
−9.607
−12.232
64.673
1.00
22.41
C

3000
C
PRO
A
386
−11.010
−11.638
64.536
1.00
21.74
C

3001
O
PRO
A
386
−11.201
−10.431
64.673
1.00
22.41
O

3002
CB
PRO
A
386
−8.939
−12.377
63.301
1.00
23.49
C

3003
CG
PRO
A
386
−8.305
−13.754
63.327
1.00
25.10
C

3004
CD
PRO
A
386
−9.282
−14.569
64.118
1.00
25.12
C

3005
N
PHE
A
387
−11.984
−12.502
64.263
1.00
19.32
N

3006
CA
PHE
A
387
−13.376
−12.080
64.081
1.00
20.35
C

3007
C
PHE
A
387
−14.261
−12.432
65.279
1.00
19.82
C

3008
O
PHE
A
387
−15.484
−12.333
65.198
1.00
19.42
O

3009
CB
PHE
A
387
−13.983
−12.748
62.837
1.00
21.20
C

3010
CG
PHE
A
387
−13.436
−12.243
61.521
1.00
20.61
C

3011
CD1
PHE
A
387
−13.680
−10.938
61.102
1.00
20.50
C

3012
CD2
PHE
A
387
−12.751
−13.102
60.662
1.00
22.06
C

3013
CE1
PHE
A
387
−13.255
−10.493
59.837
1.00
19.72
C

3014
CE2
PHE
A
387
−12.322
−12.667
59.392
1.00
21.33
C

3015
CZ
PHE
A
387
−12.578
−11.360
58.984
1.00
17.69
C

3016
N
GLY
A
388
−13.649
−12.831
66.387
1.00
19.21
N

3017
CA
GLY
A
388
−14.430
−13.210
67.543
1.00
19.33
C

3018
C
GLY
A
388
−14.940
−14.608
67.270
1.00
21.40
C

3019
O
GLY
A
388
−14.436
−15.277
66.370
1.00
22.79
O

3020
N
ALA
A
389
−15.940
−15.052
68.022
1.00
21.76
N

3021
CA
ALA
A
389
−16.490
−16.388
67.826
1.00
23.48
C

3022
C
ALA
A
389
−17.823
−16.538
68.562
1.00
25.26
C

3023
O
ALA
A
389
−18.211
−15.668
69.343
1.00
25.75
O

3024
CB
ALA
A
389
−15.486
−17.443
68.318
1.00
18.05
C

3025
N
GLY
A
390
−18.523
−17.636
68.292
1.00
27.27
N

3026
CA
GLY
A
390
−19.794
−17.891
68.940
1.00
30.25
C

3027
C
GLY
A
390
−20.878
−16.855
68.718
1.00
33.72
C

3028
O
GLY
A
390
−20.995
−16.275
67.642
1.00
34.75
O

3029
N
ARG
A
391
−21.667
−16.630
69.765
1.00
36.92
N

3030
CA
ARG
A
391
−22.791
−15.696
69.770
1.00
39.45
C

3031
C
ARG
A
391
−22.552
−14.335
69.102
1.00
39.38
C

3032
O
ARG
A
391
−23.372
−13.889
68.297
1.00
39.85
O

3033
CB
ARG
A
391
−23.254
−15.488
71.220
1.00
42.74
C

3034
CG
ARG
A
391
−24.571
−14.756
71.401
1.00
47.57
C

3035
CD
ARG
A
391
−25.715
−15.524
70.765
1.00
52.36
C

3036
NE
ARO
A
391
−25.728
−16.925
71.177
1.00
56.12
N

3037
CZ
ARG
A
391
−25.952
−17.342
72.418
1.00
56.89
C

3038
NH1
ARG
A
391
−26.187
−16.464
73.381
1.00
59.32
N

3039
NH2
ARG
A
391
−25.946
−18.638
72.694
1.00
57.42
N

3040
N
HIS
A
392
−21.442
−13.679
69.431
1.00
38.64
N

3041
CA
HIS
A
392
−21.138
−12.361
68.869
1.00
37.75
C

3042
C
HIS
A
392
−20.126
−12.351
67.720
1.00
35.96
C

3043
O
HIS
A
392
−19.507
−11.322
67.432
1.00
34.80
O

3044
CB
HIS
A
392
−20.670
−11.418
69.981
1.00
39.84
C

3045
CG
HIS
A
392
−21.724
−11.132
71.006
1.00
43.30
C

3046
ND1
HIS
A
392
−22.896
−10.471
70.704
1.00
44.80
N

3047
CD2
HIS
A
392
−21.797
−11.445
72.321
1.00
44.42
C

3048
CE1
HIS
A
392
−23.646
−10.390
71.788
1.00
43.99
C

3049
NE2
HIS
A
392
−23.002
−1 0.973
72.7831.00
46.25
N

3050
N
ARG
A
393
−19.976
−13.498
67.065
1.00
33.15
N

3051
CA
ARG
A
393
−19.074
−13.651
65.918
1.00
32.68
C

3052
C
ARG
A
393
−19.308
−12.479
64.947
1.00
29.84
C

3053
O
ARG
A
393
−20.451
−12.087
64.714
1.00
28.47
O

3054
CB
ARG
A
393
−19.387
−14.995
65.235
1.00
34.20
C

3055
CG
ARG
A
393
−18.588
−15.330
63.983
1.00
41.19
C

3056
CD
ARG
A
393
−17.112
−15.570
64.271
1.00
44.14
C

3057
NE
ARG
A
393
−16.400
−16.166
63.138
1.00
46.12
N

3058
CZ
ARG
A
393
−16.438
−15.704
61.887
1.00
48.39
C

3059
NH1
ARG
A
393
−17.167
−14.635
61.582
1.00
47.15
N

3060
NH2
ARG
A
393
−15.714
−16.294
60.941
1.00
48.01
N

3061
N
CYS
A
394
−18.238
−11.915
64.389
1.00
27.11
N

3062
CA
CYS
A
394
−18.385
−10.795
63.458
1.00
25.39
C

3063
C
CYS
A
394
−19.320
−11.138
62.306
1.00
26.72
C

3064
O
CYS
A
394
−18.984
−11.967
61.460
1.00
28.24
O

3065
CB
CYS
A
394
−17.034
−10.385
62.881
1.00
21.76
C

3066
SG
CYS
A
394
−17.144
−9.018
61.692
1.00
19.36
S

3067
N
VAL
A
395
−20.488
−10.501
62.265
1.00
27.10
N

3068
CA
VAL
A
395
−21.446
−10.772
61.196
1.00
28.26
C

3069
C
VAL
A
395
−21.008
−10.108
59.890
1.00
27.95
C

3070
O
VAL
A
395
−21.561
−10.389
58.821
1.00
26.94
O

3071
CB
VAL
A
395
−22.871
−10.272
61.553
1.00
29.21
C

3072
CG1
VAL
A
395
−23.341
−10.913
62.840
1.00
27.69
C

3073
CG2
VAL
A
395
−22.884
−8.763
61.671
1.00
28.27
C

3074
N
GLY
A
396
−20.012
−9.228
59.981
1.00
26.28
N

3075
CA
GLY
A
396
−19.519
−8.556
58.792
1.00
25.16
C

3076
C
GLY
A
396
−18.294
−9.218
58.187
1.00
24.08
C

3077
O
GLY
A
396
−17.725
−8.706
57.224
1.00
26.37
O

3078
N
ALA
A
397
−17.885
−10.358
58.735
1.00
21.72
N

3079
CA
ALA
A
397
−16.705
−11.059
58.237
1.00
22.02
C

3080
C
ALA
A
397
−16.683
−11.219
56.719
1.00
20.89
C

3081
O
ALA
A
397
−15.711
−10.841
56.057
1.00
21.86
O

3082
CB
ALA
A
397
−16.591
−12.420
58.905
1.00
21.75
C

3083
N
ALA
A
398
−17.755
−11.781
56.175
1.00
21.01
N

3084
CA
ALA
A
398
−17.874
−12.011
54.740
1.00
21.49
C

3085
C
ALA
A
398
−17.653
−10.753
53.912
1.00
20.76
C

3086
O
ALA
A
398
−16.993
−10.796
52.876
1.00
22.05
O

3087
CB
ALA
A
398
−19.241
−12.612
54.419
1.00
18.60
C

3088
N
PHE
A
399
−18.219
−9.637
54.356
1.00
22.37
N

3089
CA
PHE
A
399
−18.068
−8.368
53.647
1.00
21.41
C

3090
C
PHE
A
399
−16.627
−7.886
53.770
1.00
21.01
C

3091
O
PHE
A
399
−16.014
−7.465
52.784
1.00
19.00
O

3092
CB
PHE
A
399
−19.011
−7.320
54.243
1.00
23.87
C

3093
CG
PHE
A
399
−18.871
−5.945
53.633
1.00
25.54
C

3094
CD1
PHE
A
399
−17.834
−5.099
54.019
1.00
25.16
C

3095
CD2
PHE
A
399
−19.787
−5.492
52.690
1.00
25.70
C

3096
CE1
PHE
A
399
−17.714
−3.828
53.478
1.00
26.72
C

3097
CE2
PHE
A
399
−19.675
−4.214
52.141
1.00
25.69
C

3098
CZ
PHE
A
399
−18.640
−3.382
52.534
1.00
26.84
C

3099
N
ALA
A
400
−16.089
−7.949
54.988
1.00
20.11
N

3100
CA
ALA
A
400
−14.717
−7.514
55.243
1.00
18.29
C

3101
C
ALA
A
400
−13.737
−8.229
54.323
1.00
17.49
C

3102
O
ALA
A
400
−12.826
−7.610
53.774
1.00
17.22
O

3103
CB
ALA
A
400
−14.351
−7.777
56.692
1.00
18.87
C

3104
N
ILE
A
401
−13.934
−9.534
54.160
1.00
17.49
N

3105
CA
ILE
A
401
−13.068
−10.352
53.319
1.00
18.23
C

3106
C
ILE
A
401
−13.260
−10.021
51.852
1.00
20.62
C

3107
O
ILE
A
401
−12.290
−9.970
51.077
1.00
19.49
O

3108
CB
ILE
A
401
−13.335
−11.858
53.564
1.00
18.92
C

3109
CG1
WE
A
401
−12.756
−12.252
54.935
1.00
19.49
C

3110
CG2
WE
A
401
−12.737
−12.698
52.423
1.00
17.26
C

3111
CD1
ILE
A
401
−13.211
−13.611
55.468
1.00
18.79
C

3112
N
MET
A
402
−14.512
−9.784
51.471
1.00
19.99
N

3113
CA
MET
A
402
−14.814
−9.437
50.102
1.00
19.58
C

3114
C
MET
A
402
−14.140
−8.099
49.809
1.00
21.25
C

3115
O
MET
A
402
−13.554
−7.899
48.732
1.00
21.85
O

3116
CB
MET
A
402
−16.336
−9.353
49.920
1.00
20.93
C

3117
CG
MET
A
402
−16.807
−8.810
48.583
1.00
21.11
C

3118
SD
MET
A
402
−16.597
−7.024
48.437
1.00
22.97
S

3119
CE
MET
A
402
−17.846
−6.429
49.609
1.00
23.27
C

3120
N
GLN
A
403
−14.193
−7.183
50.775
1.00
20.82
N

3121
CA
GLN
A
403
−13.583
−5.870
50.580
1.00
21.71
C

3122
C
GLN
A
403
−12.079
−5.962
50.355
1.00
21.93
C

3123
O
GLN
A
403
−11.527
−5.244
49.519
1.00
22.08
O

3124
CB
GLN
A
403
−13.872
−4.958
51.771
1.00
22.28
C

3125
CG
GLN
A
403
−13.224
−3.585
51.664
1.00
22.64
C

3126
CD
GLN
A
403
−13.750
−2.621
52.701
1.00
25.01
C

3127
OE1
GLN
A
403
−13.130
−1.606
52.990
1.00
31.15
O

3128
NE2
GLN
A
403
−14.905
−2.928
53.260
1.00
28.19
N

3129
N
ILE
A
404
−11.418
−6.842
51.104
1.00
23.18
N

3130
CA
ILE
A
404
−9.974
−7.040
50.969
1.00
21.34
C

3131
C
ILE
A
404
−9.675
−7.603
49.582
1.00
21.62
C

3132
O
ILE
A
404
−8.769
−7.132
48.887
1.00
22.23
O

3133
CB
ILE
A
404
−9.435
−8.007
52.068
1.00
19.46
C

3134
OG1
ILE
A
404
−9.428
−7.299
53.425
1.00
17.90
C

3135
CG2
ILE
A
404
−8.037
−8.484
51.727
1.00
17.45
C

3136
CD1
ILE
A
404
−8.451
−6.118
53.525
1.00
12.12
C

3137
N
LYS
A
405
−10.440
−8.605
49.166
1.00
21.87
N

3138
CA
LYS
A
405
−10.231
−9.180
47.844
1.00
20.38
C

3139
C
LYS
A
405
−10.405
−8.107
46.782
1.00
19.88
C

3140
O
LYS
A
405
−9.603
−8.008
45.864
1.00
20.77
O

3141
CB
LYS
A
405
−11.222
−10.307
47.573
1.00
21.12
C

3142
CG
LYS
A
405
−11.043
−11.554
48.431
1.00
23.74
C

3143
CD
LYS
A
405
−12.095
−12.579
48.032
1.00
26.10
C

3144
CE
LYS
A
405
−11.878
−13.911
48.707
1.00
28.07
C

3145
NZ
LYS
A
405
−13.013
−14.822
48.398
1.00
28.73
N

3146
N
ALA
A
406
−11.459
−7.306
46.905
1.00
18.69
N

3147
CA
ALA
A
406
−11.727
−6.247
45.936
1.00
19.74
C

3148
C
ALA
A
406
−10.614
−5.192
45.861
1.00
20.54
C

3149
O
ALA
A
406
−10.112
−4.877
44.779
1.00
20.55
O

3150
CB
ALA
A
406
−13.071
−5.574
46.259
1.00
16.98
C

3151
N
ILE
A
407
−10.229
−4.649
47.012
1.00
21.74
N

3152
CA
ILE
A
407
−9.189
−3.624
47.064
1.00
20.88
C

3153
C
ILE
A
407
−7.860
−4.112
46.506
1.00
20.86
C

3154
O
ILE
A
407
−7.237
−3.448
45.667
1.00
17.68
O

3155
CB
ILE
A
407
−8.962
−3.139
48.507
1.00
22.52
C

3156
CG1
ILE
A
407
−10.190
−2.368
48.992
1.00
22.73
C

3157
CG2
ILE
A
407
−7.704
−2.271
48.588
1.00
21.36
C

3158
CD1
ILE
A
407
−10.113
−2.005
50.478
1.00
24.66
C

3159
N
PHE
A
408
−7.411
−5.274
46.955
1.00
19.80
N

3160
CA
PHE
A
408
−6.142
−5.750
46.448
1.00
20.76
C

3161
C
PHE
A
408
−6.152
−6.253
45.007
1.00
20.34
C

3162
O
PHE
A
408
−5.107
−6.263
44.345
1.00
19.91
O

3163
CB
PHE
A
408
−5.538
−6.752
47.431
1.00
20.97
C

3164
CG
PHE
A
408
−4.972
−6.089
48.657
1.00
20.82
C

3165
CD1
PHE
A
408
−3.655
−5.625
48.665
1.00
24.19
C

3166
CD2
PHE
A
408
−5.772
−5.846
49.767
1.00
22.25
C

3167
CE1
PHE
A
408
−3.141
−4.922
49.763
1.00
24.00
C

3168
CE2
PHE
A
408
−5.274
−5.146
50.874
1.00
24.20
C

3169
CZ
PHE
A
408
−3.957
−4.681
50.870
1.00
24.18
C

3170
N
SER
A
409
−7.330
−6.622
44.504
1.00
21.19
N

3171
CA
SER
A
409
−7.463
−7.071
43.113
1.00
21.01
C

3172
C
SER
A
409
−7.155
−5.882
42.202
1.00
21.03
C

3173
O
SER
A
409
−6.661
−6.045
41.082
1.00
19.33
O

3174
CB
SER
A
409
−8.887
−7.564
42.831
1.00
20.98
C

3175
OG
SER
A
409
−9.111
−8.859
43.384
1.00
21.64
O

3176
N
VAL
A
410
−7.463
−4.682
42.691
1.00
20.33
N

3177
CA
VAL
A
410
−7.206
−3.459
41.937
1.00
19.88
C

3178
C
VAL
A
410
−5.770
−2.976
42.172
1.00
19.81
C

3179
O
VAL
A
410
−5.007
−2.786
41.227
1.00
19.01
O

3180
CB
VAL
A
410
−8.203
−2.341
42.342
1.00
21.12
C

3181
OG1
VAL
A
410
−7.849
−1.032
41.645
1.00
20.77
C

3182
CG2
VAL
A
410
−9.637
−2.763
41.971
1.00
20.45
C

3183
N
LEU
A
411
−5.395
−2.798
43.432
1.00
20.05
N

3184
CA
LEU
A
411
−4.051
−2.331
43.767
1.00
22.35
C

3185
C
LW
A
411
−2.882
−3.204
43.267
1.00
23.46
C

3186
O
LEU
A
411
−1.958
−2.710
42.618
1.00
25.34
O

3187
CB
LEU
A
411
−3.909
−2.164
45.288
1.00
18.93
C

3188
CG
LEU
A
411
−4.675
−1.057
46.014
1.00
20.02
C

3189
CD1
LEU
A
411
−4.304
−1.062
47.496
1.00
14.26
C

3190
CD2
LEU
A
411
−4.347
0.279
45.395
1.00
17.57
C

3191
N
LEU
A
412
−2.909
−4.496
43.560
1.00
22.58
N

3192
CA
LEU
A
412
−1.786
−5.328
43.156
1.00
22.76
C

3193
C
LEU
A
412
−1.644
−5.571
41.664
1.00
22.73
C

3194
O
LEU
A
412
−0.584
−5.993
41.205
1.00
21.47
O

3195
CB
LEU
A
412
−1.813
−6.654
43.912
1.00
22.69
C

3196
CG
LEU
A
412
−1.885
−6.517
45.437
1.00
21.86
C

3197
CD1
LEU
A
412
−1.697
−7.887
46.064
1.00
24.51
C

3198
CD2
LEU
A
412
−0.834
−5.562
45.948
1.00
22.28
C

3199
N
ARG
A
413
−2.696
−5.301
40.899
1.00
24.45
N

3200
CA
ARG
A
413
−2.623
−5.491
39.451
1.00
26.24
C

3201
C
ARO
A
413
−2.234
−4.218
38.703
1.00
26.47
C

3202
O
ARG
A
413
−1.815
−4.279
37.550
1.00
27.30
O

3203
CB
ARG
A
413
−3.955
−6.013
38.899
1.00
27.80
C

3204
CG
ARG
A
413
−4.119
−7.529
38.985
1.00
28.38
C

3205
CD
ARG
A
413
−5.303
−7.971
38.147
1.00
31.19
C

3206
NE
ARG
A
413
−6.513
−7.254
38.545
1.00
34.34
N

3207
CZ
ARG
A
413
−7.547
−7.019
37.740
1.00
33.59
C

3208
NH1
ARG
A
413
−7.525
−7.444
36.484
1.00
34.00
N

3209
NH2
ARG
A
413
−8.597
−6.345
38.189
1.00
35.03
N

3210
N
GLU
A
414
−2.360
−3.068
39.362
1.00
27.73
N

3211
CA
GLU
A
414
−2.026
−1.788
38.739
1.00
26.36
C

3212
C
GLU
A
414
−0.658
−1.281
39.190
1.00
25.87
C

3213
O
GLU
A
414
0.097
−0.732
38.391
1.00
25.32
O

3214
CB
GLU
A
414
−3.089
−0.735
39.081
1.00
27.02
C

3215
CG
GLU
A
414
−4.523
−1.125
38.732
1.00
28.51
C

3216
CD
GLU
A
414
−4.864
−0.972
37.258
1.00
29.96
C

3217
OE1
GLU
A
414
−4.062
−0.383
36.500
1.00
29.11
O

3218
OE2
GLU
A
414
−5.954
−1.441
36.860
1.00
31.34
O

3219
N
TYR
A
415
−0.340
−1.474
40.468
1.00
25.27
N

3220
CA
TYR
A
415
0.929
−1.005
41.005
1.00
25.00
C

3221
C
TYR
A
415
1.703
−2.059
41.778
1.00
26.23
C

3222
O
TYR
A
415
1.151
−3.089
42.167
1.00
25.50
O

3223
CB
TYR
A
415
0.694
0.205
41.925
1.00
24.38
C

3224
CG
TYR
A
415
0.247
1.461
41.204
1.00
25.17
C

3225
CD1
TYR
A
415
−1.083
1.632
40.800
1.00
25.62
C

3226
CD2
TYR
A
415
1.164
2.462
40.892
1.00
24.90
C

3227
CE1
TYR
A
415
−1.482
2.779
40.095
1.00
26.47
C

3228
CE2
TYR
A
415
0.784
3.607
40.191
1.00
26.89
C

3229
CZ
TYR
A
415
−0.534
3.760
39.794
1.00
27.13
C

3230
OH
TYR
A
415
−0.885
4.883
39.085
1.00
26.25
O

3231
N
GLU
A
416
2.993
−1.786
41.978
1.00
26.62
N

3232
CA
GLU
A
416
3.896
−2.640
42.747
1.00
27.85
C

3233
C
GLU
A
416
4.175
−1.814
43.989
1.00
27.21
C

3234
O
GLU
A
416
4.225
−0.585
43.907
1.00
27.53
O

3235
CB
GLU
A
416
5.241
−2.825
42.057
1.00
30.39
C

3236
OG
GLU
A
416
5.264
−3.545
40.750
1.00
37.76
C

3237
CD
GLU
A
416
6.666
−3.499
40.154
1.00
43.05
C

3238
OE1
GLU
A
416
7.626
−3.765
40.917
1.00
46.16
O

3239
OE2
GLU
A
416
6.816
−3.196
38.944
1.00
41.83
O

3240
N
PHE
A
417
4.387
−2.469
45.125
1.00
25.74
N

3241
CA
PHE
A
417
4.665
−1.734
46.357
1.00
23.86
C

3242
C
PHE
A
417
5.929
−2.195
47.042
1.00
23.41
C

3243
O
PHE
A
417
6.227
−3.391
47.084
1.00
24.14
O

3244
CS
PHE
A
417
3.504
−1.852
47.351
1.00
20.93
C

3245
CG
PHE
A
417
2.192
−1.393
46.799
1.00
20.74
C

3246
CD1
PHE
A
417
1.416
−2.244
46.022
1.00
17.57
C

3247
CD2
PHE
A
417
1.751
−0.092
47.016
1.00
18.60
C

3248
CE1
PHE
A
417
0.219
−1.803
45.466
1.00
18.27
C

3249
CE2
PHE
A
417
0.555
0.354
46.463
1.00
19.72
C

3250
CZ
PHE
A
417
−0.211
−0.503
45.686
1.00
18.76
C

3251
N
GLU
A
418
6.665
−1.225
47.580
1.00
21.95
N

3252
CA
GLU
A
418
7.895
−1.485
48.312
1.00
22.04
C

3253
C
GLU
A
418
7.853
−0.661
49.583
1.00
21.50
C

3254
O
GLU
A
418
7.305
0.449
49.599
1.00
19.28
O

3255
CS
GLU
A
418
9.114
−1.066
47.498
1.00
26.16
C

3256
CG
GLU
A
418
9.655
−2.132
46.585
1.00
32.80
C

3257
CD
GLU
A
418
10.806
−1.618
45.752
1.00
36.64
C

3258
OE1
GLU
A
418
11.653
−0.870
46.304
1.00
38.55
O

3259
OE2
GLU
A
418
10.866
−1.964
44.552
1.00
37.36
O

3260
N
MET
A
419
8.418
−1.202
50.655
1.00
20.09
N

3261
CA
MET
A
419
8.449
−0.470
51.904
1.00
21.21
C

3262
C
MET
A
419
9.453
0.668
51.760
1.00
21.56
C

3263
O
MET
A
419
10.508
0.491
51.157
1.00
19.51
O

3264
CS
MET
A
419
8.852
−1.400
53.037
1.00
22.06
C

3265
CG
MET
A
419
7.810
−2.459
53.315
1.00
23.58
C

3266
SD
MET
A
419
8.394
−3.609
54.537
1.00
24.66
S

3267
CE
MET
A
419
9.575
−4.548
53.496
1.00
22.98
C

3268
N
ALA
A
420
9.113
1.838
52.299
1.00
23.73
N

3269
CA
ALA
A
420
9.989
3.002
52.225
1.00
24.45
C

3270
C
ALA
A
420
10.671
3.268
53.570
1.00
24.58
C

3271
O
ALA
A
420
11.308
4.301
53.771
1.00
24.49
O

3272
CB
ALA
A
420
9.195
4.225
51.766
1.00
24.78
C

3273
N
GLN
A
421
10.529
2.327
54.493
1.00
24.78
N

3274
CA
GLN
A
421
11.157
2.441
55.798
1.00
26.15
C

3275
C
GLN
A
421
11.411
1.023
56.302
1.00
27.98
C

3276
O
GLN
A
421
10.810
0.070
55.796
1.00
27.89
O

3277
CB
GLN
A
421
10.270
3.245
56.759
1.00
27.22
C

3278
CG
GLN
A
421
8.859
2.724
56.968
1.00
27.16
C

3279
CD
GLN
A
421
8.011
3.691 57.784
1.00
26.59
C

3280
OE1
GLN
A
421
7.723
4.804
57.342
1.00
26.24
O

3261
NE2
GLN
A
421
7.614
3.272
58.982
1.00
26.44
N

3282
N
PRO
A
422
12.320
0.855
57.282
1.00
28.43
N

3283
CA
PRO
A
422
12.614
−0.482
57.804
1.00
29.12
C

3284
C
PRO
A
422
11.348
−1.302
58.060
1.00
29.42
C

3285
O
PRO
A
422
10.367
−0.796
58.592
1.00
29.97
O

3286
CB
PRO
A
422
13.389
−0.190
59.089
1.00
29.49
C

3287
CG
PRO
A
422
14.102
1.081
58.759
1.00
28.74
C

3288
CD
PRO
A
422
13.025
1.885
58.067
1.00
30.13
C

3289
N
PRO
A
423
11.360
−2.582
57.669
1.00
29.44
N

3290
CA
PRO
A
423
10.229
−3.502
57.840
1.00
29.80
C

3291
C
PRO
A
423
9.686
−3.569
59.262
1.00
30.01
C

3292
O
PRO
A
423
8.491
−3.804
59.467
1.00
30.37
O

3293
CB
PRO
A
423
10.810
−4.839
57.396
1.00
30.66
C

3294
CG
PRO
A
423
11.799
−4.429
56.334
1.00
32.89
C

3295
CD
PRO
A
423
12.471
−3.235
56.953
1.00
29.05
C

3296
N
GLU
A
424
10.567
−3.366
60.239
1.00
29.84
N

3297
CA
GLU
A
424
10.188
−3.437
61.647
1.00
30.90
C

3298
C
GLU
A
424
9.636
−2.120
62.166
1.00
30.60
C

3299
O
GLU
A
424
9.100
−2.052
63.277
1.00
30.00
O

3300
CB
GLU
A
424
11.389
−3.838
62.516
1.00
33.46
C

3301
CG
GLU
A
424
12.101
−5.120
62.108
1.00
34.83
C

3302
CD
GLU
A
424
12.933
−4.953
60.846
1.00
38.37
C

3303
OE1
GLU
A
424
13.169
−3.793
60.428
1.00
36.82
O

3304
OE2
GLU
A
424
13.363
−5.983
60.279
1.00
40.20
O

3305
N
SER
A
425
9.767
−1.069
61.368
1.00
28.64
N

3306
CA
SER
A
425
9.278
0.233
61.791
1.00
28.65
C

3307
C
SER
A
425
7.762
0.337
61.731
1.00
27.35
C

3308
O
SER
A
425
7.190
1.228
62.339
1.00
29.43
O

3309
CB
SER
A
425
9.889
1.330
60.925
1.00
28.46
C

3310
OG
SER
A
425
9.365
1.256
59.613
1.00
31.88
O

3311
N
TYR
A
426
7.101
−0.557
61.002
1.00
26.92
N

3312
CA
TYR
A
426
5.647
−0.480
60.913
1.00
27.04
C

3313
C
TYR
A
426
5.047
−1.079
62.163
1.00
27.93
C

3314
O
TYR
A
426
5.367
−2.204
62.539
1.00
29.34
O

3315
CB
TYR
A
426
5.120
−1.211
59.673
1.00
27.44
C

3316
CG
TYR
A
426
5.663
−0.676
58.363
1.00
25.26
C

3317
CD1
TYR
A
426
6.930
−1.047
57.914
1.00
24.98
C

3318
CD2
TYR
A
426
4.920
0.212
57.581
1.00
24.54
C

3319
CE1
TYR
A
426
7.451
−0.550
56.721
1.00
26.72
C

3320
CE2
TYR
A
426
5.435
0.721
56.373
1.00
23.74
C

3321
CZ
TYR
A
426
6.705
0.330
55.954
1.00
25.58
C

3322
OH
TYR
A
426
7.250
0.813
54.781
1.00
26.10
O

3323
N
ARG
A
427
4.166
−0.325
62.807
1.00
29.20
N

3324
CA
ARG
A
427
3.555
−0.782
64.047
1.00
28.80
C

3325
C
ARG
A
427
2.201
−0.127
64.297
1.00
27.01
C

3326
O
ARG
A
427
1.823
0.834
63.630
1.00
27.16
O

3327
CB
ARG
A
427
4.486
−0.448
65.209
1.00
31.15
C

3328
CG
ARG
A
427
4.614
1.051
65.426
1.00
36.46
C

3329
CD
ARG
A
427
5.562
1.392
66.553
1.00
39.99
C

3330
NE
ARG
A
427
5.571
2.829
66.820
1.00
44.75
N

3331
CZ
ARG
A
427
4.586
3.485
67.433
1.00
46.56
C

3332
NH1
ARG
A
427
3.504
2.834
67.853
1.00
46.46
N

3333
NH2
ARG
A
427
4.681
4.795
67.625
1.00
47.43
N

3334
N
ASN
A
428
1.476
−0.655
65.271
1.00
26.04
N

3335
CA
ASN
A
428
0.180
−0.106
65.631
1.00
26.96
C

3336
C
ASN
A
428
0.338
0.848
66.808
1.00
27.78
C

3337
O
ASN
A
428
1.324
0.794
67.551
1.00
25.90
O

3338
CB
ASN
A
428
−0.773
−1.225
66.064
1.00
28.95
C

3339
CG
ASN
A
428
−1.501
−1.864
64.908
1.00
29.54
C

3340
OD1
ASN
A
428
−1.913
−3.025
64.993
1.00
32.60
O

3341
ND2
ASN
A
428
−1.686
−1.115
63.831
1.00
27.61
N

3342
N
ASP
A
429
−0.644
1.726
66.964
1.00
28.61
N

3343
CA
ASP
A
429
−0.682
2.641
68.088
1.00
27.70
C

3344
C
ASP
A
429
−1.757
1.994
68.968
1.00
29.04
C

3345
O
ASP
A
429
−2.942
1.976
68.602
1.00
26.28
O

3346
CB
ASP
A
429
−1.142
4.028
67.643
1.00
30.33
C

3347
CG
ASP
A
429
−1.286
4.997
68.807
1.00
30.88
C

3348
OD1
ASP
A
429
−1.517
4.535
69.944
1.00
32.76
O

3349
OD2
ASP
A
429
−1.186
6.222
68.586
1.00
30.50
O

3350
N
HIS
A
430
−1.345
1.427
70.098
1.00
29.45
N

3351
CA
HIS
A
430
−2.291
0.788
71.006
1.00
30.15
C

3352
C
HIS
A
430
−2.625
1.693
72.192
1.00
30.98
C

3353
O
HIS
A
430
−3.087
1.213
73.232
1.00
31.06
O

3354
CB
HIS
A
430
−1.733
−0.539
71.540
1.00
30.54
C

3355
CG
HIS
A
430
−1.489
−1.574
70.488
1.00
31.02
C

3356
ND1
HIS
A
430
−0.222
−1.915
70.061
1.00
33.42
N

3357
CD2
HIS
A
430
−2.345
−2.358
69.788
1.00
31.31
C

3358
CE1
HIS
A
430
−0.308
−2.864
69.144
1.00
32.70
C

3359
NE2
HIS
A
430
−1.585
−3.151
68.960
1.00
32.28
N

3360
N
SER
A
431
−2.402
2.997
72.044
1.00
31.38
N

3361
CA
SER
A
431
−2.688
3.932
73.136
1.00
31.67
C

3362
C
SER
A
431
−4.183
4.184
73.324
1.00
31.13
C

3363
O
SER
A
431
−4.588
4.752
74.336
1.00
33.49
O

3364
CB
SER
A
431
−1.971
5.276
72.909
1.00
32.28
C

3365
OG
SER
A
431
−2.579
6.034
71.874
1.00
31.36
O

3366
N
LYS
A
432
−4.998
3.760
72.358
1.00
29.52
N

3367
CA
LYS
A
432
−6.447
3.956
72.428
1.00
28.00
C

3368
C
LYS
A
432
−7.190
2.626
72.289
1.00
28.23
C

3369
O
LYS
A
432
−6.666
1.673
71.709
1.00
27.43
O

3370
CB
LYS
A
432
−6.906
4.910
71.315
1.00
26.82
C

3371
CG
LYS
A
432
−6.254
6.291
71.343
1.00
24.94
C

3372
CD
LYS
A
432
−6.624
7.057
72.616
1.00
26.70
C

3373
CE
LYS
A
432
−6.081
8.486
72.613
1.00
24.26
C

3374
NZ
LYS
A
432
−4.591
8.550
72.571
1.00
24.61
N

3375
N
MET
A
433
−8.408
2.558
72.816
1.00
27.75
N

3376
CA
MET
A
433
−9.191
1.333
72.711
1.00
28.93
C

3377
C
MET
A
433
−9.415
1.009
71.237
1.00
29.03
C

3378
O
MET
A
433
−9.638
−0.145
70.860
1.00
28.63
O

3379
CB
MET
A
433
−10.544
1.481
73.423
1.00
29.30
C

3380
CG
MET
A
433
−10.451
1.534
74.954
1.00
29.49
C

3381
SD
MET
A
433
−9.433
0.194
75.679
1.00
30.12
S

3382
CE
MET
A
433
−10.442
−1.289
75.252
1.00
27.58
C

3383
N
VAL
A
434
−9.364
2.041
70.405
1.00
28.02
N

3384
CA
VAL
A
434
−9.538
1.864
68.977
1.00
28.23
C

3385
C
VAL
A
434
−8.138
1.853
68.374
1.00
29.18
C

3386
O
VAL
A
434
−7.496
2.897
68.229
1.00
28.22
O

3387
CB
VAL
A
434
−10.388
3.007
68.381
1.00
29.12
C

3388
CG1
VAL
A
434
−10.514
2.858
66.866
1.00
30.00
C

3389
CG2
VAL
A
434
−11.759
2.988
69.013
1.00
26.92
C

3390
N
VAL
A
435
−7.664
0.652
68.053
1.00
29.78
N

3391
CA
VAL
A
435
−6.339
0.472
67.480
1.00
30.28
C

3392
C
VAL
A
435
−6.221
1.112
66.105
1.00
30.88
C

3393
O
VAL
A
435
−7.104
0.980
65.254
1.00
31.29
O

3394
CB
VAL
A
435
−5.975
−1.029
67.368
1.00
30.98
C

3395
CG1
VAL
A
435
−4.569
−1.187
66.818
1.00
30.02
C

3396
CG2
VAL
A
435
−6.072
−1.689
68.735
1.00
30.70
C

3397
N
GLN
A
436
−5.109
1.808
65.906
1.00
31.66
N

3398
CA
GLN
A
436
−4.818
2.488
64.655
1.00
31.26
C

3399
C
GLN
A
436
−3.390
2.149
64.272
1.00
30.78
C

3400
O
GLN
A
436
−2.549
1.888
65.132
1.00
30.71
O

3401
CB
GLN
A
436
−4.912
4.005
64.840
1.00
33.84
C

3402
CG
GLN
A
436
−6.256
4.503
65.318
1.00
35.40
C

3403
CD
GLN
A
436
−7.201
4.737
64.174
1.00
38.53
C

3404
OE1
GLN
A
436
−7.116
4.071
63.136
1.00
38.53
O

3405
NE2
GLN
A
436
−8.124
5.679
64.354
1.00
41.19
N

3406
N
LEU
A
437
−3.119
2.150
62.977
1.00
29.30
N

3407
CA
LEU
A
437
−1.774
1.904
62.503
1.00
28.39
C

3408
C
LEU
A
437
−1.020
3.176
62.894
1.00
29.29
C

3409
O
LEU
A
437
−1.572
4.277
62.818
1.00
30.36
O

3410
CB
LEU
A
437
−1.776
1.741
60.981
1.00
25.82
C

3411
CG
LEU
A
437
−0.414
1.557
60.315
1.00
25.86
C

3412
CD1
LEU
A
437
0.170
0.194
60.688
1.00
24.95
C

3413
CD2
LEU
A
437
−0.573
1.696
58.807
1.00
22.10
C

3414
N
ALA
A
438
0.226
3.036
63.326
1.00
28.78
N

3415
CA
ALA
A
438
1.013
4.198
63.714
1.00
28.44
C

3416
C
ALA
A
438
1.694
4.816
62.494
1.00
27.92
C

3417
O
ALA
A
438
1.895
4.157
61.472
1.00
30.06
O

3418
CB
ALA
A
438
2.061
3.798
64.752
1.00
27.23
C

3419
N
GLN
A
439
2.045
6.088
62.601
1.00
27.52
N

3420
CA
GLN
A
439
2.722
6.772
61.509
1.00
26.77
C

3421
C
GLN
A
439
4.126
7.153
61.984
1.00
26.31
C

3422
O
GLN
A
439
4.356
7.333
63.182
1.00
26.35
O

3423
CB
GLN
A
439
1.924
8.014
61.090
1.00
26.10
C

3424
CG
GLN
A
439
0.553
7.675
60.502
1.00
25.95
C

3425
CD
GLN
A
439
−0.268
8.905
60.149
1.00
26.96
C

3426
OE1
GLN
A
439
−0.611
9.709
61.021
1.00
28.97
O

3427
NE2
GLN
A
439
−0.591
9.055
58.867
1.00
20.73
N

3428
N
PRO
A
440
5.085
7.279
61.054
1.00
25.72
N

3429
CA
PRO
A
440
4.919
7.090
59.613
1.00
25.38
C

3430
C
PRO
A
440
4.751
5.633
59.193
1.00
25.22
C

3431
O
PRO
A
440
5.176
4.710
59.897
1.00
22.31
O

3432
CB
PRO
A
440
6.194
7.706
59.045
1.00
25.71
C

3433
CG
PRO
A
440
7.205
7.345
60.074
1.00
25.95
C

3434
CD
PRO
A
440
6.475
7.657
61.370
1.00
26.00
C

3435
N
ALA
A
441
4.126
5.453
58.034
1.00
23.48
N

3436
CA
ALA
A
441
3.892
4.146
57.444
1.00
23.80
C

3437
C
ALA
A
441
4.030
4.379
55.949
1.00
24.43
C

3438
O
ALA
A
441
3.084
4.175
55.181
1.00
24.24
O

3439
CB
ALA
A
441
2.490
3.659
57.779
1.00
23.58
C

3440
N
CYS
A
442
5.218
4.809
55.541
1.00
24.42
N

3441
CA
CYS
A
442
5.475
5.119
54.143
1.00
26.22
C

3442
C
CYS
A
442
5.784
3.932
53.235
1.00
25.75
C

3443
O
CYS
A
442
6.560
3.029
53.585
1.00
26.49
O

3444
CB
CYS
A
442
6.590
6.162
54.065
1.00
28.80
C

3445
SG
CYS
A
442
6.234
7.618
55.109
1.00
37.47
S

3446
N
VAL
A
443
5.178
3.966
52.051
1.00
24.21
N

3447
CA
VAL
A
443
5.329
2.922
51.050
1.00
23.37
C

3448
C
VAL
A
443
5.487
3.531
49.652
1.00
24.91
C

3449
O
VAL
A
443
4.807
4.502
49.311
1.00
24.24
O

3450
CB
VAL
A
443
4.077
2.012
51.057
1.00
24.18
C

3451
OG1
VAL
A
443
4.212
0.915
50.029
1.00
22.53
C

3452
CG2
VAL
A
443
3.871
1.434
52.448
1.00
21.44
C

3453
N
ARG
A
444
6.389
2.965
48.849
1.00
26.52
N

3454
CA
ARG
A
444
6.606
3.433
47.480
1.00
26.79
C

3455
C
ARG
A
444
5.779
2.575
46.530
1.00
26.13
C

3456
O
ARG
A
444
5.526
1.396
46.806
1.00
24.74
O

3457
CB
ARG
A
444
8.068
3.281
47.052
1.00
30.05
C

3458
CG
ARG
A
444
9.089
4.022
47.877
1.00
35.40
C

3459
CD
ARG
A
444
10.500
3.779
47.320
1.00
39.46
C

3460
NE
ARG
A
444
11.530
4.344
48.192
1.00
42.91
N

3461
CZ
ARG
A
444
11.671
5.644
48.439
1.00
44.73
C

3462
NH1
ARG
A
444
10.851
6.526
47.874
1.00
45.26
N

3463
NH2
ARG
A
444
12.622
6.062
49.265
1.00
45.08
N

3464
N
TYR
A
445
5.361
3.162
45.412
1.00
24.62
N

3465
CA
TYR
A
445
4.617
2.415
44.413
1.00
24.10
C

3466
C
TYR
A
445
5.130
2.827
43.046
1.00
26.23
C

3467
O
TYR
A
445
5.712
3.898
42.896
1.00
25.95
O

3468
CS
TYR
A
445
3.111
2.684
44.519
1.00
22.25
C

3469
CG
TYR
A
445
2.708
4.112
44.247
1.00
20.24
C

3470
CD1
TYR
A
445
2.753
4.637
42.954
1.00
19.00
C

3471
CD2
TYR
A
445
2.323
4.951
45.289
1.00
18.04
C

3472
CE1
TYR
A
445
2.427
5.971
42.704
1.00
19.90
C

3473
CE2
TYR
A
445
1.995
6.285
45.055
1.00
20.74
C

3474
CZ
TYR
A
445
2.050
6.789
43.760
1.00
20.97
C

3475
OH
TYR
A
445
1.731
8.112
43.525
1.00
21.45
O

3476
N
ARG
A
446
4.921
1.955
42.065
1.00
27.77
N

3477
CA
ARG
A
446
5.323
2.184
40.684
1.00
28.78
C

3478
C
ARG
A
446
4.384
1.332
39.849
1.00
30.08
C

3479
O
ARG
A
446
4.159
0.169
40.176
1.00
29.80
O

3480
CB
ARG
A
446
6.769
1.726
40.453
1.00
27.02
C

3481
N
ARG
A
447
3.824
1.904
38.788
1.00
33.17
N

3482
CA
ARG
A
447
2.918
1.152
37.921
1.00
35.49
C

3483
C
ARG
A
447
3.555
−0.148
37.462
1.00
37.16
C

3484
O
ARG
A
447
4.776
−0.235
37.299
1.00
36.18
O

3485
CS
ARG
A
447
2.540
1.957
36.674
1.00
34.37
C

3486
CG
ARG
A
447
1.304
2.813
36.822
1.00
36.84
C

3487
CD
ARG
A
447
0.877
3.389
35.479
1.00
35.73
C

3488
NE
ARG
A
447
−0.073
4.484
35.645
1.00
36.35
N

3489
CZ
ARG
A
447
−1.344
4.337
36.004
1.00
36.90
C

3490
NH1
ARG
A
447
−1.844
3.128
36.234
1.00
35.53
N

3491
NH2
ARG
A
447
−2.112
5.409
36.147
1.00
36.28
N

3492
N
ARG
A
448
2.721
−1.160
37.257
1.00
39.39
N

3493
CA
ARG
A
448
3.210
−2.440
36.781
1.00
42.60
C

3494
C
ARG
A
448
3.303
−2.368
35.262
1.00
44.99
C

3495
O
ARG
A
448
2.480
−1.723
34.614
1.00
43.33
O

3496
CS
ARG
A
448
2.264
−3.565
37.189
1.00
41.06
C

3497
CG
ARG
A
448
2.301
−3.913
38.659
1.00
40.78
C

3498
CD
ARG
A
448
1.455
−5.146
38.906
1.00
40.99
C

3499
NE
ARG
A
448
1.891
−6.261
38.069
1.00
40.73
N

3500
CZ
ARG
A
448
1.202
−7.382
37.896
1.00
38.31
C

3501
NH1
ARG
A
448
0.036
−7.537
38.503
1.00
39.45
N

3502
NH2
ARG
A
448
1.683
−8.349
37.124
1.00
36.69
N

3503
N
THR
A
449
4.314
−3.027
34.704
1.00
49.35
N

3504
CA
THR
A
449
4.530
−3.039
33.261
1.00
53.02
C

3505
C
THR
A
449
3.464
−3.860
32.544
1.00
54.19
C

3506
O
THR
A
449
2.826
−3.319
31.613
1.00
54.87
O

3507
CB
THR
A
449
5.912
−3.620
32.922
1.00
55.20
C

3508
OG1
THR
A
449
6.926
−2.863
33.600
1.00
56.91
O

3509
CG2
THR
A
449
6.157
−3.572
31.411
1.00
55.64
C

3510
OXT
THR
A
449
3.284
−5.038
32.921
1.00
55.91
O

[0536] It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation the invention being defined by the claims.

	Number	Date	Country
Parent	09345218	Jun 1999	US
Child	09796138	Feb 2001	US

Mycobacterium tuberculosis CYP51 high resolution structure, polypeptides and nucleic acids, and therapeutic and screening methods relating to same

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

CROSS-REFERENCE TO RELATED APPLICATIONS

GRANT STATEMENT

Continuation in Parts (1)