Modulators of RabGGT and methods of use thereof

FIELD OF THE INVENTION

[0002] The present invention is in the field of modulators of enzyme activity, in particular modulators of Rab-geranylgeranyl transferase, and their use in controlling cell proliferation.

BACKGROUND OF THE INVENTION

[0003] Apoptosis is a coordinated program for induction of-a cell suicide process. Conserved components of the apoptotic pathway such as cytochrome c, the Bcl-2 family, Apaf-1, and the caspases have been identified in most eukaryotic systems. Cytochrome c release from the mitochondria via a permeability transition pore is a key trigger for apoptosis. The Bcl-2 family are highly conserved mitochondrial proteins that can act to enhance (bax, bid, bak, bad, bcl-xs) or prevent (Bcl-2, bcl-xl) apoptosis; they may effect formation of the pore. Apaf-1 is a cytoplasmic protein that is triggered by cytochrome C to activate caspase 9, which then cleaves and activates caspase 3. Caspases are proteases that act in a cascade and cleave multiple substrates, resulting in the morphological changes associated with apoptosis. Examples of changes include chromatin condensation and aggregation to the nuclear margin, cytoplasmic shrinkage, DNA fragmentation, and the packaging of cellular components into membrane bound compartments. Such specific changes distinguish apoptotic death, which may affect single cells in otherwise healthy tissue, from necrosis, in which groups of cells lyse.

[0004] Apoptosis can be activated by a number of intrinsic or extrinsic signals. These signals include the following: mild physical signals, such as ionization radiation, ultraviolet radiation, or hyperthermia; low to medium doses of toxic compounds, such as azides or hydrogen peroxides; chemotherapeutic drugs, such as etoposides and teniposides, cytokines such as tumour necrosis factors and transforming growth factors; infection with human immunodeficiency virus (HIV); and stimulation of T-cell receptors. Various pathological processes, such as hormone deprivation, growth factor deprivation, thermal stress and metabolic stress, induce apoptosis. (Wyllie, A. H., in Bowen and Lockshin (eds.) Cell Death in Biology and Pathology (Chapman and Hall, 1981), at 9-34).

[0005] Unregulated apoptosis can cause, or be associated with, disease. An understanding of how apoptosis can be regulated by drugs is becoming of increasing importance to the pharmaceutical industry (Kinloch et al., 1999, Trends in Pharmacological Science 20:35; Nicholson, 2000, Nature 407:810). For example, unregulated apoptosis is involved in diseases such as cancer, heart disease, neurodegenerative disorders, autoimrnmune disorders, and viral and bacterial infections. Cancer, for example, not only triggers cells to proliferate but also blocks apoptosis. Cancer is partly a failure of apoptosis in the sense that the signal(s) for the cells to kill themselves by apoptosis are blocked. Thus, inducing apoptosis may be a therapeutic strategy for the treatment of cancer.

[0006] In heart disease, damage caused by trauma (e.g, resulting in shock), and cardiac cells can be induced to undergo apoptosis. For example, cells deprived of oxygen after a heart attack release signals that induce apoptosis in cells in the heart. Apoptosis may also be involved in the destruction of neurons in people afflicted by strokes or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). There is also evidence suggesting that ischemia can kill neurons by inducing apoptosis. It has been shown that neurons that are resistant to apoptosis are also resistant to ischemic damage, thus, inhibition of apoptosis may be a therapeutic strategy for the treatment of neurodegenerative or cardiovascular disorders, e.g., stroke.

[0007] Rab-geranylgeranyl transferase (RabGGT; GGTII) is a protein-prenyl transferase enzyme composed of a single alpha and beta subunit. These subunits have limited homology to the alpha subunit shared by Farnesyl transferase (FT) and geranylgeranyl transferase I (GGTI), and to the beta subunits that are distinct to each of those enzymes. RabGGT is unique among prenlyation enzymes in requiring specific accessory proteins known as Rab escort proteins (REPs) for their prenylation function. However the three prenylating enzymes are similar in the structure of their active sites and in their mechanism of substrate modification. The only RabGGT substrates identified to date are a large family of Ras-related proteins called Rabs. Rab proteins are monomeric GTPases that regulate intracellular membrane traffic. RabGGT acts on the Rab proteins to attach a geranylgeranyl moiety to one or two cysteine residues at the C-terminus of the protein. This prenylation event is important for the subcellular targeting of Rabs to membranes.

[0008] There is an ongoing need in the art for agents and methods of modulating cell proliferation. The present invention addresses this need.

[0009] Literature

[0010] Hengartner (2000) Nature 407:770; Long et al. (2002) Nature 419:645; Seabra et al., 2002, Trends in Molecular Medicine 8:23; Detter et al., 2000, Proc. Natl. Acad. Sci. USA 97:4144; Ren et al., 1997, Biochem. Pharmacol. 54:113; J. C. Reed, Nature Reviews Drug Discovery: 1 pp111-121; Kinloch et al., 1999, Trends in Pharmacological Science 20:35; Nicholson (2000) Nature 407:810; Thoma et al. (2000) Biochem. 39:12043-12052; Coxon et al. (2001) J. Biol. Chem. 276:48213-48222; Rose et al. (2001) Cancer Res. 61:7505-7517; Hunt et al. (2000) J. Med. Chem. 43:3587; Pylypenko et al. (2003) Molec. Cell 11:483-494.

SUMMARY OF THE INVENTION

[0011] The present invention provides methods for inducing apoptosis in a cell, the methods generally involving contacting the cell with an agent that reduces the level and/or activity of RabGGT. The present invention further provides methods for treating a disorder related to unwanted cell proliferation in an individual, the methods generally involving administering to the individual an agent that reduces the level and/or activity of RabGGT. The present invention further provides methods for reducing apoptosis in a cell, the methods generally involving increasing the level and/or activity of RabGGT in the cell. The present invention further provides methods for treating disorders associated with excessive apoptosis. The present invention further provides methods for identifying a cell that is amenable to treatment with the methods of the present invention. The present invention further provides methods for modulating a binding event between RabGGT and a RabGGT interacting protein. The present invention further provides a 3-dimensional structure of RabGGT, and methods of use of the structure to identify compounds that modulate RabGGT activity.

[0012] The invention also provides a computer for producing a three-dimensional representation of a molecule or molecular complex, wherein said molecule or molecular complex comprises the structural coorrdinates of the model RabGGT alpha or beta subunit in accordance with Table 11 or 12, or a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises backbone atoms that have a root mean square deviation from the backbone atoms of not more than about 4.0, 3.0. 2.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 Angstroms, wherein said computer comprises: A machine-readable data storage medium, comprising a data storage material encoded with machine readable data, wherein the data is defined by the set of structure coordinates of the model RabGGT alpha or beta subunit according to Table 11 or 12, or a homologue of said model, wherein said homologue comprises backbone atoms that have a root mean square deviation from the backbone atoms of not more than about 4.0, 3.0. 2.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 Angstroms; a working memory for storing instructions for processing said machine-readable data; a central-processing unit coupled to said working memory and to said machine-readable data storage medium for processing said machine readable data into said three-dimensional representation; and a display coupled to said central-processing unit for displaying said three-dimensional representation.

[0013] The invention also provides a machine readable storage medium which comprises the structure coordinates of RabGGT alpha or beta subunit, including all or any parts of conserved binding site regions. Such storage medium encoded with these data are capable of displaying on a computer screen or similar viewing device, a three-dimensional graphical representation of a molecule or molecular complex which comprises said regions or similarly shaped homologous regions.

[0014] The invention also provides methods for designing, evaluating and identifying compounds which bind to all or parts of the aforementioned regions. The methods include three dimensional model building (homology modeling) and methods of computer assisted-drug design which can be used to identify compounds which bind or modulate the forementioned regions of the RabGGT alpha or beta subunit polypeptide. Such compounds are potential inhibitors of RabGGT alpha or beta subunit or its homologues.

[0015] The invention also provides a machine-readable data storage medium, comprising a data storage material encoded with machine readable data, wherein the data is defined by the structure coordinates of the model RabGGT alpha or beta subunit according to Table 11 or 12 or a homologue of said model, wherein said homologue comprises any kind of surrogate atoms that have a root mean square deviation from the backbone atoms of the complex of not more than about 4.0, 3.0. 2.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or less Angstroms.

[0016] The invention also provides a machine-readable data storage medium, comprising a data storage material encoded with machine readable data, wherein the data is defined by the structure coordinates of the model RabGGT alpha or beta subunit according to Table 11 or 12 or a homologue of said model, wherein said homologue comprises any kind of surrogate atoms that have a root mean square deviation from the backbone atoms of the complex of not more than about 4.0, 3.0. 2.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or less Angstroms

[0017] The invention also provides a model comprising all or any part of the model defined by structure coordinates of RabGGT alpha or beta subunit according to Table 11 or 12, or a mutant or homologue of said molecule or molecular complex.

[0018] The invention also provides a method for identifying a mutant of RabGGT alpha or beta subunit with altered biological properties, function, or reactivity, the method comprising one or more of the following steps:

[0019] (a) use of the model or a homologue of said model according to Table 11 or 12, for the design of protein mutants with altered biological function or properties which exhibit any combination of therapeutic effects described herein; and/or (b) use of the model or a homologue of said model, for the design of a protein with mutations in the active site region according to Table 11 or 12 with altered biological function or properties which exhibit any combination of therapeutic effects described herein.

[0020] The method also relates to a method for identifying modulators of RabGGT alpha or beta subunit biological properties, function, or reactivity, the method comprising the step of modeling test compounds that fit spatially into the active site region defined by all or any portion of residues that embody this domain within the three-dimensional structural model according to Table 11 or 12, or using a homologue or portion thereof, or analogue in which the original C, N, and O atoms have been replaced with other elements

[0021] The invention also provides methods for designing, evaluating and identifying compounds which bind to all or parts of the aforementioned regions. The methods include three dimensional model building (homology modeling) and methods of computer assisted-drug design which can be used to identify compounds which bind or modulate the forementioned regions of the RabGGT alpha or beta subunit polypeptide. Such compounds are potential inhibitors of RabGGT alpha or beta subunit or its homologues.

[0022] The invention also relates to a method of using said structure coordinates as set forth in Table 11 or 12 to identify structural and chemical features of RabGGT alpha or beta subunit; employing identified structural or chemical features to design or select compounds as potential RabGGT alpha or beta subunit modulators; employing the three-dimensional structural model to design or select compounds as potential RabGGT alpha or beta subunit modulators; synthesizing the potential RabGGT alpha or beta subunit modulators; screening the potential RabGGT alpha or beta subunit modulators in an assay characterized by binding of a protein to the RabGGT alpha or beta subunit. The invention also relates to said method wherein the potential RabGGT alpha or beta subunit modulator is selected from a database. The invention further relates to said method wherein the potential RabGGT alpha or beta subunit modulator is designed de novo. The invention further relates to a method wherein the potential RabGGT alpha or beta subunit modulator is designed from a known modulator of activity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]
FIG. 1 provides a graphical display of data on the effects of compound treatments upon levels of apoptosis in the worm germline (The percentage of germline arms examined that contained greater than 2 apoptotic corpses is displayed. Compound treatments are shown on the X axis);

[0024]
FIG. 2 provides a graphical display of data on the effects of compound treatments upon levels of apoptosis in the germline of apoptosis-defective mutant worms (Average number of apoptotic corpses per germline arm in worms treated with compound 7B or vehicle. Worm genotype is displayed on the X-axis. The error bars shown standard deviation.);

[0025]
FIG. 3 provides a graphical display of data on the effects of RNAi treatments against RabGGT subunits upon levels of apoptosis in the worm germline (The percentage of germline arms that contained greater than 2 apoptotic corpses is displayed. RNAi treatments are shown on the X axis.);

[0026]
FIG. 4 provides a graphical display of data on the effects of treatment with compound and/or RNAi against RabGGT subunit alpha upon levels of apoptosis in the worm germline (The percentage of germline arms examined that contained either less than three, three or four, or greater than four apoptotic corpses is displayed. Treatments are shown on the X axis.);

[0027]
FIG. 5 provides a graphical display of data on the effects of treatment with RNAi against RabGGT alpha subunit upon levels of apoptosis in the germline of Wild Type or compound 7B-resistant mutant worms (The percentage of germline arms in wild-type or mutant worms that contained greater than two apoptotic corpses is displayed. Treatments are shown on the X axis.);

[0028]
FIG. 6 provides a graphical display of data on the effects of treatment with RNAi against RabGGT subunits upon levels of proliferation in human cells (3H-uptake by HCT116 cells as percentage of control treatment. Treatments are shown on the X-axis.);

[0029]
FIG. 7 provides a graphical display of results obtained by non-linear regression analysis of data obtained for compound 7B in a RabGGT inhibition assay (Results obtained by non-linear regression analysis of data obtained for compound 7B.);

[0030]

FIG. 8

a
provides a graphical display of the data on RabGGT inhibition and apoptotic activity for the benzodiazepine class of compounds (Data from the benzodiazepine class of compounds: The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT116 cell culture is shown on the X axis.);

[0031]

FIG. 8

b
provides a graphical display of the data on RabGGT inhibition and apoptotic activity for the tetrahydroquinolone class of compounds (Data from the tetrahydroquinolone class of compounds: The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT116 cell culture is shown on the X axis.);

[0032]

FIG. 8

c
provides a graphical display of data on RabGGT inhibition and apoptotic activity for compounds 7A-7Q (Data from compounds 7A through 7Q. Compounds 7R, 7S, and 7T are represented in FIG. 9b, and have been omitted from this figure for graphical clarity rather than because they alter the trend of the observations. The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT116 cell culture is shown on the X axis.);

[0033]
FIG. 9 provides a graphical display of data on FT inhibition and apoptotic activity for compounds 7A-7T (Data for compounds 7A through 7T. The IC50 for FT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT116 cell culture is shown on the X axis.);

[0034]
FIG. 10 provides a superposition of the homology model of the H. sapiens RabGGT protein on the crystal structure of the rat RabGGT protein (Superposition of the homology model of the human RabGGT protein (dark) on the crystal of the rat RabGGT protein. The atom of zinc found in the binding site of the rat protein is shown as a white sphere.);

[0035]

FIG. 11

a
provides free energy plots for the modeled human RabGGT alpha subunit and for the crystal structure of the rat RabGGT alpha subunit (Energy plots for the model of H. sapiens RabGGT alpha chain (dotted line), and for the crystal structure of the R. norvegicus RabGGT alpha chain (solid line)).

[0036]

FIG. 11

b
provides free energy plots for the modeled human RabGGT beta subunit and for the crystal structure of the rat RabGGT beta subunit (Energy plots for the model of H. sapiens RabGGT beta chain (dotted line), and for crystal structure of the R. norvegicus RabGGT beta chain (solid line)).

[0037]
FIG. 12 provides a superposition of the homology model of the C. elegans RabGGT protein on the crystal structure of the rat RabGGT protein (Superposition of the homology model of the C. elegans RabGGT protein (dark) on the crystal of the rat RabGGT protein. The atom of zinc found in the binding site of the rat protein is shown as a white sphere.);

[0038]

FIG. 13

a
provides free energy plots for the modeled C. elegans RabGGT alpha subunit and for the crystal structure of the rat RabGGT alpha subunit (Energy plots for the model of C. elegans RabGGT alpha chain (dotted line), and for the crystal structure of the R. norvegicus RabGGT alpha chain (solid line)).

[0039]

FIG. 13

b
provides free energy plots for the modeled C. elegans RabGGT beta subunit and for the crystal structure of the rat RabGGT beta subunit (Energy plots for the model of C. elegans RabGGT beta chain (dotted line), and for the crystal structure of the R. norvegicus RabGGT beta chain (solid line)).

[0040]

FIG. 14

a
provides a depiction of the binding site in the crystal structure of the rat RabGGT enzyme (Binding pocket from the crystal structure of rat RabGGT. The white sphere denotes the bound atom of zinc.);

[0041]

FIG. 14

b
provides a depiction of the superimposition of the binding site in the crystal structure of the rat RabGGT enzyme upon the binding site in the model of the human RabGGT enzyme (Superposition of the residues within 5 Angstrom of the binding site in the homology model of the H. sapiens RabGGT protein (dark) on the crystal structure of the homologous residues of the rat protein. The atom of zinc found in the binding site of the rat protein is shown as a white sphere.);

[0042]

FIG. 14

c
provides a depiction of the superimposition of the binding site in the crystal structure of the rat RabGGT enzyme upon the binding site in the model of the C. elegans RabGGT enzyme (Superposition of the residues within 5 Angstrom of the binding site in the homology model of the C. elegans RabGGT protein (dark) on the crystal structure of the homologous residues of the rat protein. The atom of zinc found in the binding site of the rat protein is shown as a white sphere).

[0043]
FIG. 15A depicts binding of compound 7H docked into the putative binding site of RabGGT.

[0044]
FIG. 15B depicts the binding site of the crystal structure of the complex between farnesyl transferase and the FT inhibitor U66.

[0045]
FIG. 16A-B show the polynucleotide sequence (SEQ ID NO:15) and deduced amino acid sequence (SEQ ID NO:16) of the human RabGGT alpha subunit. The standard one-letter abbreviation for amino acids is used to illustrate the deduced amino acid sequence.

[0046]
FIG. 17 show the polynucleotide sequence (SEQ ID NO:17) and deduced amino acid sequence (SEQ ID NO:18) of the human RabGGT beta subunit. The standard one-letter abbreviation for amino acids is used to illustrate the deduced amino acid sequence.

DEFINITIONS

[0047] As used herein, the term “disorder associated with undesired or uncontrolled cell proliferation” is any disorder that results from undesired or uncontrolled cell proliferation, and/or that is amenable to treatment by inducing apoptosis in the cell, such disorders including, but not limited to, cancer, viral infection, disorders associated with excessive or unwanted angiogenesis, and the like.

[0048] As used herein, the term “disorder associated with excessive apoptosis” is any disorder that results from an excessive amount of apoptosis, such disorders including, but not limited to, sepsis, atherosclerosis, muscle cachexia, ischemia/reperfusion injury, neurodegenerative disorders, and myocardial infarction.

[0049] As used herein, the terms “treatment”, “treating”, and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. “Treatment”, as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, e.g., causing regression of the disease, e.g., to completely or partially remove symptoms of the disease.

[0050] The term “biological sample” encompasses a variety of sample types obtained from an organism and can be used in a diagnostic or monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

[0051] The terms “cancer”, “neoplasm”, “tumor”, and “carcinoma”, are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. Cancerous cells can be benign or malignant.

[0052] By “individual” or “host” or “subject” or “patient” is meant any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. Other subjects may include cattle, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and so on.

[0053] The term “binds specifically,” in the context of antibody binding, refers to high avidity and/or high affinity binding of an antibody to a specific polypeptide i.e., epitope of a polypeptide, e.g., RabGGT. For example, antibody binding to an epitope on a specific RabGGT polypeptide or fragment thereof is stronger than binding of the same antibody to any other epitope, particularly those which may be present in molecules in association with, or in the same sample, as the specific polypeptide of interest, e.g., binds more strongly to a specific RabGGT epitope than to a different RabGGT epitope so that by adjusting binding conditions the antibody binds almost exclusively to the specific RabGGT epitope and not to any other RabGGT epitope, and not to any other RabGGT polypeptide (or fragment) or any other polypeptide which does not comprise the epitope. Antibodies which bind specifically to a polypeptide may be capable of binding other polypeptides at a weak, yet detectable, level (e.g., 10% or less of the binding shown to the polypeptide of interest). Such weak binding, or background binding, is readily discernible from the specific antibody binding to a subject polypeptide, e.g. by use of appropriate controls. In general, specific antibodies bind to a given polypeptide with a binding affinity of 10−7 M or more, e.g., 10−8 M or more (e.g., 10−9 M, 10−10 M, 10−11 M, etc.). In general, an antibody with a binding affinity of 10−6 M or less is not useful in that it will not bind an antigen at a detectable level using conventional methodology currently used.

[0054] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0055] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0057] It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents and reference to “the inhibitor” includes reference to one or more inhibitors and equivalents thereof known to those skilled in the art, and so forth.

[0058] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0059] Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION

[0060] The present invention provides methods for inducing apoptosis in a cell, the methods generally involving contacting the cell with an agent that reduces the level and/or activity of RabGGT. The present invention further provides methods for treating a disorder related to unwanted cell proliferation in an individual, the methods generally involving administering to the individual an agent that reduces the level and/or activity of RabGGT. The present invention further provides methods for reducing apoptosis in a cell, the methods generally involving increasing the level and/or activity of RabGGT in the cell. The present invention further provides methods for treating disorders associated with excessive apoptosis. The present invention further provides methods for identifying a cell that is amenable to treatment with the methods of the present invention. The present invention further provides methods for modulating a binding event between RabGGT and a RabGGT interacting protein. The present invention further provides a 3-dimensional structure of RabGGT, and methods of use of the structure to identify compounds that bind specifically to RabGGT.

[0061] The present invention is based in part on the observation that inhibitors of RabG GT levels and/or activity induce apoptosis and reduce cell proliferation. As discussed in the Examples section, inhibitors of RabGGT induced tumor regression in a human tumor xenograft model, and induced apoptosis of cells expressing RabGGT in cell cultures in vitro and in vivo.

Treatment Methods

[0062] In some embodiments, the invention provides methods for inducing apoptosis in a cell and/or inhibiting proliferation of the cell. The methods generally involve contacting a cell with an effective amount of an agent that inhibits a level and/or activity of RabGGT or a RabGGT/REP complex. The invention also provides methods of treating a disorder amenable to treatment by inducing apoptosis and/or inhibiting cell proliferation, the methods generally involving administering an effective amount of an agent that inhibits a level and/or activity of RabGGT or a RabGGT/REP complex in a cell in the individual.

[0063] As used herein, the term “RabGGT” refers to a protein that includes a RabGGT α subunit and a RabGGT β subunit. As used herein, an “agent that reduces the level of a RabGGT protein” includes an agent that reduces the level of a RabGGT α subunit (and does not reduce the level of a RabGGT β subunit), an agent that reduces the level of a RabGGT β subunit (and does not reduce the level of a RabGGT β subunit), and an agent that reduces the level of both a RabGGT α subunit and a RabGGT β subunit. As used herein, an “agent that reduces the level of a RabGGT mRNA” includes an agent that reduces the level of an mRNA encoding a RabGGT α subunit (and does not reduce the level of an mRNA encoding a RabGGT β subunit), an agent that reduces the level of an mRNA encoding a RabGGT β subunit (and does not reduce the level of an mRNA encoding a RabGGT β subunit), and an agent that reduces the level of both an mRNA encoding a RabGGT α subunit and an mRNA encoding a RabGGT β subunit.

[0064] An “effective amount” of an agent that inhibits a level and/or activity of RabGGT is an amount that reduces a level of RabGGT mRNA and/or protein and/or is an amount that reduces an activity of a RabGGT protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compare to the level or activity in the absence of the agent.

[0065] In other embodiments, the invention provides methods for reducing apoptosis in a cell. The methods generally involve contacting a cell with an effective amount of an agent that increases a level and/or activity of RabGGT or a RabGGT/REP complex. The invention also provides methods of treating a disorder amenable to treatment by reducing apoptosis, the methods generally involving administering an effective amount of an agent the increases a level and/or activity or RabGGT or a RabGGT/REP complex in a cell in the individual.

[0066] An “effective amount” of an agent that increases a level and/or activity of RabGGT is an amount that increases a level of RabGGT mRNA and/or protein and/or is an amount that increases an activity of a RabGGT protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the level or activity in the absence of the agent.

[0067] In some embodiments, the invention provides a method of inducing apoptosis in a eukaryotic cell, wherein the method generally involves identifying a compound that is a RabGGT inhibitor; testing the ability of the compound to modulate famesyl transferase (FT) activity; modifying the compound, wherein the modified compound exhibits reduced modulation of FT activity compared to the unmodified compound, wherein inhibition of RabGGT is retained; and contacting the cell with the modified compound.

[0068] RabGGT Modulating Agents

[0069] As noted above, in some methods of the present invention, agents that reduce a level and/or activity of RabGGT are used. In other methods of the present invention, agents that increase a level and/or activity of RabGGT are used. Agents that reduce or increase a level and/or activity of RabGGT are referred to herein as “RabGGT modulators” or “RabGGT modulating agents” and include small molecule modulators, protein (or peptide) modulators, antibody modulators, and nucleic acid modulators. The RabGGT modulating agents are typically “specific” in their interaction with RabGGT, as that term is understand in the art.

[0070] Agents that reduce a level and/or activity of RabGGT include agents that reduce the protein prenyl transferase activity of RabGGT protein; agents that reduce an interaction between RabGGT and an interacting protein, where RabGGT interacting proteins include a Rab protein, an accessory protein (e.g., a REP), and a protein that binds to a Rab/RabGGT complex; agents that reduce the level of RabGGT mRNA in a cell; agents that reduce , but are not limited to, small molecule inhibitors of RabGGT enzymatic activity; antibodies specific for RabGGT; antisense RNA specific for RabGGT; interfering RNA (RNAi) specific for RabGGT; ribozymes specific for RabGGT; and the like.

[0071] In some embodiments, an agent that reduces a level and/or activity of RabGGT does not substantially reduce a level or activity of other proteins or mRNA, including famesyl transferase, e.g., the agent reduces the level or activity of another protein or mRNA by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the activity or level of the protein or mRNA in the absence of the agent.

[0072] In some embodiments, agents that reduce a level and/or activity of a RabGGT/REP complex are used in a therapeutic method of the present invention. A RabGGT/REP complex includes RabGGT α and β subunits, and a Rab escort protein (REP) (e.g., REP-1, REP-2).

[0073] A RabGGT α subunit includes a protein having an amino acid sequence as set forth in SWISS-PROT Accession No. Q92696 (Genomics 38 (2), 133-140 (1996)), and homologs, analogs, and derivatives thereof, e.g., derivatives having one or more conservative amino acid substitutions. A RabGGT β subunit includes a protein having an amino acid sequence as set forth in SWISS-PROT Accession No. P53611 (Genomics 38 (2), 133-140 (1996)), and homologs, analogs, and derivatives thereof, e.g., derivatives having one or more conservative amino acid substitutions. A REP protein includes a protein having an amino acid sequence as set forth in GenBank Accession No. P24386 or P26374, and homologs, analogs, and derivatives thereof, e.g., derivatives having one or more conservative amino acid substitutions. Homologs include proteins that have from 1 to about 20 amino acid differences from a reference sequence. In general, homologs retain at least about 80%, or at least about 90% or more, of at least one activity of a protein having a reference sequence.

[0074] In some embodiments, an agent that reduces a level and/or activity of a RabGGT/REP complex does not substantially reduce a level or activity of other proteins or mRNA, including farnesyl transferase, e.g., the agent reduces the level or activity of another protein or mRNA by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the activity or level of the protein or mRNA in the absence of the agent.

[0075] Biological Modulators

[0076] Modulators suitable for use herein modulate a level and/or an activity of RabGGT or a RabGGT/REP complex. A suitable modulator exhibits one or more of the following activities: 1) modulates an enzymatic activity of RabGGT or a RabGGT/REP complex; 2) modulates a level of a RabGGT protein (α and/or β subunit) or the level of a RabGGT/REP protein complex; 3) modulates the level of an mRNA that encodes a RabGGT protein (α and/or β subunit), or an mRNA that encodes a REP protein; 4) modulates the level of apoptosis in a cell; and 5) modulates a binding event between a RabGGT protein and a protein that interacts with a RabGGT protein.

[0077] Modulating Enzymatic Activity

[0078] In some embodiments, a RabGGT modulating agent modulates the protein prenyl transferase activity of RabGGT protein. In some of these embodiments, an agent increases the enzymatic activity of a RabGGT protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to-the enzymatic activity of the RabGGT protein in the absence of the agent.

[0079] In other embodiments, an agent reduces the enzymatic activity of a RabGGT protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the enzymatic activity of the RabGGT protein in the absence of the agent.

[0080] In some embodiments, an agent that reduces the activity of RabGGT inhibits the activity of a RabGGT/REP complex. A suitable agent reduces the level and/or activity of a RabGGT/REP complex by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% or more, compared to the level or activity of the RabGGT/REP complex in the absence of the agent.

[0081] In many embodiments, an agent that reduces RabGGT enzymatic activity has an IC50 of less than 0.5 mM. Generally, a suitable agent that reduces RabGGT enzymatic activity has an IC50 of from about 0.5 nM to about 500 μM, e.g., from about 0.5 nM to about 1 nM, from about 1 nM to about 5 nM, from about 5 nM to about 10 nM, from 10 nM to about 25 nM, from about 25 nM to about 50 nM, from about 50 nM to about 100 nM, from about 100 nM to about 250 nM, from about 250 nM to about 500 nM, from about 500 nM to about 1 μM, from about 1 μM to about 5 μM, from about 5 μM to about 10 μM, from about 10 μM to about 25 μM, from about 25 μM to about 50 μM, from about 50 μM to about 100 μM, from about 100 μM to about 250 μM, or from about 250 μM to about 500 μM.

[0082] Whether a given agent modulates a level and/or activity of RabGGT can be determined using any known method. For example, RabGGT enzymatic activity is quantified using a filter binding assay that measures the transfer of (3H) geranylgeranyl groups (GG) from all-trans-(3H)geranylgeranyl, pyrophosphate (3H-GGPP) to recombinant Rab3A protein (Shen and Seabra (1996) J. Biol. Chem. 271:3692; Armstrong et al. (1996) Methods in Enzymology 257:30), or as described in the Examples.

[0083] Protein Level

[0084] In some embodiments, an agent modulates a level of RabGGT protein in a cell. In some of the embodiments, an agent increases the level of a RabGGT protein in a cell by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the level in a control cell in the absence of the agent.

[0085] In other embodiments, an agent decreases the level of a RabGGT protein in a cell by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the level in a control cell in the absence of the agent.

[0086] The level of RabGGT protein in a cell can be determined using a standard, well-known immunological assay, e.g., an enzyme-linked immunosorbent assay, a protein blot assay, a radioimmunoassay, and the like, using antibody specific for RabGGT, which antibody is directly or indirectly labeled.

[0087] Direct and indirect antibody labels are known in the art. An antibody may be labeled with a radioisotope, an enzyme, a fluorescer (e.g., a fluorescent protein or a fluorescent dye), a chemiluminescer, or other label for direct detection. Alternatively, a second stage antibody or reagent is used to amplify the signal. Such reagents are well known in the art. For example, the primary antibody may be conjugated to biotin, with horseradish peroxidase-conjugated avidin added as a second stage reagent. Final detection uses a substrate that undergoes a color change in the presence of the peroxidase. Alternatively, the secondary antibody conjugated to a fluorescent compound, e.g. fluorescein, rhodamine, Texas red, etc. The absence or presence of antibody binding may be determined by various methods, including flow cytometry of dissociated cells, microscopy, radiography, scintillation counting, etc.

[0088] Fluorescent proteins include, but are not limited to, a green fluorescent protein (GFP), e.g., a GFP derived from Aequoria victoria or a derivative thereof; a GFP from another species such as Renilla reniformis, Renilla mulleri, or Ptilosarcus guernyi, as described in, e.g., WO 99/49019 and Peelle et al. (2001) J. Protein Chem. 20:507-519; any of a variety of fluorescent and colored proteins from Anthozoan species, as described in, e.g., Matz et al. (1999) Nature Biotechnol. 17:969-973; and the like.

[0089] Enzyme labels include, but are not limited to, luciferase, β-galactosidase, horse radish peroxidase, and the like. Where the label is an enzyme that yields a detectable product, the product can be detected using an appropriate means, e.g., β-galactosidase can, depending on the substrate, yield colored product, which is detected spectrophotometrically, or a fluorescent product; luciferase can yield a luminescent product detectable with a luminometer; etc.

[0090] RabGGT mRNA Level

[0091] In some embodiments, an agent modulates the level of a RabGGT mRNA in a cell, e.g., the agent modulates the level of mRNA that comprises a nucleotide sequence that encodes a RabGGT protein. Agents that modulate the level of a RabGGT mRNA include agents that modulate the rate of transcription of the mRNA, agents that modulate binding of a transcription factor(s) or other regulatory protein(s) to a RabGGT gene regulatory element (e.g., enhancer, promoter, and the like); agents that modulate the stability of RabGGT mRNA stability; and the like.

[0092] In some embodiments, an agent increases the level of RabGGT mRNA by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the level in the absence of the agent.

[0093] In other embodiments, an agent decreases the level of RabGGT mRNA by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the level in the absence of the agent.

[0094] The level of RabGGT mRNA in a cell is readily determined using any known method. In general, nucleic acids that hybridize specifically to a RabGGT mRNA are used. A number of methods are available for analyzing nucleic acids for the presence and/or level of a specific mRNA in a cell or in a sample. The mRNA may be assayed directly or reverse transcribed into cDNA for analysis. Suitable methods include, but are not limited to, in situ nucleic acid hybridization methods, quantitative RT-PCR, nucleic acid blotting methods, and the like.

[0095] The nucleic acid may be amplified by conventional techniques, such as the polymerase chain reaction (PCR), to provide sufficient amounts for analysis. The mRNA may be reverse transcribed, then subjected to PCR (rtPCR). The use of the polymerase chain reaction is described in Saiki, et al. (1985), Science 239:487, and a review of techniques may be found in Sambrook, et al. Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp. 14.2-14.33.

[0096] A detectable label may be included in an amplification reaction. Suitable labels include fluorochromes, e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2′, 7′-dimethoxy-4′, 5′-dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′, 4′, 7′, 4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA), radioactive labels, e.g. 32P, 35S, 3H; etc. The label may be a two stage system, where the amplified DNA is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.

[0097] A variety of different methods for determining the nucleic acid abundance in a sample are known to those of skill in the art, where particular methods of interest include those described in: Pietu et al., Genome Res. (June 1996) 6: 492-503; Zhao et al., Gene (Apr. 24, 1995) 156: 207-213; Soares, Curr. Opin. Biotechnol. (October 1997) 8: 542-546; Raval, J. Pharmacol Toxicol Methods (November 1994) 32: 125-127; Chalifour et al., Anal. Biochem (Feb. 1, 1994) 216: 299-304; Stolz & Tuan, Mol. Biotechnol. (December 19960 6: 225-230; Hong et al., Bioscience Reports (1982) 2: 907; and McGraw, Anal. Biochem. (1984) 143: 298. Also of interest are the methods disclosed in WO 97/27317, the disclosure of which is herein incorporated by reference.

[0098] In some embodiments, RabGGT mRNA levels are quantitated using quantitative rtPCR. Methods of quantitating a given message using rtPCR are known in the art. In some of these embodiments, dye-labeled primers are used. In other embodiments, a double-stranded DNA-binding dye, such as SYBR®, is used, as described in the Examples. Quantitative fluorogenic RT-PCR assays are well known in the art, and can be used in the present methods to detect a level of RabGGT mRNA. See, e.g., Pinzani et al. (2001) Regul. Pept. 99:79-86; and Yin et al. (2001) Immunol. Cell Biol. 79:213-221.

[0099] Apoptosis

[0100] In some embodiments, an agent that modulates a level and/or activity of RabGGT mRNA and/or protein induces apoptosis in a eukaryotic cell.

[0101] Whether a given agent inhibits RabGGT and induces apoptosis in a eukaryotic cell can be determined using any known method. Assays can be conducted on cell populations or an individual cell, and include morphological assays and biochemical assays. A-non-limiting example of a method of determining the level of apoptosis in a cell population is TUNEL (TdT-mediated dUTP nick-end labeling) labeling of the 3′-OH free end of DNA fragments produced during apoptosis (Gavrieli et al. (1992) J. Cell Biol. 119:493). The TUNEL method consists of catalytically adding a nucleotide, which has been conjugated to a chromogen system or a to a fluorescent tag, to the 3′-OH end of the 180-bp (base pair) oligomer DNA fragments in order to detect the fragments. The presence of a DNA ladder of 180-bp oligomers is indicative of apoptosis. Procedures to detect cell death based on the TUNEL method are available commercially, e.g., from Boehringer Mannheim (Cell Death Kit) and Oncor (Apoptag Plus). Another marker that is currently available is annexin, sold under the trademark APOPTEST™. This marker is used in the “Apoptosis Detection Kit,” which is also commercially available, e.g., from R&D Systems. During apoptosis, a cell membrane's phospholipid asymmetry changes such that the phospholipids are exposed on the outer membrane. Annexins are a homologous group of proteins that bind phospholipids in the presence of calcium. A second reagent, propidium iodide (PI), is a DNA binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells stain positive for annexin and negative for PI, necrotic cells stain positive for both, live cells stain negative for both. Other methods of testing for apoptosis are known in the art and can be used, including, e.g., the method disclosed in U.S. Pat. No. 6,048,703.

[0102] Modulating a Binding Event

[0103] In some embodiments, an agent that modulates a RabGGT activity modulates a binding event between RabGGT and a RabGGT interacting protein. RabGGT interacting proteins include, but are not limited to, a Rab protein; a Rab escort protein (REP); and a protein that binds to a Rab/RabGGT complex.

[0104] In some embodiments, an agent increases binding between RabGGT and a RabGGT interacting protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the binding in the absence of the agent.

[0105] In some embodiments, an agent reduces binding between RabGGT and a RabGGT interacting protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, when compared to the binding in the absence of the agent.

[0106] In some embodiments, the agent reduces binding between RabGGT and a Rab protein.

[0107] Rab proteins are known in the art. For example, at least 30 human Rab proteins are known, and include Rab1a, Rab1b, Rab2a, Rab2b, Rab3a, Rab3b, Rab3c, Rab3d, Rab4a, Rab4b, Rab5a, Rab5b, Rab5c, Rab6a, Rab6b, Rab6c, Rab7, Rab8a, Rab8b, Rab9a, Rab9b, Rab10, Rab11a, Rab11b, Rab12, Rab13, Rab14, Rab15, Rab17, Rab18, Rab19, Rab20, Rab21, Rab22a, Rab22b, Rab22c, Rab23, Rab24, Rab25, Rab26, Rab27a, Rab27b, Rab28, Rab29, Rab30, Rab32, Rab33a, Rab33b, Rab34, Rab35, Rab36, Rab37, Rab38, Rab39a, Rab39b. See e.g., Seabra et al. (2002) Trends Mol. Med. 8:23-30.

[0108] In some embodiments, an agent inhibits binding between a Rab protein and REP protein. RabGGT prenylates Rab only when Rab is in a complex with REP. Therefore, an agent that reduces a Rab/REP interaction also reduces Rab/RabGGT binding. Accordingly, agents that reduce Rab/REP binding are suitable for use in a subject methods. Rab/REP interaction via a RabF motif is a target for inhibiting Rab/REP binding. The RabF motif has been described in the art. See, e.g., Pereira-Leal et al. (2003) Biochem. Biophys. Res. Comm. 301:92-97. An agent that inhibits binding of a REP protein to a RabF motif is suitable for use in a subject method. Human REP proteins are known in the art, and the amino acid sequences have been reported. See, e.g., GenBank Accession No. NP—000381 or P24386 for human REP-1; NP—001812 for human REP-2; etc.

[0109] Whether an agent modulates binding between two proteins, e.g., between a Rab protein and a RabGGT protein, between a Rab protein and a REP protein, between a Rab/REP complex and RabGGT, can be determined using standard methods that are well known in the art. Suitable methods include, but are not limited to, a yeast two-hybrid assay; a fluorescence resonance energy transfer (FRET) assay; a bioluminescence resonance energy transfer (BRET) assay; a fluorescence quenching assay; a fluorescence anisotropy assay; an immunological assay; and an assay involving binding of a detectably labeled protein to an immobilized protein.

[0110] FRET involves the transfer of energy from a donor fluorophore in an excited state to a nearby acceptor fluorophore. For this transfer to take place, the donor and acceptor molecules must in close proximity (e.g., less than 10 nanometers apart, usually between 10 and 100 Å apart), and the emission spectra of the donor fluorophore must overlap the excitation spectra of the acceptor fluorophore. In one non-limiting example, a fluorescently labeled RabGGT protein serves as a donor and/or acceptor in combination with a second fluorescent protein (e.g., a Rab protein) or dye; e.g., a fluorescent protein as described in Matz et al. (1999) Nature Biotechnology 17:969-973; a green fluorescent protein (GFP); a GFP from Aequoria victoria or fluorescent mutant thereof, e.g., as described in U.S. Pat. Nos. 6,066,476; 6,020,192; 5,985,577; 5,976,796; 5,968,750; 5,968,738; 5,958,713; 5,919,445; 5,874,304, the disclosures of which are herein incorporated by reference; a GFP from another species such as Renilla reniformis, Renilla mulleri, or Ptilosarcus guernyi, as described in, e.g., WO 99/49019 and Peelle et al. (2001) J. Protein Chem. 20:507-519; “humanized” recombinant GFP (hrGFP) (Stratagene); other fluorescent dyes, e.g., coumarin and its derivatives, e.g. 7-amino-4-methylcoumarin, aminocoumarin, bodipy dyes, such as Bodipy FL, cascade blue, fluorescein and its derivatives, e.g. fluorescein isothiocyanate, Oregon green, rhodamine dyes, e.g. texas red, tetramethylrhodamine, eosins and erythrosins, cyanine dyes, e.g. Cy3 and Cy5, macrocyclic chelates of lanthanide ions, e.g. quantum dye, etc., chemilumescent dyes, e.g., luciferases.

[0111] BRET is a protein-protein interaction assay based on energy transfer from a bioluminescent donor to a fluorescent acceptor protein. The BRET signal is measured by the amount of light emitted by the acceptor to the amount of light emitted by the donor. The ratio of these two values increases as the two proteins are brought into proximity. The BRET assay has been amply described in the literature. See, e.g., U.S. Pat. Nos. 6,020,192; 5,968,750; and 5,874,304; and Xu et al. (1999) Proc. Natl. Acad. Sci. USA 96:151-156. BRET assays may be performed by analyzing transfer between a bioluminescent donor protein and a fluorescent acceptor protein. Interaction between the donor and acceptor proteins can be monitored by a change in the ratio of light emitted by the bioluminescent and fluorescent proteins. In one non-limiting example, a RabGGT protein serves as donor and/or acceptor protein.

[0112] Fluorescent RabGGT can be produced by generating a construct encoding a protein comprising a RabGGT protein and a fluorescent fusion partner, e.g., a fluorescent protein as described in Matz et al. ((1999) Nature Biotechnology 17:969-973), a green fluorescent protein from any species or a derivative thereof; e.g., a GFP from another species such as Renilla reniformis, Renilla mulleri, or Ptilosarcus guernyi, as described in, e.g., WO 99/49019 and Peelle et al. (2001) J. Protein Chem. 20:507-519; a GFP from Aequoria victoria or fluorescent mutant thereof, e.g., as described in U.S. Pat. Nos. 6,066,476; 6,020,192; 5,985,577; 5,976,796; 5,968,750; 5,968,738; 5,958,713; 5,919,445; 5,874,304. Generation of such a construct, and production of a RabGGT/fluorescent protein fusion protein is well within the skill level of those of ordinary skill in the art.

[0113] Alternatively, binding may be assayed by fluorescence anisotropy. Fluorescence anisotropy assays are amply described in the literature. See, e.g., Jameson and Sawyer (1995) Methods Enzymol. 246:283-300.

[0114] In some embodiments, the method of determining whether an agent modulates a protein/protein interaction is a yeast two-hybrid assay system or a variation thereof The yeast two-hybrid screen has been described in the literature. See, e.g., Zhu and Kahn (1997) Proc. Natl. Acad. Sci. U.S.A. 94:13063-13068; Fields and Song (1989) Nature 340:245-246; and U.S. Pat. No. 5,283,173; Chien et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88:9578-9581.

[0115] Protein/protein binding can also be assayed by other methods well known in the art, for example, immunoprecipitation with an antibody that binds to the protein in a complex, followed by analysis by size fractionation of the immunoprecipitated proteins (e.g. by denaturing or nondenaturing polyacrylamide gel electrophoresis); Western analysis; non-denaturing gel electrophoresis, etc.

[0116] Chemical Features of Modulators

[0117] In some embodiments, an agent that modulates a level and/or an activity of a RabGGT protein and/or a RabGGT/REP complex is a compound that binds to the binding pocket for the substrate prenyl moiety and/or the peptide substrate in the RabGGT active site. A suitable compound comprises moieties that provide for interactions with amino acid side chains that normally interact with substrate prenyl moiety and/or peptide substrate in the RabGGT active site. Features that a suitable compound possesses include one or more of: (1) zinc binding; (2) hydrogen bonding to specific amino acid side chains; (3) a hydrophobic moiety; (4) a size sufficient to occlude the binding site for the prenyl and/or the peptide substrate; and/or a size sufficient to interface with the size limitations embodied by the binding pocket of the RabGGT alpha and beta subunits, and defined by their respective structure coordinates.

[0118] In some embodiments, a suitable modulator of enzymatic activity of RabGGT or a RabGGT/REP complex is a benzodiazepine. In other embodiments, a suitable modulator of enzymatic activity of RabGGT or a RabGGT/REP complex is a tetrahydroquinoline.

[0119] In other embodiments, a suitable modulator of enzymatic activity of RabGGT or a RabGGT/REP complex may comprise one or more of the side chains, moieties, or groups, or any combinations thereof, of the compounds disclosed in U.S. Pat. No. 6,011,029; U.S. Pat. No. 6,387,926; and/or U.S. Pat. No. 6,458,783, which are hereby incorporated by reference herein in their entirety.

[0120] In one embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may comprise a side chain, moiety, or group capable of chelating zinc, and/or coordinating with zinc. Examples of zinc chelators and/or cooridinators include, but are not limited to the following: thiol, cysteine, cysteine derivative, hydroxamic acid, hydroxamic acid derivative, barbituric acid, barbituric acid derivative, pyridyl, imidazolyl, methionine, nitrogen-containing heterocycles, or other groups known in the art that are capable of chelating and/or coordinating with zinc, or disclosed or referenced herein.

[0121] In another embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may comprise a hydrophobic or aromatic side chain, moiety, or group. Examples of such groups include, but are not limited to the following: phenyl, planar phenyl, aryl, substituted phenyl, cyano substituted phenyl, a cyanobenzene, substituted aryl, heteroaryl, substituted heteroaryl, or other hydrophobic or aromatic side chain, moiety, or group known in the art, or disclosed or referenced herein.

[0122] In another embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may comprise one, two, three, four, or more hydrophobic or aromatic side chains, moieties, or groups.

[0123] In another embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may comprise a side chain, moiety, or group capable of ligating with a water molecule and/or forming one or more hydrogen bonds with a water molecule.

[0124] In yet another embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may comprise a large multicyclic aromatic and/or hydrophobic side chain, moiety, or group. In yet another embodiment, a suitable modulator of RabGGT or a RabGGT/REP complex may not comprise a large multicyclic aromatic and/or hydrophobic side chain, moiety, or group. Examples of such multicyclic aromatic and/or hydrophobic side chains, moieties, or groups may be found in the teachings of I. M. Bell et al, J. Med. Chem. 45:2388 (2002), which is hereby incorporated herein by reference in its entirety.

[0125] A suitable modulator of RabGGT or a RabGGT/REP complex may comprise any combination of one, two, three, four, five, six, seven, eight, nine, ten, or more of the above specified characteristics.

[0126] Pharmacophores

[0127] Suitable modulators of RabGGT or RabGGT/REP activity are pharmacophores that possess appropriate size, volume, charge, and hydrophobicity features to allow interactions with amino acid side chains in the active site that normally interact with prenyl and/or peptide substrates. Such features may be used to identify compounds that are modulators of RabGGT or RabGGT/REP complex activity.

[0128] Features can include topological indices, physicochemical properties, electrostatic field parameters, volume and surface parameters, etc. Other features include, but are not limited to, molecular volume and surface areas, dipole moments, octanol-water partition coefficients, molar refractivities, heats of formation, total energies, ionization potentials, molecular connectivity indices, substructure keys. Such descriptors and their use in the fields of Quantitative Structure-Activity Relationships (QSAR) and molecular diversity are reviewed in Kier, L. B. and Hall L. H., Molecular Connectivity in Chemistry and Drug Research, Academic Press, New York (1976); Kier, L. B. and Hall L. H., Molecular Connectivity in Structure-Activity Analysis, Research Studies Press, Wiley, Letchworth (1986); Kubinyi, H., Methods and Principles in Medicinal Chemistry, Vol. 1, VCH, Weinheim (1993); and P. V. R. Scheyler, Encyclopedia of Computational Chemistry, Wiley (1998).

[0129] In some embodiments, a modulator of an activity of RabGGT or a RabGGT/REP complex is identified by computational quantitative structure activity relationship (QSAR) modeling techniques as a screening device for potency as an inhibitor or activator. Structure-activity relationship (SAR) analysis is performed using any known method. See, e.g., U.S. Pat. No. 6,344,334; U.S. Pat. No. 6,208,942; U.S. Pat. No. 6,453,246; U.S. Pat. No. 6,421,612.

[0130] Suitable compounds can be identified using a selection approach that involves (1) identifying a set of compounds for analysis; (2) collecting, acquiring or synthesizing the identified compounds; (3) analyzing the compounds to determine one or more physical, chemical and/or bioactive properties (structure-property data); and (4) using the structure-property data to identify another set of compounds for analysis in the next iteration. These steps can be repeated multiple times, as necessary to derive suitable compounds with desired properties.

[0131] Suitable compounds may also be identified by subjecting putative modulators of the RabGGTase protein to virtual screens that predict the overall fit of the modulator to the putative binding site(s) of the RabGGTase protein, its alpha subunit, its beta subunit, the RabGGTase/Rep complex, and/or the RabGGTase/Rep/substrate ternary complex. The DOCK3.5 algorithm, among others described herein, may be used for virtually screening RabGGTase modulators. DOCK3.5 is an automatic algorithm to screen small-molecule databases for ligands that could bind to a given receptor (Meng, E. C., et al., 1992, J. Comp. Chem. 15:505). DOCK3.5 characterizes the surface of the active site to be filled with sets of overlapping spheres. The generated sphere centers constitute an irregular grid that is matched to the atomic centers of the potential ligands. The quality of the fit of the ligand to the site is judged by either the shape complementarity or by a simplified estimated interaction energy. Putative RabGGTase modulators having the best shape complementarity scores and the best force field scores may be selected from the screen. The resulting virtual modulators may then be visually screened independently in the context of the RabGGTase binding pocket described herein using the molecular display software Insight II (Biosym Inc., San Diego, Calif.). Such compounds can then be confirmed to have RabGGTase modulating activity by subjecting these compounds to screening assays described herein.

[0132] Preferred RabGGTase modulators have a complementarity score of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, or greater. In this context, “about” should be construed to represent 1 to 13 more or less than the stated complementarity score.

[0133] Small Molecule Modulators

[0134] In some embodiments, an agent that increases or reduces a level and/or an activity of RabGGT or a RabGGT/REP complex is a small molecule. Small molecule agents are generally small organic or inorganic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Specifically, small molecule agents may be at least about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, or 2500. In this context, “about” should be construed to represent more or less than 1 to 25 daltons than the indicated amount.

[0135] Suitable agents may comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and may include at least an amine, carbonyl, hydroxyl or carboxyl group, and may contain at least two of the functional chemical groups. The agents may comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Suitable active agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.

[0136] In some embodiments, agents that reduce enzymatic activity of RabGGT or level of enzymatically active RabGGT are of the following formula:

[0137] or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, or solvate thereof, where m, n, r, s, and 1 are 0 or 1;

[0138] p is 0, 1, or 2;

[0139] V, W, and X are selected from oxygen, hydrogen, R1, R2, or R3;

[0140] Z and Y are selected from CHR9, SO2, SO3, CO, CO2, O, NR10, SO2NR11, CONR12,

[0141] or Z may be absent;

[0142] R6, R7, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 R33, R34, R35, R36, R37, and R38, are each independently selected from hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl;

[0143] R4 and R5 are independently selected from hydrogen, halo, nitro, cyano, and U-R23;

[0144] U is selected from sulfur, oxygen, NR24, CO, SO, SO2, CO2, NR25CO2, NR26CONR27; NR28SO2, NR29SO2NR30, SO2NR31, NR32CO, CONR33, PO2R34, and PO3R35 or U is absent;

[0145] R1, R2, and R3 are each independently selected from hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arakyl, cycolalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxyl, carbamyl (e.g., CONH2) or substituted carbamyl further selected from CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl, or aralkyl, ; R8 and R23 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aalkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;

[0146] any two of R1, r2, and R3 can be joined to form a cycloalkyl group;

[0147] R, S, and T are selected from CH2, CO, and CH(CH2)pQ, wherein Q is NR36R37, OR38, or CN; and

[0148] A, B, and D are carbon, oxygen, sulfur or nitrogen, with the proviso that

[0149] 1) when m is zero, then V and W are not both oxygen; or

[0150] 2) W and X together can be oxygen only if Z is either absent, O, NR10, CHR9,

[0151] 3) R23 may be hydrogen except with U is SO2, CO2, or

[0152] 4) R8 may be hydrogen except when Z is SO2, CO2 or

[0153] In other embodiments, agents that reduce enzymatic activity of RabGGT or level of enzymatically active RabGGT are of the following formula:

[0154] or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, or solvate thereof,

[0155] l, m, r, s, and t are 0 or 1;

[0156] N is 0, 1, or 2;

[0157] Y is selected from CHR12, SO2, SO3, CO, CO2, Y is selected from the group consisting of CHR12 SO2, SO3, CO, CO2, O, NR13, SO2NR14, CONR15, C(NCN), C(NCN)NR16, NR17CO, NR18SO2, CONR19NR20, SO2NR21NR22, S(O)(NR23), S(NR24)NR25), or without Y;

[0158] Z is selected from the group consisting of CR12,S, SO, SO2,SO3CO,CO2, O,NR13SO2NR14,CONR15,NR26NR27,ONR28,NR29O,NR30SO2NR31,NR32SO,NR33C(NCN), NR34,C(NCN)NR35, NR36CO, NR37CO, NR37CONR38, NR39CO2, OCONR40, S(O)(NR41), S(NR42)(NR43) or CHR12;

[0159] or without Z;

[0160] R7, R8 are selected from the group consisting of hydrogen, halo, nitro, cyano and U—R44;

[0161] U is selected from the group consisting of S, O, NR45, CO, SO, SO2, CO2, NR46CO2, NR47CONR48, NR49SO2, NR50SO2NR51, SO2NR52, NR53CO, CONR54, PO2R55 and PO2R56 or without U;

[0162] R9, R10, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58 and R59 are selected from the group consisting of hydrogen, lower alkyl, aryl, heterocyclo, substituted alkyl or aryl or substituted heterocyclo;

[0163] R11 and R44 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;

[0164] R1, R2, R3, R4, R5, and R6 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. CONH2) substituted carbamyl (where nitrogen may be substituted by groups selected from hydrogen, alkyl, substituted alkyl, aryl or aralkyl, substituted aryl, heterocyclo, sub-situated heterocyclo) alkoxycarbonyl; any two of R1, R2, R3, R4, R5, and R6 can join to form a cycloalkyl group; any two of R1, R2, R3, R4, R5, and R6 together can by oxo, except when the carbon atom bearing the substituent is part of a double bond;

[0165] R, S, T are selected from the group consisting of CH2, CO and CH(CH2)Q wherein Q is NR57R58, OR59, or CN; and p is 0, 1 or 2;

[0166] A, B, C are carbon, oxygen, sulfur or nitrogen; D is carbon, oxygen, sulfur or nitrogen or without D,

[0167] with the provisos that:

[0168] 1. When l and m are both 0, n is not 0;

[0169] 2. R11 may be hydrogen except when Z is SO, or when Z is O, NR13 or S and the carbon to which it is attached is part of a double bond or when Y is SO2, CO2, NR18SO2, S(O)(NR23), or S(NR24)(NR25); and

[0170] 3. R44 may be hydrogen except when U is SO, SO2, NR46CO2 or NR49SO2.

[0171] In some embodiments, the agents disclosed in U.S. Pat. No. 6,011,029; U.S. Pat. No. 6,387,926; and/or U.S. Pat. No. 6,458,783 are specifically excluded from the present invention.

[0172] Protein Modulators

[0173] Agents that modulate an activity of a RabGGT include protein modulators. In some embodiments, an active agent is a peptide. Suitable peptides include peptides of from about 3 amino acids to about 50, from about 5 to about 30, or from about 10 to about 25 amino acids in length. In some embodiments, a peptide exhibits one or more of the following activities: inhibits binding of RabGGT to a RabGGT interacting protein; inhibits interaction between an α and a β subunit of RabGGT; inhibits an enzymatic activity of RabGGT. Peptides can include naturally-occurring and non-naturally occurring amino acids. Peptides may comprise D-amino acids, a combination of D- and L-amino acids, and various “designer” amino acids (e.g., β-methyl amino acids, Cα-methyl amino acids, and Nα-methyl amino acids, etc.) to convey special properties to peptides. Additionally, peptide may be a cyclic peptide. Peptides may include non-classical amino acids in order to introduce particular conformational motifs. Any known non-classical amino acid can be used. Non-classical amino acids include, but are not limited to, 1,2,3,4-tetrahydroisoquinoline-3-carboxylate; (2S,3S)-methylphenylalanine, (2S,3R)-methyl-phenylalanine, (2R,3S)-methyl-phenylalanine and (2R,3R)-methyl-phenylalanine; 2-aminotetrahydronaphthalene-2-carboxylic acid; hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate; β-carboline (D and L); HIC (histidine isoquinoline carboxylic acid); and HIC (histidine cyclic urea). Amino acid analogs and peptidomimetics may be incorporated into a peptide to induce or favor specific secondary structures, including, but not limited to, LL-Acp (LL-3-amino-2-propenidone-6-carboxylic acid), a β-turn inducing dipeptide analog; β-sheet inducing analogs; β-turn inducing analogs; α-helix inducing analogs; γ-turn inducing analogs; Gly-Ala turn analog; amide bond isostere; tretrazol; and the like.

[0174] A peptide may be a depsipeptide, which may be a linear or a cyclic depsipeptide. Kuisle et al. (1999) Tet. Letters 40:1203-1206. “Depsipeptides” are compounds containing a sequence of at least two alpha-amino acids and at least one alpha-hydroxy carboxylic acid, which are bound through at least one normal peptide link and ester links, derived from the hydroxy carboxylic acids, where “linear depsipeptides” may comprise rings formed through S—S bridges, or through an hydroxy or a mercapto group of an hydroxy-, or mercapto-amino acid and the carboxyl group of another amino- or hydroxy-acid but do not comprise rings formed only through peptide or ester links derived from hydroxy carboxylic acids. “Cyclic depsipeptides” are peptides containing at least one ring formed only through peptide or ester links, derived from hydroxy carboxylic acids.

[0175] Peptides may be cyclic or bicyclic. For example, the C-terminal carboxyl group or a C-terminal ester can be induced to cyclize by internal displacement of the —OH or the ester (—OR) of the carboxyl group or ester respectively with the N-terminal amino group to form a cyclic peptide. For example, after synthesis and cleavage to give the peptide acid, the free acid is converted to an activated ester by an appropriate carboxyl group activator such as dicyclohexylcarbodiimide (DCC) in solution, for example, in methylene chloride (CH2Cl2), dimethyl formamide (DMF) mixtures. The cyclic peptide is then formed by internal displacement of the activated ester with the N-terminal amine. Internal cyclization as opposed to polymerization can be enhanced by use of very dilute solutions. Methods for making cyclic peptides are well known in the art

[0176] The term “bicyclic” refers to a peptide in which there exists two ring closures. The ring closures are formed by covalent linkages between amino acids in the peptide. A covalent linkage between two nonadjacent amino acids constitutes a ring closure, as does a second covalent linkage between a pair of adjacent amino acids which are already linked by a covalent peptide linkage. The covalent linkages forming the ring closures may be amide linkages, i.e., the linkage formed between a free amino on one amino acid and a free carboxyl of a second amino acid, or linkages formed between the side chains or “R” groups of amino acids in the peptides. Thus, bicyclic peptides may be “true” bicyclic peptides, i.e., peptides cyclized by the formation of a peptide bond between the N-terminus and the C-terminus of the peptide, or they may be “depsi-bicyclic” peptides, i.e., peptides in which the terminal amino acids are covalently linked through their side chain moieties.

[0177] A desamino or descarboxy residue can be incorporated at the terminii of the peptide, so that there is no terminal amino or carboxyl group, to decrease susceptibility to proteases or to restrict the conformation of the peptide. C-terminal functional groups include amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lower ester derivatives thereof, and the pharmaceutically acceptable salts thereof.

[0178] In addition to the foregoing N-terminal and C-terminal modifications, a peptide or peptidomimetic can be modified with or covalently coupled to one or more of a variety of hydrophilic polymers to increase solubility and circulation half-life of the peptide. Suitable nonproteinaceous hydrophilic polymers for coupling to a peptide include, but are not limited to, polyalkylethers as exemplified by polyethylene glycol and polypropylene glycol, polylactic acid, polyglycolic acid, polyoxyalkenes, polyvinylalcohol, polyvinylpyrrolidone, cellulose and cellulose derivatives, dextran and dextran derivatives, etc. Generally, such hydrophilic polymers have an average molecular weight ranging from about 500 to about 100,000 daltons, from about 2,000 to about 40,000 daltons, or from about 5,000 to about 20,000 daltons. The peptide can be derivatized with or coupled to such polymers using any of the methods set forth in Zallipsky, S., Bioconjugate Chem., 6:150-165 (1995); Monfardini, C, et al., Bioconjugate Chem., 6:62-69 (1995); U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; 4,179,337 or WO 95/34326.

[0179] Another suitable agent for modulating an activity of RabGGT is a peptide aptamer. Peptide aptamers are peptides or small polypeptides that act as dominant inhibitors of protein function. Peptide aptamers specifically bind to target proteins, blocking their function ability. Kolonin and Finley, PNAS (1998) 95:14266-14271. Due to the highly selective nature of peptide aptamers, they may be used not only to target a specific protein, but also to target specific functions of a given protein (e.g a signaling function). Further, peptide aptamers may be expressed in a controlled fashion by use of promoters which regulate expression in a temporal, spatial or inducible manner. Peptide aptamers act dominantly; therefore, they can be used to analyze proteins for which loss-of-function mutants are not available.

[0180] Peptide aptamers that bind with high affinity and specificity to a target protein may be isolated by a variety of techniques known in the art. Peptide aptamers can be isolated from random peptide libraries by yeast two-hybrid screens (Xu et al., PNAS (1997) 94:12473-12478). They can also be isolated from phage libraries (Hoogenboom et al., Immunotechnology (1998) 4:1-20) or chemically generated peptides/libraries.

[0181] Antibody Modulators

[0182] In some embodiments, an agent that increases or reduces a level and/or activity of RabGGT is an antibody specific for RabGGT. Antibodies include naturally-occurring antibodies, artificial antibodies, intrabodies, antibody fragments, and the like, that specifically bind a RabGGT polypeptide. In some embodiments, a subject antibody binds specifically to native RabGGT protein, e.g., to native RabGGT protein present in vivo in an individual.

[0183] In many embodiments, a subject antibody is isolated, e.g., is in an environment other than its naturally-occurring environment. In some embodiments, a subject antibody is synthetic. Suitable antibodies are obtained by immunizing a host animal with peptides comprising all or a portion of the subject protein. Suitable host animals include mouse, rat, sheep, goat, hamster, rabbit, etc. The host animal is any mammal that is capable of mounting an immune response to a RabGGT protein, where representative host animals include, but are not limited to, e.g., rabbits, goats, mice, etc.

[0184] The immunogen may comprise the complete protein, or fragments and derivatives thereof. Preferred immunogens comprise all or a part of the protein. Immunogens are produced in a variety of ways known in the art, e.g., expression of cloned genes using conventional recombinant methods, followed by in vitro production of the RabGGT polypeptide; isolation of a RabGGT polypeptide; preparation of fragments of a RabGGT polypeptide using well-known methods, etc.

[0185] In some embodiments, a subject antibody is bound to a solid support or an insoluble support. Insoluble supports include, but are not limited to, beads (including plastic beads, magnetic beads, and the like); plastic plates (e.g., microtiter plates); membranes (e.g., polyvinyl pyrrolidone, nitrocellulose, and the like); and the like.

[0186] For preparation of polyclonal antibodies, the first step is immunization of the host animal with the target protein, where the target protein will preferably be in substantially pure form, comprising less than about 1% contaminant. The immunogen may comprise the complete target protein, fragments or derivatives thereof. To increase the immune response of the host animal, the target protein may be combined with an adjuvant, where suitable adjuvants include alum, dextran, sulfate, large polymeric anions, oil & water emulsions, e.g. Freund's adjuvant, Freund's complete adjuvant, and the like. The target protein may also be conjugated to a carrier, e.g., KLH, BSA, a synthetic carrier protein, and the like. A variety of hosts may be immunized to produce the polyclonal antibodies. Such hosts include rabbits, guinea pigs, rodents, e.g. mice, rats, sheep, goats, and the like. The target protein is administered to the host, e.g., intradermally, with an initial dosage followed by one or more, usually at least two, additional booster dosages. Following immunization, the blood from the host will be collected, followed by separation of the serum from the blood cells. The Ig present in the resultant antiserum may be further fractionated using known methods, such as ammonium salt fractionation, DEAE chromatography, and the like.

[0187] Monoclonal antibodies are produced by conventional techniques. Generally, the spleen and/or lymph nodes of an immunized host animal provide a source of plasma cells. The plasma cells are immortalized by fusion with myeloma cells to produce hybridoma cells. Culture supernatant from individual hybridomas is screened using standard techniques to identify those producing antibodies with the desired specificity. Suitable animals for production of monoclonal antibodies to the human protein include mouse, rat, hamster, etc. The antibody may be purified from the hybridoma cell supernatants or ascites fluid by conventional techniques, e.g. affinity chromatography using protein bound to an insoluble support, protein A sepharose, etc.

[0188] The antibody may be produced as a single chain, instead of the normal multimeric structure. Single chain antibodies are described in Jost et al. (1994) J. Biol. Chem. 269:26267-73, and elsewhere. DNA sequences encoding the variable region of the heavy chain and the variable region of the light chain are ligated to a spacer encoding at least about 4 amino acids of small neutral amino acids, including glycine and/or serine. The protein encoded by this fusion allows assembly of a functional variable region that retains the specificity and affinity of the original antibody.

[0189] Also provided are “artificial” antibodies, e.g., antibodies and antibody fragments produced and selected in vitro. In some embodiments, such antibodies are displayed on the surface of a bacteriophage or other viral particle. In many embodiments, such artificial antibodies are present as fusion proteins with a viral or bacteriophage structural protein, including, but not limited to, M13 gene III protein. Methods of producing such artificial antibodies are well known in the art. See, e.g., U.S. Pat. Nos. 5,516,637; 5,223,409; 5,658,727; 5,667,988; 5,498,538; 5,403,484; 5,571,698; and 5,625,033.

[0190] Also of interest are humanized antibodies. Methods of humanizing antibodies are known in the art. The humanized antibody may be the product of an animal having transgenic human immunoglobulin constant region genes (see for example International Patent Applications WO 90/10077 and WO 90/04036). Alternatively, the antibody of interest may be engineered by recombinant DNA techniques to substitute the CH1, CH2, CH3, hinge domains, and/or the framework domain with the corresponding human sequence (see WO 92/02190).

[0191] The use of Ig cDNA for construction of chimeric immunoglobulin genes is known in the art (Liu et al. (1987) Proc. Natl. Acad. Sci. USA. 84:3439 and (1987) J. Immunol. 139:3521). mRNA is isolated from a hybridoma or other cell producing the antibody and used to produce cDNA. The cDNA of interest may be amplified by the polymerase chain reaction using specific primers (U.S. Pat. Nos. 4,683,195 and 4,683,202). Alternatively, a library is made and screened to isolate the sequence of interest. The DNA sequence encoding the variable region of the antibody is then fused to human constant region sequences. The sequences of human constant regions genes may be found in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, N.I.H. publication no. 91-3242. Human C region genes are readily available from known clones. The choice of isotype will be guided by the desired effector functions, such as complement fixation, or activity in antibody-dependent cellular cytotoxicity. Exemplary isotypes are IgG1, IgG3 and IgG4. Either of the human light chain constant regions, kappa or lambda, may be used. The chimeric, humanized antibody is then expressed by conventional methods. Other methods for preparing chimeric antibodies are described in, e.g., U.S. Pat. No. 5,565,332.

[0192] Antibody fragments, such as Fv, F(ab′)2 and Fab may be prepared by cleavage of the intact protein, e.g. by protease or chemical cleavage. Alternatively, a truncated gene is designed. For example, a chimeric gene encoding a portion of the F(ab′)2 fragment would include DNA sequences encoding the CH1 domain and hinge region of the H chain, followed by a translational stop codon to yield the truncated molecule.

[0193] Consensus sequences of H and L J regions may be used to design oligonucleotides for use as primers to introduce useful restriction sites into the J region for subsequent linkage of V region segments to human C region segments. C region cDNA can be modified by site directed mutagenesis to place a restriction site at the analogous position in the human sequence.

[0194] Expression vectors include plasmids, retroviruses, YACs, BACs; EBV-derived episomes, and the like. A convenient vector is one that encodes a functionally complete human CH or CL immunoglobulin sequence, with appropriate restriction sites engineered so that any VH or VL sequence can be easily inserted and expressed. In such vectors, splicing usually occurs between the splice donor site in the inserted J region and the splice acceptor site preceding the human C region, and also at the splice regions that occur within the human CH exons. Polyadenylation and transcription termination occur at native chromosomal sites downstream of the coding regions. The resulting chimeric antibody may be joined to any strong promoter, including retroviral long terminal repeats (LTRs) and other promoters, e.g. SV-40 early promoter, (Okayama et al. (1983) Mol. Cell. Bio. 3:280), Rous sarcoma virus LTR (Gorman et al. (1982) Proc. Natl. Acad. Sci. USA 79:6777), and moloney murine leukemia virus LTR (Grosschedl et al. (1985) Cell 41:885); native Ig promoters, etc.

[0195] Intrabodies that specifically bind RabGGT polypeptide are expressed in a cell in an individual, where they reduce levels of enzymatically active RabGGT. See, e.g., Marasco et al. (1999) J. Immunol. Methods 231:223-238. Intracellularly expressed antibodies, or intrabodies, are single-chain antibody molecules designed to specifically bind and inactivate target molecules inside cells. See, e.g., Chen et al., Hum. Gen. Ther. (1994) 5:595-601; Hassanzadeh et al., Febs Lett. (1998) 16(1, 2):75-80 and 81-86; Marasco (1997) Gene Ther. 4:11-15; and “Intrabodies: Basic Research and Clinical Gene Therapy Applications” W. A. Marasco, eg., (1998) Springer-Verlag, NY. Inducible expression vectors can be constructed that encode intrabodies that bind specifically to RabGGT polypeptide. These vectors are introduced into an individual, and production of the intrabody induced by administration to the individual of the inducer. Alternatively, the expression vector encoding the intrabody provides for constitutive production of the intrabody.

[0196] A subject antibody may be labeled. Suitable labels include radioisotopes; enzymes whose products are detectable (e.g., luciferase, β-galactosidase, and the like); fluorescent labels (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g., 152Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA; chemiluminescent compounds, e.g., luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g., luciferin, aequorin (a green fluorescent protein), and the like.

[0197] Suitable detectable moieties include, but are not limited to, fluorescent, metallic, enzymatic and radioactive markers such as fluorescent proteins, biotin, gold, ferritin, alkaline phosphatase, β-galactosidase, luciferase, horse radish peroxidase, peroxidase, urease, fluorescein, rhodamine, tritium, 14C, and iodination. The binding agent, e.g., an antibody, can be used as a fusion protein, where the fusion partner is a fluorescent protein. Fluorescent proteins include, but are not limited to, a green fluorescent protein from Aequoria victoria or a mutant or derivative thereof e.g., as described in U.S. Pat. Nos. 6,066,476; 6,020,192; 5,985,577; 5,976,796; 5,968,750; 5,968,738; 5,958,713; 5,919,445; 5,874,304; e.g., Enhanced GFP, many such GFP which are available commercially, e.g., from Clontech, Inc.; any of a variety of fluorescent and colored proteins from Anthozoan species, as described in, e.g., Matz et al. (1999) Nature Biotechnol. 17:969-973; and the like.

[0198] Nucleic Acid Modulators

[0199] In some embodiments, an agent that modulates a level of RabGGT is a nucleic acid. Nucleic acid modulators of RabGGT levels include RNAi, ribozymes, and antisense RNA.

[0200] In some embodiments, the active agent is an interfering RNA (RNAi). RNAi includes double-stranded RNA interference (dsRNAi). Use of RNAi to reduce a level of a particular mRNA and/or protein is based on the interfering properties of double-stranded RNA derived from the coding regions of gene. In one example of this method, complementary sense and antisense RNAs derived from a substantial portion of the RabGGT gene are synthesized in vitro. The resulting sense and antisense RNAs are annealed in an injection buffer, and the double-stranded RNA injected or otherwise introduced into the subject (such as in their food or by soaking in the buffer containing the RNA). See, e.g., WO99/32619. In another embodiment, dsRNA derived from a RabGGT gene is generated in vivo by simultaneous expression of both sense and antisense RNA from appropriately positioned promoters operably linked to RabGGT coding sequences in both, sense and antisense orientations.

[0201] Antisense molecules can be used to down-regulate expression of the gene encoding RabGGT in cells. Antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.

[0202] The anti-sense reagent may be antisense oligonucleotides (ODN), particularly synthetic ODN having chemical modifications from native nucleic acids, or nucleic acid constructs that express such anti-sense molecules as RNA. The antisense sequence is complementary to the mRNA of the targeted gene, and inhibits expression of the targeted gene products. Antisense molecules inhibit gene expression through various mechanisms, e.g. by reducing the amount of mRNA available for translation, through activation of RNAse H, or steric hindrance. One or a combination of antisense molecules may be administered, where a combination may comprise multiple different sequences.

[0203] Antisense molecules may be produced by expression of all or a part of the target gene sequence in an appropriate vector, where the transcriptional initiation is oriented such that an antisense strand is produced as an RNA molecule. Alternatively, the antisense molecule is a synthetic oligonucleotide. Antisense oligonucleotides will generally be at least about 7, usually at least about 12, more usually at least about 20 nucleotides in length, and not more than about 500, usually not more than about 50, more usually not more than about 35 nucleotides in length, where the length is governed by efficiency of inhibition, specificity, including absence of cross-reactivity, and the like. It has been found that short oligonucleotides, of from 7 to 8 bases in length, can be strong and selective inhibitors of gene expression (see Wagner et al. (1996), Nature Biotechnol. 14:840-844).

[0204] A specific region or regions of the endogenous sense strand mRNA sequence is chosen to be complemented by the antisense sequence. Selection of a specific sequence for the oligonucleotide may use an empirical method, where several candidate sequences are assayed for inhibition of expression of the target gene in an in vitro or animal model. A combination of sequences may also be used, where several regions of the mRNA sequence are selected for antisense complementation.

[0205] Antisense oligonucleotides may be chemically synthesized by methods known in the art (see Wagner et al. (1993), supra, and Milligan et al., supra.) Preferred oligonucleotides are chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. A number of such modifications have been described in the literature, which modifications alter the chemistry of the backbone, sugars or heterocyclic bases.

[0206] Among useful changes in the backbone chemistry are phosphorothioates; phosphorodithioates, where both of the non-bridging oxygens are substituted with sulfur; phosphoroamidites; alkyl phosphotriesters and boranophosphates. Achiral phosphate derivatives include 3′-O′-5′-S-phosphorothioate, 3′-S-5′-O-phosphorothioate, 3′-CH2-5′-O-phosphonate and 3′-NH-5′-O-phosphoroamidate. Peptide nucleic acids replace the entire ribose phosphodiester backbone with a peptide linkage. Sugar modifications are also used to enhance stability and affinity. The β-anomer of deoxyribose may be used, where the base is inverted with respect to the natural α-anomer. The 2′-OH of the ribose sugar may be altered to form 2′-O-methyl or 2′-O-allyl sugars, which provides resistance to degradation without comprising affinity. Modification of the heterocyclic bases must maintain proper base pairing. Some useful substitutions include deoxyuridine for deoxythymidine; 5-methyl-2′-deoxycytidine and 5-bromo-2′-deoxycytidine for deoxycytidine. 5-propynyl-2′-deoxyuridine and 5-propynyl-2′-deoxycytidine have been shown to increase affinity and biological activity when substituted for deoxythymidine and deoxycytidine, respectively.

[0207] Exemplary modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts.

[0208] Oligonucleotides having a morpholino backbone structure (Summerton, J. E. and Weller D. D., U.S. Pat. No. 5,034,506) or a peptide nucleic acid (PNA) backbone (P. E. Nielson, M. Egholm, R. H. Berg, O. Buchardt, Science 1991, 254: 1497) can also be used. Morpholino antisense oligonucleotides are amply described in the literature. See, e.g., Partridge et al. (1996) Antisense Nucl. Acid Drug Dev. 6:169-175; and Summerton (1999) Biochem. Biophys. Acta 1489:141-158.

[0209] In another embodiment, the antisense oligomer is a phosphothioate morpholino oligomer (PMO). PMOs are assembled from four different morpholino subunits, each of which contain one of four genetic bases (A, C, G, or T) linked to a six-membered morpholine ring. Polymers of these subunits are joined by non-ionic phosphodiamidate intersubunit linkages. Details of how to make and use PMOs and other antisense oligomers are well known in the art (e.g. see WO99/18193; Probst J C, Antisense Oligodeoxynucleotide and Ribozyme Design, Methods. (2000) 22(3):271-281; Summerton J, and Weller D. 1997 Antisense Nucleic Acid Drug Dev. :7:187-95; U.S. Pat. No. 5,235,033; and U.S. Pat. No. 5,378,841).

[0210] As an alternative to anti-sense inhibitors, catalytic nucleic acid compounds, e.g. ribozymes, anti-sense conjugates, etc. may be used to inhibit gene expression. Ribozymes may be synthesized in vitro and administered to the patient, or may be encoded on an expression vector, from which the ribozyme is synthesized in the targeted cell (for example, see International patent application WO 9523225, and Beigelman et al. (1995), Nucl. Acids Res. 23:4434-42). Examples of oligonucleotides with catalytic activity are described in WO 9506764. Conjugates of anti-sense ODN with a metal complex, e.g. terpyridylCu(II), capable of mediating mRNA hydrolysis are described in Bashkin et al. (1995), Appl. Biochem. Biotechnol. 54:43-56.

[0211] Alternative RabGGT nucleic acid modulators are double-stranded RNA species mediating RNA interference (RNAi). RNAi is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) that is homologous in sequence to the silenced gene. Methods relating to the use of RNAi to silence genes in C. elegans, Drosophila, plants, and humans are known in the art (Fire A, et al., 1998 Nature 391:806-811; Fire, A. Trends Genet. 15, 358-363 (1999); Sharp, P. A. RNA interference 2001. Genes Dev. 15, 485-490 (2001); Hammond, S. M., et al., Nature Rev. Genet. 2, 110-1119 (2001); Tuschl, T. Chem. Biochem. 2, 239-245 (2001); Hamilton, A. et al., Science 286, 950-952 (1999); Hammond, S. M., et al., Nature 404, 293-296 (2000); Zamore, P. D., et al., Cell 101, 25-33 (2000); Bernstein, E., et al., Nature 409, 363-366 (2001); Elbashir, S. M., et al., Genes Dev. 15, 188-200 (2001); WO0129058; WO9932619; Elbashir S M, et al., 2001 Nature 411:494-498).

Methods of Determining Tumor Susceptibility

[0212] In some embodiments, the present invention provides methods for determining the susceptibility of a tumor to treatment by administration of a RabGGT inhibitor. In some embodiments, the methods comprise: a) detecting a level of RabGGT protein in a cell in an individual; and b) administering to the individual an effective amount of a RabGGT modulating agent. In other embodiments, the methods comprise: a) detecting a level of RabGGT enzymatic activity in a cell in an individual; and b) administering to the individual an effective amount of a RabGGT modulating agent. In other embodiments, the methods comprise: a) detecting a level of RabGGT mRNA in a cell in an individual; and b) administering to the individual an effective amount of a RabGGT modulating agent.

[0213] Methods of detecting a level of RabGGT protein, methods of detecting a level of RabGGT enzymatic activity, and methods of detecting a level of RabGGT mRNA are described above.

[0214] In some embodiments, the methods further comprise administering an effective amount of amount of a RabGGT inhibitor to an individual having a tumor that is susceptible to treatment with a RabGGT inhibitor.

Disorders Amenable to Treatment

[0215] Disorders amenable to treatment with the methods of the present invention include disorders associated with or caused by uncontrolled cell proliferation; disorders amenable to treatment by inducing apoptosis; and disorders associated with or caused by excessive apoptosis.

[0216] Disorders which can be treated using methods of the invention for inducing apoptosis include, but are not limited to, undesired, excessive, or uncontrolled cellular proliferation, including, for example, neoplastic cells; as well as any undesired cell or cell type in which induction of cell death is desired, e.g., virus-infected cells and self-reactive immune cells. The methods may be used to treat follicular lymphomas, carcinomas associated with p53 mutations; autoimmune disorders, such as, for example, systemic lupus erythematosus (SLE), immune-mediated glomerulonephritis; hormone-dependent tumors, such as, for example, breast cancer, prostate cancer and ovary cancer; and viral infections, such as, for example, herpesviruses, poxviruses and adenoviruses.

[0217] Disorders which can be treated using the methods of the invention for reducing apoptosis in a eukaryotic cell, include, but are not limited to, cell death associated with Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, septic shock, sepsis, stroke, central nervous system inflammation, osteoporosis, ischemia, reperfusion injury, cell death associated with cardiovascular disease, polycystic kidney disease, cell death of endothelial cells in cardiovascular disease, degenerative liver disease, multiple sclerosis, amyotropic lateral sclerosis, cerebellar degeneration, ischemic injury, cerebral infarction, myocardial infarction, acquired immunodeficiency syndrome (AIDS), myelodysplastic syndromes, aplastic anemia, male pattern baldness, and head injury damage. Also included are conditions in which DNA damage to a cell is induced by, e.g., irradiation, radiomimetic drugs, and the like. Also included are any hypoxic or anoxic conditions, e.g., conditions relating to or resulting from ischemia, myocardial infarction, cerebral infarction, stroke, bypass heart surgery, organ transplantation, neuronal damage, and the like.

[0218] Cancer

[0219] Generally, cells in a benign tumor retain their differentiated features and do not divide in a completely uncontrolled manner. A benign tumor is usually localized and nonmetastatic. Specific types benign tumors that can be treated using the present invention include hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal, nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.

[0220] In a malignant tumor cells become undifferentiated, do not respond to the body's growth control signals, and multiply in an uncontrolled manner. The malignant tumor is invasive and capable of spreading to distant sites (metastasizing). Malignant tumors are generally divided into two categories: primary and secondary. Primary tumors arise directly from the tissue in which they are found. A secondary tumor, or metastasis, is a tumor which originated elsewhere in the body but has now spread to a distant organ. The common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid, cerebrospinal fluid, etc.)

[0221] Specific types of cancers or malignant tumors, either primary or secondary, that can be treated using this invention include leukemia, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma, glioblastoma multiforme, leukemias, lymphomas, malignant melanomas, epidermoid carcinomas, and other carcinomas and sarcomas.

[0222] Subjects to be treated according to the methods of the invention include any individual having any of the above-mentioned disorders. Further included are individuals who are at risk of developing any of the above-mentioned disorders, including, but not limited to, an individual who has suffered a myocardial infarction, and is therefore at risk for experiencing a subsequent myocardial infarction; an individual who has undergone organ or tissue transplantation; an individual who has had a stroke and is at risk for having a subsequent stroke; and an individual at risk of developing an autoimmune disorder due to genetic predisposition, or due to the appearance of early symptoms of autoimmune disorder.

[0223] Determining Efficacy of Treatment

[0224] Whether a tumor load has been decreased can be determined using any known method, including, but not limited to, measuring solid tumor mass; counting the number of tumor cells using cytological assays; fluorescence-activated cell sorting (e.g., using antibody specific for a tumor-associated antigen); computed tomography scanning, magnetic resonance imaging, and/or x-ray imaging of the tumor to estimate and/or monitor tumor size; measuring the amount of tumor-associated antigen in a biological sample, e.g., blood; and the like.

Formulations, Dosages, and Routes of Administration

[0225] Formulations

[0226] An agent that modulates a level and/or activity of RabGGT may be formulated in a variety of ways. For example, and agent may include a buffer, which is selected according to the desired use of the agent, and may also include other substances appropriate to the intended use. Those skilled in the art can readily select an appropriate buffer, a wide variety of which are known in the art, suitable for an intended use. In some instances, the composition can comprise a pharmaceutically acceptable excipient, a variety of which are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, “Remington: The Science and Practice of Pharmacy”, 19th Ed. (1995), or latest edition, Mack Publishing Co; A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy”, 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H. C. Ansel et al., eds 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.

[0227] In the subject methods, the active agent(s) may be administered to the host using any convenient means capable of resulting in the desired modulation in a level and/or an activity of RabGGT. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[0228] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[0229] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[0230] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0231] The agents can be utilized in aerosol formulation to be administered via inhalation. The compounds of the present invention can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.

[0232] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present invention can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[0233] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[0234] The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.

[0235] The specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0236] Other modes of administration will also find use with the subject invention. For instance, an agent of the invention can be formulated in suppositories and, in some cases, aerosol and intranasal compositions. For suppositories, the vehicle composition will include traditional binders and carriers such as, polyalkylene glycols, or triglycerides. Such suppositories may be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10% (w/w), preferably about 1% to about 2%.

[0237] Intranasal formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function. Diluents such as water, aqueous saline or other known substances can be employed with the subject invention. The nasal formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride. A surfactant may be present to enhance absorption of the subject proteins by the nasal mucosa.

[0238] An agent of the invention can be administered as injectables. Typically, injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.

[0239] Suitable excipient vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985. The composition or formulation to be administered will, in any event, contain a quantity of the agent adequate to achieve the desired state in the subject being treated.

[0240] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[0241] Dosages

[0242] Although the dosage used will vary depending on the clinical goals to be achieved, a suitable dosage range is one which provides up to about 1 μg to about 1,000 μg or about 10,000 μg of an agent that reduces a level and/or an activity of RabGGT can be administered in a single dose. Alternatively, a target dosage of an agent that modulates a level and/or an activity of RabGGT can be considered to be about in the range of about 0.1-1000 μM, about 0.5-500 μM, about 1-100 μM, or about 5-50 μM in a sample of host blood drawn within the first 24-48 hours after administration of the agent.

[0243] Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0244] Routes of Administration

[0245] An agent that modulates a level and/or activity of RabGGT may be administered (including self-administered) orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, intratumorally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.

[0246] An agent that modulates a level and/or activity of RabGGT may be administered by a variety of routes, and may be administered in any conventional dosage form. In some embodiments, an agent that modulates a level and/or activity of RabGGT is administered in combination therapy (e.g., is “coadministered) with at least a second therapeutic agent. Coadministration in the context of this invention is defined to mean the administration of more than one therapeutic in the course of a coordinated treatment to achieve an improved clinical outcome. Such coadministration may also be coextensive, that is, occurring during overlapping periods of time.

[0247] One route of administration or coadministration is local delivery. Local delivery of an effective amount of an agent that modulates an activity and/or level of RabGGT can be by a variety of techniques and devices that administer the agent(s) at or near a desired site. Examples of local delivery techniques and structures are not intended to be limiting but rather as illustrative of the techniques and structures available. Examples include local delivery catheters, site specific carriers, implants, direct injection, or direct applications.

[0248] Local delivery by a catheter allows the administration of an agent directly to the desired site. Examples of local delivery using a balloon catheter are described in EP 383 492 A2 and U.S. Pat. No. 4,636,195 to Wolinsky. Additional examples of local, catheter-based techniques and structures are disclosed in U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat No. 5,286,254 to Shapland et al.

[0249] Generally, the catheter must be placed such that the agent is delivered at or near the desired site. Dosages delivered through the catheter can vary, according to determinations made by one of skill, but often are in amounts effective to generate the desired effect at the local site. Preferably, these total amounts are less than the total amounts for systemic administration of an agent, and are less than the maximum tolerated dose. The agent(s) delivered through catheters is generally formulated in a viscosity that enables delivery through a small treatment catheter, and may be formulated with pharmaceutically acceptable additional ingredients (active and inactive).

[0250] Local delivery by an implant describes the placement of a matrix that contains an agent into the desired site. The implant may be deposited by surgery or other means. The implanted matrix releases the agent by diffusion, chemical reaction, solvent activators, or other equivalent mechanisms. Examples are set forth in Lange, Science 249:1527-1533 (September, 1990). Often the implants may be in a form that releases the agent over time; these implants are termed time-release implants. The material of construction for the implants will vary according to the nature of the implant and the specific use to which it will be put. For example, biostable implants may have a rigid or semi-rigid support structure, with agent delivery taking place through a coating or a porous support structure. Other implants made be made of a liquid that stiffens after being implanted or may be made of a gel. The amounts of agent present in or on the implant may be in an amount effective to treat cell proliferation generally, or a specific proliferation indication, such as the indications discussed herein. One example of local delivery of an agent by an implant is use of a biostable or bioabsorbable plug or patch or similar geometry that can deliver the agent once placed in or near the desired site.

[0251] A non-limiting example of local delivery by an implant is the use of a stent. Stents are designed to mechanically prevent the collapse and reocclusion of the coronary arteries. Incorporating an agent into the stent may deliver the agent directly to or near the proliferative site. Certain aspects of local delivery by such techniques and structures are described in Kohn, Pharmaceutical Technology (October, 1990). Stents may be coated with the agent to be delivered. Examples of such techniques and structures may be found in U.S. Pat. No. 5,464,650 to Berg et al., U.S. Pat. No. 5,545,208 to Wolff et al., U.S. Pat. No. 5,649,977 to Campbell, U.S. Pat. No. 5,679,400 to Tuch, EP 0 716 836 to Tartaglia et al. Alternatively, the agent-loaded stent may be bioerodable, i.e. designed to dissolve, thus releasing the agent in or near the desired site, as disclosed in U.S. Pat. No. 5,527,337 to Stack et al. The present invention can be used with a wide variety of stent configurations, including, but not limited to shape memory alloy stents, expandable stents, and stents formed in situ.

[0252] Another example is a delivery system in which a polymer that contains an agent is injected into the target cells in liquid form. The polymer then cures to form the implant in situ. One variation of this technique and structure is described in WO 90/03768.

[0253] Another example is the delivery of an agent by polymeric endoluminal sealing. This technique and structure uses a catheter to apply a polymeric implant to the interior surface of the lumen. The agent incorporated into the biodegradable polymer implant is thereby released at the desired site. One example of this technique and structure is described in WO 90/01969.

[0254] Another example of local delivery by an implant is by direct injection of vesicles or microparticulates into the desired site. These microparticulates may comprise substances such as proteins, lipids, carbohydrates or synthetic polymers. These microparticulates have an agent incorporated throughout the microparticle or over the microparticle as a coating. Examples of delivery systems incorporating microparticulates are described in Lange, Science, 249:1527-1533 (September, 1990) and Mathiowitz, et al., J. App. Poly Sci. 26:809 (1981).

[0255] Local delivery by site specific carriers may involve linking an agent to a carrier which will direct the drug to the desired site. Examples of this delivery technique and structure include the use of carriers such as a protein ligand or a monoclonal antibody. Certain aspects of these techniques and structures are described in Lange, Science 249:1527-1533.

[0256] Local delivery also includes the use of topical applications. An example of a local delivery by topical application is applying an agent directly to an arterial bypass graft during a surgical procedure. Other equivalent examples will no doubt occur to one of skill in the art.

[0257] Combination Therapies

[0258] An agent that reduces the level and/or activity of RabGGT may be administered in combination therapy with one or more additional therapeutic agents.

[0259] An agent that reduces the level and/or activity of RabGGT may be administered in combination therapy with one or more antiangiogenesis agents to inhibit undesirable and uncontrolled angiogenesis. Examples of anti-angiogenesis agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™ protein, ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor of metalloproteinase-I, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulphate (clupeine), sulfated chitin derivatives, sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((I-azetidine-2-carboxylic acid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline], α, α-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, β-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), β-1-anticollagenase-serum, α2-antiplasmin, bisantrene, lobenzarit disodium, n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”, thalidomide; angostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, e.g., monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. Ferrara N. and Alitalo, K. “Clinical application of angiogenic growth factors and their inhibitors” (1999) Nature Medicine 5:1359-1364.

[0260] An agent that reduces the level and/or activity of RabGGT may be administered in combination therapy with one or more antiproliferative agents, or as an adjuvant to a standard cancer treatment. Standard cancer therapies include surgery (e.g., surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations of the foregoing.

[0261] Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.

[0262] Chemotherapeutic agents are non-peptidic (i.e., non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.

[0263] Agents that act to reduce cellular proliferation are known in the art and widely used. Such agents include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (Cytoxan™), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.

[0264] Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5-fluorouracil (5-FU), methotrexate, 10-propargyl-5,8-dideazafolate (PDDF, CB3717), 5,8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemeitabine.

[0265] Suitable natural products and their derivatives, (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), include, but are not limited to, Ara-C, paclitaxel (Taxol®), docetaxel (Taxotere®), deoxycoformycin, mitomycin-C, L-asparaginase, azathioprine; brequinar; alkaloids, e.g. vincristine, vinblastine, vinorelbine, vindesine, etc.; podophyllotoxins, e.g. etoposide, teniposide, etc.; antibiotics, e.g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc.; phenoxizone biscyclopeptides, e.g. dactinomycin; basic glycopeptides, e.g. bleomycin; anthraquinone glycosides, e.g. plicamycin (mithramycin); anthracenediones, e.g mitoxantrone; azirinopyrrolo indolediones, e.g. mitomycin; macrocyclic immunosuppressants, e.g. cyclosporine, FK-506 (tacrolimus, prograf), rapamycin, etc.; and the like.

[0266] Other anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0267] Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol™), Taxol™ derivatives, docetaxel (Taxotere™), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.

[0268] Hormone modulators and steroids (including synthetic analogs) that are suitable for use include, but are not limited to, adrenocorticosteroids, e.g. prednisone, dexamethasone, etc.; estrogens and pregestins, e.g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc.; and adrenocortical suppressants, e.g. aminoglutethimide; 17α-ethinylestradiol; diethylstilbestrol, testosterone, fluoxymesterone, dromostanolone propionate, testolactone, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, Flutamide (Drogenil), Toremifene (Fareston), and Zoladex™. Estrogens stimulate proliferation and differentiation, therefore compounds that bind to the estrogen receptor are used to block this activity. Corticosteroids may inhibit T cell proliferation.

[0269] Other chemotherapeutic agents include metal complexes, e.g. cisplatin (cis-DDP), carboplatin, etc.; ureas, e.g. hydroxyurea; and hydrazines, e.g. N-methylhydrazine; epidophyllotoxin; a topoisomerase inhibitor; procarbazine; mitoxantrone; leucovorin; tegafur; etc. Other anti-proliferative agents of interest include immunosuppressants, e.g. mycophenolic acid, thalidomnide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa® (ZD 1839, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline); etc.

[0270] “Taxanes” include paclitaxel, as well as any active taxane derivative or pro-drug. “Paclitaxel” (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOL™, TAXOTERE™ (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3′N-desbenzoyl-3′N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP 590,267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Mo. (T7402 from Taxus brevifolia; or T-1912 from Taxus yannanensis).

[0271] Paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogs and derivatives (e.g., Taxotere™ docetaxel, as noted above) and paclitaxel conjugates (e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylose).

[0272] Also included within the term “taxane” are a variety of known derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U.S. Pat. No. 5,869,680; 6-thio derivatives described in WO 98/28288; sulfenamide derivatives described in U.S. Pat. No. 5,821,263; and taxol derivative described in U.S. Pat. No. 5,415,869. It further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U.S. Pat. No. 5,824,701.

[0273] Biological response modifiers suitable for use in connection with the methods of the invention include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen; (4) apoptosis receptor agonists; (5) interleukin-2; (6) IFN-α; (7) IFN-γ (8) colony-stimulating factors; (9) inhibitors of angiogenesis; and (10) antagonists of tumor necrosis factor.

Screening Methods

[0274] The present invention provides methods of identifying an agent that induces apoptosis and/or inhibits cell proliferation. The method comprises screening a test agent in an assay system that detects changes in RabGGT level or activity. Any of the methods previously discussed for determining RagGGT protein level, RabGGT mRNA level, RabGGT enzymatic activity, RabGGT binding activity, etc. can be used in the assay system. For the discovery of small molecule modulators, the assay system may employ high-throughput screening of a combinatorial library. A small molecule that is identified as reducing RabGGT levels or activity is then further tested to determine whether it induces apoptosis in a cell and/or inhibit cell proliferation. In an alternative embodiment, a compound already known to induce apoptosis and/or inhibit cell proliferation may serve as the test agent to determine whether the mechanism of action of the compound is through targeting RabGGT. A compound identified as inhibiting RabGGT activity and having an apoptotic and/or anti-proliferative effect on cells may serve as a “lead compound” from which further “analog compounds” are designed and synthesized in a drug development/optimization process to improve structure-activity relationship and other properties such as absorption, distribution, metabolism and excretion (ADME), etc. Typically, the analog compounds are synthesized to have an electronic configuration and a molecular conformation similar to that of the lead compound.

[0275] Identification of analog compounds can be performed through use of techniques such as self-consistent field (SCF) analysis, configuration interaction (CI) analysis, and normal mode dynamics analysis. Computer programs for implementing these techniques are available. See, e.g., Rein et al., (1989) Computer-Assisted Modeling of Receptor-Ligand Interactions (Alan Liss, New York). Once analogs have been prepared, they can be screened using the methods disclosed herein to identify those analogs that exhibit an increased ability to modulate RabGGT activity. Such compounds can then be subjected to further analysis to identify those compounds that have the greatest potential as pharmaceutical agents. Alternatively, analogs shown to have activity through the screening methods can serve as lead compounds in the preparation of still further analogs, which can be screened by the methods described herein. The cycle of screening, synthesizing analogs and re-screening can be repeated multiple times.

[0276] Compounds identified as having the greatest potential as pharmaceutical agents are identified as “clinical compounds” and their safety and efficacy are further evaluated in clinical trials. Kits may be prepared comprising a clinical compound and instructions for administering the clinical compound to a patient afflicted with a disorder associated with undesired or uncontrolled cell proliferation.

[0277] The present invention further provides methods of identifying agents that selectively modulate a level and/or an activity, e.g., an enzymatic activity, of RabGGT. The present invention further provides methods of identifying agents that selectively modulate a level and/or activity of a RabGGT/REP complex.

[0278] An agent that selectively modulates a level and/or an enzymatic activity of RabGGT is an agent that does not substantially modulate a level or an enzymatic activity of another (non-RabGGT) enzyme, including farnesyl transferase, e.g., the agent modulates the level or activity of another enzyme by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the activity the enzyme in the absence of the agent. Thus, in some embodiments, an agent that selectively modulates a level and/or an enzymatic activity of RabGGT modulates the activity of a farnesyl transferase by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the level or the activity the farnesyl transferase in the absence of the agent. An agent that selectively modulates the level and/or enzymatic activity of RabGGT is suitable for use in a method of the present invention.

[0279] Certain screening methods involve screening for a compound that modulates the expression of the RabGGT gene. Such methods generally involve conducting cell-based assays in which test compounds are contacted with one or more cells expressing RabGGT and then detecting an increase in RabGGT gene expression (either transcript or translation product). Some assays are performed with cells that express endogenous RabGGT. Other expression assays are conducted with cells that do not express endogenous RabGGT, but that express an exogenous RabGGT sequence.

[0280] RabGGT expression can be detected in a number of different ways. The expression level of a RabGGT in a cell can be determined by probing the mRNA expressed in a cell with a probe that specifically hybridizes with a transcript (or complementary nucleic acid derived therefrom) of RabGGT. Probing can be conducted by lysing the cells and conducting Northern blots or without lysing the cells using in situ-hybridization techniques. Alternatively, RabGGT protein can be detected using immunological methods in which a cell lysate is probe with antibodies that specifically bind to RabGGT protein.

[0281] Other cell-based assays are reporter assays conducted with cells that do not express RabGGT. Certain of these assays are conducted with a heterologous nucleic acid construct that includes a RabGGT promoter that is operably linked to a reporter gene that encodes a detectable product. A number of different reporter genes can be utilized. Some reporters are inherently detectable. An example of such a reporter is green fluorescent protein that emits fluorescence that can be detected with a fluorescence detector. Other reporters generate a detectable product. Often such reporters are enzymes. Exemplary enzyme reporters include, but are not limited to, β-glucuronidase, CAT (chloramphenicol acetyl transferase; Alton and Vapnek (1979) Nature 282:864-869), luciferase, β-galactosidase and alkaline phosphatase (Toh, et al. (1980) Eur. J. Biochem. 182:231-238; and Hall et al. (1983) J. Mol. Appl. Gen. 2:101).

[0282] In these assays, cells harboring the reporter construct are contacted with a test compound. A test compound that either activates the promoter by binding to it or triggers a cascade that produces a molecule that activates the promoter causes expression of the detectable reporter. Certain other reporter assays are conducted with cells that harbor a heterologous construct that includes a transcriptional control element that activates expression of RabGGT and a reporter operably linked thereto. Here, too, an agent that binds to the transcriptional control element to activate expression of the reporter or that triggers the formation of an agent that binds to the transcriptional control element to activate reporter expression, can be identified by the generation of signal associated with reporter expression.

[0283] The level of expression or activity can be compared to a baseline value. As indicated above, the baseline value can be a value for a control sample or a statistical value that is representative of RabGGT expression levels for a control population (e.g., healthy individuals not at risk for neurological injury such as stroke). Expression levels can also be determined for cells that do not express a RabGGT as a negative control. Such cells generally are otherwise substantially genetically the same as the test cells.

[0284] A variety of different types of cells can be utilized in the reporter assays. In general, eukaryotic cells are used. The eukaryotic cells can be any of the cells typically utilized in generating cells that harbor recombinant nucleic acid constructs. Exemplary eukaryotic cells include, but are not limited to, yeast, and various higher eukaryotic cells such as the COS, CHO and HeLa cell lines.

[0285] Various controls can be conducted to ensure that an observed activity is authentic including running parallel reactions with cells that lack the reporter construct or by not contacting a cell harboring the reporter construct with test compound. Compounds can also be further validated as described below.

[0286] Compounds that are initially identified by any of the foregoing screening methods can be further tested to validate the apparent activity. The basic format of such methods involves administering a lead compound identified during an initial screen to a non-human animal that serves as a model for humans and then determining if a RabGGT activity is in fact modulated. The non-human animal models utilized in validation studies generally are mammals. Specific examples of suitable animals include, but are not limited to, primates, mice, and rats.

[0287] The present invention provides a method for identifying an agent that selectively modulates the enzymatic activity of a RabGGT enzyme, the method generally involving measuring the enzymatic activity of a RabGGT enzyme in the presence of a test agent; and measuring the enzymatic activity of a famesyl transferase enzyme in the presence of the test agent. A test agent that modulates the enzymatic activity of the RabGGT enzyme, and that does not substantially modulate the enzymatic activity of the farnesyl transferase enzyme, is considered to selectively modulate the enzymatic activity of the RabGGT enzyme. In general, a test ageni that modulates the enzymatic activity of RabGGT by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, compared to the RabGGT enzymatic activity in the absence of the agent, and that modulates the enzymatic activity of the farnesyl transferase activity by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the activity the farnesyl transferase in the absence of the agent, is considered to selectively modulate the enzymatic activity of the RabGGT enzyme.

[0288] The enzymatic activity of RabGGT can be determined using any known method. For example, RabGGT enzymatic activity is quantified using a filter binding assay that measures the transfer of (3H) geranylgeranyl groups (GG) from all-trans-(3H)geranylgeranyl pyrophosphate (3H-GGPP) to recombinant Rab3A protein (Shen and Seabra (1996) J. Biol. Chem. 271:3692; Armstrong et al. (1996) Methods in Enzymology 257:30), or as described in the Examples.

[0289] The enzymatic activity of farnesyl transferase can be measured using any known method, e.g., the method described in Mann et al. (1995) Drug Dev. Res. 34:121, or in Ding et al. (1999) J. Med. Chem. 42:5241.

[0290] The terms “candidate agent,” “test agent,” “agent”, “substance” and “compound” are used interchangeably herein. Candidate agents encompass numerous chemical classes, typically synthetic, semi-synthetic, or naturally-occurring inorganic or organic molecules. Candidate agents include those found in large libraries of synthetic or natural compounds. For example, synthetic compound libraries are commercially available from Maybridge Chemical Co. (Trevillet, Cornwall, UK), ComGenex (South San Francisco, Calif.), and MicroSource (New Milford, Conn.). A rare chemical library is available from Aldrich (Milwaukee, Wis.). Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available from Pan Labs (Bothell, Wash.) or are readily producible.

[0291] Candidate agents may be small organic or inorganic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents may comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and may include at least an amine, carbonyl, hydroxyl or carboxyl group, and may contain at least two of the functional chemical groups. The candidate agents may comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.

[0292] Of particular interest are agents that inhibit the enzymatic activity of RabGGT and that induce apoptosis in a cell. Thus, in some embodiments, the methods involve: a) measuring the enzymatic activity of a RabGGT enzyme in the presence of a test agent; b) measuring the enzymatic activity of a farnesyl transferase enzyme in the presence of the test agent; and c) determining whether the test agent induces apoptosis in a eukaryotic cell.

[0293] A test agent that (1) reduces the enzymatic activity of RabGGT by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90%, or more, compared to the RabGGT enzymatic activity in the absence of the agent; (2) reduces the enzymatic activity of the farnesyl transferase activity by less than about 10%, less than about 5%, less than about 2%, or less than about 1%, compared to the activity the farnesyl transferase in the absence of the agent; and (3) induces apoptosis in a eukaryotic cell is considered to be a candidate agent for the treatment of disorders amenable to treatment by inducing apoptosis, as described above.

[0294] Whether a given agent inhibits RabGGT and induces apoptosis in a eukaryotic cell can be determined using any known method. Assays can be conducted on cell populations or an individual cell, and include morphological assays and biochemical assays. A non-limiting example of a method of determining the level of apoptosis in a cell population is TUNEL (TdT-mediated dUTP nick-end labeling) labeling of the 3′-OH free end of DNA fragments produced during apoptosis (Gavrieli et al. (1992) J. Cell Biol. 119:493). The TUNEL method consists of catalytically adding a nucleotide, which has been conjugated to a chromogen system or a to a fluorescent tag, to the 3′-OH end of the 180-bp (base pair) oligomer DNA fragments in order to detect the fragments. The presence of a DNA ladder of 180-bp oligomers is indicative of apoptosis. Procedures to detect cell death based on the TUNEL method are available commercially, e.g., from Boehringer Mannheim (Cell Death Kit) and Oncor (Apoptag Plus). Another marker that is currently available is annexin, sold under the trademark APOPTEST™. This marker is used in the “Apoptosis Detection Kit,” which is also commercially available, e.g., from R&D Systems. During apoptosis, a cell membrane's phospholipid asymmetry changes such that the phospholipids are exposed on the outer membrane. Annexins are a homologous group of proteins that bind phospholipids in the presence of calcium. A second reagent, propidium iodide (PI), is a DNA binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells stain positive for annexin and negative for PI, necrotic cells stain positive for both, live cells stain negative for both. Other methods of testing for apoptosis are known in the art and can be used, including, e.g., the method disclosed in U.S. Pat. No. 6,048,703.

RabGGT Structure

[0295] The present invention provides a three-dimensional (3-D) structure of RabGGT. A 3-D structure of a RabGGT is useful for predicting whether a given compound will bind to RabGGT, and is therefore useful for determining whether a given compound will modulate an activity of RabGGT. As discussed above, agents that modulate an activity of RabGGT are useful for the treatment of various disorders. Thus, a 3-D structure of RabGGT is useful for identifying agents that are useful for the treatment of disorders, as described herein.

[0296] The subject homology model is useful for drug design; for determining whether a given compound will modulate a RabGGT activity; and for determining whether a given compound will preferentially modulate a RabGGT activity, e.g., whether a compound will modulate a RabGGT activity, but will substantially not modulate an FT activity. Accordingly, in some embodiments, the present invention provides methods for identifying agents that modulate a RabGGT activity, but that do not substantially modulate an FT activity.

[0297] The subject 3-D structure is useful for structure-based drug design. Three dimensional structural information is useful to specify the characteristics of peptides and small molecules that might bind to or mimic a target of interest. These descriptors may then be used to search small molecule databases and to establish constraints for use in the design of combinatorial libraries. Accordingly, in some embodiments, the invention provides a method for structure-based drug design, the method comprising positioning a test compound in a subject 3-D structure of RabGGT; and modifying the test compound such that the fit within a target binding site within the 3-D structure is increased.

[0298] Target binding sites within the RabGGT 3-D structure include a Rab binding site; a prenyl moiety binding site; a REP binding site; and the like. A non-limiting example of a target binding site is a Rab binding pocket of human RabGGT. The Rab binding pocket of human RabGGT contains a bound Zn atom, coordinated by His B290, Cys B240, and Asp B238; the floor of the pocket is composed of Phe B289, Trp B52; and the back of the pocket is composed of Leu B45, Ser B48, and Tyr B44.

[0299] A test compound is positioned, using computer modeling, within the 3-D structure of RabGGT using any known program. A non-limiting example of a suitable program is Insight (Accelrys, San Diego, Calif.), as described in Example XIV. In these embodiments, positioning of a test compound within a binding site of the RabGGT 3-D structure is accomplished using a computer-generated model of the structure of the test compound. The computer-generated model of the test structure is positioned within the binding site of the RabGGT 3-D structure by rotating the structure until the best fit is achieved.

[0300] To arrive at the best fit within the active site, the structure of the test compound is altered using computer modeling. As such, the invention provides a method for rational drug design, comprising positioning a test compound within a 3-D structure of RabGGT; and altering, by computer modeling, the structure of the test compound, such that the altered test compound has an enhanced fit within the binding site of the RabGGT 3-D structure. In some embodiments, a test agent is modeled within the FT structure; and agents that modulate RabGGT activity, but that do not substantially modulate FT enzymatic activity, are identified and/or designed.

[0301] In some embodiments, rational drug design using computer modeling is carried out in conjunction with in vitro testing of the test compound, and/or the altered test compound. Thus, the present invention provides a method of identifying an agent that modulates RabGGT enzymatic activity, the method comprising selecting a test agent by performing rational drug design with a subject 3-D structure of RabGGT, wherein the selecting is performed in conjunction with computer modeling; and measuring the enzymatic activity of a RabGGT polypeptide contacted in vitro with the test agent. In some of these embodiments, the activity of the test compound and/or the altered test compound are further tested for their effect on FT enzymatic activity. In other embodiments, the activity of the test compound and/or the altered test compound are further tested for their effect on apoptosis.

[0302] In some embodiments, the invention provides methods of designing a compound such that it modulates an activity of RabGGT, but does not substantially modulate an activity of an FT. In some embodiments, the invention provides methods of identifying a compound that modulates an activity of RabGGT and that does not substantially modulate an activity of an FT.

[0303] A 3-D model (“homology model”) of RabGGT was generated by homology modeling, as described in Example XIII and Example IV, and presented in FIGS. 11-15. The program LOOK was used for alignments, and the model-building module within LOOK, SEGMOD, was used to build the homology models. The 3-D model includes a model of the binding pocket for modulators of RabGGT enzymatic activity. The structure information may be provided in a computer readable form, e.g. as a database of atomic coordinates, or as a three-dimensional model. The present invention provides three-dimensional coordinates for the RabGGT structure. Such a data set may be provided in computer readable form. Methods of using such coordinates (including in computer readable form) in drug assays and drug screens as exemplified herein, are also part of the present invention. In a particular embodiment of this type, the coordinates contained in the data set of can be used to identify potential modulators of the RabGGT polypeptide.

[0304] In one embodiment, a potential agent for modulation of RabGGT is selected by performing rational drug design with the three-dimensional coordinates provided herein. Typically, the selection is performed in conjunction with computer modeling. The potential agent is then contacted with the RabGGT polypeptide in vitro, and the activity of the RabGGT is determined. A potential agent is identified as an agent that affects the enzymatic activity of RabGGT, or binding of RabGGT to one or more of Rab, REP, a Rab/REP complex, or other protein.

[0305] Computer analysis may be performed with one or more of the computer programs including: O (Jones et al. (1991) Acta Cryst. A47:110); QUANTA, CHARMM, INSIGHT, SYBYL, MACROMODEL; ICM, and CNS (Brunger et al. (1998) Acta Cryst. D54:905). In a further embodiment of this aspect of the invention, an initial drug screening assay is performed using the three-dimensional structure so obtained, preferably along with a docking computer program. Such computer modeling can be performed with one or more Docking programs such as DOC, GRAM and AUTO DOCK. See, for example, Dunbrack et al. (1997) Folding & Design 2:27-42.

[0306] It should be understood that in the drug screening and protein modification assays provided herein, a number of iterative cycles of any or all of the steps may be performed to optimize the selection. For example, assays and drug screens that monitor the activity of the RabGGT in the presence and/or absence of a potential modulator (or potential drug) are also included in the present invention and can be employed as the sole assay or drug screen, or more preferably as a single step in a multi-step protocol.

[0307] RabGGT structure models and databases of structure information are provided. The structure model may be implemented in hardware or software, or a combination of both. For most purposes, in order to use the structure coordinates generated for the structure, it is necessary to convert them into a three-dimensional shape. This is achieved through the use of commercially available software that is capable of generating three-dimensional graphical representations of molecules or portions thereof from a set of structure coordinates.

[0308] In one embodiment of the invention, a machine-readable storage medium is provided, the medium comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of any of the structures of this invention that have been described above. Specifically, the computer-readable storage medium is capable of displaying a graphical three-dimensional representation of the RabGGT protein, of a complex of a test agent bound to RabGGT protein, or RabGGT complexed to one or more of a prenyl moiety, a Rab protein, a Rab/REP complex, etc.

[0309] Thus, in accordance with the present invention, data providing structural coordinates, alone or in combination with software capable of displaying the resulting three dimensional structure of the enzyme, enzyme complex, and structural elements as described above, portions thereof, and their structurally similar homologues, is stored in a machine-readable storage medium. Such data may be used for a variety of purposes, such as drug discovery, identification of agents that modulate RabGGT activity, but do not substantially modulate FT activity, and the like.

[0310] Generally, the invention is implemented in computer programs executing on programmable computers, comprising a processor, a data storage system (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. Program code is applied to input data to perform the functions described above and generate output information. The output information is applied to one or more output devices, in known fashion. The computer may be, for example, a personal computer, microcomputer, or workstation of conventional design.

[0311] Each program is preferably implemented in a high level procedural or object oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language.

[0312] Each such computer program is preferably stored on a storage media or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

[0313] The structure of the RabGGT polypeptide, complexes, and elements thereof, are useful in the design of agents that modulate the activity and/or specificity of the enzyme, which agents may then alter cellular proliferation and/or apoptosis. Agents of interest may comprise mimetics of the structural elements. Alternatively, the agents of interest may be binding agents, for example a structure that directly binds to a region of the RabGGT polypeptide by having a physical shape that provides the appropriate contacts and space filling.

[0314] For example, the structure encoded by the data may be computationally evaluated for its ability to associate with chemical entities. This provides insight into an element's ability to associate with chemical entities. Chemical entities that are capable of associating with these domains may alter apoptosis. Such chemical entities are potential drug candidates. Alternatively, the structure encoded by the data may be displayed in a graphical format. This allows visual inspection of the structure, as well as visual inspection of the structure's association with chemical entities.

[0315] In one embodiment of the invention, a invention is provided for evaluating the ability of a chemical entity to associate with any of the molecules or molecular complexes set forth above. This method comprises the steps of employing computational means to perform a fitting operation between the chemical entity and the interacting surface of the RabGGT polypeptide; and analyzing the results of the fitting operation to quantify the association. The term “chemical entity”, as used herein, refers to chemical compounds, complexes of at least two chemical compounds, and fragments of such compounds or complexes.

[0316] Molecular design techniques are used to design and select chemical entities, including inhibitory compounds, capable of binding to a RabGGT structural or functional element. Such chemical entities may interact directly with certain key features of the structure, as described above. Such chemical entities and compounds may interact with one or more structural functional elements (e.g., binding sites), in whole or in part.

[0317] It will be understood by those skilled in the art that not all of the atoms present in a significant contact residue need be present in a binding agent. In fact, it is only those few atoms which shape the loops and actually form important contacts that are likely to be important for activity. Those skilled in the art will be able to identify these important atoms based on the structure model of the invention, which can be constructed using the structural data herein.

[0318] The design of compounds that bind to and modulate the activity of a RabGGT polypeptide according to this invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with the domains described above. Non-covalent molecular interactions important in this association include hydrogen bonding, van der Waals interactions, hydrophobic interactions and electrostatic interactions.

[0319] Second, the compound must be able to assume a conformation that allows it to associate or compete with a RabGGT structural element. Although certain portions of the compound will not directly participate in these associations, those portions of the may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity in relation to all or a portion of a binding pocket, or the spacing between functional groups of an entity comprising several interacting chemical moieties.

[0320] Computer-based methods of analysis fall into two broad classes: database methods and de novo design methods. In database methods the compound of interest is compared to all compounds present in a database of chemical structures and compounds whose structure is in some way similar to the compound of interest are identified. The structures in the database are based on either experimental data, generated by NMR or x-ray crystallography, or modeled three-dimensional structures based on two-dimensional data. In de novo design methods, models of compounds whose structure is in some way similar to the compound of interest are generated by a computer program using information derived from known structures, e.g. data generated by x-ray crystallography and/or theoretical rules. Such design methods can build a compound having a desired structure in either an atom-by-atom manner or by assembling stored small molecular fragments. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within the interacting surface of the RNA.

[0321] Docking may be accomplished using software such as Quanta (Molecular Simulations, San Diego, Calif.) and Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics force fields, such as CHARMM and AMBER.

[0322] Specialized computer programs may also assist in the process of selecting fragments or chemical entities. These include: GRID (Goodford (1985) J. Med. Chem., 28, pp. 849-857; Oxford University, Oxford, UK; MCSS (Miranker et al. (1991) Proteins: Structure, Function and Genetics, 11, pp. 29-34; Molecular Simulations, San Diego, Calif.); AUTODOCK (Goodsell et al., (1990) Proteins: Structure, Function, and Genetics, 8, pp. 195-202; Scripps Research Institute, La Jolla, Calif.); and DOCK (Kuntz et al. (1982) J. Mol. Biol., 161:269-288; University of California, San Francisco, Calif.)

[0323] Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or complex. Assembly may be preceded 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. Useful program-s to aid one of skill in the art in connecting the individual chemical entities or fragments include: CAVEAT (Bartlett et al. (1989) In Molecular Recognition in Chemical and Biological Problems”, Special Pub., Royal Chem. Soc., 78, pp. 182-196; University of California, Berkeley, Calif.); 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif); and HOOK (available from Molecular Simulations, San Diego, Calif.).

[0324] Other molecular modeling techniques may also be employed in accordance with this invention. See, e.g., N. C. Cohen et al., “Molecular Modeling Software and Methods for Medicinal Chemistry, J. Med. Chem., 33, pp. 883-894 (1990). See also, M. A. Navia et al., “The Use of Structural Information in Drug Design”, Current Opinions in Structural Biology, 2, pp. 202-210 (1992).

[0325] Once the binding entity has been optimally selected or designed, as described above, substitutions may 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 may then be analyzed for efficiency of fit by the same computer methods described above.

[0326] Another approach made possible and enabled by this invention, is the computational-screening of small molecule databases for chemical entities or compounds that can bind in whole, or in part, to the RabGGT polypeptide. In this screening, the quality of fit of such entities to the binding site may be judged either by shape complementarity or by estimated interaction energy. Generally the tighter the fit, the lower the steric hindrances, and the greater the attractive forces, the more potent the potential modulator since these properties are consistent with a tighter binding constant. Furthermore, the more specificity in the design of a potential drug the more likely that the drug will not interact as welt with other proteins. This will minimize potential side effects due to unwanted interactions with other proteins.

[0327] Compounds known to bind RabGGT, including those described above, can be systematically modified by computer modeling programs until one or more promising potential analogs are identified. In addition systematic modification of selected analogs can then be systematically modified by computer modeling programs until one or more potential analogs are identified. Alternatively a potential modulator could be obtained by initially screening a random peptide library, for example one produced by recombinant bacteriophage. A peptide selected in this manner would then be systematically modified by computer modeling programs as described above, and then treated analogously to a structural analog.

[0328] Once a potential modulator/inhibitor is identified it can be either selected from a library of chemicals as are commercially available from most large chemical companies including Merck, Glaxo Welcome, Bristol Meyers Squib, Monsanto/Searle, Eli Lilly, Novartis and Pharmacia Upjohn, or alternatively the potential modulator may be synthesized de novo. The de novo synthesis of one or even a relatively small group of specific compounds is reasonable in the art of drug design.

[0329] The success of both database and de novo methods in identifying compounds with activities similar to the compound of interest depends on the identification of the functionally relevant portion of the compound of interest. For drugs, the functionally relevant portion may be referred to as a pharmacophore, i.e. an arrangement of structural features and functional groups important for biological activity. Not all identified compounds having the desired pharmacophore will act as a modulator of apoptosis. The actual activity can be finally determined only by measuring the activity of the compound in relevant biological assays. However, the methods of the invention are extremely valuable because they can be used to greatly reduce the number of compounds which must be tested to identify an actual inhibitor.

[0330] In order to determine the biological activity of a candidate pharmacophore it is preferable to measure biological activity at several concentrations of candidate compound. The activity at a given concentration of candidate compound can be tested in a number of ways.

[0331] In some embodiments, the activity of the candidate compound is tested for its activity in modulating RabGGT enzymatic activity. RabGGT enzymatic activity is quantified using a filter binding assay that measures the transfer of (3H) geranylgeranyl groups (GG) from all-trans-(3H)geranylgeranyl pyrophosphate (3H-GGPP) to recombinant Rab3A protein (Shen and Seabra (1996) J. Biol. Chem. 271:3692; Armstrong et al. (1996) Methods in Enzymology 257:30), or as described in the Examples.

[0332] In some embodiments, the activity of the candidate compound is tested for its activity in modulating an interaction between RabGGT and a RabGGT interacting protein, as described above. Suitable assays include a yeast two-hybrid assay, a FRET assay, a BRET assay, a fluorescence quenching assay; a fluorescence anisotropy assay; an immunological assay; and an assay involving binding of a detectably labeled protein to an immobilized protein.

[0333] In other embodiments, the activity of the candidate compound is tested for its activity in modulating FT enzymatic activity. The enzymatic activity of farnesyl transferase can be measured using any known method, e.g., the method described in Mann et al. (1995) Drug Dev. Res. 34:121, or in Ding et al. (1999) J. Med. Chem. 42:5241.

[0334] In other embodiments, the activity of the candidate compound is tested for its activity in increasing or decreasing apoptosis. Assays can be conducted on cell populations or an individual cell, and include morphological assays and biochemical assays. A non-limiting example of a method of determining the level of apoptosis in a cell population is TUNEL (TdT-mediated dUTP nick-end labeling) labeling of the 3′-OH free end of DNA fragments produced during apoptosis (Gavrieli et al. (1992) J. Cell Biol. 119:493).

EXAMPLES

[0335] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl, picoliter(s); s, second(s); min, minute(s); hr, hour(s); and the like.

Example 1

Methods for Preparation of Compounds 7A-7T

[0336] This example provides methods for synthesis of compounds 7A through 7T.

[0337] Compounds 7A, 7B, 7H, 7I, and 7J. (structures shown below) may be prepared by the general procedures described by Ding et al., in U.S. Pat. No. 6,011,029, issued Jan. 4th, 2000. Compounds 7C, 7D, 7N, 7O, 7P, 7Q, 7R, 7S, and 7T (structures shown below) may be prepared by the general procedures described by Bhide et al., in U.S. Pat. No. 6,387,926, issued May 14th, 2002. The contents of U.S. Pat. Nos. 6,011,029, and 6,387,926 are hereby incorporated by reference in their entireties.

Example II

Compound-Induced Apoptosis in HCT-116 Human Colon Tumor Cells

[0338] This example demonstrates that a specific apoptotic phenotype can be obtained by treatment of mammalian tissue culture cells with compounds that come from two major structural classes.

[0339] Methods

[0340] HCT-116 human colon tumor cells obtained from the American Type Culture Collection (ATCC) were grown in McCoy's 5A culture medium with 10% heat inactivated FBS, 1× penicillin/streptomycin, and 25 mM HEPES, in an incubator maintained at 37° C. with CO2 at 6-7% and humidity at 95%. Cells were treated with compounds using a dose range from 0.04 μM to 100 μM. After 48 hours they were examined by microscopy for signs of cell rounding, vaccuolation, and nuclear condensation. These are morphological markers associated with apoptosis, and are consistent with results obtained by performing an assay for nucleosomal DNA, or a TdT-mediated dUTP nick end labeling (TUNEL) assay.

[0341] Results and Conclusions

[0342] Results of the apoptosis assay are presented in Table 1. The concentrations cited are the minimal concentration required to induce these morphological changes in 50% of the treated cells. Compounds 7A, 7B, 7D, 7H, 7I, 7J, and 7N induce apoptosis with varying potency: compound 7I is the most potent, with a minimum effective concentration of 40 nM, while 7A, 7D and 7N require treatment at 3.7 μM to produce apoptosis in 50% of cells. Compound 7C and compounds 70 through 7T are very weak effectors of apoptosis, requiring concentrations over 250 times higher than compounds 7B and 7H.

1TABLE 1Induction of apoptosis in HCT116 cells by compounds fromtwo structural classesCompoundStructural class50% APOPTOTIC, μM7ABenzodiazepine3.37BBenzodiazepine0.377CTetrahydroquinoline107DTetrahydroquinoline3.37HBenzodiazepine0.377IBenzodiazepine0.047JBenzodiazepine2.507NTetrahydroquinoline3.37OTetrahydroquinoline107PTetrahydroquinoline257QTetrahydroquinoline307RTetrahydroquinoline307STetrahydroquinoline507TTetrahydroquinoline90

Example III

Compound Induced Regression of Tumors In Vivo

[0343] This example demonstrates that tumor regression resulting in complete cure was observed in a human tumor xenograft model in which one of the compounds was evaluated.

[0344] Methods

[0345] Compound 7H was evaluated against a human tumor xenograft model; this data has been presented by Hunt et al. (2000, J. Med. Chem. 43:3587). Fragments of the HCT116 colon tumor were implanted subcutaneously in mice, and allowed to grow. The period of time required for tumor volume to double, TVDT, was determined. Compound administration was initiated when tumors were between 100 and 300 mg. Compound was dissolved in 10% ethanol and dosed orally once daily at 600 mg/kg for ten doses, Monday through Friday. Groups of eight mice were treated. Cures were evaluated after elapse of a post-treatment period that was greater than ten TVDT. A mouse was considered cured when no mass that was larger than 35 mg was present at the site of tumor implant. Drug-treated mice that died before the first death in the parallel control group were considered to have died from drug-related toxicity. Groups of mice with more than one death were not used in the evaluation of efficacy.

[0346] Results and Conclusions

[0347] Among the eight mice treated with compound 7H, seven mice experienced cure of the tumor, with one death that was attributed to drug related toxicity. The observation that treatment with compound 7H produces tumor regression resulting in complete cure is consistent with a model in which the compound acts on a cellular target to cause death.

Example IV

Compound-Induced Apoptosis in the C. elegans Germline

[0348] This example demonstrates that treatment with the compounds also produces a specific apoptotic effect on the nematode C. elegans.

[0349] Methods

[0350] The compounds were applied to early larval and adult C. elegans hermaphrodites by mixing a concentrated DMSO solution of the compound with heat-killed OP50 bacteria in a salt solution. The bacteria were then applied to agar plates and worms of the appropriate age seeded onto the plates. Compounds 7A, 7B, 7C, 7D, 7H, 7I and 7J were applied to worms at a final concentration of 1.5 mM. and the resulting visible phenotypes analyzed. The phenotype of apoptosis in C. elegans was quantified as follows: Germ cells in the C. elegans hermaphrodite gonad progress through various stages of differentiation to become mature ova. At the pachytene stage of meiotic prophase, some germ cells undergo programmed cell death (apoptosis) as part of normal development. The apoptotic corpses resulting from this process can be visualized by high-resolution Nomarski optics and are readily distinguishable cells to the trained eye from viable germ cells by their compact, button-like appearance. Necrotic cells, which are rarer, have a less compact appearance. Apoptosis is most reliably distinguished from necrosis, however, by its requirement for the core apoptotic machinery, such as a functional caspase/ced-3 gene. Since C. elegans has symmetrical anterior and posterior gonad structures, referred to as “arms”, apoptosis is scored by visually counting the apoptotic corpses present in a 1-2 day old adult in each germline arm. Normal, untreated worms rarely contain more than 2 corpses per arm. In a treated sample, the number of worms that contain more than 2 corpses provides a very accurate indicator of the apoptotic effect of the treatment.

[0351] Results and Conclusions

[0352] Compounds 7A, 7B, 7C, 7D, 7H, 7I and 7J were applied to groups of 10-19 worms, and worms were examined for an apoptosis phenotype in the germline. The results are presented in Table 2. Adult worms treated with compound 7B showed the most striking increase in the number of apoptotic corpses in the adult germline. For example, while a typical germline arm in untreated wild-type adult worms contains 0-2 apoptotic corpses at any time (the average is 0.6 corpses/arm); treatment with compound 7B at 0.8 mM or higher increased the observed number of corpses to 5-7. Compounds 7A, 7C, 7D, 7H, 7I and 7J were found to have a similar effect to compound 7B, increasing the mean number of apoptotic corpses in the germline. In FIG. 1, the percentage of the germline arms from each treated group that contain more than 2 apoptotic corpses is displayed.

2TABLE 2Frequency of observation of the stated number of apoptotic corpses pergermline arm in wild-type worms treated witheither compound or a vehicle control.% armsCorpses/germline armNwith >201234>4testedmeanSDcorpsesVehicle740000110.40.507A142301112.01.4367B0011010126.92.8927C000406104.41.31007D023221103.02.1507H54A320171.61.4297I133121122.31.7337J341443192.82.3597K536311191.71.426

Example V

The Compounds Mediate Apoptosis Via the Canonical Pathway

[0353] This example demonstrates that the specific apoptotic effects of the compounds on C. elegans are abolished by a mutation in caspase/ced-3 or in APAF-1/ced-4, indicating that the compounds mediate their effects via the canonical apoptotic pathway.

[0354] Methods

[0355] Early larval and adult C. elegans hermaphrodites were treated with compound and the phenotype of apoptosis in the germline arm was quantified as described in Example IV.

[0356] Results and Conclusions

[0357] Early larval and adult C. elegans hermaphrodites that were mutant for the genes for caspase/ced-3 or APAF-1/ced-4 were treated with compound 7B at 1.6 mM, and the phenotype of apoptosis in the germline arm was quantified. Table 3 contains the numerical data from this experiment, and FIG. 2 provides a graphical display of the data. While treatment of wild-type worms with compound 7B increases the average number of apoptotic corpses per germline arm from an average of 0.4 per arm to an average of 6.9 per arm, no increase in corpses was observed when caspase/ced-3 or in APAF-1/ced-4 mutants were treated. This observation shows that the drug-induced increase in frequency of germline corpses described in Example IV is dependent on the presence of functional components of the canonical apoptotic pathway, and supports the assertion that the increase in corpses is indeed due to an increase in apoptosis.

3TABLE 3Frequency of observation of the stated number of apoptotic corpses pergermline arm in wild-type or mutant worms treated with 7B or vehicle.Geno-Corpses/germline armN% arms with >2type01234>4testedmeanSDcorpsesWTVehicle1100000110007B0001010116.251.25100ced3Vehicle1120000130.150.3807B1210000130.080.280ced4Vehicle1000000100007B1120000130.150.380

Example VI

RNAi of mRNA for RabGGT Subunits Causes Apoptosis in C. elegans

[0358] This example demonstrates that treatment of the nematode C. elegans with a reagent that destroys the messenger RNA (RNAi) against either subunit of RabGGT results in a specific apoptotic phenotype.

[0359] Methods

[0360] DNA encoding GGTase alpha/M57.2 (GenBank entry NM-067966) and GGTase beta/B0280.1 (GenBank entry NM 066158) was amplified from a C. elegans genomic DNA template by PCR (Takara LA Taq DNA polymerase) using oligonucleotides containing gene-specific priming sequences that were flanked by sequences encoding the T7 polymerase priming site. The gene-specific priming sequences targeted the first 5 exons of B0280.1 (product size˜2 kiloBases) and the first four exons of M57.2 (product size˜1 kiloBases). The PCR products were analyzed by gel electrophoresis to confirm that the correct product size was obtained. RNA was transcribed from the PCR product using the MEGAscript High Yield Transcription Kit (Ambion) according to manufacturer's instructions. Directly after transcription, the RNA was annealed by heating to 68° C. for 20 minutes. The double stranded RNA (dsRNA) was checked for product quality by gel electrophoresis. The dsRNA was then ethanol-precipitated, washed once with 100% ethanol and twice with 70% ethanol and the pellet was allowed to air dry for 30 minutes. The dsRNA was re-suspended in 1× IM buffer (20 mM KPO4, 3 mM potassium citrate, 2% PEG 6000) in volume equal to the original in vitro transcription reaction, and stored at −20° C.

[0361] For RNAi treatment of worms, wild type animals at the L2/L3 stage of development were collected in M9 buffer at˜50 animals/μl (M9 is 0.044 M KH2PO4, 0.085 M Na2HPO4, 0.18 M NaCl and 1 mM MgSO4). 1 μl of this nematode suspension was added to 3 μl of dsRNA and incubated for 24 hours in a sealed 96 well plate at 20° C. in a humidified chamber.

[0362] Animals were allowed to develop to adulthood before compound treatment and/or assay of germline apoptosis as described in Example IV.

[0363] Results and Conclusions

[0364] Use of an RNAi reagent against either the alpha or beta subunit of the nematode RabGGT enzyme was found to induce the formation of apoptotic corpses in the germline of C. elegans. While a typical germline arm in untreated adults contains, on average, less than one apoptotic corpse; treatment with an RNAi reagent against the RabGGT alpha subunit increased the average number observed to 2.4 corpses/arm. Treatment with an RNAi reagent against the RabGGT beta subunit increased the average number observed to 9 corpses/arm. The graph displayed in FIG. 3 shows the percentage of germline arms that contained greater than 2 apoptotic corpses. Ablation of the mRNA for a protein by RNAi or other methods has been demonstrated to result in a reduction of the quantity and hence cellular function of the encoded protein. Thus, it appears that a reduction in RabGGT function is sufficient to induce apoptosis in cells of the C. elegans germline.

Example VII

Genetic Analysis of Sensitivity Connects the Compound Activity and Rab GGTase in Inducing Apoptosis

[0365] This example demonstrates that treatment of the nematode C. elegans with a low dose of RNAi against a RabGGT subunit acts in synergy with low doses of this same set of compounds, to result in a specific apoptotic phenotype.

[0366] Methods

[0367] Early larval and adult C. elegans hermaphrodites were treated with compound as described in Example IV. RNAi preparation and treatment was performed as described in Example VI. The phenotype of apoptosis in the germline arm was quantified as described in Example IV.

[0368] Results and Conclusions

[0369] To test the hypothesis that RabGGT is a direct target of the 7B compound, we examined the effect of a low dose of compound 7B (0.3 mM) on the amount of apoptosis induced by a reduction in RabGGT function. The rationale behind the experiment is as follows: the effect of a submaximal compound dose will be substantially increased if the target activity is already partially compromised. Since RNAi directed against the alpha subunit of RabGGT induces a lower level of germline apoptosis than RNAi directed against the beta subunit, RNAi directed against the alpha subunit of RabGGT (RabGGT-alpha RNAi) was used to mimic a partial loss of function of the enzyme in adult worms. Table 4 contains data for each treatment administered separately, and for the treatments administered together. Co-administration of the RabGGT-alpha RNAi reagent with 0.3 mM of compound 7B causes an increase in the level of observed apoptosis which is far greater than the additive value of the independent treatments. This can be seen very clearly when the number of germline arms containing more than four apoptotic corpses is quantified (Table 4) and displayed graphically (FIG. 4). In compound treated worms, 17% of arms have greater than four corpses, while in RNAi treated worms, 9% of arms have greater than four corpses. Co-administration of the RabGGT-alpha RNAi reagent with compound 7B increases the percentage of arms with more than 4 corpses to 88%. Thus, hypersensitivity to the compound is observed when RabGGT activity is compromised. These findings are consistent with a model in which compound 7B induces apoptosis in C. elegans by inhibiting the activity of the RabGGT enzyme.

4TABLE 4Frequency of observation of the stated number of apoptotic corpses pergermline arm in wild-type worms treated with compound 7Band/or RNAi against the RabGGT alpha subunit.% arms% arms% armsCorpses/armNwith 0-2with 3-4with >401234>4testedmeanSDcorpsescorpsescorpsesVehicle9103000220.730.7100007B552534242.31.8503317RNAi234562222.71.5415097B and0100221248.03.04888RNAi

Example VIII

Genetic Analysis of Resistance Connects the Compound Activity and Rab GGTase in Inducing Apoptosis

[0370] This example demonstrates that a mutation in the nematode C. elegans that confers resistance to the apoptotic effects of the compounds also confers resistance to the apoptotic effects of RNAi against a RabGGT subunit.

[0371] Methods

[0372] Early larval and adult C. elegans hermaphrodites were treated with compound as described in Example IV. RNAi preparation and treatment was performed as described in Example VI. The phenotype of apoptosis in the germline arm was quantified as described in Example IV.

[0373] Results and Conclusions

[0374] As a further genetic test of the interaction between compound 7B and RabGGT, we examined the effect of a reduction in RabGGT activity in mutants that are resistant to compound 7B. The rationale was as follows: if compound 7B induces apoptosis by inactivation of RabGGT, then the same mutations that decrease 7B-induced apoptosis would be expected to decrease the apoptotic effect induced by lack of RabGGT. We examined a mutant strain that is strongly resistant to induction of apoptosis by compounds 7A-J. The resistance conferred by this mutation appears specific to compounds of the type exemplified by 7A-7J, since the mutant does not display any cross-resistance to the effects of a range of unrelated compounds (data not shown). RNAi treatment against the RabGGT alpha subunit was performed on this strain as described in Example VI. In the mutant strain the apoptotic effect of RNAi treatment against the RabGGT alpha subunit was strongly reduced (FIG. 5). Thus we have shown that a mutant that is resistant to compound 7B-induced apoptosis is also insensitive to RabGGT (RNAi)-induced apoptosis. These findings are consistent with the model that compound 7B induces apoptosis in C. elegans by inactivating the RabGGT enzyme.

Example IX

RNAi of mRNA for RabGGT Subunits Inhibits Proliferation in a Human Cell Line

[0375] This example demonstrates that RNAi treatment of a human cell line with reagents against either the alpha or the beta subunit of the RabGGT enzyme has an anti-proliferative effect.

[0376] Methods

[0377] HCT-116 human colon tumor cells obtained from the ATCC were grown in RPMI culture medium supplemented with 10% heat inactivated FBS, 1× penicillin/streptomycin, and 25 mM HEPES, in an incubator maintained at 37° C. with CO2 at 6% and humidity at 95%. HCT116 cells were plated in 96 well plates at 2000 cells/100 μl media per well and incubated for 24 hours before RNAi treatment. For treatment, a 2× solution of Lipofectamine 2000/siRNA complexes was generated for each individual siRNA as follows. The siRNA oligonucleotides (Xeragon; Huntsville Ala.) were diluted to a final concentration of 1 μM in Optimem serum-free media (Invitrogen; Carlsbad, Calif.) and incubated for 5 minutes at room temperature. The Lipofectamine 2000 reagent (Invitrogen; Carlsbad, Calif.) was diluted to 10 μg/ml in Optimem serum-free media and incubated for 5 minutes at room temperature. Equal volumes of the 1 μM siRNA oligonucleotides and the 10 μg/ml Lipofectamine 2000 were mixed together, giving a 5× stock of siRNA/Lipofectamine 2000 complexes. After incubation for 20 minutes at room temperature, 1.5 volumes of RPMI medium containing 10% heat inactivated FBS was added to the 5× stock, resulting in a 2× stock of siRNA/Lipofectamine 2000 complexes. For RNAi treatment, 100 μof the 2× stock of siRNA/Lipofectamine 2000 complexes was added to each well containing HCT116 cells, to give a final concentration of 1× siRNA/Lipofectamine 2000 complexes. Cells were incubated for 72 hours prior to the proliferation assay. Three replicates were performed for each siRNA treatment.

[0378] The effect of RNAi treatment directed against RabGGT subunits on cellular proliferation was assayed using a 3H-thymidine incorporation assay. The principle of this assay is as follows: During S-phase of the cell cycle, cells incorporate thymidine into the new strand of genomic DNA. Tritiated thymidine can be added to the culture medium and will be incorporated into genomic DNA in proportion to the number of rounds of DNA synthesis that occur. Incorporation can be quantified following lysis of the cells and removal of unincorporated nucleotides. RNAi-treated cells prepared as described above were assayed for 3H-thymidine uptake as follows. The cells were pulsed with 3H-thymidine by addition of 20 μl of a 44 μCi/ml solution of 3H-thymidine in RPMI to each well, to obtain a final concentration of 3H-thymidine of 4 μCi/ml. After incubation for 3 h at 37° C., the medium was removed and 50 μl of 0.25% trypsin in phosphate buffered saline (140 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4 and 1.8 mM KH2PO4, pH 7.4) was added. After 10 minutes, the contents of the wells were harvested onto a 96-well GF/C filter plate (Whatman; Clifton N.J.) using a Hewlett Packard Filtermate. The filter plate was washed 10 times with distilled water, then left to dry overnight. After the addition of 50 μl of Microscint-20 scintillation fluid (Perkin Elmer; Boston, Mass.) per well, the filter plates were sealed and the amount of radioactivity retained on the filter was determined by scintillation counting. The average of the three replicate samples is reported.

Results and Conclusions

[0379] We designed synthetic double-stranded oligonucleotides (siRNAs) suitable for performing RNAi treatment against either the alpha subunit (Genbank entry NM—004581) or beta subunit (Genbank entry NM—004582) of the human RabGGT enzyme (Table 5). Treatment of the HCT 116 human colon cell line with siRNA reagents against the alpha subunit resulted in a reduction of 3H-thymidine incorporation that ranged from 17% to 63% of control values (Table 5). Treatment of the HCT 116 human colon cell line with siRNA reagents against the beta subunit resulted in a reduction of 3H-thmidine incorporation that ranged from 36% to 77% of control values (Table 5). Thus, RNAi treatment with all six of the siRNA reagents against RabGGT resulted in a reduction in 3H-thymidine uptake. This result is displayed graphically in FIG. 6. Varying efficacy among siRNAs targeting the same gene is not uncommon, since the characteristics that are required for effective destruction of the target mRNA are not understood (Elbashir et al., 2002; Methods 26:199). The observed reduction in 3H-thymidine incorporation resulting from RNAi treatment against RabGGT could be the result of an inhibition of proliferation, or the result of increased cell death among the treated cells. This data is consistent with a model in which a reduction in function of the RabGGT enzyme results in apoptosis.

5TABLE 5Structure of siRNA reagents andeffect on 3H-thymidine incorporation in HCT116 cellsBases of3H-thysiRNA sensesiRNA antisensecoding regionincorp. %siRNAGene targetedstrandstrandtargetedof controlAlpha-1RabGGT-alphaGGCAGAACUCAGGAAGCC268-29133GGGCUUCCUCAGUUCUGCGTT (SEQ IDCTT (SEQ IDNO:01)NO:02)Alpha-2RabGGT-alphaAGAGCUGGACUGCACCAGC628-65117GCUGGUGCAUCCAGCUCUTGTT (SEQ IDT (SEQ IDNO:03)NO:04)Alpha-3RabGGT-alphaGAUGGAGUACACCUCGGCA1309-133263UGCCGAGGUUACUCCAUCTGTT (SEQ IDT (SEQ IDNO:05)NO:06)Beta-1RabGGT-betaCUUUGGCUUUUCCCCAACA493-51677UGUUGGGGAAAGCCAAAGTATT (SEQ IDT (SEQ IDNO:07)NO:08)Beta-2RabGGT-betaCGACAAUUACGCCUGAGG662-68539CCCUCAGGCGGUAAUUGUCTT (SEQ IDGTT (SEQ IDNO:09)NO:10)Beta-3RabGGT-betaGAUGAAGAAAUCCCCCCGU812-83536ACGGGGGGAUUCUUCAUCTUTT (SEQ IDT (SEQ IDNO:11)NO:12)Non-noneUUCUCCGAAACGUGACACnone100 silencingCGUGUCACGGUUCGGAGAUTT (SEQ IDATT (SEQ IDNO:13)NO:14)

Example X

Biochemical Assay of Compound Inhibition of RabGGT Activity In Vitro

[0380] This example demonstrates that certain compounds inhibit RabGGT activity with nanomolar potency using a direct in vitro assay, and that different structural classes of compound may differ in the dose-response relationship for inhibition.

[0381] Methods

[0382] The effect of compounds 7A through 7T on RabGGT activity was quantified using a filter binding assay that measures the transfer of (3H) geranylgeranyl groups (GG) from all-trans-(3H)geranylgeranyl pyrophosphate (3H-GGPP) to recombinant Rab3A protein (Shen & Seabra, 1996, JBC, 271 :3692; Armstrong et al., 1996, Methods in Enzymology 257:30). Modifications to published protocols are noted explicitly below.

[0383] Recombinant rat RabGGT, expressed using the Sf9/baculovirus system, was purchased from Calbiochem (cat. no. 345855). Recombinant unprenylated human Rab3A was obtained from Panvera.(cat. no. P2173). Human REβ-1, expressed in Sf9 cells, was obtained from Calbiochem (cat. no. 554000). Tritium labeled geranylgeranyl pyrophosphate was purchased from Amersham Pharmacia Biotech (15 Ci/mmol). Unlabeled GGPP was purchased from Sigma (cat. no. G-6025).

[0384] The reaction buffer contained 50 mM HEPES pH7.4, 5 mM MgCl2, 1 mM DTT, 1 mM Nβ-40. Solutions of RabGGT, Rab3A, REP-1, and GGPP were prepared in this reaction buffer. Final protein concentrations in the reaction mixture were modified from the published protocols, with the standard reaction mixture containing 2 μM Rab3A, 0.2 μM REP-1, 5 μM unlabeled GGPP, 0.5 μM labeled GGPP, and 10-50 nM RabGGT in a total volume of 20 μl. The specific activity of (3H)GGPP used in the assay was 3000 dpm/pmol.

[0385] Compounds were prepared as 50 mM stocks in DMSO and diluted to give an appropriate concentration for the assay as a 20% DMSO stock. 2 μl of the diluted compound stock was added to a 20 μl reaction to give a final DMSO concentration of 2% in the assay.

[0386] The order of addition of reagents was altered from the published protocols. Reaction mixtures were prepared by sequentially adding Rab3A and REP-1 proteins to the reaction buffer, followed by compound and RabGGT enzyme to a volume of 18 μl. Reactions were initiated by the addition of 2 μl of a solution that contained unlabeled and labeled GGPP. After a 30 minute incubation at 37° C., 1 ml of stop solution (1 volume of concentrated HCl acid with 9 volumes of ethanol) was added and mixed. The solution was then incubated at room temperature for 1 hour to completely precipitate proteins.

[0387] The precipitate was collected by vacuum filtration using a vacuum filtration manifold (Millipore model 1225) onto 25 mm GF/A filters (Whatman) that were prewetted with ethanol. The tubes were rinsed twice with 1 ml ethanol which was also poured over the filters. Each filter was subsequently washed three times with 2 mls of ethanol per wash, dried under vacuum, and then put in scintillation vials. Four milliliters of scintillation fluid was added and the radioactivity was quantified on a scintillation counter. Several types of blank reactions were conducted including withholding the enzyme, the substrate, or the accessory protein REP-1, or replacing the compound solution with a 20% DMSO solution. For the substrate titration experiment, the equimolar amounts of Rab3A and REP-1 were mixed and preincubated for 30 min at room temperature before addition of the enzyme.

[0388] The data was analyzed by non-linear regression analysis methods using the program PRIZM (GraphPad Software, Inc.). Inhibition constants were obtained by analyzing the data using the one site competition equation provided by the software. FIG. 7 presents a typical data series obtained for compound 7B using these methods.

[0389] Results and Conclusions

[0390] Data presented in Table 6 shows that compounds 7A, 7B, 7H, 7I, 7J, 7N, 7O, 7P, 7Q, and 7S inhibit the activity of rat RabGGT enzyme with IC50 values of less than 100 nM, while 7R and 7T are weaker inhibitors. IC90 values for inhibition of RabGGT are also presented in Table 6. The multiple of the IC90 value relative to the IC90 value is also presented in Table 6. For the benzodiazepine compounds 7A, 7B, 7H, 7I, and 7J, the IC90 value is between 5 and 9 times the IC50 value. For the tetrahydroquinoline compounds 7N, 7O, 7P, 7Q, 7R, 7S and 7T the IC90 value is between 12 and 49 times the IC50 value. The difference in the multiple of the IC90 value relative to the IC90 value for the two classes of compounds indicates that the dose-response relationship is different for each class. Such a difference in dose response may have consequences in an in vivo situation. If it is necessary to completely eliminate the function of an enzyme to produce a given measured effect, IC90 values for inhibition of that enzyme will show a closer relationship to that effect than IC50 values.

6TABLE 6Results of an in vitro assay that measures RabGGT activityin the presence of compounds.RabGGTRabGGTCompoundStructural classIC50, nMIC90, nMIC90/IC507ABenzodiazepine3629587BBenzodiazepine2119997HBenzodiazepine2111557IBenzodiazepine169367JBenzodiazepine125857NTetrahydroquinoline25309127OTetrahydroquinoline581117197PTetrahydroquinoline842162267QTetrahydroquinoline472298497RTetrahydroquinoline54110064197STetrahydroquinoline731404197TTetrahydroquinoline1433>15000>10

Example XI

Relationship Between Inhibition of RabGGT In Vitro and Induction of Apoptosis In Vivo

[0391] This example demonstrates a relationship between the level of inhibition of RabGGT enzyme activity in vitro and the ability of the compound to induce apoptosis in an HCTI 16 cell line.

[0392] Methods

[0393] The assay for compound inhibition of RabGGT function is described in Example X.

[0394] Methods for assaying apoptotic activity of compounds on HCTI 16 cells are described in Example II.

[0395] Results and Conclusions.

[0396] Table 7 provides the IC50 and IC90 values established by biochemical assays for inhibition of RabGGT, and also provides the minimum concentration required to achieve apoptosis of 50% of the HCT116 cells in a culture system. The data for IC90 values and apoptosis values are also presented in a graphical form in FIGS. 8a, 8b, and 8c. In Table 7, compounds are ranked according to their potency in the apoptosis assay and are presented according to structural class.

[0397] When IC90 values for RabGGT inhibition are examined, a correlation between potency in the RabGGT inhibition assay and potency in the apoptosis assay is apparent. The square of the Pearson product moment correlation coefficient (the R-squared value) for the apoptosis values and the RabGGT IC90 values is 0.7, which can be interpreted as 70% of the variance in apoptosis values being attributable to the variance in RabGGT inhibition. Of the 12 compounds assayed, only two compounds deviate from their rank order position in Table 7: Compounds 7J and 7S show lower potency in the apoptosis assay than would be predicted by their potency in the RabGGT inhibition assay. Such occasional deviation (2 compounds out of 12) between rank in one assay and rank in another is not unexpected given the number of variables in each assay. We conclude that inhibition of RabGGT activity is related to the apoptotic activity of these compounds.

[0398] A correlation between potency in the RabGGT inhibition assay and potency in the apoptosis assay is also apparent when IC50 values for RabGGT inhibition are examined for their relationship to potency in the apoptosis assay. The R-squared value for the apoptosis values and the RabGGT IC90 values is 0.7, which can be interpreted as 70% of the variance in apoptosis values being attributable to the variance in RabGGT inhibition. Compounds 7J, 7P and 7Q deviate from their rank order position. However we note that the tetrahydroquinoline class in general is less potent at inducing apoptosis than would be predicted based on their IC50 value as a measure of potency in the RabGGT inhibition assay. For example, compounds 7A and 7Q have similar IC50 values for RabGGT inhibition, whereas they show a 9-fold difference in potency in the apoptosis assay. The difference in potency in the apoptosis assay is in closer agreement with IC90 values for RabGGT inhibition by 7A and 7Q, which show an 8-fold difference. The observation that IC90 values for RabGGT inhibition show a better relationship to potency in the apoptosis assay than do IC50 values indicates that an almost total loss of cellular RabGGT activity may be required for induction of apoptosis. RabGGT cellular activity may be present in an amount that exceeds the general need, and a cell may be able to subsist with only 50% of that activity present.

7TABLE 7Results of an in vitro assay upon RabGGT activity andresults of an assay of apoptotic activity upon human cells.HCT11650%apoptosis,RabGGTRabGGTCompoundStructural classμMIC50, nMIC90, nM7IBenzodiazepine0.0416937HBenzodiazepine0.37211157BBenzodiazepine0.37211997JBenzodiazepine2.512587ABenzodiazepine3.3362957NTetrahydroquinoline3.3253097OTetrahydroquinoline105811177PTetrahydroquinoline258421627QTetrahydroquinoline304722987RTetrahydroquinoline30541100647STetrahydroquinoline507314047TTetrahydroquinoline901433>15000

[0399] In FIG. 8a, Data from the benzodiazepine class of compounds: The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT116 cell culture is shown on the X axis.

[0400] In FIG. 8b, Data from the tetrahydroquinolone class of compounds: The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT 116 cell culture is shown on the X axis.

[0401] In FIG. 8c, Data from compounds 7A through 7Q. Compounds 7R, 7S, and 7T are represented in FIG. 8b, and have been omitted from this figure for graphical clarity rather than because they alter the trend of the observations. The IC90 for RabGGT inhibition in nanomoles is shown on the Y axis and the minimum concentration required for induce 50% apoptosis in an HCT 116 cell culture is shown on the X axis.

Example XII

Lack of Relationship Between Inhibition of Farnesyl Transferase (FT) In Vitro and Induction of Apoptosis In Vivo

[0402] This example demonstrates that there is no obvious relationship between the level of inhibition of FT enzyme activity in vitro and the ability of the compound to induce apoptosis in an HCT116 cell line.

[0403] Methods

[0404] Biochemical assays for inhibition of FT were performed as described by Mann et al. (1995, Drug Dev. Res. 34: 121) with the modifications described by Ding et al. (1999, J. Med. Chem., 42:5241)

[0405] Methods for assaying apoptotic activity of compounds on HCT116 cells are described in Example II.

[0406] Results and Conclusions

[0407] Compounds 7A-7J are from a class of compounds that is predicted to have FT-inhibitory activity (Ding et al., 1999, J. Med. Chem., 42:5241), while compounds 7N-7T also possess structural characteristics that make them potential FT inhibitors. We examined the possibility that inhibition of FT activity was related to the apoptotic activity of these compounds. Table 8 presents the compounds grouped according to structural class and provides the IC50 and IC90 values for inhibition of FT. Table 8 also provides the minimum concentration required to achieve apoptosis of 50% of the HCT116 cells in a culture system. The data for IC50 values and apoptosis values are also presented in a graphical form in FIG. 9.

8TABLE 8Results of an in vitro assay upon FT activity and results ofan assay of apoptotic activity upon human cells.HCT11650%apoptosis,FTFTCompoundStructural classμMIC50, nMIC90, nM7IBenzodiazepine0.041.4117HBeazodiazepine0.374.13607BBenzodiazepine0.377.81107JBenzodiazepine2.50.877ABenzodiazepine3.32.4307NTetrahydroquinoline3.30.797OTetrahydroquinoline101.487PTetrahydroquinoline250.747QTetrahydroquinoline300.667RTetrahydroquinoline301.597STetrahydroquinoline5015.52557TTetrahydroquinoline903.748

[0408] In the data presented in Table 8, compounds are ranked according to their potency in the apoptosis assay. The compounds are all potent inhibitors of FT, with only a 20-fold range being observed in the IC50 values (0.7 nM to 15.5 nM) whereas values in the apoptosis assay range over 2200-fold. When IC50 values for FT inhibition are examined for their relationship to potency in the apoptosis assay, no correlation is apparent. The R-squared value for the apoptosis values and the FT IC50 values is less than 0.1, which can be interpreted as less than 10% of the variance in apoptosis values being attributable to the variance in inhibition of 50% of FT activity. No general correlation with rank order position can be seen; at least 8 compounds deviate between ranking their potency for FT inhibition and ranking their potency for apoptosis induction. The conclusion that there is no correlation between potency in the apoptosis assay and potency in the FT inhibition assay is not altered by examination of IC90 values for FT inhibition. The R-squared value for the apoptosis values and the FT IC90 values is less than 0.01, indicating that none of the variance in apoptosis values is attributable to the variance in inhibiting 90% of FT activity.

[0409]
FIG. 9 provides a graphical display of the data from Table 8. No trend can be observed in the data by visual inspection. We conclude that inhibition of FT activity is not related to the apoptotic activity of these compounds.

Example XIII

Conservation of Structure Between the RabGGT Enzymes from C. elegans, R. norvegicus and H. sapiens

[0410] This example demonstrates that the active site of the RabGGT enzyme is conserved between C. elegans, R. norvegicus and H. sapiens, such that a compound which blocks the active site in one species would be reasonably expected to show the same activity in all species.

[0411] Methods

[0412] Structural models of the RabGGT alpha subunits from C. elegans (GenBank entry NM—067966) and from Homo sapiens (GenBank entry NM—004581) were developed based on sequence alignment with the homologous protein rat RabGGT alpha (GenBank entry NM—031654) whose structure in the RabGGT complex is available in the Protein Data Bank as 1DCE (Zhang et al., 2000, Structure 8:241). Sequence alignments of the RabGGT alpha subunit are shown in Table 9a and Table 10a.

[0413] Structural models of the RabGGT beta subunits from C. elegans (GenBank entry NM—066158) and from H. sapiens (GenBank entry NM-004582) were developed based on sequence alignment with the homologous protein rat RabGGT beta (GenBank entry NM—138708) whose structure in the RabGGT complex is available in the Protein Data Bank as 1DCE (Zhang et al., 2000, Structure 8:241). Sequence alignments of the RabGGT beta subunit are shown in Table 9b and Table 10b.

[0414] The program LOOK was used for alignments and the model building module within LOOK, SEGMOD, was used to build the homology models (Levitt, (1992), J. Mol. Biol. 226: 507-533; Levitt, (1983), J. Mol. Biol. 170: 723-764). The co-ordinates for the structural model of H. sapiens RabGGT are presented in Table 11 (RabGGT alpha subunit) and Table 12 (RabGGT beta subunit). In both Tables 11 and 12, “Atom No” refers to the atom number within the RabGGT alpha or beta subunit homology model; “Atom name” refers to the element whose coordinates are measured, the first letter in the column defines the element; “Residue” refers to the amino acid within which the atom resides, with the number representing the amino acid number of the “residue”; “X Coord”, “Y Coord”, and “Z Coord” structurally define the atomic position of the element measured in three dimensions.

[0415] The quality of the models was evaluated as follows: In order to recognize errors in three-dimensional structures knowledge based mean fields can be used to judge the quality of protein folds (Hendlich et al., 1990, J. Mol. Biol. 216:167). These methods can be used to recognize misfolded structures as well as faulty parts of structural models. The technique generates an energy graph where the energy distribution for a given protein fold is displayed on the y-axis and residue position in the protein fold is displayed on the x-axis. The knowledge based mean fields compose a force field derived from a set of globular protein structures taken as a subset from the Protein Data Bank (Bernstein et al., 1977, J. Mol. Biol. 112:535). An energy value of less than zero is considered to represent a stable 3-dimensional structure. To analyze the quality of a model, the energy distribution of residues is plotted and compared to the energy distribution of the template from which the model was generated.

[0416] Results and Conclusions

[0417] The amino acid sequence of the H. sapiens RabGGT alpha subunit (HsA) has 91% identity and 93% similarity with that of Rattus norvegicus (RatA). The proteins are both 567 amino acids in length. The amino acid sequence of the H. sapiens RabGGT beta subunit (HsB) has 95% identity and 97% similarity with that of R. norvegicus (RatB). The proteins are both 331 amino acids in length. The crystal structure of a RabGGT complex consisting of the rat alpha and beta subunits has been described at 2 angstrom (A) resolution (H Zhang et al., 2000, Struct. Fold. Des. 8:241). The sequences of HsA and HsB were overlaid onto the crystal structure of the RatA/RatB complex (FIG. 10). There were no insertions or deletions. The free energy plots for the models are shown in FIG. 11. There is near identity between the energy distribution of the model and that of the template from which the model was generated, with the majority of residues having energy values below zero. This indicates that the human RabGGT as modeled represents a stable 3-dimensional structure of high quality.

[0418] The putative binding pocket for inhibitors of RabGGT activity can be hypothesized by comparison with farnesyl transferase (FT), a closely related enzyme that has very similar structure and function (Long et al., 2002, Nature 419:645). The structure of FT in complex with known inhibitory compounds has been determined; in this example we used an overlay of an FT/inhibitor complex described by Long et al. (2001, Proc. Natl. Acad. Sci. USA, 98:12948). Of the residues lining the putative binding pocket, all three within the alpha subunit and all 12 within the beta subunit are identical between the two proteins and exist within a region of high conservation and high identity (Table 9a and b). In the enzyme from R. norvegicus, and the enzyme from H. sapiens, the residues within 5A of the active site are Asn A103, Lys A105, Tyr A107, Ser B42, Tyr B44, Leu B45, Trp B52, Arg B144, Asp B238, Cys B240, Tyr B241, Asp B280, Asp B287, Phe B289, His B290, where A refers to the alpha subunit and B to the beta subunit.

[0419] The amino acid sequence of the C. elegans RabGGT alpha subunit (CeA) has 38% identity and 53% similarity with that of R. norvegicus (RatA). RatA is 567 amino acids in length and CeA is 580 amino acids. The amino acid sequence of the C. elegans RabGGT beta subunit (CeB) has 53% identity and 72% similarity with that of R. norvegicus (RatB). RatB is 331 amino acids in length and CeB is 335 amino acids. The sequences of CeA and CeB were overlaid onto the crystal structure of the RatA/RatB complex (FIG. 12). One large insertion in CeA (80-94) corresponded to a loop between helices 3 and 4 in RatA. A substantial deletion in CeA at residue 316, corresponding to RatA residues 300-305, occurs within a beta-sheet at some distance from the proposed binding site and near a large loop. Another insertion in CeA (residues 439-442 at RatA 428) is also at some distance from the binding site and appears to occur with helix 17 of the RatA structure. The free energy plots for the models are shown in FIG. 13. There is a strong correspondence between the energy distribution of the model and that of the template from which the model was generated, with the majority of residues having energy values below zero. This indicates that the C. elegans RabGGT as modeled represents a stable 3-dimensional structure of high quality.

[0420] Of the residues lining the putative binding pocket of RabGGT, all three residues within the alpha subunit are identical between the two proteins and exist within a region of high conservation and high identity. Of the 12 residues in the beta subunit determined to be in the binding pocket, all but two were identical and existed in regions of high identity (Table 9a and 9b). In the enzyme from C. elegans, the residues within 5A of the active site are Asn A119, Lys A121, Tyr A123, Ala B48 (non-identity to rat), His B50 (non-identity to rat), Leu B51, Trp B58, Arg B150, Asp B244, Cys B246, Tyr B247, Asp B286, Asp 293, Phe B295, His B296, where A refers to the alpha subunit and B to the beta subunit.

[0421] The data presented in this example demonstrates that high quality structural models of human and nematode RabGGT structure can be generated based on the crystal structure that has been obtained for the rat protein. In these models, the active site of the RabGGT enzyme is conserved between C. elegans, R. norvegicus and H. sapiens, such that a compound which blocks the active site in one species would be reasonably expected to show the same activity in all species. Therefore the observation that certain compounds inhibit the rat RabGGT enzyme with nanomolar potency (data presented in Example X), indicates that these compounds would have the same inhibitory effect when applied to the human RabGGT enzyme. The apoptotic effect of the same compounds when applied to C. elegans (data presented in Example IV) may also be interpreted as arising from inhibition of RabGGT, given that the active site of the nematode enzyme is conserved with respect to that of the rat enzyme, and that loss of the enzyme function has been directly linked to an apoptotic effect (data presented in Example VI).

Example XIV

Modeling Interaction of Compounds with the Active Site of RabGGT

[0422] This example demonstrates that compounds with apoptotic activity and RabGGT inhibitory activity have the potential to block the active site of the RabGGT enzyme.

[0423] Methods

[0424] The program Insight (Accelrys, Inc., San Diego, Calif.) was used to visualize and compare possible binding interactions of compounds with the active site of RabGGT. The putative binding pocket for inhibitors of RabGGT activity can be hypothesized by comparison with farnesyl transferase (FT), a closely related enzyme that has very similar structure and function (Long et al., 2002, Nature 419:645). The structure of FT in complex with known inhibitory compounds has been determined (for example Long et a.,2001, Proc. Natl. Acad. Sci. USA, 98:12948; Bell et al., 2002, J. Med. Chem. 45:2388).

[0425] Results and Conclusions

[0426] The active site of RabGGT contains binding sites for a prenyl moiety and the peptide substrate of the enzyme. The crystal structure of the RabGGT complex from R. norvegicus is available in the Protein Data Bank as 1DCE (Zhang et al., 2000, Structure 8:241). In the enzyme from R. norvegicus, the active site is composed of residues His B290, Cys B240, Asp B238, Tyr B241, Trp B244, Phe B289, Trp B52, Ser B48, Leu B45, Tyr B44, Asp A61, Arg B144, and Lys A105, where A refers to the alpha subunit and B to the beta subunit (FIG. 14a). The derivation of the 3-dimensional model of the human enzyme from the rat enzyme crystal structure resulted in no significant change to the pocket. The pockets are constitutively identical: the only changes seen were those expected from use of different optimization procedures, which is known to result in slight shifts in amino acid side chain positions (FIG. 14b).

[0427] The binding pocket of the predicted human RabGGT enzyme is large and substantially open to solvent on one side (the left side in FIGS. 14a-c). It contains a bound atom of zinc, coordinated by histidine B290, cysteine B240, and aspartic acid B238, identical to the motif found in the rat protein. The floor of the pocket (at the base in FIGS. 14a-c) is composed of phenylalanine B289 and tryptophan B52, and the back of the pocket (to the rear in FIGS. 14a-c) of leucine B45, serine B48, and tyrosine B44. In the crystal structure, the top of the pocket (at the top in FIGS. 14a-c) contains a substantial quantity of bound water molecules in addition to aspartic acid A6 1; the homology model maintains this empty pocket that is occupied by the water molecules in the crystal structure. RabGGT contains substantial functional, sequence, and structural similarities to farnesyl transferase (FT). In FT, the side of the pocket opposite to that exposed to bulk solvent is known to be a binding site for a prenyl group. The geranyl-geranyl prenyl group that is bound and transferred by RabGGT should occupy the analogous location (to the right in FIGS. 14a-c) (Zhang et al., 2000, Structure 8:241).

[0428] There is good indication that compounds 7A through 7T would bind in this pocket. FT and RabGGT are similar in the structure of their active sites and in their mechanism of substrate modification (Long et al., 2002, Nature 419:645). Compounds 7A through 7T show the ability to inhibit FT with high potency (Table 8), indicating that they bind to the enzyme. Crystal structures of FT in complex with compounds structurally similar to 7A through 7H have been reported (Bell et al., 2002, J. Med. Chem. 45:2388). Like 7A through 7H, these compounds contain an imidazole ring, a cyanobenzene, and an aromatic moiety, and they have been found to occlude the peptide-substrate binding site of the FT enzyme. The imidazole ring functions in its well-known role as a ligand for zinc, while the cyanobenzene moiety was found to form hydrophobic contacts with the prenyl group. As noted, the RabGGT pocket also contains a zinc ion at the analogous position, and a similar prenyl group is expected to bind to the pocket in the analogous location. The imidazole and cyanobenzene moieties of 7A through 7H are predicted to orient the compounds in an analogous manner within the RabGGT pocket, occluding the peptide-binding site of the enzyme. All the compounds have additional aromatic moieties that may form significant interactions with the enzymes. However, the substrate binding sites of FT and RabGGT have some differences that are expected to have a substantial influence on the type of molecules that can function as effective and specific inhibitors. The binding site of FT is more hydrophobic and, in particular, is more aromatic. It has been determined that the aromatic “back” region of the FT pocket is constrained and places strict orientation demands on ligands of high affinity (Bell et al., 2002, J. Med. Chem 45:2388). The differences between the pockets of FT and RabGGT in this region, in particular the substitution of tryptophan B602 by leucine B54, would be expected to alter the binding specificity by making fewer requirements on orientation and aromaticity. Consequently, compounds of high-affinity for FT might not bind as tightly, if at all, to RabGGT and conversely, specific inhibitors of RabGGT can be designed.

[0429]
FIG. 15A depicts two views of compound 7H docked into the putative binding site of RABGGT. The left view is facing directly into the cavity opening viewed from outside of the protein, the right is viewed from a 90 degree rotation. The protein residues are heavy sticks.

[0430] The ligand is represented by thin sticks. The putative bound atom of zinc is represented as a sphere.

[0431]
FIG. 15B depicts analogous views of the binding site of the crystal structure of the complex between farnesyl transferase (FT) and the FT inhibitor U66 (PDB 1LD7; Bell et al. (2002) J. Med. Chem. 45:2388). The views show similar binding patterns between the putative Rab ligand and the Rab binding site and that of the FT ligand and the FT binding site. Both show a liganding of an imidazole group to an atom of zinc, a close packing of a cyanophenyl group with a bound prenyl group (shown at the right hand side of the left images and in the middle of the right images) and additional hydrophobic functionality, a phenyl group in the putative Rab ligand and a napthyl group in the FT ligand.

[0432] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

[0433] The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, Genbank Accession Numbers, SWISS-PROT Accession Numbers, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is hereby incorporated herein by reference. Further, the hard copy of the sequence listing submitted herewith and the corresponding computer readable form are both incorporated herein by reference in their entireties.

Tables 9a and 9b

[0434] Alignment of the indicated polypeptides chains. (a) RatA: R. norvegicus RabGGT alpha chain (SEQ ID NO:19), with HsA: H. sapiens RabGGT alpha chain (SEQ ID NO:16). (b) RatB: R. norvegicus RabGGT beta chain (SEQ ID NO:20), with HsB: H. sapiens RabGGT beta chain (SEQ ID NO:18). “{circumflex over ( )}” indicates residues within 5 Angstrom of the binding site. “*” indicates identity. “:” indicates conserved properties.

9TABLE 9aRatA---HGRLKVKTSEEQAEAKRLEREQKLKLYQSATQAVFQKRQAGELDESVLELTSQILGAHsAM--HGRLKVKTSEEQAEAKRLEREQKLKLYQSATQAVFQKRQAGELDESVLELTSQILGA *********************************************************RatANPDFATLWNCRREVLQHLETEKSPEESAALVKAELGFLESCLRVNPKSYGTWHHRCWLLSHsANPDFATLWNCRREVLQQLETQKSPEELAALVKAELGFLESCLRVNPKSYGTWHHRCWLLG****************:***:***** ********************************. {circumflex over ( )} {circumflex over ( )} {circumflex over ( )}RatARLPEPNWARELELCARFLEADERNFHCWDYRRFVAAQAAVAPAEELAFTDSLITRNFSNYHsARLPEPNWTRELELCARFLEVDERNFHCWDYRRFVATQAAVPPAEELAFTDSLITRNFSNY*******:***********.***************:****.*******************RatASSWHYRSCLLPQLHPQPDSGPQGRLPENVLLKELELVQNAFFTDPNDQSAWFYHRWLLGRHsASSWHYRSCLLPQLHPQPDSGPQGRLPEDVLLKELELVQNAFFTDPNDQSAWFYHRWLLGR***************************:********************************RatAAEPHDVLCCVHVSREEACLSVCFSRPLTVGSRMGTLLLMVDEAPLSVEWRTPDGRNRPSHHsAADPQDALRCLHVSRDEACLTVSFSRPLLVGSRMEILLLMVDDSPLIVEWRTPDGRNRPSH*:*:*.* *:****:****:*.***** ***** ******::** **************RatAVWLCDLPAASLNDQLPQNTFRVIWTGSDSQKECVLLKDRPECWCRDSATDEQLFRCELSVHsAVWLCDLPAASLNDQLPQHTFRVTWTAGDVQKECVLLKGRQEGWCRDSTTDEQLFRCELSV*************************..* ********.* * *****:************RatAEKSTVLQSELESCKELQELEPENKWCLLTIILLMRALDPLLYEKETLQYFSTLKAVDPMRHsAEKSTVLQSELESCKELQELEPENKWCLLTIILLMRALDPLLYEKETLQYFQTLKAVDPMR**************************************************.*********RatAAAYLDDLRSKFLLENSVLKMEYADVRVLHLAHKDLTVLCHLEQLLLVTHLDLSHNRLRALHsAATYLDDLRSKFLLENSVLKMEYAEVRVLHLAHKDLTVLCHLEQLLLVTHLDLSHNRLRTL*:******************:*************************************:*RatAPPALAALRCLEVLQASDNALENVDGVANLPRLQELLLCNNRLQQSAAIQPLVSCPRLVLLHsAPPALAALRCLEVLQASDNAIESLDGVTNLPRLQELLLCNNRLQQPAVLQPLASCPRLVLL*******************:*.:***.*****************.*.:***.********RatANLQGNSLCQEEGTQERLAEMLPSVSSILT-------------------------------HsANLQGNPLCQAVGTLEQLAELLPSVSSVLT-------------------------------*****.*** ** *:***:******:**

[0435]

10

TABLE 9b

RatB
-------------------------------TQQKDVTTKSDAPDTLLLEKHADYIAS

HsB
-----------------------------MGTPQKDVIIKSDAPDTLLLEKHADYIAS

* **** ********************

RatB
YGSKKDDYEYCMSEYLRMSGVYWGLTVMDLMGQLHRMNKEEILVFIKSCQHECGGVSASI

HsB
YGSKKDDYEYCMSEYLRMSGIYWGLTVMDLMGQLHRMNREETLAFIKSCQHECGGISASI

********************:*****************:****.***********:****

{circumflex over ( )} {circumflex over ( )}{circumflex over ( )} {circumflex over ( )}

RatB
GHDPHLLYTLSAVQILTLYDSIHVINVDKVVAYVQSLQKEDGSFAGDIWGEIDTRFSFCA

HsB
GHDPHLLYTLSAVQILTLYDSINVIDVNKVVEYVKGLQKEDGSFAGDIWGEIDTRFSFCA

**********************:**:*:*** **:.************************

{circumflex over ( )}

RatB
VATLALLGKLDAINVEKATEFVLSCMNFDGGFGCRPGSESHAGQIYCCTGFLAITSQLHQ

HsB
VATLALLGKLDAINVEKAIEFVLSCMNFDGGFGCRPGSESHAGQIYCCTGFLAITSQLHQ

************************************************************

RatB
VNSDLLGWWLCERQLPSGGLNGRPEKLPDVCYSWWVLASLKIIGRLHWIDREKLRSFILA

HsB
VNSDLLGWWLCERQLPSGGLNGRPEKLPDVCYSWWVLASLKIIGRLHWIDREKLRNFILA

*******************************************************.****

{circumflex over ( )} {circumflex over ( )}{circumflex over ( )}

RatB
CQDEETGGFADRPGDMVDPFHTLFGIAGLSLLGEEQIKPVSPVFCMPEEVLQRVNVQPEL

HsB
CQDEETGGFADRPGDMVDPFHTLFGIAGLSLLGEEQIKPVNPVFCMPEEVLQRVNVQPEL

****************************************.*******************

{circumflex over ( )} {circumflex over ( )} {circumflex over ( )}{circumflex over ( )}

RatB
VS-

HsB
VS-

**

Tables 10a and 10b

[0436] Alignment of the polypeptides indicated. (a) RatA: R. norvegicus RabGGT alpha chain (SEQ ID NO:19), with CeA: C. elegans RabGGT alpha chain (SEQ ID NO:2 1). (b) RatB: R. norvegicus RabGGT beta chain (SEQ ID NO:20), with CeB: C. elegans RabGGT beta chain (SEQ ID NO:22). “{circumflex over ( )}” indicates residues within 5 Angstrom of the binding site. “*” indicates identity. “:” indicates conserved properties.

11TABLE 10a (i)RatA-HGRLKVKTSEEQAEAKRLEREQKLKLYQSATQAVFQKRQAGELDESVLELTSQILGANPCeAMHFVKKVPTTEEEKAAKQKEHTKRSQQFLHVRDKIVAKREKGEYDDEILSLTQAILEKNA * ** *:**: **: *: :: : : . : :. **: ** *:.:*.**. ** *.RatADFATLWNCRREVLQ-HLET---------------EKSPEESAALVKAELGFLE-SCLRVNCeADIYTFWNIRRTTIELRMEANEKVQQSADAEEEEKTKSSQKIENLLAGEL-FLSYECIKSN*: *:** ** .:: ::*: **.:: *: .** **. .*:: * {circumflex over ( )}RatAPKSYGTWHHRCWLLSRLPEPNWARELELCARFLEADERNFHCWDYRRFVAAQAAVAPAEECeAPKSYSAWYQRAWALQRQSAPDFKKELALCEKALQLDCRNFHCWDHRRIVARMAKRSEAEE****.:*::*.* *.* . *:: :** ** : *: * *******:**:** * : *** {circumflex over ( )} {circumflex over ( )}RatALAFTDSLITRNFSNYSSWHYRSCLLPQLHPQPDSGPQGRLPENVLLKELELVQNAFFTDPCeALEFSNKLINDNFSNYSAWHYRSIALKNIHRDEKTGAP-KIDDELIASELQKVKNAFFMDA* *::.**. ******:***** * ::* : .:*. :: :::: .**: *:**** *.RatANDQSAWFYHRWLLGPAEPRDVLCC-VHVSREEACLSVCFSRPLTVGSRNGTL--LLMVDECeAEDQSAWTYTRWLLEVGSGKEFLRPESHTPIELISASFRGNNTTLVFSRAVTIQFLLTFVD:***** * **** .. ::.* *.. * . *. ... * ** *: ** . :RatAAPLSVEWRTPDGRNRPSHVWLCDLPAASLNDQLPQHTFRVIWTGSDSQKECVLLKDRPECCeATENTTGWRAFSSTS-PNPT------SSRVWQYLSDTPLRVV-TSNPTDLENISWTELNEQ: :. **: .. . *. . :: : : *.: .:**: *.. :: * : .: *

[0437]

12

TABLE 10a (ii)

RatA
WCRDSATDEQLFRCELSVEKSTVLQSELESCKELQELEPENKWCLLTIILLMRALDPLLY

CeA
PYVNLDRLKTIYDV-VEVPQPAYIGELLEDCKQLIELEPKNKWPLYMRTLVLLEYQPIKS

: : :: :.* :.: : . **.**:* ****:*** * *:: :*:

RatA
EKETLQYFSTLKA-VDPMRAAYLDDLRSK----FLLENSVLKMEYADVRVLHLAHKDLTV

CeA
YEEIIKNLENLSENLDPKRSELYKSLISRQNLNFSIREQFERILGPDTDWLTCRYSKLTS

:* :: :..*. ** *: ..* *: * :.:.. :: .*. * :..**

RatA
LCHLEQLL-LVTHLDLSHNRLRALPPALAALRCLEVLQASDNALENVDGVANLPRLQELL

CeA
LEGVEYLAGFVGSADFSGNRLKEIQR--IVLPNLKSLTINENPIESLPPSPCLSHLTFFS

* :* * :* *:* ***: : .* *: * .:*.:*.: . *.:* :

RatA
LCNNRLQQSAAIQPLV-SCPRLVLLNLQGNSLCQE-EGIQERLAEMLPSVSSILT-----

CeA
IAGTQIASVSAVMPFFQTIPSLDRLVFCETPLVEKTEELRAQLPGVRLIPHWL-------

:...:: . :*: *:. : * * * : ..* :: * :: :*. : :

[0438]

13

TABLE 10b

1DCE
------------------------------------------------------------

Ceb
-------------------------------------------------------MSFAG

1DCE
---TQQKDVTIKSDAPDTLLLEKHADYIASYGSKKDDYEYCMSEYLRMSGVYWGLTVMDL

Ceb
LLDFARKDVDLPQNSPNELLKDLHANFINQYEKNKNSYHYIMAEHLRVSGIYWCVNAMDL

:*** : .::*: ** : **::* .* .:*:.*.* *:*:**:**:** :..***

{circumflex over ( )} {circumflex over ( )}{circumflex over ( )} {circumflex over ( )}

1DCE
MGQLHRMNKEEILVFIKSCQHECGGVSASIGHDPHLLYTLSAVQILTLYDSIHVINVDKV

Ceb
SKQLERMSTEEIVNYVLGCRNTDGGYGPAPGHDSHLLHTLCAVQTLIIFNSIEKADADTI

**.**..***: :: .*:: ** ..: ***.***:**.*** * :::**. :.*.:

1DCE
VAYVQSLQKEDGSFAGDIWGEIDTRFSFCAVATLALLGKLDAINVEKAIEFVLSCMNFDG

Ceb
SEYVKGLQQEDGSFCGDLSGEVDTRFTLCSLATCHLLGRLSTLNIDSAVRFLMRCYNTDG

**:.**:*****.**: **:****::*::** ***:*.::*::.*:.*:: * * **

{circumflex over ( )}

1DCE
GFGCRPGSESHAGQIYCCTGFLAITSQLHQVNSDLLGWWLCERQLPSGGLNGRPEKLPDV

Ceb
GFGTRPGSESHSGQIYCCVGALAIAGRLDEIDRDRTAEWLAFRQCDSGGLNGRPEKLPDV

*** *******:******.* ***:.:*.::: * . **. ** **************

{circumflex over ( )}

1DCE
CYSWWVLASLKIIGRLHWIDREKLRSFILACQDEETGGFADRPGDMVDPFHTLFGIAGLS

Ceb
CYSWWVLASLAILGRLNFIDSDAMKKFIYACQDDETGGFADRPGDCADPFHTVFGIAALS

********** *:***::** : ::.** ****:*********** .*****:****.**

{circumflex over ( )}{circumflex over ( )} {circumflex over ( )} {circumflex over ( )} {circumflex over ( )}{circumflex over ( )}

1DCE
LLGEEQIKPVSPVFCMPEEVLQRVNVQPELVS

Ceb
LFGDDTLESVDPIFCMTKRCLGDKQVEMYY--

*:*:: ::.*.*:***.:. * :*:

[0439]

14

TABLE 11

Residue/Residue

Atom No.
Position
Atom Type
X Coord.
Y Coord.
Z Coord.

1
MET1
N
40.653
31.02
43.155

2
MET1
CA
41.733
30.626
42.225

3
MET1
CB
42.562
29.486
42.796

4
MET1
CG
43.356
29.876
44.046

5
MET1
SD
44.746
31.016
43.814

6
MET1
CE
43.928
32.613
44.03

7
MET1
C
41.152
30.205
40.88

8
MET1
O
39.987
30.488
40.569

9
HIS2
N
41.95
29.458
40.134

10
HIS2
CA
41.596
29.033
38.771

11
HIS2
CB
42.849
28.472
38.107

12
HIS2
CG
44.026
29.429
38.102

13
HIS2
ND1
45.264
29.172
38.567

14
HIS2
CE1
46.039
30.263
38.397

15
HIS2
NE2
45.28
31.216
37.81

16
HIS2
CD2
44.038
30.716
37.619

17
HIS2
C
40.506
27.962
38.757

18
HIS2
O
40.782
26.764
38.881

19
GLY3
N
39.271
28.422
38.637

20
GLY3
CA
38.109
27.533
38.582

21
GLY3
C
37.613
27.167
39.979

22
GLY3
O
36.847
26.208
40.142

23
ARG4
N
38.005
27.948
40.972

24
ARG4
CA
37.645
27.604
42.351

25
ARG4
CB
38.847
27.832
43.257

26
ARG4
CG
39.963
26.85
42.922

27
ARG4
CD
39.495
25.415
43.127

28
ARG4
NE
40.539
24.455
42.74

29
ARG4
CZ
40.293
23.154
42.577

30
ARG4
NH1
39.058
22.681
42.765

31
ARG4
NH2
41.279
22.326
42.226

32
ARG4
C
36.45
28.404
42.847

33
ARG4
O
36.592
29.5
43.402

34
LEU5
N
35.275
27.83
42.652

35
LEU5
CA
34.042
28.459
43.133

36
LEU5
CB
32.87
27.909
42.325

37
LEU5
CG
31.585
28.69
42.577

38
LEU5
CD1
31.774
30.171
42.266

39
LEU5
CD2
30.432
28.116
41.762

40
LEU5
C
33.859
28.174
44.625

41
LEU5
O
33.747
27.017
45.052

42
LYS6
N
33.824
29.245
45.399

43
LYS6
CA
33.719
29.156
46.862

44
LYS6
CB
34.246
30.49
47.403

45
LYS6
OG
34.657
30.483
48.878

46
LYS6
CD
33.484
30.587
49.849

47
LYS6
CE
33.971
30.644
51.29

48
LYS6
NZ
34.837
31.811
51.512

49
LYS6
C
32.27
28.908
47.299

50
LYS6
O
31.495
29.848
47.504

51
VAL7
N
31.904
27.64
47.395

52
VAL7
CA
30.565
27.283
47.882

53
VAL7
CB
29.863
26.409
46.842

54
VAL7
CG1
28.404
26.162
47.222

55
VAL7
CG2
29.927
27.039
45.457

56
VAL7
C
30.666
26.525
49.203

57
VAL7
O
30.582
27.136
50.279

58
LYS8
N
31.179
25.307
49.097

59
LYS8
CA
31.24
24.358
50.223

60
LYS8
CB
31.282
22.949
49.649

61
LYS8
CG
30.039
22.674
48.813

62
LYS8
CD
30.044
21.261
48.242

63
LYS8
CE
28.78
20.993
47.431

64
LYS8
NZ
28.78
19.623
46.893

65
LYS8
C
32.426
24.565
51.165

66
LYS8
O
32.687
23.736
52.04

67
THR9
N
33.147
25.655
50.966

68
THR9
CA
34.276
25.989
51.832

69
THR9
CB
35.443
26.463
50.975

70
THR9
OG1
35.045
27.648
50.305

71
THR9
CG2
35.826
25.426
49.923

72
THR9
C
33.877
27.077
52.829

73
THR9
O
34.734
27.613
53.54

74
SER10
N
32.62
27.49
52.776

75
SER10
CA
32.126
28.488
53.727

76
SER10
CB
31.028
29.322
53.074

77
SER10
OG
29.901
28.485
52.855

78
SER10
C
31.569
27.824
54.98

79
SER10
O
30.988
26.734
54.922

80
GLU11
N
31.487
28.619
56.037

81
GLU11
CA
30.953
28.127
57.32

82
GLU11
CB
31.451
29.033
58.442

83
GLU11
CG
32.976
29.108
58.496

84
GLU11
CD
33.598
27.741
58.789

85
GLU11
OE1
33.833
27.465
59.957

86
GLU11
OE2
33.935
27.06
57.831

87
GLU11
C
29.422
28.105
57.312

88
GLU11
O
28.797
27.338
58.054

89
GLU12
N
28.873
28.7
56.264

90
GLU12
CA
27.431
28.778
56.014

91
GLU12
CB
27.107
30.028
55.189

92
GLU12
CG
27.208
31.353
55.958

93
GLU12
CD
28.646
31.859
56.096

94
GLU12
OE1
29.481
31.411
55.317

95
GLU12
OE2
28.924
32.504
57.096

96
GLU12
C
26.907
27.542
55.276

97
GLU12
O
25.853
27.612
54.635

98
GLN13
N
27.726
26.505
55.185

99
GLN13
CA
27.257
25.216
54.675

100
GLN13
CB
28.354
24.607
53.805

101
GLN13
CG
28.79
25.554
52.684

102
GLN13
CD
27.804
25.627
51.511

103
GLN13
OE1
28.034
24.995
50.472

104
GLN13
NE2
26.775
26.45
51.643

105
GLN13
C
26.891
24.283
55.83

106
GLN13
O
26.528
23.124
55.596

107
ALA14
N
27.051
24.783
57.05

108
ALA14
CA
26.655
24.074
58.276

109
ALA14
CB
25.136
23.938
58.312

110
ALA14
C
27.309
22.706
58.395

111
ALA14
O
26.639
21.669
58.356

112
GLU15
N
28.629
22.71
58.441

113
GLU15
CA
29.374
21.458
58.596

114
GLU15
CB
29.979
21.029
57.258

115
GLU15
CG
28.925
20.696
56.197

116
GLU15
CD
28.065
19.498
56.609

117
GLU15
OE1
27.15
19.183
55.861

118
GLU15
OE2
28.516
18.771
57.485

119
GLU15
C
30.468
21.636
59.641

120
GLU15
O
31.247
22.596
59.59

121
ALA16
N
30.475
20.747
60.618

122
ALA16
CA
31.461
20.839
61.701

123
ALA16
CB
30.865
20.228
62.964

124
ALA16
C
32.744
20.112
61.327

125
ALA16
O
32.85
18.902
61.557

126
LYS17
N
33.757
20.898
60.992

127
LYS17
CA
35.038
20.384
60.473

128
LYS17
CB
35.821
19.703
61.593

129
LYS17
CG
36.221
20.685
62.685

130
LYS17
CD
37.179
21.744
62.154

131
LYS17
CE
37.533
22.751
63.239

132
LYS17
NZ
36.321
23.416
63.742

133
LYS17
C
34.835
19.393
59.33

134
LYS17
O
34.484
19.784
58.21

135
ARG18
N
35.076
18.126
59.639

136
ARG18
CA
34.983
17.02
58.672

137
ARG18
CB
33.555
16.922
58.139

138
ARG18
OG
32.539
16.738
59.259

139
ARG18
CD
31.115
16.866
58.736

140
ARG18
NE
30.145
16.788
59.839

141
ARG18
CZ
29.063
16.006
59.802

142
ARG18
NH1
28.228
15.974
60.843

143
ARG18
NH2
28.821
15.251
58.727

144
ARG18
C
35.941
17.232
57.508

145
ARG18
O
35.532
17.176
56.341

146
LEU19
N
37.217
17.383
57.821

147
LEU19
CA
38.216
17.626
56.776

148
LEU19
CB
39.294
18.555
57.322

149
LEU19
CG
40.188
19.086
56.206

150
LEU19
CD1
39.359
19.788
55.134

151
LEU19
CD2
41.256
20.022
56.758

152
LEU19
C
38.82
16.302
56.311

153
LEU19
O
39.966
15.956
56.621

154
GLU20
N
38.012
15.553
55.586

155
GLU20
CA
38.441
14.242
55.117

156
GLU20
CB
37.259
13.285
55.047

157
GLU20
CG
36.922
12.721
56.43

158
GLU20
CD
37.967
11.695
56.89

159
GLU20
OE1
37.553
10.572
57.15

160
GLU20
OE2
39.15
11.962
56.735

161
GLU20
C
39.191
14.32
53.804

162
GLU20
O
39.491
15.417
53.319

163
ARG21
N
39.718
13.156
53.438

164
ARG21
CA
40.594
12.947
52.271

165
ARG21
CB
40.106
13.73
51.054

166
ARG21
CG
38.694
13.277
50.69

167
ARG21
CD
37.921
14.351
49.933

168
ARG21
NE
36.489
14.008
49.895

169
ARG21
CZ
35.601
14.459
50.788

170
ARG21
NH1
35.978
15.32
51.738

171
ARG21
NH2
34.322
14.086
50.7

172
ARG21
C
42.011
13.319
52.69

173
ARG21
O
42.95
13.337
51.885

174
GLU22
N
42.179
13.227
54

175
GLU22
CA
43.451
13.502
54.655

176
GLU22
CB
43.173
14.109
56.032

177
GLU22
CG
42.12
13.321
56.807

178
GLU22
CD
41.759
14.027
58.115

179
GLU22
OE1
40.721
13.683
58.669

180
GLU22
OE2
42.607
14.746
58.625

181
GLU22
C
44.252
12.211
54.738

182
GLU22
O
45.486
12.239
54.779

183
GLN23
N
43.565
11.123
54.43

184
GLN23
CA
44.193
9.812
54.312

185
GLN23
CB
43.112
8.742
54.446

186
GLN23
OG
42.268
8.926
55.706

187
GLN23
CD
40.867
9.443
55.366

188
GLN23
OE1
40.706
10.528
54.78

189
GLN23
NE2
39.881
8.634
55.708

190
GLN23
C
44.858
9.694
52.946

191
GLN23
O
45.968
9.158
52.843

192
LYS24
N
44.33
10.45
51.994

193
LYS24
CA
44.931
10.514
50.664

194
LYS24
CB
43.893
11.031
49.677

195
LYS24
CG
44.535
11.295
48.322

196
LYS24
CD
43.591
12.014
47.368

197
LYS24
CE
44.325
12.404
46.09

198
LYS24
NZ
45.481
13.265
46.402

199
LYS24
C
46.113
11.47
50.685

200
LYS24
O
47.16
11.167
50.1

201
LEU25
N
46.041
12.449
51.573

202
LEU25
CA
47.154
13.382
51.743

203
LEU25
CB
46.684
14.573
52.567

204
LEU25
CG
45.593
15.352
51.844

205
LEU25
CD1
45.027
16.453
52.731

206
LEU25
CD2
46.11
15.926
50.529

207
LEU25
C
48.328
12.704
52.437

208
LEU25
O
49.436
12.76
51.894

209
LYS26
N
48.044
11.819
53.38

210
LYS26
CA
49.12
11.068
54.039

211
LYS26
CB
48.577
10.457
55.322

212
LYS26
CG
48.181
11.536
56.323

213
LYS26
CD
47.574
10.921
57.579

214
LYS26
CE
46.356
10.073
57.234

215
LYS26
NZ
45.742
9.501
58.439

216
LYS26
C
49.698
9.967
53.153

217
LYS26
O
50.908
9.723
53.218

218
LEU27
N
48.923
9.49
52.192

219
LEU27
CA
49.45
8.521
51 .225

220
LEU27
CB
48.272
7.84
50.536

221
LEU27
CG
48.735
6.807
49.513

222
LEU27
CD1
49.589
5.727
50.169

223
LEU27
CD2
47.543
6.184
48.795

224
LEU27
C
50.323
9.218
50.184

225
LEU27
O
51.427
8.739
49.894

226
TYR28
N
49.963
10.449
49.865

227
TYR28
CA
50.736
11.291
48.949

228
TYR28
CB
49.875
12.534
48.717

229
TYR28
CG
50.383
13.618
47.77

230
TYR28
CO1
49.901
13.677
46.468

231
TYR28
CE1
50.336
14.681
45.611

232
TYR28
CZ
51.246
15.628
46.064

233
TYR28
OH
51.649
16.648
45.23

234
TYR28
CE2
51.722
15.578
47.367

235
TYR28
CD2
51.283
14.576
48.223

236
TYR28
C
52.071
11.668
49.588

237
TYR28
O
53.133
11.412
49.002

238
GLN29
N
52.012
11.973
50.875

239
GLN29
CA
53.208
12.313
51.649

240
GLN29
CB
52.768
12.743
53.04

241
GLN29
CG
51.923
14.008
53.01

242
GLN29
CD
51.212
14.145
54.351

243
GLN29
OE1
50.063
14.599
54.429

244
GLN29
NE2
51.865
13.631
55.378

245
GLN29
C
54.145
11.124
51.799

246
GLN29
O
55.306
11.232
51.39

247
SER30
53.59
49.958
52.097

248
SER30
CA
54.429
8.777
52.335

249
SER30
CB
53.602
7.745
53.087

250
SER30
OG
53.224
8.332
54.326

251
SER30
C
54.976
8.167
51.051

252
SER30
O
56.117
7.686
51.052

253
ALA31
N
54.311
8.413
49.935

254
ALA31
CA
54.847
7.961
48.653

255
ALA31
CB
53.723
7.938
47.622

256
ALA31
C
55.966
8.886
48.187

257
ALA31
O
57
8.388
47.727

258
THR32
N
55.899
10.143
48.595

259
THR32
CA
56.954
11.105
48.259

260
THR32
CB
56.387
12.513
48.416

261
THR32
OG1
55.249
12.637
47.575

262
THR32
CG2
57.389
13.582
48.003

263
THR32
C
58.164
10.934
49.176

264
THR32
O
59.308
10.998
48.705

265
GLN33
N
57.913
10.463
50.387

266
GLN33
CA
58.996
10.184
51.33

267
GLN33
CB
58.392
10.07
52.725

268
GLN33
CG
57.783
11.402
53.151

269
GLN33
CD
56.975
11.254
54.437

270
GLN33
OE1
56.121
10.367
54.565

271
GLN33
NE2
57.181
12.2
55.336

272
GLN33
C
59.718
8.894
50.962

273
GLN33
O
60.957
8.892
50.913

274
ALA34
N
58.971
7.95
50.409

275
ALA34
CA
59.568
6.707
49.922

276
ALA34
CB
58.464
5.684
49.69

277
ALA34
G
60.351
6.933
48.634

278
ALA34
O
61.491
6.462
48.535

279
VAL35
N
59.891
7.865
47.814

280
VAL35
CA
60.644
8.228
46.612

281
VAL35
CB
59.814
9.173
45.752

282
VAL35
CG1
60.666
9.824
44.671

283
VAL35
CG2
58.628
8.458
45.129

284
VAL35
C
61.954
8.92
46.961

285
VAL35
O
63.002
8.48
46.473

286
PHE36
N
61.943
9.761
47.984

287
PHE36
CA
63.167
10.481
48.344

288
PHE36
CB
62.82
11.684
49.212

289
PHE36
CG
62.135
12.83
48.472

290
PHE36
CD1
61.298
13.696
49.163

291
PHE36
OE1
60.678
14.743
48.495

292
PHE36
CZ
60.896
14.927
47.136

293
PHE36
CE2
61.739
14.066
46.446

294
PHE36
CD2
62.362
13.021
47.115

295
PHE36
C
64.174
9.605
49.079

296
PHE36
O
65.381
9.784
48.87

297
GLN37
N
63.717
8.563
49.754

298
GLN37
CA
64.677
7.682
50.42

299
GLN37
CB
64.069
7.128
51.704

300
GLN37
CG
62.783
6.351
51.47

301
GLN37
CD
62.066
6.161
52.799

302
GLN37
OE1
60.833
6.065
52.855

303
GLN37
NE2
62.85
6.168
53.863

304
GLN37
C
65.194
6.582
49.492

305
GLN37
O
66.371
6.218
49.604

306
LYS38
N
64.466
6.29
148.427

307
LYS38
CA
65
5.377
47.418

308
LYS38
CB
63.852
4.812
46.597

309
LYS38
CG
62.916
3.961
47.443

310
LYS38
CD
61.707
3.513
46.634

311
LYS38
CE
60.754
2.682
47.484

312
LYS38
NZ
61.43
1.484
48.004

313
LYS38
C
65.956
6.128
46.504

314
LYS38
O
67.062
5.638
46.237

315
ARG39
N
65.674
7.407
46.327

316
ARG39
CA
66.528
8.285
45.528

317
ARG39
CB
65.786
9.608
45.381

318
ARG39
CG
66.475
10.59
44.442

319
ARG39
CD
65.692
11.898
44.407

320
ARG39
NE
66.223
12.832
43.402

321
ARG39
CZ
65.737
14.064
43.238

322
ARG39
NH1
64.791
14.519
44.063

323
ARG39
NH2
66.234
14.861
42.29

324
ARG39
C
67.874
8.524
46.208

325
ARG39
O
68.909
8.289
45.571

326
GLN40
N
67.863
8.662
47.528

327
GLN40
CA
69.117
8.884
48.266

328
GLN40
CB
68.815
9.633
49.564

329
GLN40
CG
68.052
8.783
50.574

330
GLN40
CD
67.561
9.644
51.734

331
GLN40
OE1
67.735
9.301
52.909

332
GLN40
NE2
66.843
10.695
51.381

333
GLN40
C
69.871
7.582
48.561

334
GLN40
O
71.033
7.629
48.981

335
ALA41
N
69.251
6.445
48.28

336
ALA41
CA
69.937
5.157
48.382

337
ALA41
CB
68.955
4.121
48.916

338
ALA41
C
70.486
4.698
47.029

339
ALA41
O
71.154
3.66
46.947

340
GLY42
N
70.172
5.441
45.977

341
GLY42
CA
70.682
5.123
44.638

342
GLY42
C
69.757
4.168
43.888

343
GLY42
O
70.156
3.534
42.903

344
GLU43
N
68.509
4.113
44.319

345
GLU43
CA
67.538
3.194
43.721

346
GLU43
CB
66.577
2.715
44.801

347
GLU43
CG
67.297
2.019
45.947

348
GLU43
CD
66.284
1.643
47.023

349
GLU43
OE1
65.116
1.52
46.683

350
GLU43
OE2
66.672
1.603
48.182

351
GLU43
C
66.732
3.886
42.633

352
GLU43
O
65.535
4.142
42.808

353
LEU44
N
67.353
4.083
41.483

354
LEU44
CA
66.677
4.749
40.359

355
LEU44
CB
67.705
5.54
39.562

356
LEU44
CG
68.365
6.614
40.419

357
LEU44
CO1
69.482
7.309
39.651

358
LEU44
CD2
67.34
7.626
40.925

359
LEU44
C
65.976
3.74
39.451

360
LEU44
O
66.282
3.62
38.261

361
ASP45
N
65.002
3.051
40.021

362
ASP45
CA
64.279
2.002
39.299

363
ASP45
CB
64.678
0.645
39.878

364
ASP45
CG
64.491
0.607
41.394

365
ASP45
OD1
65.474
0.774
42.102

366
ASP45
OD2
63.357
0.407
41.809

367
ASP45
C
62.766
2.216
39.355

368
ASP45
O
62.282
3.253
39.831

369
GLU46
N
62.03
1.164
39.029

370
GLU46
CA
60.569
1.259
38.905

371
GLU46
CB
59.99
0.088
38.099

372
GLU46
CG
59.955
−1.256
38.835

373
GLU46
CD
61.224
−2.072
38.594

374
GLU46
OE1
61.214
−2.877
37.677

375
GLU46
OE2
62.233
−1.729
39.201

376
GLU46
C
59.822
1.364
40.239

377
GLU46
O
58.672
1.808
40.215

378
SER47
N
60.487
1.206
41.376

379
SER47
CA
59.798
1.442
42.651

380
SER47
CB
60.593
0.822
43.798

381
SER47
OG
61.847
1.486
43.909

382
SER47
C
59.604
2.941
42.889

383
SER47
O
58.501
3.348
43.267

384
VAL48
N
60.503
3.743
42.337

385
VAL48
CA
60.365
5.194
42.441

386
VAL48
CB
61.735
5.823
42.227

387
VAL48
CG1
61.654
7.343
42.186

388
VAL48
CG2
62.713
5.367
43.297

389
VAL48
C
59.408
5.694
41.371

390
VAL48
O
58.499
6.475
41.681

391
LEU49
N
59.39
4.974
40.262

392
LEU49
CA
58.535
5.333
39.133

393
LEU49
CB
58.97
4.47
37.957

394
LEU49
CG
58.603
5.097
36.621

395
LEU49
OD1
59.419
6.366
36.413

396
LEU49
CD2
58.864
4.12
35.48

397
LEU49
C
57.06
5.061
39.44

398
LEU49
O
56.222
5.948
39.242

399
GLU50
N
56.797
3.989
40.17

400
GLU50
CA
55.415
3.643
40.52

401
GLU50
CB
55.322
2.133
40.728

402
GLU50
CG
56.119
1.664
41.939

403
GLU50
CD
56.406
0.168
41.847

404
GLU50
OE1
56.595
−0.306
40.735

405
GLU50
OE2
56.612
−0.432
42.893

406
GLU50
C
54.902
4.393
41.753

407
GLU50
O
53.693
4.368
42.015

408
LEU51
N
55.766
5.115
42.449

409
LEU51
CA
55.286
5.967
43.535

410
LEU51
CB
56.301
5.97
44.668

411
LEU51
CG
56.423
4.605
45.329

412
LEU51
OD1
57.6
4.577
46.295

413
LEU51
CD2
55.129
4.217
46.036

414
LEU51
C
55.078
7.381
43.014

415
LEU51
O
53.993
7.949
43.208

416
THR52
N
55.95
7.783
42.1

417
THR52
CA
55.831
9.107
41.473

418
THR52
CB
57.125
9.492
40.758

419
THR52
OG1
57.453
8.479
39.818

420
THR52
CG2
58.296
9.648
41.714

421
THR52
C
54.69
9.156
40.467

422
THR52
O
54.066
10.211
40.337

423
SER53
N
54.244
8.003
39.996

424
SER53
CA
53.07
7.963
39.121

425
SER53
CB
52.986
6.583
38.476

426
SER53
OC
52.87
5.613
39.509

427
SER53
C
51.762
8.256
39.859

428
SER53
O
50.881
8.897
39.277

429
GLN54
N
51.732
8.049
41.166

430
GLN54
CA
50.515
8.354
41.916

431
GLN54
CB
50.509
7.501
43.177

432
GLN54
CG
50.595
6.019
42.839

433
GLN54
CD
50.702
5.198
44.119

434
GLN54
OE1
49.888
5.335
45.039

435
GLN54
NE2
51.725
4.365
44.168

436
GLN54
C
50.506
9.824
42.306

437
GLN54
O
49.529
10.54
42.039

438
ILEA55
N
51.695
10.312
42.617

439
ILEA55
CA
51.835
11.687
43.091

440
ILEA55
CB
53.197
11.803
43.752

441
ILEA55
CG2
53.298
13.124
44.5

442
ILEA55
OG1
53.417
10.646
44.715

443
ILEA55
CD1
54.876
10.568
45.136

444
ILEA55
C
51.741
12.694
41.951

445
ILEA55
O
51.023
13.689
42.09

446
LEU56
N
52.232
12.318
40.781

447
LEU56
CA
52.15
13.19
39.605

448
LEU56
CB
53.305
12.867
38.67

449
LEU56
CG
54.641
13.172
39.333

450
LEU56
CD1
55.801
12.611
38.527

451
LEU56
CD2
54.807
14.667
39.551

452
LEU56
C
50.823
13.027
38.871

453
LEU56
O
50.382
13.961
38.19

454
GLY57
N
50.106
11.961
39.188

455
GLY57
CA
48.735
11.794
38.702

456
GLY57
C
47.828
12.818
39.377

457
GLY57
O
47.03
13.488
38.711

458
ALA58
N
48.031
13
40.674

459
ALA58
CA
47.297
14.026
41.428

460
ALA58
CB
47.194
13.566
42.879

461
ALA58
C
47.954
15.413
41.379

462
ALA58
O
47.393
16.379
41.911

463
ASN59
N
49.113
15.505
40.747

464
ASN59
CA
49.849
16.769
40.637

465
ASN59
CB
50.54
17.031
41.973

466
ASN59
OG
51.275
18.373
42.02

467
ASN59
OD1
51.473
19.056
41.004

468
ASN59
ND2
51.832
18.629
43.188

469
ASN59
C
50.893
16.689
39.525

470
ASN59
O
52.077
16.434
39.789

471
PRO60
N
50.507
17.158
38.348

472
PRO60
CA
51.395
17.139
37.175

473
PR060
CB
50.48
17.388
36.018

474
PRO60
CG
49.117
17.82
36.534

475
PRO60
CD
49.189
17.722
38.046

476
PR060
C
52.504
18.204
37.192

477
PRO60
O
53.34
18.238
36.283

478
ASP61
N
52.531
19.057
38.201

479
ASP61
CA
53.538
20.114
38.267

480
ASP61
CB
52.852
21.459
38.443

481
ASP61
CG
52.193
21.843
37.125

482
ASP61
OD1
52.927
22.254
36.234

483
ASP61
OD2
51.025
21.515
36.953

484
ASP61
C
54.559
19.886
39.373

485
ASP61
O
55.335
20.8
39.681

486
PHE62
N
54.549
18.711
39.984

487
PHE62
CA
55.586
18.388
40.973

488
PHE62
CB
55.057
17.277
41.876

489
PHE62
CG
55.701
17.16
43.259

490
PHE62
CD1
54.944
16.673
44.317

491
PHE62
CE1
55.506
16.558
45.581

492
PHE62
CZ
56.826
16.934
45.791

493
PHE62
CE2
57.583
17.426
44.736

494
PHE62
CD2
57.02
17.541
43.471

495
PHE62
C
56.86
17.95
40.242

496
PHE62
O
57.216
16.764
40.224

497
ALA63
N
57.653
18.947
39.876

498
ALA63
CA
58.828
18.75
39.018

499
ALA63
CB
59.249
20.105
38.46

500
ALA63
C
60.017
18.089
39.704

501
ALA63
O
60.829
17.463
39.017

502
THR64
N
59.961
17.957
41.018

503
THR64
CA
61.016
17.233
41.725

504
THR64
CB
60.927
17.575
43.206

505
THR64
OG1
61.077
18.982
43.337

506
THR64
CG2
62.034
16.906
44.01

507
THR64
C
60.855
15.728
41.518

508
THR64
O
61.854
15.04
41 .275

509
LEU65
N
59.624
15.306
41 .271

510
LEU65
CA
59.362
13.895
41.001

511
LEU65
CB
57.995
13.532
41.551

512
LEU65
CG
57.951
13.757
43.057

513
LEU65
CD1
56.569
13.454
43.597

514
LEU65
CD2
58.991
12.912
43.783

515
LEU65
C
59.446
13.607
39.508

516
LEU65
O
59.743
12.472
39.119

517
TRP66
N
59.445
14.663
38.711

518
TRP66
CA
59.762
14.518
37.29

519
TRP66
CB
59.236
15.716
36.509

520
TRP66
CG
57.732
15.771
36.339

521
TRP66
CD1
56.893
16.775
36.765

522
TRP66
NE1
55.625
16.46
36.403

523
TRP66
CE2
55.582
15.281
35.758

524
TRP66
CZ2
54.544
14.556
35.195

525
TRP66
CH2
54.808
13.342
34.575

526
TRP66
CZ3
56.108
12.852
34.514

527
TRP66
CE3
57.154
13.574
35.073

528
TRP66
CD2
56.896
14.787
35.693

529
TRP66
C
61.271
14.404
37.092

530
TRP66
O
61.705
13.643
36.219

531
ASN67
N
62.04
14.936
38.033

532
ASN67
CA
63.489
14.714
38.034

533
ASN67
CB
64.164
15.667
39.012

534
ASN67
GG
63.947
17.128
38.648

535
ASN67
OD1
63.841
17.496
37.473

536
ASN67
ND2
63.977
17.959
39.675

537
ASN67
C
63.804
13.297
38.492

538
ASN67
O
64.677
12.645
37.903

539
CYS68
N
62.958
12.758
39.356

540
CYS68
CA
63.113
11.367
39.787

541
CYS68
CB
62.19
11.103
40.967

542
CYS68
SG
62.506
12.099
42.438

543
CYS68
C
62.777
10.399
38.659

544
CYS68
O
63.586
9.503
38.389

545
ARG69
N
61.794
10.741
37.839

546
ARG69
CA
61.474
9.9
36.68

547
ARG69
CB
60.095
10.27
36.155

548
ARG69
CG
59.026
10.002
37.203

549
ARG69
CD
57.633
10.262
36.647

550
ARG69
NE
57.328
9.369
35.519

551
ARG69
CZ
56.5
8.328
35.628

552
ARG69
NH1
56.247
7.554
34.571

553
ARG69
NH2
55.919
8.062
36.797

554
ARG69
C
62.497
10.045
35.557

555
ARG69
O
62.819
9.044
34.909

556
ARG70
N
63.174
11.18
35.497

557
ARG70
CA
64.273
11.339
34.543

558
ARG70
CB
64.652
12.813
34.459

559
ARG70
CG
63.817
13.518
33.403

560
ARG70
CD
64.152
14.998
33.28

561
ARG70
NE
63.384
15.803
34.238

562
ARG70
CZ
62.513
16.729
33.832

563
ARG70
NH1
62.35
16.958
32.527

564
ARG70
NH2
61.823
17.44
34.725

565
ARG70
C
65.499
10.53
34.946

566
ARG70
O
66.071
9.84
34.094

567
GLU71
N
65.728
10.403
36.241

568
GLU71
CA
66.874
9.635
36.731

569
GLU7I
CB
67.137
10.077
38.162

570
GLU71
CG
67.534
11.546
38.196

571
GLU71
CD
67.372
12.096
39.608

572
GLU71
OE1
66.439
11.673
40.277

573
GLU71
OE2
68.106
13.013
39.949

574
GLU71
C
66.603
8.135
36.687

575
GLU71
O
67.472
7.377
36.239

576
VAL72
N
65.347
7.763
36.875

577
VAL72
CA
64.952
6.359
36.753

578
VAL72
CB
63.543
6.191
37.316

579
VAL72
CG1
62.954
4.833
36.955

580
VAL72
CG2
63.511
6.411
38.823

581
VAL72
C
64.963
5.915
35.297

582
VAL72
O
65.538
4.866
34.987

583
LEU73
N
64.605
6.818
34.398

584
LEU73
CA
64.592
6.466
32.98

585
LEU73
CB
63.706
7.436
32.205

586
LEU73
CG
62.358
6.823
31.819

587
LEU73
CD1
61.513
6.447
33.033

588
LEU73
CD2
61.575
7.764
30.911

589
LEU73
C
65.989
6.457
32.38

590
LEU73
O
66.269
5.559
31.582

591
GLN74
N
66.91
7.236
32.924

592
GLN74
CA
68.289
7.195
32.427

593
GLN74
CB
68.987
8.495
32.804

594
GLN74
CG
68.389
9.663
32.028

595
GLN74
CD
68.938
10.988
32.545

596
GLN74
OE1
70.088
11.078
32.991

597
GLN74
NE2
68.087
11.998
32.522

598
GLN74
C
69.052
5.996
32.979

599
GLN74
O
69.75
5.315
32.214

600
GLN75
N
68.668
5.562
34.169

601
GLN75
CA
69.263
4.356
34.74

602
GLN75
CB
68.913
4.305
36.223

603
GLN75
CG
69.492
3.08
36.926

604
GLN75
CD
71.018
3.121
36.954

605
GLN75
OE1
71.615
3.822
37.781

606
GLN75
NE2
71.63
2.363
36.06

607
GLN75
C
68.732
3.111
34.034

608
GLN75
O
69.532
2.28
33.578

609
LEU76
N
67.473
3.187
33.639

610
LEU76
CA
66.824
2.1
32.9

611
LEU76
CB
65.31
2.293
32.988

612
LEU76
CG
64.619
1.454
34.069

613
LEU76
CD1
65.251
1.564
35.455

614
LEU76
CD2
63.136
1.797
34.139

615
LEU76
C
67.24
42.069
31.43

616
LEU76
O
67.28
10.983
30.843

617
GLU77
N
67.80
83.16
30.935

618
GLU77
CA
68.31
33.201
29.558

619
GLU77
CB
68.34
34.649
29.082

620
GLU77
CG
66.93
75.128
28.743

621
GLU77
CD
66.88
96.644
28.596

622
GLU77
OE1
67.54
27.316
29.383

623
GLU77
OE2
66.07
87.107
27.806

624
GLU77
C
69.69
92.58
29.432

625
GLU77
O
70.15
22.304
28.316

626
THR78
N
70.33
62.311
30.559

627
THR78
CA
71.58
11.545
30.543

628
THR78
CB
72.6
2.207
31.464

629
THR78
OG1
72.20
41.988
32.81

630
THR78
CG2
72.70
93.707
31.218

631
THR78
C
71.3
50.107
31.011

632
THR78
O
72.324
−0.631
31.201

633
GLN79
N
70.106
−0.263
31.283

634
GLN79
CA
69.84
−1.599
31.833

635
GLN79
CB
69.275
−1.43
33.237

636
GLN79
CG
70.288
−0.799
34.178

637
GLN79
CD
69.644
−0.556
35.535

638
GLN79
OE1
68.737
0.275
35.667

639
GLN79
NE2
70.167
−1.233
36.541

640
GLN79
C
68.847
−2.427
31.023

641
GLN79
O
69.016
−3.647
30.897

642
LYS80
N
67.798
−1.789
30.536

643
LYS80
CA
66.708
−2.52
29.879

644
LYS80
CB
65.439
−1.675
29.918

645
LYS80
CG
64.964
−1.421
31 .344

646
LYS80
CD
64.719
−2.726
32.094

647
LYS80
CE
64.104
−2.476
33.465

648
LYS80
NZ
62.786
−1.835
33.333

649
LYS80
C
67.016
−2.878
28.433

650
LYS80
O
67.642
−2.111
27.693

651
SER81
N
66.515
−4.036
28.038

652
SER81
CA
66.603
−4.479
26.642

653
SER81
CB
66.015
−5.883
26.544

654
SER81
OG
64.636
−5.801
26.877

655
SER81
C
65.808
−3.511
25.772

656
SER81
O
64.814
−2.948
26.245

657
PRO82
N
66.189
−3.344
24.514

658
PRO82
CA
65.751
−2.158
23.755

659
PRO82
CB
66.517
−2.216
22.468

660
PRO82
CG
67.431
−3.433
22.472

661
PRO82
CD
67.239
−4.099
23.824

662
PRO82
C
64.244
−2.083
23.478

663
PRO82
O
63.663
−1.003
23.629

664
GLU83
N
63.579
−3.224
23.382

665
GLU83
CA
62.128
−3.219
23.134

666
GLU83
CB
61.678
−4.471
22.361

667
GLU83
CG
61.622
−5.784
23.156

668
GLU83
CD
62.991
−6.447
23.294

669
GLU83
OE1
63.347
−7.205
22.407

670
GLU83
OE2
63.738
−6.003
24.159

671
GLU83
C
61.34
−3.083
24.442

672
GLU83
O
60.24
−2.52
24.445

673
GLU84
N
62.014
−3.332
25.553

674
GLU84
CA
61.405
−3.181
26.871

675
GLU84
CB
62.162
−4.11
27.807

676
GLU84
CG
61.732
−4.009
29.262

677
GLU84
CD
62.705
−4.849
30.079

678
GLU84
OE1
63.841
−4.975
29.633

679
GLU84
OE2
62.305
−5.362
31.114

680
GLU84
C
61.571
−1.739
27.325

681
GLU84
O
60.652
−1.148
27.902

682
LEU85
N
62.621
−1.123
26.811

683
LEU85
CA
62.88
0.289
27.061

684
LEU85
CB
64.347
0.53
26.73

685
LEU85
CG
64.786
1.941
27.084

686
LEU85
CD1
64.585
2.206
28.573

687
LEU85
CD2
66.241
2.149
26.683

688
LEU85
C
61.987
1.159
26.179

689
LEU85
O
61.461
2.17
26.656

690
ALA86
N
61 .603
0.627
25.028

691
ALA86
CA
60.646
1.324
24.164

692
ALA86
CB
60.728
0.728
22.763

693
ALA86
C
59.219
1.197
24.692

694
ALA86
O
58.455
2.169
24.621

695
ALA87
N
58.955
0.134
25.435

696
ALA87
CA
57.655
−0.005
26.095

697
ALA87
CB
57.457
−1.463
26.492

698
ALA87
C
57.573
0.885
27.333

699
ALA87
O
56.533
1.516
27.562

700
LEU88
N
58.721
1.151
27.938

701
LEU88
CA
58.786
2.087
29.068

702
LEU88
CB
60.133
1.931
29.775

703
LEU88
CG
60.042
1.16
31.092

704
LEU88
CD1
59.089
1.856
32.058

705
LEU88
CD2
59.64
−0.3
30.904

706
LEU88
C
58.638
3.531
28.595

707
LEU88
O
57.907
4.304
29.225

708
VAL89
N
59.101
3.808
27.387

709
VAL89
CA
58.939
5.143
26.805

710
VAL89
CB
59.923
5.275
25.646

711
VAL89
CG1
59.604
6.475
24.762

712
VAL89
CG2
61.36
5.335
26.149

713
VAL89
C
57.516
5.387
26.305

714
VAL89
O
56.978
6.481
26.521

715
LYS90
N
56.831
4.332
25.894

716
LYS90
CA
55.447
4.498
25.446

717
LYS90
CB
55.08
3.332
24.537

718
LYS90
CG
53.699
3.528
23.924

719
LYS90
CD
53.359
2.418
22.938

720
LYS90
CE
51.986
2.64
22.314

721
LYS90
NZ
51.679
1.594
21.326

722
LYS90
C
54.487
4.574
26.632

723
LYS90
O
53.552
5.386
26.608

724
ALA91
N
54.874
3.965
27.743

725
ALA91
CA
54.092
4.096
28.977

726
ALA91
CB
54.473
2.963
29.923

727
ALA91
C
54.37
5.439
29.648

728
ALA91
O
53.458
6.05
30.219

729
GLU92
N
55.535
5.992
29.353

730
GLU92
CA
55.875
7.336
29.807

731
GLU92
CB
57.365
7.557
29.57

732
GLU92
CG
57.826
8.924
30.061

733
GLU92
CD
57.723
8.995
31.578

734
GLU92
OE1
58.446
8.25
32.224

735
GLU92
OE2
56.968
9.825
32.061

736
GLU92
C
55.078
8.38
29.036

737
GLU92
O
54.51
9.271
29.671

738
LEU93
N
54.824
8.14
27.758

739
LEU93
CA
54.006
9.076
26.974

740
LEU93
CB
54.212
8.792
25.491

741
LEU93
CG
55.632
9.145
25.074

742
LEU93
CD1
55.89
8.78
23.619

743
LEU93
CD2
55.9
10.625
25.314

744
LEU93
C
52.526
8.956
27.319

745
LEU93
O
51.839
9.981
27.423

746
GLY94
N
52.12
7.766
27.728

747
GLY94
CA
50.77
7.557
28.256

748
GLY94
C
50.555
8.376
29.525

749
GLY94
O
49.645
9.215
29.576

750
PHE95
N
51.505
8.288
30.443

751
PHE9S
CA
51.4
9.018
31 .709

752
PHE95
CB
52.444
8.461
32.667

753
PHE95
CG
52.37
9.072
34.059

754
PHE95
CD1
51.247
8.856
34.846

755
PHE95
CE1
51.171
9.414
36.114

756
PHE9S
CZ
52.218
10.19
36.593

757
PHE95
CE2
53.339
10.41
35.804

758
PHE95
CD2
53.414
9.854
34.535

759
PHE95
C
51.607
10.529
31.555

760
PHE95
O
50.902
11.296
32.222

761
LEU96
N
52.356
10.949
30.548

762
LEU96
CA
52.511
12.383
30.278

763
LEU96
CB
53.657
12.582
29.292

764
LEU96
CG
55.01
12.297
29.932

765
LEU96
CD1
56.106
12.151
28.884

766
LEU96
CD2
55.372
13.366
30.952

767
LEU96
C
51.232
12.977
29.699

768
LEU96
O
50.773
14.018
30.184

769
GLU97
N
50.511
12.178
28.929

770
GLU97
CA
49.229
12.628
28.386

771
GLU97
CB
48.834
11.694
27.248

772
GLU97
CG
47.492
12.087
26.641

773
GLU97
CD
47.143
11.133
25.506

774
GLU97
OE1
46.517
11.58
24.555

775
GLU97
OE2
47.555
9.983
25.585

776
GLU97
C
48.145
12.615
29.457

777
GLU97
O
47.351
13.559
29.519

778
SER98
N
48.3
11.745
30.442

779
SER98
CA
47.346
11.687
31.551

780
SER98
CB
47.548
10.372
32.295

781
SER98
OG
47.35
9.313
31.368

782
SER98
C
47.547
12.851
32.516

783
SER98
O
46.56
13.471
32.932

784
CYS99
N
48.78
13.318
32.636

785
CYS99
CA
49.05
14.482
33.48

786
CYS99
CB
50.516
14.473
33.876

787
CYS99
SG
51.009
13.115
34.954

788
CYS99
C
48.701
15.789
32.775

789
CYS99
O
48.227
16.717
33.439

790
LEU100
N
48.642
15.753
31.453

791
LEU100
CA
48.15
16.905
30.69

792
LEU100
CB
48.744
16.853
29.291

793
LEU100
CG
50.251
17.052
29.338

794
LEU100
CD1
50.885
16.82
7.975

795
LEU100
CD2
50.598
18.437
29.871

796
LEU100
C
46.624
16.927
30.609

797
LEU100
O
46.032
17.981
30.357

798
ARG101
N
45.996
15.819
30.965

799
ARG101
CA
44.541
15.79
31.121

800
ARG101
CB
44.048
14.377
30.842

801
ARG101
CG
44.279
13.988
29.388

802
ARG101
CD
43.923
12.526
29.153

803
ARG101
NE
42.535
12.26
29.558

804
ARG101
CZ
41.576
11.903
28.701

805
ARG101
NH1
41.86
11.758
27.405

806
ARG101
NH2
40.336
11.683
29.142

807
ARG101
C
44.134
16.204
32.535

808
ARG101
O
42.97
16.548
32.772

809
VAL102
N
45.094
16.212
33.449

810
VAL102
CA
44.85
16.749
34.79

811
VAL102
CB
45.724
15.989
35.788

812
VAL102
CG1
45.539
16.509
37.21

813
VAL102
CG2
45.437
14.493
35.74

814
VAL102
C
45.191
18.239
34.809

815
VAL102
O
44.574
19.022
35.544

816
ASN103
N
46.141
18.618
33.97

817
ASN103
CA
46.472
20.03
33.767

818
ASN103
CB
47.376
20.502
34.904

819
ASN103
CG
47.604
22.007
34.801

820
ASN103
OD1
46.99
22.68
33.966

821
ASN103
ND2
48.587
22.492
35.537

822
ASN103
C
47.172
20.235
32.422

823
ASN103
O
48.385
20.019
32.294

824
PRO104
N
46.439
20.82
31.486

825
PRO104
CA
46.962
21.09
30.137

826
PRO104
CB
45.746
21.394
29.316

827
PR0104
CG
44.546
21.556
30.237

828
PRO104
CD
45.041
21.234
31.637

829
PRO104
C
47.961
22.254
30.047

830
PRO104
O
48.514
22.492
28.964

831
LYS105
N
48.18
22.975
31.137

832
LYS105
CA
49.199
24.028
31.157

833
LYS105
08
48.563
25.35
31.584

834
LYS105
CG
48.037
25.326
33.012

835
LYS105
CD
47.396
26.653
33.4

836
LYS105
CE
46.867
26.613
34.829

837
LYS105
NZ
46.241
27.892
35.198

838
LYS105
C
50.365
23.661
32.079

839
LYS105
O
51.108
24.545
32.525

840
SER106
N
50.475
22.383
32.413

841
SER106
CA
51.538
21.926
33.315

842
SER106
CB
51.307
20.462
33.666

843
SER106
OG
52.457
20.016
34.375

844
SER106
C
52.926
22.04
32.712

845
SER106
O
53.342
21.16
31.951

846
TYR107
N
53.722
22.912
33.309

847
TYR107
CA
55.115
23.087
32.885

848
TYR107
CB
55.696
24.335
33.544

849
TYR107
CG
55.112
25.667
33.082

850
TYR107
CD1
54.097
26.279
33.808

851
TYR107
CE1
53.576
27.494
33.385

852
TYR107
CZ
54.08
28.098
32.24

853
TYR107
OH
53.526
29.276
31.787

854
TYR107
CE2
55.103
27.497
31.52

855
TYR107
CD2
55.621
26.28
31.943

856
TYR107
C
55.956
21.886
33.295

857
TYR107
O
56.807
21.445
32.513

858
GLY108
N
55.548
21.231
34.371

859
GLY108
CA
56.198
19.995
34.807

860
GLY108
C
56.077
18.91
33.739

861
GLY108
O
57.09
18.499
33.154

862
THR109
N
54.849
18.62
33.339

863
THR109
CA
54.631
17.534
32.383

864
THR109
CB
53.15
17.191
32.404

865
THR109
OG1
52.775
16.927
33.749

866
THR109
CG2
52.874
15.949
31.574

867
THR109
C
55.049
17.897
30.956

868
THR109
O
55.648
17.05
30.279

869
TRP110
N
54.989
19.174
30.607

870
TRP110
CA
55.441
19.594
29.277

871
TRP110
CB
54.961
21.015
28.985

872
TRP110
CG
53.507
21.137
28.567

873
TRP110
CD1
52.533
21.897
29.178

874
TRP110
NE1
51.371
21.738
28.496

875
TRP110
CE2
51.532
20.912
27.446

876
TRP110
CZ2
50.662
20.457
26.468

877
TRP110
CH2
51.124
19.59
25.485

878
TRP110
CZ3
52.453
19.18
25.477

879
TRP110
CE3
53.332
19.632
26.454

880
TRP110
CD2
52.875
20.495
27.438

881
TRP110
C
56.959
19.547
29.147

882
TRP110
O
57.448
19.012
28.145

883
HIS111
N
57.675
19.821
30.225

884
HIS111
CA
59.136
19.773
30.163

885
HIS111
CB
59.705
20.527
31.36

886
HIS111
CG
61.221
20.554
31.45

887
HIS111
ND1
62.102
20.501
30.43

888
HIS111
CE1
63.357
20.554
30.921

889
HIS111
NE2
63.266
20.638
32.268

890
HIS111
CD2
61.957
20.642
32.607

891
HIS111
C
59.638
18.334
30.165

892
HIS111
O
60.534
18.019
29.371

893
HIS112
N
58.902
17.437
30.798

894
HIS112
CA
59.326
16.038
30.802

895
HIS112
CB
58.646
15.331
31.966

896
HIS112
CG
59.235
13.973
32.287

897
HIS112
ND1
60.228
13.722
33.16

898
HIS112
CE1
60.478
12.398
33.182

899
HIS112
NE2
59.635
11.807
32.308

900
HIS112
CD2
58.862
12.764
31.748

901
HIS112
C
58.985
15.35
29.479

902
HIS112
O
59.794
14.553
28.982

903
ARG113
N
57.969
15.848
28.791

904
ARG113
CA
57.638
15.283
27.483

905
ARG113
CB
56.165
15.532
27.186

906
ARG113
CG
55.722
14.677
26.008

907
ARG113
CD
54.223
14.765
25.757

908
ARG113
NE
53.847
13.857
24.663

909
ARG113
CZ
52.874
12.948
24.763

910
ARG113
NH1
52.149
12.874
25.879

911
ARG113
NH2
52.593
12.149
23.731

912
ARG113
C
58.517
15.874
26.38

913
ARG113
O
58.925
15.135
25.474

914
CY5114
N
59.017
17.083
26.593

915
CY5114
CA
59.991
17.661
25.659

916
CY5114
CB
60.117
19.162
25.902

917
CY5114
SG
58.678
20.174
25.491

918
CY5114
C
61.365
17.027
25.846

919
CY5114
O
62.069
16.776
24.862

920
TRP115
N
61.634
16.577
27.06

921
TRP115
CA
62.873
15.857
27.349

922
TRP115
CB
62.951
15.67
28.862

923
TRP115
CG
64.03
14.716
29.333

924
TRP115
CD1
65.378
14.974
29.432

925
TRP115
NE1
65.998
13.853
29.879

926
TRP115
CE2
65.115
12.858
30.088

927
TRP115
CZ2
65.256
11.546
30.517

928
TRP115
CH2
64.134
10.735
30.639

929
TRP115
CZ3
62.872
11.231
30.331

930
TRP115
CE3
62.721
12.541
29.896

931
TRP115
CD2
63.839
13.353
29.769

932
TRP115
C
62.889
14.502
26.651

933
TRP115
O
63.794
14.239
25.846

934
LEU116
N
61.768
13.801
26.724

935
LEU116
CA
61.703
12.465
26.134

936
LEU116
CB
60.459
11.764
26.663

937
LEU116
CG
60.431
10.303
26.232

938
LEU116
CD1
61.669
9.565
26.73

939
LEU116
CD2
59.166
9.619
26.73

940
LEU116
C
61.662
12.517
24.61

941
LEU116
O
62.497
11.864
23.974

942
LEU116
N
60.961
13.497
24.063

943
LEU117
CA
60.844
13.619
22.6

944
LEU117
CB
59.565
14.375
22.236

945
LEU117
CG
58.33
13.481
22.079

946
LEU117
CD1
58.584
12.359
21.084

947
LEU117
CD2
57.805
12.904
23.389

948
LEU117
C
62.052
14.316
21.964

949
LEU117
O
62.186
14.342
20.734

950
GLY118
N
62.945
14.82
22.797

951
GLY118
CA
64.205
15.367
22.313

952
GLY118
C
65.251
14.265
22.199

953
GLY118
O
66
14.224
21.214

954
ARG119
N
65.264
13.362
23.168

955
ARG119
CA
66.284
12.304
23.193

956
ARG119
CB
66.677
12.04
24.643

957
ARG119
CG
65.511
11.518
25.473

958
ARG119
CD
65.918
11.317
26.926

959
ARG119
NE
67.026
10.356
27.04

960
ARG119
CZ
68.172
10.619
27.676

961
ARG119
NH1
69.145
9.706
27.703

962
ARG119
NH2
68.361
11.808
28.251

963
ARG119
C
65.871
10.988
22.523

964
ARG119
O
66.705
10.077
22.438

965
LEU120
N
64.632
10.863
22.074

966
LEU120
CA
64.237
9.645
21.352

967
LEU120
CB
62.726
9.625
21.152

968
LEU120
CG
61.997
9.268
22.438

969
LEU120
CD1
60.486
9.295
22.234

970
LEU120
CD2
62.449
7.905
22.951

971
LEU120
C
64.921
9.541
19.994

972
LEU120
O
64.866
10.47
19.184

973
PRO121
N
65.485
8.371
19.729

974
PRO12I
CA
66.201
8.125
18.467

975
PRO121
CB
66.947
6.846
18.698

976
PRO121
CG
66.498
6.229
20.015

977
PRO121
CD
65.525
7.218
20.634

978
PRO121
C
65.279
7.991
17.249

979
PRO121
O
65.731
8.147
16.109

980
GLU122
N
64.007
7.712
17.485

981
GLU122
CA
63.011
7.743
16.406

982
GLU122
CB
62.948
6.356
15.764

983
GLU122
CG
62.595
6.386
14.274

984
GLU122
CD
61.173
6.881
14.012

985
GLU122
OE1
61.012
8.087
13.888

986
GLU122
OE2
60.294
6.042
13.877

987
GLU122
C
61.648
8.124
16.991

988
GLU122
O
60.804
7.245
17.196

989
PRO123
N
61.443
9.407
17.25

990
PRO123
CA
60.234
9.86
17.944

991
PRO123
CB
60.569
11.238
18.422

992
PRO123
CG
61.889
11.676
17.808

993
PRO123
CD
62.361
10.513
16.96

994
PRO123
C
59.012
9.875
17.027

995
PRO123
O
59.113
10.194
15.837

996
ASN124
N
57.865
9.525
17.588

997
ASN124
CA
56.624
9.531
16.807

998
ASN124
CB
55.643
8.532
17.417

999
ASN124
CG
54.414
8.344
16.524

1000
ASN124
OD1
54.074
9.207
15.703

1001
ASN124
ND2
53.732
7.232
16.724

1002
ASN124
C
56.02
10.931
16.787

1003
ASN124
O
55.146
11.264
17.597

1004
TRP125
N
56.283
11.629
15.697

1005
TRP125
CA
55.813
13.005
15.567

1006
TRP125
CB
56.693
13.727
14.556

1007
TRP125
CG
58.12
13.919
15.033

1008
TRP125
CD1
59.271
13.659
14.322

1009
TRP125
NE1
60.339
13.96
15.104

1010
TRP125
CE2
59.946
14.4
16.313

1011
TRP125
CZ2
60.645
14.787
17.445

1012
TRP125
CH2
59.956
15.205
18.577

1013
TRP125
CZ3
58.567
15.227
18.583

1014
TRP125
CE3
57.859
14.824
17.459

1015
TRP125
CD2
58.541
14.406
16.327

1016
TRP125
C
54.343
13.124
15.179

1017
TRP125
O
53.71
14.098
15.606

1018
THR126
N
53.733
12.046
14.711

1019
THR126
CA
52.309
12.124
14.372

1020
THR126
CB
51.953
11.086
13.313

1021
THR126
OG1
52.041
9.785
13.876

1022
THR126
CG2
52.89
11.163
12.113

1023
THR126
C
51.467
11.918
15.627

1024
THR126
O
50.421
12.56
15.771

1025
ARG127
N
52.072
11.304
16.633

1026
ARG127
CA
51.42
11.171
17.937

1027
ARG127
CB
52.129
10.063
18.712

1028
ARG127
CG
51.631
9.955
20.149

1029
ARG127
CD
52.406
8.897
20.926

1030
ARG127
NE
52.217
7.562
20.335

1031
ARG127
CZ
53.161
6.618
20.334

1032
ARG127
NH1
52.898
5.411
19.828

1033
ARG127
NH2
54.356
6.868
20.874

1034
ARG127
C
51.524
12.472
18.723

1035
ARG127
O
50.556
12.874
19.378

1036
GLU128
N
52.551
13.251
18.426

1037
GLU128
CA
52.748
14.508
19.151

1038
GLU128
CB
54.218
14.896
19.076

1039
GLU128
CG
55.143
13.723
19.38

1040
GLU128
CD
54.91
13.144
20.77

1041
GLU128
OE1
54.929
13.924
21.708

1042
GLU128
OE2
54.929
11.925
20.878

1043
GLU128
C
51.899
15.613
18.53

1044
GLU128
O
51.288
16.408
19.257

1045
LEU129
N
51.662
15.497
17.233

1046
LEU129
CA
50.782
16.452
16.557

1047
LEU129
CB
51.068
16.43
15.061

1048
LEU129
CG
52.483
16.907
14.756

1049
LEU129
CD1
52.797
16.775
13.27

1050
LEU129
CD2
52.695
18.341
15.227

1051
LEU129
C
49.319
16.108
16.803

1052
LEU129
O
48.504
17.019
16.987

1053
GLU130
N
49.045
14.842
17.073

1054
GLU130
CA
47.681
14.446
17.422

1055
GLU130
CB
47.537
12.943
17.211

1056
GLU130
CG
46.086
12.494
17.341

1057
GLU130
CD
45.235
13.14
16.25

1058
GLU130
OE1
45.743
13.273
15.145

1059
GLU130
OE2
44.074
13.409
16.517

1060
GLU130
C
47.368
14.799
18.873

1061
GLU130
O
46.247
15.236
19.153

1062
LEU131
N
48.4
14.871
19.699

1063
LEU131
CA
48.248
15.308
21.087

1064
LEU131
CB
49.599
15.155
21.775

1065
LEU131
CG
49.526
15.567
23.238

1066
LEU131
CD1
48.847
14.479
24.06

1067
LEU131
CD2
50.916
15.855
23.788

1068
LEU131
C
47.848
16.778
21.146

1069
LEU131
O
46.821
17.118
21.752

1070
CYS132
N
48.499
17.589
20.327

1071
CYS132
CA
48.159
19.011
20.295

1072
CYS132
CB
49.372
19.813
19.856

1073
CYS132
SG
50.526
20.07
21.215

1074
CYS132
C
46.941
19.328
19.438

1075
CYS132
O
46.283
20.339
19.701

1076
ALA133
N
46.502
18.385
18.622

1077
ALA133
CA
45.227
18.555
17.926

1078
ALA133
CB
45.149
17.557
16.776

1079
ALA133
C
44.07
18.318
18.892

1080
ALA133
O
43.158
19.151
18.96

1081
ARG134
N
44.256
17.384
19.813

1082
ARG134
CA
43.234
17.123
20.831

1083
ARG134
CB
43.594
15.848
21.581

1084
ARG134
CG
43.635
14.641
20.655

1085
ARG134
CD
44.109
13.399
21.402

1086
ARG134
NE
44.245
12.259
20.483

1087
ARG134
CZ
43.437
11.197
20.5

1088
ARG134
NH1
42.456
11.117
21.402

1089
ARG134
NH2
43.623
10.205
19.627

1090
ARG134
C
43.159
18.267
21.831

1091
ARG134
O
42.072
18.822
22.039

1092
PHE135
N
44.313
18.791
22.214

1093
PHE135
CA
44.322
19.9
23.171

1094
PHE135
CB
45.685
19.98
23.843

1095
PHE135
CG
45.901
18.877
24.874

1096
PHE135
CD1
47.119
18.216
24.95

1097
PHE135
CE1
47.303
17.21
25.89

1098
PHE135
CZ
46.271
16.866
26.754

1099
PHE135
CE2
45.055
17.531
26.681

1100
PHE135
CD2
44.871
18.537
25.741

1101
PHE135
C
43.949
21.244
22.552

1102
PHE135
O
43.353
22.06
23.258

1103
LEU136
N
44.026
21.36
21.237

1104
LEU136
CA
43.551
22.572
20.561

1105
LEU136
CB
44.343
22.767
19.273

1106
LEU136
CG
45.371
23.896
19.357

1107
LEU136
CD1
46.247
23.83
20.606

1108
LEU136
CD2
46.231
23.92
18.101

1109
LEU136
C
42.058
22.49
20.243

1110
LEU136
O
41.396
23.521
20.088

1111
GLU137
N
41.493
21.298
20.318

1112
GLU137
CA
40.042
21.181
20.166

1113
GLU137
CB
39.693
19.859
19.493

1114
GLU137
CG
40.277
19.773
18.086

1115
GLU137
CD
39.822
20.95
17.224

1116
GLU137
OE1
40.665
21.784
16.92

1117
GLU137
OE2
38.71
20.881
16.721

1118
GLU137
C
39.339
21.289
21.517

1119
GLU137
O
38.125
21.514
21.567

1120
VAL138
N
40.1
21.161
22.593

1121
VAL138
CA
39.558
21.424
23.929

1122
VAL138
CB
40.229
20.461
24.907

1123
VAL138
CG1
39.785
20.708
26.345

1124
VAL138
CG2
39.964
19.011
24.515

1125
VAL138
C
39.846
22.871
24.332

1126
VAL138
O
39.072
23.509
25.056

1127
A5P139
N
40.929
23.394
23.786

1128
A5P139
CA
41.346
24.775
24.026

1129
A5P139
CB
42.022
24.83
25.398

1130
A5P139
CG
42.276
26.264
25.864

1131
A5P139
OD1
42.534
27.111
25.015

1132
A5P139
OD2
42.306
26.465
27.068

1133
A5P139
C
42.329
25.19
22.931

1134
A5P139
O
43.549
25.07
23.106

1135
GLU14O
N
41.817
25.916
21.95

1136
GLU14O
CA
42.637
26.322
20.793

1137
GLU14O
CB
41.728
26.643
19.611

1138
GLU14O
CG
40.745
27.764
19.924

1139
GLU14O
CD
39.961
28.126
18.667

1140
GLU14O
OE1
38.749
28.251
18.774

1141
GLU14O
OE2
40.585
28.247
17.622

1142
GLU14O
C
43.549
27.519
21.056

1143
GLU14O
O
44.267
27.956
20.149

1144
ARG141
N
43.501
28.056
22.264

1145
ARG141
CA
44.365
29.164
22.649

1146
ARG141
CB
43.507
30.246
23.292

1147
ARG141
CG
42.483
30.799
22.305

1148
ARG141
CD
43.158
31.518
21.14

1149
ARG141
NE
43.932
32.669
21.628

1150
ARG141
CZ
43.547
33.936
21.459

1151
ARG141
NH1
42.481
34.215
20.703

1152
ARG141
NH2
44.276
34.926
21.978

1153
ARG141
C
45.454
28.699
23.613

1154
ARG141
O
46.132
29.54
24.217

1155
A5N142
N
45.558
27.393
23.824

1156
A5N142
CA
46.624
26.87
24.684

1157
A5N142
CB
46.345
25.411
25.046

1158
A5N142
CG
47.367
24.918
26.074

1159
A5N142
OD1
48.138
25.713
26.627

1160
A5N142
ND2
47.424
23.611
26.254

1161
A5N142
C
47.965
26.985
23.968

1162
A5N142
O
48.385
26.074
23.241

1163
PHE143
N
48.734
27.963
24.42

1164
PHE143
CA
50.018
28.287
23.797

1165
PHE143
CB
50.442
29.706
24.183

1166
PHE143
CG
50.738
29.965
25.664

1167
PHE143
CD1
52.031
29.809
26.147

1168
PHE143
CE1
52.309
30.05
27.486

1169
PHE143
CZ
51.294
30.457
28.343

1170
PHE143
CE2
50.003
30.627
27.859

1171
PHE143
CD2
49.727
30.387
26.519

1172
PHE143
C
51.11
27.289
24.161

1173
PHE143
O
52.043
27.124
23.37

1174
HIS144
N
50.844
26.427
25.13

1175
H15144
CA
51.796
25.373
25.466

1176
H15144
CB
51.401
24.752
26.797

1177
H15144
CG
51.393
25.704
27.973

1178
H15144
ND1
50.32
26.334
28.486

1179
H15144
CE1
50.706
27.099
29.527

1180
H15144
NE2
52.039
26.934
29.679

1181
H15144
CO2
52.476
26.074
28.732

1182
H15144
C
51.787
24.286
24.4

1183
H15144
O
52.864
23.85
23.979

1184
CYS145
N
50.645
24.081
23.761

1185
CYS145
CA
50.595
23.08
22.695

1186
CYS145
CB
49.227
22.418
22.653

1187
CYS145
SG
49.287
20.611
22.712

1188
CYS145
C
50.941
23.704
21 .346

1189
CYS145
O
51.488
23.012
20.48

1190
TRP146
N
50.884
25.024
21.271

1191
TRP146
CA
51.406
25.709
20.084

1192
TRP146
CD
50.872
27.139
20.039

1193
TRP146
CG
49.412
27.26
19.648

1194
TRP146
CD1
48.326
27.378
20.487

1195
TRP146
NE1
47.202
27.46
19.73

1196
TRP146
CE2
47.497
27.407
18.418

1197
TRP146
CZ2
46.711
27.456
17.277

1198
TRP146
CH2
47.311
27.379
16.025

1199
TRP146
CZ3
48.692
27.259
15.912

1200
TRP146
CE3
49.486
27.212
17.051

1201
TRP146
CD2
48.892
27.285
18.302

1202
TRP146
C
52.934
25.722
20.119

1203
TRP146
O
53.574
25.364
19.121

1204
ASP147
N
53.479
25.817
21.324

1205
ASP147
CA
54.927
25.731
21.528

1206
ASP147
CB
55.266
26.173
22.951

1207
ASP147
CG
54.916
27.636
23.211

1208
ASP147
001
55.111
28.436
22.307

1209
ASP147
002
54.614
27.948
24.357

1210
ASP147
C
55.424
24.301
21.364

1211
ASP147
O
56.499
24.094
20.79

1212
TYR148
N
54.572
23.332
21.655

1213
TYR148
CA
54.969
21.938
21.479

1214
TYR148
CB
54.103
21.05
22.361

1215
TYR148
CG
54.695
19.657
22.55

1216
TYR148
CO1
55.754
19.493
23.433

1217
TYR148
CE1
56.32
18.239
23.614

1218
TYR148
CZ
55.826
17.153
22.909

1219
TYR148
OH
56.436
15.929
23.048

1220
TYR148
CE2
54.764
17.31
22.028

1221
TYR148
CD2
54.198
18.566
21.847

1222
TYR148
C
54.85
21.503
20.023

1223
TYR148
O
55.678
20.707
19.569

1224
ARG149
N
54.03
22.193
19.246

1225
ARG149
CA
53.995
21.917
17.81

1226
ARG149
CB
52.68
22.4
17.212

1227
ARG149
CG
52.637
22.043
15.732

1228
ARG149
CD
51.31
22.379
15.068

1229
ARG149
NE
51.341
21.93
13.667

1230
ARG149
CZ
50.659
20.876
13.211

1231
ARG149
NH1
49.797
20.241
14.009

1232
ARG149
NH2
50.776
20.511
11.932

1233
ARG149
C
55.168
22.596
17.107

1234
ARG149
O
55.754
22.002
16.195

1235
ARG150
N
55.676
23.665
17.7

1236
ARG150
CA
56.909
24.276
17.193

1237
ARG150
CB
56.989
25.71
17.706

1238
ARG150
CG
55.952
26.568
16.992

1239
ARG150
CD
56.019
28.045
17.366

1240
ARG150
NE
55.239
28.349
18.575

1241
ARG150
CZ
54.219
29.213
18.563

1242
ARG150
NH1
53.582
29.513
19.696

1243
ARG15O
NH2
53.873
29.821
17.426

1244
ARG150
C
58.144
23.472
17.608

1245
ARG150
O
59.082
23.335
16.811

1246
PHE151
N
58.024
22.739
18.703

1247
PHE151
CA
59.073
21.804
19.112

1248
PHE151
CB
58.804
21.379
20.553

1249
PHE151
CG
59.705
20.262
21.073

1250
PHE151
CD1
61.016
20.537
21.44

1251
PHE151
CE1
61.834
19.518
21.91

1252
PHE151
CZ
61.342
18.223
22.013

1253
PHE 151
CE2
60.031
17.948
21.648

1254
PHE 151
CD2
59.213
18.967
21.179

1255
PHE151
C
59.091
20.578
18.205

1256
PHE151
O
60.165
20.192
17.729

1257
PHE151
N
57.92
20.133
17.778

1258
VAL152
CA
57.848
19.003
16.848

1259
VAL152
CB
56.409
18.504
16.795

1260
VAL152
CG1
56.227
17.45
15.709

1261
VAL152
CG
55.966
17.963
18.148

1262
VAL152
C
58.296
19.409
15.448

1263
VAL152
O
59.078
18.678
14.829

1264
ALA153
N
58.051
20.658
15.087

1265
ALA153
CA
58.495
21.16
13.788

1266
ALA153
CB
57.845
22.516
13.535

1267
ALA153
C
60.012
21.296
13.724

1268
ALA153
O
60.619
20.786
12.773

1269
THR154
N
60.627
21.713
14.817

1270
THR154
CA
62.091
21.823
14.821

1271
THR154
CB
62.537
22.756
15.944

1272
THR154
OG1
62.022
22.282
17.183

1273
THR154
CG2
62.02
24.173
15.731

1274
THR154
C
62.781
20.463
14.959

1275
THR154
O
63.717
20.197
14.196

1276
GLN155
N
62.148
19.534
15.659

1277
GLN155
CA
62.73
18.199
15.855

1278
GLN155
CB
62.137
17.62
17.13

1279
GLN155
CG
62.64
18.292
18.399

1280
GLN155
CD
64.077
17.875
18.689

1281
GLN155
OE1
64.975
18.722
18.756

1282
GLN155
NE
64.261
16.588
18.934

1283
GLN155
C
62.459
17.229
14.701

1284
GLN155
O
62.994
16.113
14.693

1285
ALA156
N
61.582
17.612
13.789

1286
ALA156
CA
61.358
16.827
12.574

1287
ALA156
CB
59.859
16.628
12.387

1288
ALA156
C
61.935
17.514
11.339

1289
ALA156
O
61.86
16.958
10.236

1290
ALA157
N
62.508
18.694
11.544

1291
ALA157
GA
63.024
19.542
10.457

1292
ALA157
CB
64.214
18.863
9.782

1293
ALA157
C
61.937
19.866
9.435

1294
ALA157
O
62.094
19.625
8.232

1295
VAL158
N
60.844
20.42
9.932

1296
VAL158
CA
59.705
20.785
9.087

1297
VAL158
CB
58.446
20.761
9.954

1298
VAL158
OG1
57.221
21.297
9.221

1299
VAL158
CG2
58.182
19.358
10.482

1300
VAL158
C
59.91
22.172
8.489

1301
VAL158
O
60.086
23.157
9.218

1302
PRO159
N
59.887
22.238
7.168

1303
PRO159
CA
60.044
23.514
6.469

1304
PRO159
CB
59.999
23.171
5.011

1305
PRO159
GG
59.775
21.675
4.848

1306
PRO159
CD
59.7
21.107
6.254

1307
PRO159
C
58.938
24.497
6.839

1308
PRO159
O
57.754
24.136
6.907

1309
PRO160
N
59.312
25.762
6.955

1310
PRO160
CA
58.363
26.806
7.37

1311
PRO160
CB
59.205
28.025
7.601

1312
PRO160
CG
60.643
27.732
7.2

1313
PRO160
CD
60.674
26.274
6.774

1314
PRO160
C
57.262
27.096
6.341

1315
PRO160
O
56.157
27.473
6.741

1316
ALA161
N
57.462
26.696
5.092

1317
ALA161
CA
56.412
26.85
4.078

1318
ALA161
CB
57.061
26.833
2.699

1319
ALA161
C
55.355
25.746
4.166

1320
ALA161
O
54.177
26.009
3.902

1321
GLU162
N
55.707
24.64
4.803

1322
GLU162
CA
54.748
23.555
5.02

1323
GLU162
CB
55.531
22.258
5.187

1324
GLU162
CG
54.62
21.064
5.447

1325
GLU162
CD
55.472
19.82
5.671

1326
GLU162
OE1
56.613
19.988
6.081

1327
GLU162
OE2
54.996
18.734
5.371

1328
GLU162
C
53.947
23.847
6.284

1329
GLU162
O
52.74
23.582
6.348

1330
GLU163
N
54.557
24.648
7.14

1331
GLU163
CA
53.888
25.114
8.348

1332
GLU163
CB
54.973
25.598
9.297

1333
GLU163
CG
54.478
25.655
10.731

1334
GLU163
CD
54.331
24.239
11.277

1335
GLU163
OE1
55.103
23.391
10.852

1336
GLU163
OE2
53.552
24.066
12.204

1337
GLU163
C
52.95
26.274
8.011

1338
GLU163
O
51.863
26.389
8.591

1339
LEU164
N
53.272
26.974
6.935

1340
LEU164
CA
52.412
28.042
6.435

1341
LEU164
CB
53.251
28.944
5.538

1342
LEU164
CG
52.483
30.186
5.107

1343
LEU164
CD1
52.085
31.02
6.319

1344
LEU164
CD2
53.31
31.019
4.134

1345
LEU164
C
51.238
27.466
5.648

1346
LEU164
O
50.121
27.979
5.775

1347
ALA165
N
51.409
26.269
5.111

1348
ALA165
CA
50.288
25.578
4.465

1349
ALA165
CB
50.835
24.421
3.637

1350
ALA165
C
49.296
25.053
5.503

1351
ALA165
O
48.079
25.203
5.317

1352
PHE166
N
49.81
24.741
6.683

1353
PHE166
CA
48.945
24.352
7.798

1354
PHE166
CB
49.809
23.777
8.915

1355
PHE166
CG
49.04
23.487
10.2

1356
PHE166
CD1
48.052
22.512
10.216

1357
PHE166
CE1
47.348
22.255
11.385

1358
PHE166
CZ
47.632
22.974
12.539

1359
PHE166
CE2
48.62
23.95
12.523

1360
PHE166
CD2
49.324
24.207
11.354

1361
PHE166
C
48.153
25.545
8.329

1362
PHE166
O
46.93
25.44
8.475

1363
THR167
N
48.767
26.717
8.35

1364
THR167
CA
48.031
27.903
8.801

1365
THR167
CB
49.009
28.978
9.261

1366
THR167
OG1
49.822
29.369
8.167

1367
THR167
CG2
49.915
28.476
10.38

1368
THR167
C
47.093
28.45
7.722

1369
THR167
O
46.034
28.985
8.069

1370
ASP16B
N
47.324
28.066
6.474

1371
ASP168
CA
46.403
28.41
5.386

1372
ASP168
CB
47.027
28.033
4.042

1373
ASP168
CG
48.284
28.841
3.731

1374
ASP168
OD1
49.134
28.313
3.023

1375
ASP168
OD2
48.321
30.008
4.094

1376
ASP168
C
45.096
27.635
5.528

1377
A3P168
O
44.02
28.244
5.475

1378
SER169
N
45.19
26.39
5.973

1379
SER169
CA
43.975
25.586
6.16

1380
SER169
CB
44.315
24.102
6.071

1381
SER169
CG
45.147
23.759
7.17

1382
SER169
C
43.286
25.888
7.493

1383
SER169
O
42.059
25.744
7.587

1384
LEU170
N
43.99
26.559
8.393

1385
LEU170
CA
43.356
27.006
9.636

1386
LEU170
CB
44.422
27.406
10.649

1387
LEU170
CG
45.301
26.236
11.069

1388
LEU170
CD1
46.375
26.708
12.039

1389
LEU170
CD2
44.476
25.113
11.689

1390
LEU170
C
42.461
28.215
9.386

1391
LEU170
O
41.373
28.3
9.972

1392
ILEA171
N
42.748
28.945
8.322

1393
ILEA171
CA
41.93
30.111
7.988

1394
ILEA171
CB
42.806
31.078
7.191

1395
ILEA171
CG2
42.05
32.347
6.808

1396
ILEA171
CG1
44.055
31.443
7.986

1397
ILEA171
CD1
43.711
32.088
9.325

1398
ILEA171
C
40.688
29.721
7.183

1399
1LEA171
O
39.694
30.457
7.199

1400
THR172
N
40.654
28.499
6.674

1401
THR172
GA
39.519
28.101
5.838

1402
THR172
CB
40.OD2
27.177
4.726

1403
THR172
OG1
40.422
25.949
5.302

1404
THR172
CG2
41.166
27.783
3.953

1405
THR172
C
38.396
27.406
6.609

1406
THR172
O
37.29
27.311
6.066

1407
ARG173
N
38.646
26.949
7.83

1408
ARG173
CA
37.554
26.333
8.605

1409
ARG173
CB
37.2
24.98
7.987

1410
ARG173
CG
35.777
24.56
8.349

1411
ARG173
CD
35.427
23.175
7.816

1412
ARG173
NE
34.053
22.808
8.199

1413
ARG173
VZ
33.763
21.959
9.187

1414
ARG173
NH1
34.745
21.361
9.865

1415
ARG173
NH2
32.49
21 .685
9.48

1416
ARG173
C
37.894
26.143
10.087

1417
ARG173
O
37.136
25.499
10.824

1418
ASN174
N
39.012
26.673
10.542

1419
ASN174
CA
39.328
26.506
11.962

1420
ASN174
CB
40.818
26.225
12.133

1421
ASN174
CG
41.146
25.798
13.56

1422
ASN174
OD1
42.199
26.154
14.103

1423
ASN174
ND2
40.255
25.011
14.14

1424
ASN174
C
38.902
27.755
12.723

1425
ASN174
O
37.811
27.768
13.307

1426
PHE175
N
39.693
28.81
12.615

1427
PHE175
CA
39.389
30.049
13.338

1428
PHE175
CB
39.488
29.769
14.839

1429
PHE175
CG
38.631
30.676
15.719

1430
PHE175
CD1
37.307
30.913
15.375

1431
PHE175
CE1
36.519
31.735
16.171

1432
PHE175
CZ
37.056
32.317
17.311

1433
PHE175
CE2
38.38
32.079
17.656

1434
PHE175
OD2
39.168
31.257
16.86

1435
PHE175
C
40.397
31.131
12.963

1436
PHE175
O
41.432
30.837
12.352

1437
SER176
N
40.043
32.376
13.245

1438
SER176
CA
41.016
33.472
13.148

1439
SER176
CB
40.335
34.823
13.39

1440
SER176
OG
39.504
34.778
14.544

1441
SER176
C
42.174
33.171
14.111

1442
SER176
O
43.208
32.702
13.626

1443
ASN177
N
42.096
33.622
15.358

1444
ASN177
CA
42.903
33.035
16.444

1445
ASN177
CB
43.037
31.518
16.252

1446
ASN177
CG
43.77
30.824
17.401

1447
ASN177
OD1
44.69
31.383
18.009

1448
ASN177
ND2
43.378
29.591
17.663

1449
ASN177
C
44.252
33.739
16.496

1450
ASN177
O
45.111
33.532
15.634

1451
TYR178
N
44.509
34.384
17.62

1452
TYR178
CA
45.681
35.254
17.732

1453
TYR178
CB
45.447
36.185
18.914

1454
TYR178
CG
46.53
37.232
19.138

1455
TYR178
CD1
46.609
38.334
18.297

1456
TYR178
CE1
47.594
39.292
18.499

1457
TYR178
CZ
48.496
39.143
19.545

1458
TYR178
OH
49.463
40.099
19.756

1459
TYR178
CE2
48.419
38.042
20.388

1460
TYR178
CD2
47.434
37.085
20.184

1461
TYR178
C
46.995
34.492
17.9

1462
TYR178
O
48.028
34.994
17.446

1463
SER179
N
46.938
33.225
18.275

1464
SER179
CA
48.179
32.453
18.365

1465
SER179
CB
48.079
31.413
19.475

1466
SER179
OG
47.051
30.494
19.143

1467
SER179
C
48.497
31.79
17.024

1468
SER179
O
49.675
31.598
16.701

1469
SER180
N
47.5
31.677
16.158

1470
SER180
CA
47.78
31.182
14.807

1471
SER180
CB
46.608
30.373
14.261

1472
SER180
OG
45.499
31.234
14.081

1473
SER180
C
48.11
32.353
13.883

1474
SER180
O
48.948
32.201
12.987

1475
TRP181
N
47.678
33.546
14.266

1476
TRP181
CA
48.131
34.762
13.583

1477
TRP181
CB
47.196
35.919
13.912

1478
TRP181
CG
45.851
35.935
13.205

1479
TRP181
CD1
44.638
36.22
13.79

1480
TRP181
NE1
43.678
36.186
12.834

1481
TRP181
CE2
44.198
35.884
11.632

1482
TRP181
CZ2
43.638
35.777
10.367

1483
TRP181
CH2
44.444
35.458
9.28

1484
TRP181
CZ3
45.805
35.244
9.457

1485
TRP181
CE3
46.376
35.353
10.72

1486
TRP181
CD2
45.579
35.679
11.808

1487
TRP181
C
49.547
35.129
14.02

1488
TRP181
O
50.341
35.599
13.198

1489
HIS182
N
49.917
34.711
15.22

1490
HIS182
CA
51.3
34.84
15.683

1491
HIS182
CB
51.305
34.599
17.188

1492
HIS182
CG
52.675
34.403
17.806

1493
HIS182
ND1
53.777
35.149
17.596

1494
HIS182
CE1
54.794
34.652
18.331

1495
HIS182
NE2
54.327
33.576
19.005

1496
HIS182
CD2
53.023
33.411
18.692

1497
HIS182
C
52.21
33.828
14.994

1498
HIS182
O
53.326
34.183
14.594

1499
TYR183
N
51.661
32.68
14.637

1500
TYR183
CA
52.452
31.706
13.894

1501
TYR183
CB
51.724
30.369
13.925

1502
TYR183
CG
52.649
29.157
13.914

1503
TYR183
CD1
54.002
29.309
13.636

1504
TYR183
CE1
54.842
28.203
13.641

1505
TYR183
CZ
54.324
26.947
13.933

1506
TYR183
OH
55.156
25.847
13.943

1507
TYR183
CE2
52.976
26.793
14.221

1508
TYR183
CD2
52.138
27.9
14.214

1509
TYR183
C
52.645
32.18
12.454

1510
TYR183
O
53.784
32.165
11.968

1511
ARG184
N
51.654
32.867
11.906

1512
ARG184
CA
51.812
33.424
10.558

1513
ARG184
CB
50.45
33.758
9.972

1514
ARG184
CD
49.584
32.516
9.848

1515
ARG184
CD
48.428
32.776
8.895

1516
ARG184
NE
48.966
33.118
7.57

1517
ARG184
CZ
48.43
32.69
6.427

1518
ARG184
NH1
47.289
32.O01
6.445

1519
ARG184
NH2
48.999
33.01
5.264

1520
ARG184
C
52.675
34.682
10.538

1521
ARG184
O
53.419
34.874
9.572

1522
SER185
N
52.766
35.379
11.661

1523
SER185
CA
53.664
36.536
11.766

1524
SER185
CB
53.16
37.509
12.825

1525
SER185
OG
53.298
36.906
14.1

1526
SER185
C
55.098
36.122
12.096

1527
SER185
O
55.95
36.99
12.311

1528
CYS186
N
55.336
34.828
12.236

1529
CYS186
CA
56.701
34.315
12.241

1530
CYS186
CB
56.815
33.2
13.274

1531
GY5186
SG
56.497
33.68
14.987

1532
CY3186
C
57.028
33.764
10.856

1533
CYS186
O
57.937
34.281
10.19

1534
LEU187
N
56.113
32.961
10.335

1535
LEU 187
CA
56.332
32.255
9.061

1536
LEU187
CB
55.159
31.312
8.82

1537
LEU187
CG
55.082
30.226
9.885

1538
LEU187
CD1
53.774
29.451
9.781

1539
LEU187
CD2
56.281
29.289
9.814

1540
LEU187
C
56.465
33.188
7.865

1541
LEU187
O
57.463
33.105
7.138

1542
LEU188
N
55.605
34.189
7.78

1543
LEU188
CA
55.699
35.159
6.677

1544
LEU188
CB
54.488
36.087
6.694

1545
LEU188
CC
53.19
35.313
6.489

1546
LEU188
CD1
51.984
36.192
6.772

1547
LEU188
CD2
53.102
34.709
5.094

1548
LEU188
G
57.024
35.945
6.684

1549
LEU188
O
57.732
35.831
5.675

1550
PRO189
N
57.439
36.622
7.757

1551
PRO189
CA
58.778
37.238
7.745

1552
PRO189
CB
58.861
38.065
8.988

1553
PRO189
CG
57.604
37.867
9.809

1554
PRO189
CD
56.732
36.914
9.015

1555
PRO189
C
59.978
36.274
7.672

1556
PRO189
O
61.06
36.728
7.283

1557
GLN190
N
59.793
34.982
7.894

1558
GLN190
CA
60.892
34.031
7.692

1559
GLN190
CB
60.682
32.845
8.626

1560
GLN190
CG
60.77
33.257
10.089

1561
GLN190
GD
60.446
32.066
10.986

1562
GLN190
OE1
59.278
31.708
11.192

1563
GLN190
NE2
61.496
31.47
11.521

1564
GLN190
C
60.967
33.509
6.257

1565
GLN190
O
61.983
32.913
5.88

1566
LEU191
N
59.931
33.738
5.466

1567
LEU191
CA
59.911
33.21
64.095

1568
LEU191
CB
58.644
32.38
3.936

1569
LEU191
CG
58.635
31.14
94.833

1570
LEU191
CD1
57.247
30.52
4.874

1571
LEU191
CD2
59.685
30.13
84.388

1572
LEU191
C
59.885
34.29
3.01

1573
LEU1Y1
O
60.181
33.98
71.847

1574
HIS192
N
59.477
35.50
13.346

1575
HIS192
CA
59.23
36.48
72.278

1576
HIS192
CB
57.736
36.80
72.239

1577
HIS192
CG
56.856
35.60
41.966

1578
HIS192
ND1
57.049
34.66
11.023

1579
HIS192
CE1
56.055
33.75
31.091

1580
HIS192
NE2
55.228
34.12
62.093

1581
HIS192
CD2
55.709
35.26
52.642

1582
HIS192
C
60.071
37.77
82.287

1583
HIS192
O
60.721
38.02
21.264

1584
PRO193
N
60.006
38.64
3.301

1585
PRO193
CA
60.485
40.01
83.097

1586
PRO193
CB
60.03
40.798
4.29

1587
PRO193
CG
59.33
39.868
5.26

1588
PRO193
CD
59.308
38.50
94.586

1589
PRO193
C
61.995
40.14
12.945

1590
PRO193
O
62.765
39.78
43.842

1591
GLN194
N
62.391
40.667
1.8

1592
GLN194
CA
63.785
41.05
81.582

1593
GLN194
CB
64.203
40.60
60.185

1594
GLN194
OG
63.131
40.924
−0.853

1595
GLN194
CD
63.603
40.51
−2.241

1596
GLN194
OE1
63.764
39.319
−2.532

1597
GLN194
NE2
63.819
41.505
−3.083

1598
GLN194
C
63.936
42.57
11.756

1599
GLN194
O
63.465
43.36
30.929

1600
PRO195
N
64.527
42.95
72.876

1601
PRO195
CA
64.609
44.37
33.243

1602
PRO195
CB
65.082
44.38
74.663

1603
PRO195
CG
65.422
42.96
65.091

1604
PRO195
CD
65.082
42.07
73.907

1605
PRO195
C
65.569
45.13
42.337

1606
PRO195
O
66.778
44.88
12.322

1607
ASP196
N
65.009
46.04
71.565

1608
ASP196
CA
65.821
46.87
50.675

1609
ASP196
CB
65.139
46.901
−0.693

1610
ASP196
CG
66.095
47.35
−1.797

1611
ASP196
OD1
65.967
48.504
−2.189

1612
ASP196
OD2
66.832
46.518
−2.303

1613
ASP196
C
65.983
48.26
41.305

1614
ASP196
O
66.663
48.385
2.33

1615
SER197
N
65.392
49.28
90.711

1616
SER197
CA
65.491
50.64
1.273

1617
SER197
CB
66.804
51.25
80.804

1618
SER197
OG
66.894
52.56
51.357

1619
SER197
C
64.326
51.51
90.825

1620
SER197
O
64.006
52.526
1.469

1621
GLY198
N
63.706
51.128
−0.276

1622
GLY198
CA
62.587
51.892
−0.847

1623
GLY198
C
61.318
51.828
0.002

1624
GLY198
O
61.172
52.578
0.975

1625
PRO199
N
60.392
50.981
−0.419

1626
PRO199
CA
59.086
50.871
0.24

1627
PRO199
CB
58.296
49.916
−0.601

1628
PRO199
CG
59.169
49.406
−1.738

1629
PRO199
CD
60.507
50.11
−1.591

1630
PRO199
C
59.209
50.368
1.674

1631
PRO199
O
60.011
49.477
1.974

1632
GLN200
N
58.381
50.932
2.537

1633
GLN200
CA
58.395
50.591
3.965

1634
GLN200
CB
58.256
51.903
4.724

1635
GLN200
OG
58.723
51.821
6.17

1636
GLN200
CD
58.63
53.214
6.769

1637
GLN200
OE1
57.586
53.877
6.685

1638
GLN200
NE2
59.743
53.657
7.324

1639
GLN200
C
57.282
49.611
4.375

1640
GLN200
O
56.898
49.571
5.549

1641
GLY201
N
56.766
48.839
3.432

1642
GLY201
CA
55.678
47.894
3.741

1643
GLY201
C
56.143
46.831
4.733

1644
GLY201
O
57.35
46.602
4.872

1645
ARG202
N
55.213
46.298
5.508

1646
ARG202
CA
55.569
45.263
6.485

1647
ARG202
CB
54.336
44.894
7.3

1648
ARG202
CG
54.753
44.296
8.636

1649
ARG202
CD
55.572
45.324
9.405

1650
ARG202
NE
56.039
44.812
10.701

1651
ARG202
CZ
55.731
45.41
1.859

1652
ARG202
NH1
54.857
46.407
11.883

1653
ARG202
NH2
56.229
44.923
13.002

1654
ARG202
C
56.085
44.036
5.742

1655
ARG202
O
57.276
43.706
5.794

1656
LEU203
N
55.183
43.393
5.025

1657
LEU203
CA
55.57
42.332
4.094

1658
LEU203
CB
54.458
41.288
4.045

1659
LEU203
CG
54.283
40.571
5.377

1660
LEU203
CD1
53.088
39.627
5.32

1661
LEU203
CD2
55.547
39.811
5.764

1662
LEU203
C
55.774
42.959
2.717

1663
LEU203
O
55.332
44.094
2.498

1664
PRO204
N
56.453
42.26
1.816

1665
PRO204
CA
56.416
42.65
0.405

1666
PRO204
CB
57.184
41.598
−0.331

1667
PRO204
CG
57.659
40.546
0.659

1668
PRO204
CD
57.145
40.985
2.021

1669
PRO204
C
54.963
42.715
−0.04

1670
PRO204
O
54.164
41.847
0.332

1671
GLU205
N
54.649
43.632
−0.94

1672
GLU205
CA
53.236
43.949
−1.207

1673
GLU205
CB
53.168
45.225
−2.039

1674
GLU205
CG
51.748
45.779
−2.046

1675
GLU205
CD
51.635
47.007
−2.94

1676
GLU205
OE1
52.117
48.057
−2.536

1677
GLU205
OE2
51.076
46.876
−4.02

1678
GLU205
C
52.452
42.833
−1.908

1679
GLU205
O
51.26
42.686
−1.621

1680
ASP206
N
53.147
41.887
−2.522

1681
ASP206
CA
52.469
40.754
−3.164

1682
ASP206
CB
53.434
40.083
−4.148

1683
ASP206
GG
54.714
39.593
−3.465

1684
ASP206
OD1
55.618
40.404
−3.302

1685
ASP206
OD2
54.748
38.436
−3.073

1686
ASP206
C
51.942
39.725
−2.154

1687
ASP206
O
50.943
39.058
−2.44

1688
VAL207
N
52.485
39.709
−0.945

1689
VAL207
CA
51.935
38.83
0.084

1690
VAL207
CB
53.048
37.972
0.694

1691
VAL207
CG1
54.289
38.775
1.057

1692
VAL207
CG2
52.559
37.162
1.89

1693
VAL207
C
51.209
39.665
1.133

1694
VAL207
O
50.206
39.219
1.703

1695
LEU208
N
51.519
40.95
1.147

1696
LEU208
CA
50.912
41.852
2.118

1697
LEU208
CB
51.742
43.128
2.16

1698
LEU208
CG
51.301
44.037
3.296

1699
LEU208
CD1
51.351
43.287
4.62

1700
LEU208
CD2
52.168
45.287
3.352

1701
LEU208
C
49.474
42.189
1.752

1702
LEU208
O
48.614
42.131
2.638

1703
LEU209
N
49.163
42.223
0.465

1704
LEU209
CA
47.787
42.54
0.069

1705
LEU209
CB
47.731
42.945
−1.4

1706
LEU209
CG
48.528
44.212
−1.68

1707
LEU209
CD1
48.351
44.644
−3.131

1708
LEU209
CD2
48.131
45.341
−0.737

1709
LEU209
C
46.853
41.359
0.29

1710
LEU209
O
45.751
41.562
0.817

1711
LYS210
N
47.375
40.148
0.177

1712
LYS210
CA
46.521
38.991
0.436

1713
LYS210
CB
46.984
37.78
−0.373

1714
LYS210
CB
48.387
37.307
−0.018

1715
LYS210
CD
48.792
36.106
−0.863

1716
LYS210
CE
50.17
35.59
−0.469

1717
LYS210
NZ
50.565
34.443
−1.301

1718
LYS210
C
46.451
38.683
1.93

1719
LYS210
O
45.401
38.223
2.385

1720
GLU211
N
47.388
39.204
2.708

1721
GLU211
CA
47.286
39.077
4.163

1722
GLU211
CB
48.653
39.288
4.793

1723
GLU211
CG
49.591
38.128
4.506

1724
GLU211
CD
48.954
36.827
4.974

1725
GLU211
OE1
48.749
35.975
4.122

1726
GLU211
OE2
48.813
36.661
6.178

1727
GLU211
C
46.311
40.096
4.732

1728
GLU211
O
45.496
39.74
5.594

1729
LEU212
N
46.22
41.241
4.073

1730
LEU212
CA
45.237
42.256
4.451

1731
LEU212
CB
45.526
43.533
3.669

1732
LEU212
CG
46.782
44.242
4.16

1733
LEU212
CD1
47.221
45.323
3.181

1734
LEU212
CD2
46.572
44.823
5.552

1735
LEU212
C
43.828
41.779
4.133

1736
LEU212
O
42.959
41.86
5.007

1737
GLU213
N
43.702
41.006
3.065

1738
GLU213
CA
42.405
40.436
2.687

1739
GLU213
CB
42.462
40.152
1.194

1740
GLU213
CG
42.651
41.457
0.429

1741
GLU213
CD
43.107
41.172
−0.997

1742
GLU213
OE1
42.854
42.004
−1.857

1743
GLU213
OE2
43.787
40.171
−1.185

1744
GLU213
C
42.051
39.163
3.461

1745
GLU213
O
40.863
38.897
3.68

1746
LEU214
N
43.04
38.509
4.048

1747
LEU214
CA
42.752
37.347
4.896

1748
LEU214
CB
44.014
36.521
5.121

1749
LEU214
CG
44.386
35.713
3.885

1750
LEU214
CO1
45.669
34.925
4.119

1751
LEU214
CD2
43.251
34.777
3.485

1752
LEU214
C
42.195
37.784
6.24

1753
LEU214
O
41.133
37.29
6.641

1754
VAL215
N
42.739
38.857
6.793

1755
VAL215
CA
42.174
39.371
8.041

1756
VAL215
CB
43.223
40.157
8.817

1757
VAL215
OG1
44.223
39.223
9.478

1758
VAL215
CG2
43.942
41.175
7.947

1759
VAL215
C
40.932
40.216
7.778

1760
VAL215
O
39.994
40.149
8.582

1761
GLN216
N
40.798
40.707
6.555

1762
GLN216
CA
39.6
41.435
6.14

1763
GLN216
CB
39.866
42.025
4.757

1764
GLN216
CG
38.704
42.861
4.241

1765
GLN216
CD
39.031
43.462
2.876

1766
GLN216
OE1
40.14
43.297
2.35

1767
GLN216
NE2
38.087
44.232
2.359

1768
GLN216
C
38.397
40.504
6.095

1769
GLN216
O
37.415
40.754
6.806

1770
ASN217
N
38.596
39.316
5.552

1771
ASN217
CA
37.503
38.345
5.502

1772
ASN217
CB
37.813
37.294
4.441

1773
ASN217
CG
37.594
37.833
3.028

1774
ASN217
OD1
37.54
39.046
2.784

1775
ASN217
ND2
37.385
36.902
2.114

1776
A3N217
C
37.281
37.659
6.848

1777
ASN217
O
36.123
37.451
7.228

1778
ALA218
N
38.323
37.574
7.66

1779
ALA218
CA
38.178
36.97
8.987

1780
ALA218
CB
39.564
36.74
9.579

1781
ALA218
C
37.349
37.848
9.921

1782
ALA218
O
36.333
37.373
10.449

1783
PHE219
N
37.587
39.15
9.893

1784
PHE219
CA
36.793
40.037
10.744

1785
PHE219
CB
37.629
41.198
11.284

1786
PHE219
CG
38.335
42.163
10.326

1787
PHE219
CD1
37.643
42.816
9.314

1788
PHE219
CE1
38.307
43.706
8.478

1789
PHE219
CZ
39.661
43.954
8.662

1790
PHE219
CE2
40.349
43.317
9.685

1791
PHE219
CD2
39.685
42.431
10.52

1792
PHE219
C
35.492
40.503
10.086

1793
PHE219
O
34.66
41.122
10.753

1794
PHE220
N
35.258
40.121
8.841

1795
PHE220
CA
33.926
40.327
8.262

1796
PHE220
CB
34.025
40.662
6.779

1797
PHE220
CG
34.533
42.072
6.498

1798
PHE220
CD1
35.065
42.386
5.255

1799
PHE220
CE1
35.528
43.671
5.007

1800
PHE220
CZ
35.454
44.642
5.996

1801
PHE220
CE2
34.903
44.335
7.231

1802
PHE220
CD2
34.437
43.052
7.478

1803
PHE220
C
33.048
39.096
8.466

1804
PHE220
O
31.825
39.165
8.298

1805
THR221
N
33.666
37.996
8.867

1806
THR221
CA
32.906
36.812
9.266

1807
THR221
CB
33.75
35.575
8.972

1808
THR221
OG1
34.03
35.562
7.58

1809
THR221
CG2
33.017
34.282
9.318

1810
THR221
C
32.601
36.901
10.758

1811
THR221
O
31.58
36.393
11.238

1812
ASP222
N
33.477
37.584
11.475

1813
ASP222
CA
33.202
37.911
12.878

1814
ASP222
CB
33.673
36.758
13.765

1815
ASP222
CG
33.321
36.993
15.236

1816
ASP222
OD1
32.643
37.977
15.514

1817
ASP222
OD2
33.99
36.386
16.057

1818
ASP222
C
33.884
39.222
13.262

1819
ASP222
O
35.012
39.218
13.773

1820
PRO223
N
33.077
40.274
13.286

1821
PRO223
CA
33.573
41.635
13.541

1822
PRO223
CB
32.432
42.527
13.165

1823
PRO223
CG
31.195
41.686
12.891

1824
PRO223
CD
31.64
40.24
12.999

1825
PRO223
C
33.964
41.906
14.992

1826
PRO223
O
34.672
42.875
15.279

1827
ASN224
N
33.582
41.021
15.895

1828
ASN224
CA
33.907
41.212
17.304

1829
ASN224
CB
32.695
40.769
18.115

1830
ASN224
CG
31.449
41.489
17.593

1831
ASN224
OD1
31.449
42.713
17.404

1832
ASN224
ND2
30.411
40.713
17.331

1833
ASN224
C
35.155
40.422
17.697

1834
ASN224
O
35.647
40.552
18.825

1835
A3P225
N
35.7
39.664
16.757

1836
ASP225
CA
36.896
38.87
17.038

1837
ASP225
CB
36.889
37.64
16.134

1838
ASP225
CG
37.893
36.588
16.6

1839
ASP225
OD1
39.022
36.962
16.894

1840
ASP225
OD2
37.568
35.416
16.489

1841
ASP225
C
38.143
39.709
16.788

1842
ASP225
O
38.667
39.745
15.666

1843
GLN226
N
38.764
40.091
17.893

1844
GLN226
CA
39.907
41.01
17.886

1845
GLN226
CB
40.109
41.461
19.325

1846
GLN226
CG
40.272
40.272
20.267

1847
GLN226
CD
40.253
40.746
21.716

1848
GLN226
QE1
39.343
41.474
22.126

1849
GLN226
NE2
41.22
40.279
22.485

1850
GLN226
C
41.225
40.452
17.34

1851
GLN226
O
42.081
41.257
16.952

1852
SER227
N
41.296
39.159
17.054

1853
SER227
CA
42.549
38.59
16.555

1854
SER227
CB
42.491
37.069
16.682

1855
SER227
OG
41.519
36.528
15.791

1856
SER227
C
42.808
38.988
15.103

1857
SER227
O
43.943
39.351
14.773

1858
ALA228
N
41.742
39.245
14.36

1859
ALA228
CA
41.912
39.638
12.963

1860
ALA228
CB
40.653
39.262
12.196

1861
ALA228
C
42.182
41.134
12.836

1862
ALA228
O
42.936
41.544
11.946

1863
TRP229
N
41.835
41.875
13.877

1864
TRP229
CA
42.075
43.318
13.887

1865
TRP229
CB
41.114
43.966
14.876

1866
TRP229
CG
39.655
43.71
14.574

1867
TRP229
OD1
38.819
42.825
15.218

1868
TRP229
NE1
37.588
42.903
14.652

1869
TRP229
CE2
37.572
43.805
13.656

1870
TRP229
CZ2
36.568
44.244
12.807

1871
TRP229
CH2
36.852
45.213
11.856

1872
TRP229
CZ3
38.131
45.753
11.756

1873
TRP229
CE3
39.139
45.325
12.609

1874
TRP229
CD2
38.861
44.354
13.557

1875
TRP229
C
43.501
43.617
14.32

1876
TRP229
O
44.179
44.442
13.692

1877
PHE230
N
44.022
42.77
15.194

1878
PHE230
CA
45.406
42.931
15.641

1879
PHE230
CB
45.641
42.085
16.887

1880
PHE230
CG
44.918
42.563
18.143

1881
PHE230
CO1
44.407
41.637
19.044

1882
PHE230
CE1
43.751
42.07
20.189

1883
PHE230
CZ
43.611
43.429
20.438

1884
PHE230
CE2
44.13
44.355
19.542

1885
PHE230
CO2
44.785
43.923
18.397

1886
PHE230
C
46.379
42.504
14.552

1887
PHE230
O
47.341
43.234
14.277

1888
TYR231
N
45.994
41.509
13.768

1889
TYR231
CA
46.881
41.093
12.687

1890
TYR231
CB
46.587
39.653
12.302

1891
TYR231
CG
47.747
39.01
11.552

1892
TYR231
CD1
48.992
38.944
12.163

1893
TYR231
CE1
50.061
38.36
11.499

1894
TYR231
CZ
49.883
37.844
10.224

1895
TYR231
OH
50.938
37.234
9.584

1896
TYR231
CE2
48.643
37.915
9.605

1897
TYR231
CD2
47.574
38.502
10.271

1898
TYR231
C
46.745
42.007
11.47

1899
TYR231
O
47.764
42.285
10.829

1900
HIS232
N
45.615
42.688
11.338

1901
HIS232
CA
45.461
43.669
10.259

1902
HIS232
CB
43.99
44.052
10.129

1903
HIS232
CG
43.697
45.029
9.004

1904
HIS232
ND1
43.473
44.723
7.712

1905
HIS232
GE1
43.25
45.855
7.015

1906
HIS232
NE2
43.336
46.891
7.88

1907
HIS232
CD2
43.608
46.398
9.11

1908
HIS232
C
46.28
44.922
10.544

1909
HIS232
O
46.973
45.404
9.639

1910
ARG233
N
46.433
45.256
11.816

1911
ARG233
CA
47.267
46.405
12.178

1912
ARG233
CB
46.906
46.85
13.593

1913
ARG233
OG
47.64
48.133
13.972

1914
ARG233
CD
47.261
48.62
15.366

1915
ARG233
NE
47.944
49.888
15.673

1916
ARG233
CZ
47.365
50.902
16.32

1917
ARG233
NH1
46.105
50.789
16.746

1918
ARG233
NH2
48.048
52.025
16.552

1919
ARG233
C
48.757
46.062
12.096

1920
ARG233
O
49.551
46.92
11.692

1921
TRP234
N
49.083
44.782
12.196

1922
TRP234
CA
50.475
44.357
12.02

1923
TRP234
CB
50.641
42.951
12.592

1924
TRP234
CG
52.071
42.442
12.578

1925
TRP234
CD1
53.023
42.667
13.548

1926
TRP234
NE1
54.175
42.056
13.172

1927
TRP234
CE2
54.031
41.43
11.99

1928
TRP234
CZ2
54.906
40.696
11.202

1929
TRP234
CH2
54.464
40.156
10

1930
TRP234
CZ3
53.152
40.351
9.583

1931
TRP234
CE3
52.271
41.09
10.365

1932
TRP234
CD2
52.706
41.632
11.563

1933
TRP234
C
50.859
44.347
10.542

1934
TRP234
O
51.943
44.83
10.197

1935
LEU235
N
49.892
44.062
9.683

1936
LEU235
CA
50.128
44.054
8.231

1937
LEU235
CB
49.029
43.219
7.592

1938
LEU235
CG
49.053
41.78
8.079

1939
LEU235
CD1
47.736
41.084
7.769

1940
LEU235
CD2
50.239
41.017
7.506

1941
LEU235
C
50.068
45.456
7.628

1942
LEU235
O
50.586
45.695
6.531

1943
LEU236
N
49.48
46.377
8.372

1944
LEU236
CA
49.418
47.78
7.966

1945
LEU236
OB
48.109
48.342
8.515

1946
LEU236
CG
47.73
49.673
7.878

1947
LEU236
OD1
47.582
49.517
6.369

1948
LEU236
CD2
46.442
50.214
8.487

1949
LEU236
C
50.611
48.555
8.533

1950
LEU236
O
50.86
49.705
8.148

1951
GLY237
N
51.377
47.894
9.387

1952
GLY237
CA
52.548
48.512
10.002

1953
GLY237
C
53.713
48.628
9.028

1954
GLY237
O
53.719
48.045
7.936

1955
ARG238
N
54.645
49.479
9.413

1956
ARG238
CA
55.831
49.742
8.605

1957
ARG238
CB
56.201
51.2
8.804

1958
ARG238
CG
55.042
52.123
8.46

1959
ARG238
CD
55.354
53.55
8.891

1960
ARG238
NE
55.551
53.625
10.349

1961
ARG238
CZ
56.685
54.03
10.928

1962
ARG238
NH1
57.736
54.37
10.181

1963
ARG238
NH2
56.773
54.075
12.259

1964
ARG238
C
57.012
48.885
9.041

1965
ARG238
O
57.183
48.585
10.231

1966
ALA239
N
57.828
48.513
8.072

1967
ALA239
CA
59.082
47.814
8.364

1968
ALA239
CB
59.543
47.064
7.121

1969
ALA239
C
60.152
48.817
8.784

1970
ALA239
O
60.785
49.474
7.948

1971
ASP24O
N
60.311
48.955
10.089

1972
ASP24O
CA
61.326
49.852
10.65

1973
ASP24O
CB
61.039
49.994
12.143

1974
ASP24O
CG
61.91
51.072
12.786

1975
ASP24O
OD1
62.053
52.121
12.173

1976
ASP24O
OD2
62.265
50.892
13.942

1977
ASP24O
C
62.72
49.272
10.421

1978
ASP24O
O
62.982
48.112
10.757

1979
PRO241
N
63.578
50.06
9.791

1980
PRO241
CA
64.949
49.634
9.481

1981
PRO241
CB
65.488
50.691
8.564

1982
PRO241
CG
64.49
51.832
8.469

1983
PRO241
CD
63.287
51 .406
9.292

1984
PRO241
C
65.824
49.515
10.73

1985
PRO241
O
65.342
49.265
11.844

1986
GLN242
N
67.125
49.509
10.497

1987
GLN242
CA
68.084
49.557
11.604

1988
GLN242
CB
68.549
48.129
11.896

1989
GLN242
CG
69.303
47.973
13.222

1990
GLN242
CD
68.403
48.002
14.469

1991
GLN242
OE1
68.922
47.941
15.59

1992
GLN242
NE2
67.092
48.044
14.287

1993
GLN242
C
69.238
50.486
11.231

1994
GLN242
O
70.248
50.627
11.932

1995
ASP243
N
69
51.201
10.149

1996
ASP243
CA
70.014
52.057
9.542

1997
ASP243
CB
70.642
51.301
8.359

1998
ASP243
CG
69.608
50.707
7.389

1999
ASP243
OD1
69.053
49.66
7.707

2000
ASP243
OD2
69.395
51.305
6.346

20D1
ASP243
C
69.398
53.384
9.107

20D2
ASP243
O
68.97
53.542
7.957

2003
ALA244
N
69.354
54.331
10.028

2004
ALA244
CA
68.753
55.627
9.701

2005
ALA244
CB
67.237
55.496
9.777

2006
ALA244
C
69.216
56.773
10.598

2007
ALA244
O
68.821
56.88
11.768

2008
LEU245
N
70.074
57.61
10.037

2009
LEU245
CA
70.447
58.874
10.688

2010
LEU245
CB
71.886
59.232
10.341

2011
LEU245
CG
72.877
58.161
10.772

2012
LEU245
CD1
74.278
58.508
10.283

2013
LEU245
CD2
72.865
57.98
12.282

2014
LEU245
C
69.524
59.942
10.132

2015
LEU245
O
69.834
60.565
9.112

2016
ARG246
N
68.46
60.23
10.857

2017
ARG246
CA
67.362
60.966
10.239

2018
ARG246
CB
66.064
60.592
10.94

2019
ARG246
CG
65.84
59.084
10.872

2020
ARG246
CD
64.398
58.74
11.217

2021
ARG246
NE
64.16
57.288
11.279

2022
ARG246
CZ
63.746
56.522
10.264

2023
ARG246
NH1
63.595
57.041
9.042

2024
ARG246
NH2
63.542
55.217
10.46

2025
ARG246
C
67.53
62.479
10.221

2026
ARG246
O
66.905
63.123
9.372

2027
CYS247
N
68.428
63.035
11.015

2028
CYS247
CA
68.612
64.49
10.941

2029
CYS247
CR
67.529
65.167
11.774

2030
CYS247
5G
67.568
66.973
11.773

2031
CYS247
C
69.98
64.963
11.417

2032
CYS247
O
70.23
65.06
12.626

2033
LEU248
N
70.838
65.291
10.466

2034
LEU248
CA
72.111
65.945
10.799

2035
LEU248
CR
73.143
65.761
9.694

2036
LEU248
CG
73.587
64.325
9.478

2037
LEU248
CO1
74.794
64.332
8.548

2038
LEU248
CD2
73.96
63.659
10.795

2039
LEU248
C
71.908
67.444
10.943

2040
LEU248
O
71.003
68.019
10.322

2041
HIS249
N
72.738
68.059
11.762

2042
HIS249
CA
72.762
69.519
11.843

2043
HIS249
CR
71.626
69.992
12.736

2044
HIS249
CG
71.601
71.497
12.858

2045
HIS249
NO1
71.255
72.362
11.889

2046
HIS249
CE1
71.367
73.619
12.357

2047
HIS249
NE2
71.802
73.545
13.635

2048
HIS249
CD2
71.954
72.242
13.959

2049
HIS249
C
74.075
70.056
12.405

2050
HIS249
O
74.352
69.914
13.602

2051
VAL250
N
74.86
70.695
11.556

2052
VAL250
CA
76.046
71.392
12.057

2053
VAL250
CB
77.219
71.283
11.084

2054
VAL250
CG1
77.82
69.889
11.094

2055
VAL250
CG2
76.869
71.712
9.665

2056
VAL250
C
75.737
72.859
12.328

2057
VAL250
O
75.3
73.615
11.45

2058
SER251
N
75.893
73.233
13.579

2059
SER251
CA
75.807
74.64
13.93

2060
SER251
CB
75.082
74.8
15.256

2061
SER251
OG
75.196
76.17
15.615

2062
SER251
C
77.203
75.22
14.054

2063
SER251
O
77.958
74.851
14.961

2064
ARG252
N
77.463
76.245
13.263

2065
ARG252
CA
78.733
76.962
13.347

2066
ARG252
CB
78.946
77.742
12.053

2067
ARG252
CG
80.243
78.544
12.083

2068
ARG252
CD
80.45
79.341
10.798

2069
ARG252
NE
80.612
78.455
9.634

2070
ARG252
CZ
80.957
78.9
8.424

2071
ARG252
NH1
81.165
80.204
8.229

2072
ARG252
NH2
81.096
78.044
7.409

2073
ARG252
C
78.678
77.919
14.53

2074
ARG252
O
79.661
78.042
15.269

2075
ASP253
N
77.46
78.314
14.873

2076
ASP253
CA
77.229
79.174
16.042

2077
ASP253
CB
75.749
79.533
16.11

2078
ASP253
CG
75.244
80.072
14.78

2079
ASP253
OD1
75.759
81.09
14.334

2080
ASP253
OD2
74.352
79.447
14.223

2081
ASP253
C
77.579
78.458
17.343

2082
ASP253
O
78.358
78.977
18.148

2083
GLU254
N
77.107
77.227
17.485

2084
GLU254
CA
77.392
76.458
18.705

2085
GLU254
CB
76.258
75.46
18.94

2086
GLU254
CG
74.87
76.092
18.939

2087
GLU254
CD
74.739
77.163
20.015

2088
GLU254
OE1
74.231
76.836
21.078

2089
GLU254
OE2
74.933
78.316
19.656

2090
GLU254
C
78.69
75.653
18.632

2091
GLU254
O
79.071
75.06
19.649

2092
ALA255
N
79.38
75.703
17.5

2093
ALA255
CA
80.48
74.774
17.202

2094
ALA255
CB
81.725
75.192
17.978

2095
ALA255
C
80.078
73.348
17.566

2096
ALA255
O
80.707
72.716
18.427

2097
CYS256
N
79.048
72.842
16.905

2098
CYS256
CA
78.488
71.546
17.312

2099
CYS256
CB
77.596
71.801
18.524

2100
GY5256
SG
76.875
70.343
19.312

2101
GY5256
C
77.675
70.849
16.22

2102
GY5256
O
76.751
71.424
15.631

2103
LEU257
N
78.014
69.591
15.994

2104
LEU257
CA
77.259
68.727
15.075

2105
LEU257
CB
78.249
67.886
14.271

2106
LEU257
CG
77.613
66.691
13.551

2107
LEU257
CD1
76.533
67.087
12.548

2108
LEU257
CD2
78.685
65.868
12.857

2109
LEU257
C
76.311
67.821
15.859

2110
LEU257
O
76.743
66.985
16.661

2111
THR258
N
75.025
68.01
15.625

2112
THR258
CA
73.992
67.195
16.266

2113
THR258
CB
72.887
68.15
16.701

2114
THR258
OG1
73.503
69.235
17.382

2115
THR258
CG2
71.885
67.492
17.642

2116
THR258
C
73.438
66.148
15.296

2117
THR258
O
73.237
66.436
14.111

2118
VAL259
N
73.334
64.916
15.767

2119
VAL259
CA
72.716
63.842
14.978

2120
VAL259
CB
73.729
62.711
14.815

2121
VAL259
CG1
73.15
61.553
14.008

2122
VAL259
CG2
75.01
63.216
14.165

2123
VAL259
C
71.456
63.294
15.655

2124
VAL259
O
71.509
62.756
16.771

2125
SER260
N
70.328
63.495
14.995

2126
SER260
CA
69.067
62.891
15.433

2127
SER260
CB
67.901
63.797
15.068

2128
SER260
OG
68.052
65.009
15.792

2129
SER260
C
68.877
61.516
14.8

2130
SER260
O
68.975
61.329
13.578

2131
PHE261
N
68.63
60.561
15.673

2132
PHE261
CA
68.479
59.158
15.294

2133
PHE261
CB
69.106
58.285
16.376

2134
PHE261
CG
70.629
58.247
16.383

2135
PHE261
CD1
71.359
59.184
17.102

2136
PHE261
CE1
72.746
59.131
17.098

2137
PHE261
CZ
73.401
58.138
16.383

2138
PHE261
CE2
72.672
57.199
15.669

2139
PHE261
CD2
71.285
57.256
15.668

2140
PHE261
C
67.025
58.749
15.148

2141
PHE261
O
66.088
59.556
15.208

2142
SER262
N
66.872
57.467
14.883

2143
SER262
CA
65.551
56.852
14.838

2144
SER262
CB
65.662
55.551
14.057

2145
SER262
OG
66.344
55.819
12.841

2146
SER262
C
65.142
56.523
16.263

2147
SER262
O
64.689
57.384
17.029

2148
ARG263
N
65.399
55.274
16.61

2149
ARG263
CA
65.213
54.751
17.966

2150
ARG263
CB
65.281
53.231
17.834

2151
ARG263
CG
66.659
52.799
17.349

2152
ARG263
CD
66.622
51.472
16.597

2153
ARG263
NE
65.873
51.613
15.335

2154
ARG263
CZ
66.434
51.961
14.173

2155
ARG263
NH1
65.669
52.158
13.097

2156
ARG263
NH2
67.749
52.189
14.102

2157
ARG263
C
66.323
55.284
18.88

2158
ARG263
O
67.296
55.858
18.374

2159
PRO264
N
66.121
55.222
20.19

2160
PRO264
CA
67.153
55.67
21.132

2161
PRO264
CB
66.502
55.637
22.479

2162
PRO264
CG
65.129
54.996
22.355

2163
PRO264
CD
64.929
54.711
20.876

2164
PRO264
G
68.37
54.753
21.089

2165
PRO264
O
68.331
53.608
21.553

2166
LEU265
N
69.455
55.284
20.559

2167
LEU265
CA
70.68
54.501
20.401

2168
LEU265
CB
71.122
54.572
18.944

2169
LEU265
CG
70.174
53.763
18.065

2170
LEU265
CD1
70.431
53.992
16.581

2171
LEU265
CD2
70.256
52.278
18.404

2172
LEU265
C
71.793
54.969
21.327

2173
LEU265
O
71.618
55.877
22.15

2174
LEU266
N
72.871
54.209
21.294

2175
LEU266
CA
74.073
54.517
22.074

2176
LEU266
CB
74.288
53.411
23.1

2177
LEU266
CG
73.487
53.636
24.372

2178
LEU266
CD1
73.473
52.383
25.239

2179
LEU266
CD2
74.06
54.818
25.141

2180
LEU266
C
75.303
54.588
21.181

2181
LEU266
O
75.776
53.556
20.691

2182
VAL267
N
75.832
55.784
20.996

2183
VAL267
CA
77.076
55.924
20.233

2184
VAL267
CB
77.193
57.348
19.706

2185
VAL267
CG1
78.505
57.552
18.961

2186
VAL267
CG2
76.017
57.669
18.797

2187
VAL267
C
78.262
55.569
21.124

2188
VAL267
O
78.675
56.337
22.001

2189
GLY268
N
78.771
54.374
20.893

2190
GLY268
CA
79.857
53.813
21.69

2191
GLY268
C
79.424
52.467
22.258

2192
GLY268
O
80.055
51.944
23.185

2193
SER269
N
78.349
51.921
21.713

2194
SER269
CA
77.838
50.639
22.216

2195
SER269
CB
76.318
50.592
22.095

2196
SER269
OG
75.952
50.738
20.73

2197
SER269
C
78.459
49.448
21.493

2198
SER269
O
79.583
49.522
20.978

2199
ARG270
N
77.746
48.334
21.568

2200
ARG270
CA
78.146
47.075
20.922

2201
ARG270
CB
76.969
46.117
21.051

2202
ARG270
CG
76.525
46.016
22.505

2203
ARG270
CD
75.191
45.294
22.634

2204
ARG270
NE
75.271
43.924
22.109

2205
ARG270
CZ
74.368
42.988
22.405

2206
ARG270
NH1
73.33
43.287
23.189

2207
ARG270
NH2
74.494
41.757
21.905

2208
ARG270
C
78.444
47.339
19.454

2209
ARG270
O
79.601
47.279
19.018

2210
MET271
N
77.404
47.668
18.709

2211
MET271
CA
77.628
48.268
17.399

2212
MET271
CB
76.418
48.048
16.514

2213
MET271
CG
76.871
47.441
15.193

2214
MET271
SD
77.802
45.897
15.313

2215
MET271
CE
78.163
45.671
13.558

2216
MET271
C
77.905
49.738
17.681

2217
MET271
O
77.05
50.461
18.204

2218
GLU272
N
79.098
50.166
17.325

2219
GLU272
CA
79.709
51.303
18.015

2220
GLU272
CB
81.211
51.206
17.803

2221
GLU272
CG
81.745
49.951
18.486

2222
GLU272
CD
83.235
49.796
18.214

2223
GLU272
OE1
84.012
50.428
18.916

2224
GLU272
OE2
83.551
49.206
17.189

2225
GLU272
C
79.214
52.716
17.704

2226
GLU272
O
78.275
53.193
18.352

2227
ILEA273
N
79.793
53.344
16.697

2228
ILEA273
CA
79.841
54.816
16.691

2229
ILEA273
CB
81.266
55.255
17.032

2230
ILEA273
CG2
81.596
55.043
18.504

2231
ILEA273
CG1
82.283
54.546
16.143

2232
ILEA273
CD1
83.706
54.986
16.468

2233
ILEA273
C
79.476
55.466
15.362

2234
ILEA273
O
78.996
54.819
14.423

2235
LEU274
N
79.593
56.786
15.371

2236
LEU274
CA
79.457
57.608
14.164

2237
LEU274
CB
78.585
58.814
14.488

2238
LEU274
CG
77.168
58.442
14.898

2239
LEU274
OD1
76.456
59.647
15.498

2240
LEU274
OD2
76.391
57.891
13.711

2241
LEU274
C
80.821
58.138
13.722

2242
LEu274
O
81.483
58.875
14.465

2243
LEU275
N
81.214
57.793
12.511

2244
LEU275
CA
82.468
58.308
11.946

2245
LEU275
CB
82.974
57.331
10.892

2246
LEU275
OG
83.284
55.962
11.482

2247
LEU275
OD1
83.634
54.967
10.38

2248
LEU275
OD2
84.406
56.045
12.512

2249
LEU275
C
82.248
59.666
11.29

2250
LEU275
O
81.483
59.777
10.323

2251
LEU276
N
82.896
60.685
11.824

2252
LEU276
CA
82.789
62.02
11.231

2253
LEU276
OB
82.933
63.068
12.331

2254
LEU276
CG
82.772
64.494
11.805

2255
LEU276
OD1
81.464
64.671
11.042

2256
LEU276
OD2
82.864
65.51
12.934

2257
LEU276
C
83.846
62.221
10.147

2258
LEU276
O
85.047
62.019
10.362

2259
MET277
N
83.365
62.531
8.958

2260
MET277
CA
84.233
62.836
7.823

2261
MET277
OB
83.872
61.907
6.671

2262
MET277
OG
84.065
60.444
7.048

2263
MET277
SD
85.759
59.958
7.445

2264
MET277
CE
86.561
60.426
5.894

2265
MET277
C
84.057
64.287
7.385

2266
MET277
O
83.119
64.63
6.652

2267
VAL278
N
84.986
65.118
7.821

2268
VAL278
CA
84.992
66.531
7.44

2269
VAL278
CB
85.671
67.349
8.532

2270
VAL278
OG1
85.705
68.831
8.17

2271
VAL278
CG2
84.967
67.144
9.865

2272
VAL278
C
85.745
66.681
6.126

2273
VAL278
O
86.983
66.76
6.096

2274
ASP279
N
84.966
66.841
5.067

2275
ASP279
CA
85.418
66.838
3.66

2276
ASP279
CB
86.325
68.045
3.421

2277
ASP279
CG
85.555
69.337
3.689

2278
ASP279
OD1
84.686
69.646
2.888

2279
ASP279
OD2
85.732
69.902
4.761

2280
ASP279
C
86.114
65.533
3.248

2281
ASP279
O
85.553
64.745
2.48

2282
ASP280
N
87.344
65.341
3.695

2283
ASP280
CA
88.073
64.1
3.426

2284
ASP280
CB
89.095
64.333
2.312

2285
ASP280
CG
90.094
65.433
2.678

2286
ASP280
OD1
91.145
65.101
3.206

2287
ASP280
OD2
89.794
66.586
2.392

2288
ASP280
C
88.763
63.594
4.694

2289
ASP280
O
89.252
62.46
4.735

2290
SER281
N
88.755
64.417
5.73

2291
SER281
CA
89.447
64.072
6.976

2292
SER281
CB
89.944
65.361
7.62

2293
SER281
OG
90.424
65.028
8.916

2294
SER281
C
88.543
63.356
7.968

2295
SER281
O
87.474
63.865
8.324

2296
PRO282
N
88.987
62.199
8.426

2297
PRO282
CA
88.39
61.591
9.612

2298
PRO282
CB
89.085
60.275
9.769

2299
PRO282
CG
90.232
60.197
8.77

2300
PRO282
CD
90.185
61.492
7.974

2301
PRO282
C
88.608
62.486
10.826

2302
PRO282
O
89.73
62.922
11.108

2303
LEU283
N
87.517
62.816
11.49

2304
LEU283
CA
87.592
63.658
12.682

2305
LEU283
CB
86.774
64.922
12.441

2306
LEU283
CG
87.028
65.97
13.521

2307
LEU283
CD1
88.51
66.32
13.601

2308
LEU283
CD2
86.201
67.226
13.276

2309
LEU283
C
87.076
62.903
13.904

2310
LEU283
O
85.901
62.517
13.984

2311
ILEA284
N
87.973
62.71
14.857

2312
ILEA284
CA
87.634
61.998
16.097

2313
ILEA284
CB
88.909
61.386
16.676

2314
ILEA284
CG2
88.602
60.61
17.953

2315
ILEA284
CG1
89.585
60.468
15.661

2316
ILEA284
CD1
88.72
59.253
15.334

2317
ILEA284
C
86.993
62.948
17.11

2318
ILEA284
O
87.676
63.646
17.868

2319
VAL285
N
85.676
63.022
17.041

2320
VAL285
CA
84.904
63.88
17.942

2321
VAL285
CB
83.859
64.6
17.108

2322
VAL285
CG1
84.475
65.756
16.333

2323
VAL285
CG2
83.153
63.622
16.177

2324
VAL285
C
84.232
63.096
19.064

2325
VAL285
O
83.856
61.928
18.909

2326
GLU286
N
84.108
63.751
20.205

2327
GLU286
CA
83.45
63.126
21.358

2328
GLU286
CB
84.006
63.74
22.637

2329
GLU286
CG
83.389
63.107
23.881

2330
GLU286
CD
84.006
63.726
25.13

2331
GLU286
OE1
85.143
64.168
25.033

2332
GLU286
OE2
83.336
63.747
26.152

2333
GLU286
C
81.938
63.324
21.306

2334
GLU286
O
81.44
64.442
21.483

2335
TRP287
N
81.24
62.236
21.029

2336
TRP287
CA
79.774
62.238
21.005

2337
TRP287
CB
79.294
61.061
20.163

2338
TRP287
CG
79.727
61.099
18.712

2339
TRP287
CD1
80.763
60.396
18.134

2340
TRP287
NE1
80.811
60.711
16.813

2341
TRP287
CE2
79.848
61.593
16.489

2342
TRP287
CZ2
79.505
62.214
15.299

2343
TRP287
CH2
78.429
63.094
15.266

2344
TRP287
CZ3
77.699
63.357
16.421

2345
TRP287
CE3
78.04
62.743
17.62

2346
TRP287
CD2
79.114
61.869
17.657

2347
TRP287
C
79.177
62.105
22.404

2348
TRP287
O
79.64
61.312
23.237

2349
ARG288
N
78.163
62.913
22.651

2350
ARG288
CA
77.409
62.823
23.9

2351
ARG288
CB
78.091
63.697
24.944

2352
ARG288
CG
78.003
65.162
24.55

2353
ARG288
CD
78.842
66.052
25.455

2354
ARG288
NE
78.645
67.466
25.1

2355
ARG288
CZ
79.319
68.105
24.14

2356
ARG288
NH1
80.286
67.482
23.46

2357
ARG288
NH2
79.042
69.384
23.882

2358
ARG288
C
75.959
63.271
23.712

2359
ARG288
O
75.628
64.067
22.825

2360
THR289
N
75.085
62.681
24.503

2361
THR289
CA
73.684
63.108
24.531

2362
THR289
CB
72.874
61.951
25.118

2363
THR289
OG1
71.533
62.353
25.348

2364
THR289
CG2
73.441
61.506
26.448

2365
THR289
C
73.604
64.386
25.37

2366
THR289
O
74.442
64.57
26.262

2367
PRO290
N
72.637
65.263
25.112

2368
PRO290
CA
72.676
66.641
25.651

2369
PRO290
CB
71 .577
67.375
24.946

2370
PRO290
CG
70.809
66.41
24.061

2371
PRO290
CD
71.552
65.09
24.138

2372
PRO290
C
72.481
66.777
27.169

2373
PRO290
O
72.536
67.892
27.695

2374
ASP291
N
72.238
65.679
27.865

2375
ASP291
CA
72.142
65.708
29.323

2376
ASP291
CB
71.039
64.747
29.765

2377
ASP291
CG
71.378
63.309
29.379

2378
ASP291
OD1
72.021
62.66
30.188

2379
ASP291
OD2
71.028
62.914
28.274

2380
ASP291
C
73.47
65.342
29.996

2381
ASP291
O
73.531
65.284
31.23

2382
GLY292
N
74.489
65.016
29.212

2383
GLY292
CA
75.804
64.687
29.781

2384
GLY292
C
76.004
63.179
29.936

2385
GLY292
O
76.975
62.609
29.422

2386
ARG293
N
75.155
62.581
30.754

2387
ARG293
CA
75.162
61.129
30.957

2388
ARG293
CB
74.095
60.812
31.993

2389
ARG293
CG
74.328
61.556
33.3

2390
ARG293
CD
73.082
61.481
34.171

2391
ARG293
NE
72.602
60.094
34.259

2392
ARG293
CZ
71.454
59.756
34.849

2393
ARG293
NH1
70.698
60.694
35.424

2394
ARG293
NH2
71.069
58.479
34.875

2395
ARG293
C
74.782
60.419
29.667

2396
ARG293
O
73.629
60.509
29.238

2397
ASN294
N
75.697
59.623
29.137

2398
ASN294
CA
75.471
58.925
27.859

2399
ASN294
CB
76.823
58.646
27.211

2400
ASN294
CG
77.337
59.92
26.541

2401
ASN294
OD1
76.558
60.842
26.27

2402
ASN294
ND2
78.608
59.907
26.176

2403
ASN294
C
74.645
57.638
27.97

2404
ASN294
O
75.152
56.522
27.81

2405
ARG295
N
73.36
57.832
28.215

2406
ARG295
CA
72.36
56.761
28.228

2407
ARG295
CB
71.46
57.001
29.44

2408
ARG295
CG
71.077
58.468
29.59

2409
ARG295
CD
70.343
58.698
30.905

2410
ARG295
NE
70.17
60.133
31.174

2411
ARG295
CZ
69.229
60.618
31.986

2412
ARG295
NH1
68.371
59.788
32.583

2413
ARG295
NH2
69.144
61.933
32.198

2414
ARG295
C
71.601
56.795
26.9

2415
ARG295
O
71.81
57.745
26.139

2416
PRO296
N
70.869
55.736
26.565

2417
PRO296
CA
70.252
55.621
25.233

2418
PRO296
CB
69.44
54.364
25.268

2419
PRO296
CG
69.705
53.64
26.578

2420
PRO296
CD
70.673
54.516
27.358

2421
PRO296
C
69.41
56.842
24.882

2422
PRO296
O
68.479
57.228
25.598

2423
SER297
N
69.777
57.445
23.768

2424
SER297
CA
69.204
58.731
23.378

2425
SER297
CB
70.203
59.808
23.794

2426
SER297
OG
69.762
61.074
23.317

2427
SER297
C
68.945
58.822
21.882

2428
SER297
O
69.599
58.168
21.061

2429
HIS298
N
67.961
59.634
21.542

2430
HIS298
CA
67.679
59.937
20.145

2431
HIS298
CB
66.243
60.424
20.032

2432
HIS298
CG
65.151
59.469
20.463

2433
HIS298
NO1
64.566
58.527
19.702

2434
HIS298
CE1
63.621
57.893
20.424

2435
HIS298
NE2
63.611
58.443
21 .659

2436
HIS298
CD2
64.545
59.42
21 .697

2437
HIS298
C
68.559
61.066
19.608

2438
HIS298
O
68.541
61.308
18.397

2439
VAL299
N
69.31
61.751
20.457

2440
VAL299
CA
70.083
62.894
19.979

2441
VAL299
CB
69.338
64.168
20.381

2442
VAL299
CG1
68.827
64.108
21.817

2443
VAL299
CG2
70.159
65.427
20.133

2444
VAL299
C
71.503
62.852
20.537

2445
VAL299
O
71.717
62.825
21.757

2446
TRP300
N
72.448
62.713
19.622

2447
TRP300
CA
73.868
62.663
19.983

2448
TRP300
CB
74.427
61.292
19.623

2449
TRP300
CG
73.938
60.18
20.529

2450
TRP300
CO1
72.742
59.5
20.45

2451
TRP300
NE1
72.694
58.598
21 .461

2452
TRP300
CE2
73.812
58.643
22.207

2453
TRP300
CZ2
74.212
57.959
23.344

2454
TRP300
CH2
75.459
58.216
23.898

2455
TRP300
CZ3
76.302
59.164
23.326

2456
TRP300
CE3
75.898
59.871
22.201

2457
TRP300
CD2
74.655
59.618
21.647

2458
TRP300
C
74.649
63.753
19.265

2459
TRP300
O
74.679
63.819
18.031

2460
LEU301
N
75.269
64.614
20.047

2461
LEU301
CA
76.007
65.742
19.48

2462
LEU301
CB
75.338
67.094
19.801

2463
LEU301
CG
75.01
67.483
21.256

2464
LEU301
CD1
73.752
66.832
21.819

2465
LEU301
CD2
76.17
67.425
22.241

2466
LEU301
C
77.483
65.716
19.863

2467
LEU301
O
77.886
65.074
20.838

2468
CYS302
N
78.288
66.298
18.997

2469
CYS302
CA
79.722
66.416
19.259

2470
CYS302
CB
80.471
65.48
18.322

2471
CYS302
SG
80.335
65.886
16.567

2472
CYS302
C
80.204
67.839
19.016

2473
CYS302
O
79.676
68.553
18.153

2474
ASP303
N
81.211
68.241
19.771

2475
ASP303
CA
81.831
69.547
19.523

2476
ASP303
CB
82.799
69.912
20.64

2477
ASP303
CG
82.027
70.362
21.874

2478
ASP303
OD1
80.913
70.836
21.707

2479
ASP303
OD2
82.546
70.173
22.966

2480
ASP303
C
82.56
69.543
18.188

2481
ASP303
O
83.279
68.6
17.839

2482
LEU304
N
82.315
70.596
17.435

2483
LEU304
CA
82.884
70.743
16.099

2484
LEU304
CB
81.737
71.093
15.16

2485
LEU304
CG
82.093
70.894
13.696

2486
LEU304
CO1
82.455
69.436
13.433

2487
LEU304
CD2
80.922
71.316
12.819

2488
LEU304
C
83.927
71.857
16.11

2489
LEU304
O
83.593
73.038
16.249

2490
PRO305
N
85.18
71.465
15.962

2491
PRO305
CA
86.304
72.39
16.138

2492
PRO305
CB
87.534
71.54
16.057

2493
PRO305
CG
87.136
70.102
15.763

2494
PRO305
CD
85.617
70.088
15.722

2495
PRO305
C
86.339
73.486
15.081

2496
PRO305
O
85.788
73.339
13.983

2497
ALA306
N
87.175
74.481
15.342

2498
ALA306
CA
87.363
75.608
14.414

2499
ALA306
CB
88.061
76.74
15.157

2500
ALA306
C
88.173
75.239
13.167

2501
ALA306
O
88.073
75.919
12.14

2502
ALA307
N
88.752
74.048
13.168

2503
ALA307
CA
89.4
73.515
11.967

2504
ALA307
CB
90.358
72.404
12.383

2505
ALA307
C
88.377
72.966
10.965

2506
ALA307
O
88.714
72.738
9.799

2507
SER308
N
87.129
72.859
11.394

2508
SER308
CA
86.035
72.469
10.512

2509
SER308
CB
85.326
71.285
11.153

2510
SER308
OG
86.292
70.261
11.345

2511
SER308
C
85.041
73.616
10.321

2512
SER308
O
83.977
73.41
9.73

2513
LEU309
N
85.338
74.774
10.892

2514
LEU309
CA
84.414
75.916
10.814

2515
LEU309
CB
83.877
76.213
12.21

2516
LEU309
CG
83.025
75.082
12.771

2517
LEU309
CD1
82.625
75.378
14.209

2518
LEU309
CD2
81.788
74.849
11.912

2519
LEU309
C
85.08
77.187
10.288

2520
LEU309
O
84.451
78.251
10.264

2521
ASN310
N
86.354
77.089
9.95

2522
ASN310
CA
87.14
78.264
9.558

2523
ASN310
CB
88.615
77.87
9.489

2524
ASN310
CG
88.841
76.726
8.502

2525
ASN310
OD1
88.575
76.853
7.299

2526
ASN310
N02
89.425
75.658
9.009

2527
ASN310
C
86.721
78.879
8.228

2528
ASN310
O
86.128
78.234
7.358

2529
ASP311
N
87.234
80.078
8.014

2530
ASP311
CA
87.017
80.838
6.772

2531
ASP311
CB
87.177
82.326
7.089

2532
ASP311
CG
88.546
82.608
7.715

2533
ASP311
OD1
88.6
82.705
8.932

2534
ASP311
OD2
89.522
82.647
6.976

2535
ASP311
C
87.982
80.467
5.638

2536
ASP311
O
88.142
81.248
4.695

2537
GLN312
N
88.694
79.36
5.775

2538
GLN312
CA
89.706
78.993
4.786

2539
GLN312
CB
90.858
78.324
5.528

2540
GLN312
CG
91.489
79.25
6.567

2541
GLN312
CD
92.454
80.232
5.905

2542
GLN312
OE1
93.593
79.867
5.594

2543
GLN312
NE2
92.026
81.475
5.765

2544
GLN312
C
89.125
78.029
3.759

2545
GLN312
O
89.592
77.968
2.616

2546
LEU313
N
88.075
77.329
4.151

2547
LEU313
CA
87.389
76.449
3.203

2548
LEU313
CB
87.452
75.022
3.737

2549
LEU313
CG
86.969
73.997
2.716

2550
LEU313
CO1
87.886
73.971
1.498

2551
LEU313
CD2
86.902
72.611
3.339

2552
LEU313
C
85.939
76.892
3.024

2553
LEU313
O
85.143
76.838
3.966

2554
PRO314
N
85.584
77.215
1.787

2555
PRO314
CA
84.272
77.808
1.464

2556
PRO314
CB
84.414
78.307
0.058

2557
PRO314
CG
85.751
77.863
−0.512

2558
PRO314
CD
86.469
77.153
0.62

2559
PRO314
C
83.062
76.863
1.554

2560
PRO314
O
81.93
77.311
1.33

2561
GLN315
N
83.278
75.599
1.879

2562
GLN315
CA
82.177
74.646
2.027

2563
GLN315
CB
81.639
74.257
0.653

2564
GLN315
CG
82.732
73.871
−0.339

2565
GLN315
CD
82.079
73.408
−1.634

2566
GLN315
OE1
82.749
73.205
−2.653

2567
GLN315
NE2
80.767
73.26
−1.577

2568
GLN315
C
82.62
73.411
2.808

2569
GLN315
O
83.112
72.429
2.237

2570
HIS316
N
82.391
73.447
4.107

2571
HIS316
CA
82.761
72.312
4.953

2572
HIS316
CB
82.947
72.788
6.383

2573
HIS316
CG
84.253
73.511
6.615

2574
HIS316
ND1
85.467
72.936
6.71

2575
HIS316
CE1
86.395
73.89
6.927

2576
HIS316
NE2
85.757
75.082
6.96

2577
HIS316
CD2
84.437
74.866
6.766

2578
HIS316
C
81.721
71.202
4.901

2579
HIS316
O
80.642
71.28
5.5

2580
THR317
N
82.059
70.182
4.138

2581
THR317
CA
81.231
68.98
4.03

2582
THR317
CB
81.738
68.197
2.823

2583
THR317
OG1
81.674
69.05
1.688

2584
THR317
CG2
80.913
66.949
2.531

2585
THR317
C
81.368
68.146
5.3

2586
THR317
O
82.48
67.947
5.8

2587
PHE318
N
80.247
67.711
5.846

2588
PHE318
CA
80.271
66.885
7.057

2589
PHE318
CB
79.684
67.668
8.222

2590
PHE318
CG
80.46
68.921
8.605

2591
PHE318
CD1
79.917
70.176
8.365

2592
PHE318
GE1
80.622
71.316
8.725

2593
PHE318
CZ
81.869
71.201
9.32

2594
PHE318
CE2
82.413
69.946
9.556

2595
PHE318
CD2
81.708
68.805
9.201

2596
PHE318
C
79.477
65.598
6.877

2597
PHE318
O
78.239
65.586
6.951

2598
ARG319
N
80.206
64.522
6.647

2599
ARG319
CA
79.581
63.204
6.54

2600
ARG319
CB
80.305
62.369
5.495

2601
ARG319
CG
80.353
63.087
4.154

2602
ARG319
CD
80.774
62.145
3.032

2603
ARG319
NE
82.084
61.526
3.288

2604
ARG319
CZ
82.259
60.203
3.339

2605
ARG319
NH1
81.204
59.388
3.277

2606
ARG319
NH2
83.479
59.699
3.534

2607
ARG319
C
79.608
62.478
7.88

2608
ARG319
O
80.578
62.564
8.641

2609
VAL320
N
78.503
61.829
8.188

2610
VAL320
CA
78.393
61.032
9.413

2611
VAL320
CB
77.323
61.646
10.311

2612
VAL320
CG1
77.124
60.823
11.577

2613
VAL320
CG2
77.677
63.083
10.675

2614
VAL320
C
78.04
59.59
9.062

2615
VAL320
O
76.934
59.303
8.587

2616
1LEA321
N
79.013
58.713
9.257

2617
1LEA321
CA
78.853
57.29
8.934

2618
1LEA321
CB
80.152
56.803
8.304

2619
1LEA321
CG2
80.017
55.356
7.837

2620
1LEA321
CG1
80.548
57.7
7.137

2621
1LEA321
CD1
81.844
57.228
6.49

2622
1LEA321
C
78.533
56.444
10.169

2623
1LEA321
O
79.388
56.218
11.034

2624
TRP322
N
77.302
55.969
10.223

2625
TRP322
CA
76.856
55.09
11.313

2626
TRP322
CB
75.329
55.048
11.235

2627
TRP322
CG
74.543
54.331
12.322

2628
TRP322
CD1
73.333
53.698
12.124

2629
TRP322
NE1
72.909
53.189
13.308

2630
TRP322
CE2
73.783
53.463
14.295

2631
TRP322
CZ2
73.79
53.169
15.651

2632
TRP322
CH2
74.848
53.59
16.447

2633
TRP322
CZ3
75.899
54.31
15.888

2634
TRP322
CE3
75.9
54.606
14.531

2635
TRP322
CD2
74.849
54.188
13.73

2636
TRP322
C
77.468
53.7
11.14

2637
TRP322
O
77.334
53.08
10.081

2638
THR323
N
78.152
53.222
12.167

2639
THR323
CA
78.831
51.919
12.078

2640
THR323
08
80.155
51.944
12.839

2641
THR323
OG1
79.908
51.984
14.234

2642
THR323
CG2
81.011
53.144
12.454

2643
THR323
C
77.986
50.731
12.551

2644
THR323
O
78.551
49.664
12.821

2645
ALA324
N
76.699
50.932
12.783

2646
ALA324
CA
75.818
49.78
12.999

2647
ALA324
CB
74.682
50.146
13.941

2648
ALA324
C
75.261
49.363
11.649

2649
ALA324
O
75.547
48.279
11.128

2650
GLY325
N
74.453
50.251
11.104

2651
GLY325
CA
74.069
50.174
9.696

2652
GLY325
C
74.764
51.357
9.043

2653
GLY325
O
74.565
52.486
9.504

2654
ASP326
N
75.535
51.102
7.994

2655
ASP326
CA
76.438
52.107
7.385

2656
ASP326
CB
77.444
51.389
6.492

2657
ASP326
CG
78.39
50.525
7.326

2658
ASP326
OD1
79.453
51.023
7.668

2659
ASP326
OD2
78.082
49.354
7.5

2660
ASP326
C
75.76
53.216
6.577

2661
ASP326
O
75.896
53.297
5.351

2662
VAL327
N
75.113
54.114
7.297

2663
VAL327
CA
74.469
55.282
6.706

2664
VAL327
CB
73.305
55.671
7.608

2665
VAL327
CG1
72.549
56.877
7.069

2666
VAL327
CG2
72.362
54.494
7.782

2667
VAL327
C
75.463
56.424
6.642

2668
VAL327
O
76.061
56.777
7.661

2669
GLN328
N
75.675
56.948
5.448

2670
GLN328
CA
76.599
58.068
5.272

2671
GLN328
CB
77.55
57.723
4.135

2672
GLN328
CG
78.262
56.408
4.429

2673
GLN328
CD
79.182
56.022
3.279

2674
GLN328
OE1
79.176
56.651
2.216

2675
GLN328
NE2
79.955
54.975
3.506

2676
GLN328
C
75.839
59.352
4.96

2677
GLN328
O
75.788
59.803
3.81

2678
LYS329
N
75.256
59.932
5.995

2679
LYS329
CA
74.521
61.19
5.83

2680
LYS329
CB
73.659
61.431
7.059

2681
LYS329
CG
72.332
60.692
6.97

2682
LYS329
CD
71.494
61.233
5.818

2683
LYS329
CE
70.104
60.61
5.791

2684
LYS329
NZ
70.178
59.15
5.64

2685
LYS329
C
75.498
62.338
5.622

2686
LYS329
O
76.609
62.312
6.157

2687
GLU330
N
75.113
63.313
4.819

2688
GLU330
CA
76.046
64.401
4.504

2689
GLU330
CB
76.628
64.131
3.121

2690
GLU330
CG
77.58
65.24
2.685

2691
GLU330
CD
78.049
64.999
1.255

2692
GLU330
OE1
79.085
64.369
1.096

2693
GLU330
OE2
77.377
65.467
0.347

2694
GLU330
C
75.397
65.782
4.506

2695
GLU330
O
74.627
66.121
3.601

2696
CYS331
N
75.759
66.585
5.491

2697
CYS331
CA
75.379
68.002
5.476

2698
CYS331
CB
74.959
68.449
6.872

2699
CYS331
5G
76.146
68.153
8.198

2700
CYS331
C
76.56
68.819
4.957

2701
CYS331
O
77.671
68.29
4.827

2702
VAL332
N
76.298
70.036
4.516

2703
VAL332
CA
77.398
70.876
4.021

2704
VAL332
CB
77.485
70.762
2.497

2705
VAL332
CG1
76.152
71.042
1.811

2706
VAL332
CG2
78.597
71.634
1.921

2707
VAL332
C
77.253
72.327
4.483

2708
VAL332
O
76.302
73.041
4.135

2709
LEU333
N
78.228
72.755
5.264

2710
LEU333
CA
78.225
74.107
5.815

2711
LEU333
CB
78.87
74.04
7.19

2712
LEU333
CG
78.602
75.292
8.01

2713
LEU333
CD1
77.107
75.559
8.108

2714
LEU333
C02
79.203
75.142
9.399

2715
LEU333
C
78.991
75.064
4.904

2716
LEU333
O
80.221
75.197
4.984

2717
LEU334
N
78.243
75.681
4.006

2718
LEU334
CA
78.797
76.665
3.068

2719
LEU334
CB
77.698
77.069
2.091

2720
LEU334
CG
77.111
75.871
1.354

2721
LEU334
CD1
75.824
76.254
0.633

2722
LEU334
CD2
78.118
75.268
0.383

2723
LEU334
C
79.263
77.906
3.817

2724
LEU334
O
78.781
78.186
4.921

2725
LYS335
N
80.216
78.616
3.241

2726
LYS335
CA
80.699
79.86
3.848

2727
LYS335
CB
81.797
80.455
2.972

2728
LYS335
CG
81.324
80.67
1.539

2729
LYS335
CD
82.408
81.31
0.684

2730
LYS335
CE
81.949
81.47
−0.76

2731
LYS335
NZ
83.018
82.05
−1.588

2732
LYS335
C
79.557
80.857
4.023

2733
LYS335
O
78.725
81.054
3.131

2734
GLY336
N
79.415
81.319
5.252

2735
GLY336
CA
78.353
82.27
5.58

2736
GLY336
C
77.187
81.594
6.301

2737
GLY336
O
76.427
82.255
7.019

2738
ARG337
N
77.028
80.299
6.083

2739
ARG337
CA
75.944
79.565
6.731

2740
ARG337
CB
75.735
78.232
6.024

2741
ARG337
CG
75.365
78.432
4.561

2742
ARG337
CD
74.039
79.168
4.414

2743
ARG337
NE
73.756
79.443
2.998

2744
ARG337
CZ
73.41
80.652
2.553

2745
ARG337
NH1
73.293
81.67
3.409

2746
ARG337
NH2
73.17
80.841
1.253

2747
ARG337
C
76.289
79.325
8.19

2748
ARG337
O
77.355
78.8
8.529

2749
GLN338
N
75.374
79.726
9.051

2750
GLN338
CA
75.571
79.535
10.484

2751
GLN338
CB
74.838
80.664
11.191

2752
GLN338
CG
75.341
82.022
10.721

2753
GLN338
CD
74.497
83.125
11.349

2754
GLN338
OE1
73.733
83.809
10.658

2755
GLN338
NE2
74.591
83.237
12.662

2756
GLN338
C
75.01
78.195
10.943

2757
GLN338
O
75.391
77.685
12.006

2758
GLU339
N
74.146
77.62
10.119

2759
GLU339
CA
73.51
76.327
10.413

2760
GLU339
CB
72.156
76.589
11.07

2761
GLU339
CG
72.293
77.182
12.471

2762
GLU339
CD
70.923
77.452
13.078

2763
GLU339
OE1
70.351
78.481
12.745

2764
GLU339
OE2
70.449
76.601
13.817

2765
GLU339
C
73.312
75.515
9.13

2766
GLU339
O
72.672
75.987
8.182

2767
GLY340
N
73.838
74.302
9.12

2768
GLY340
CA
73.742
73.425
7.941

2769
GLY340
C
73.234
72.025
8.296

2770
GLY340
O
73.964
71.184
8.837

2771
TRP341
N
71.989
71.769
7.945

2772
TRP341
CA
71.357
70.492
8.295

2773
TRP341
CB
69.985
70.768
8.902

2774
TRP341
CG
69.062
71.626
8.061

2775
TRP341
CD1
68.229
71.199
7.051

2776
TRP341
NE1
67.576
72.278
6.548

2777
TRP341
CE2
67.936
73.407
7.186

2778
TRP341
CZ2
67.564
74.734
7.034

2779
TRP341
CH2
68.12
75.705
7.858

2780
TRP341
CZ3
69.047
75.353
8.834

2781
TRP341
CE3
69.424
74.026
8.994

2782
TRP341
CD2
68.875
73.055
8.171

2783
TRP341
C
71.224
69.53
7.116

2784
TRP341
O
71.519
69.866
5.963

2785
CYS342
N
70.88
68.302
7.465

2786
CYS342
CA
70.591
67.233
6.497

2787
CYS342
CB
71.858
66.44
6.209

2788
CYS342
SG
71.677
65.093
5.019

2789
CYS342
C
69.526
66.305
7.08

2790
CYS342
O
69.838
65.288
7.718

2791
ARG343
N
68.276
66.687
6.88

2792
ARG343
CA
67.147
65.981
7.498

2793
ARG343
CB
66.281
67.039
8.178

2794
ARG343
CG
65.123
66.42
8.949

2795
ARG343
CD
64.16
67.468
9.484

2796
ARG343
NE
63.042
66.812
10.175

2797
ARG343
CZ
61.85
66.603
9.612

2798
ARG343
NH1
61.607
67.049
8.377

2799
ARG343
NH2
60.89
65.983
10.3

2800
ARG343
C
66.291
65.19
6.501

2801
ARG343
O
65.952
65.676
5.417

2802
ASP344
N
65.973
63.964
6.883

2803
ASP344
CA
64.991
63.142
6.171

2804
ASP344
CB
65.065
61.717
6.715

2805
ASP344
CG
66.4
61.059
6.388

2806
ASP344
OD1
66.826
61.23
5.253

2807
ASP344
0D2
66.783
60.177
7.146

2808
ASP344
C
63.585
63.666
6.445

2809
ASP344
O
63.187
63.803
7.607

2810
SER345
N
62.833
63.93
5.392

2811
SER345
CA
61.455
64.379
5.581

2812
SER345
CB
60.942
65.099
4.337

2813
SER345
OG
60.414
64.125
3.444

2814
SER345
C
60.566
63.179
5.861

2815
SER345
O
60.749
62.087
5.304

2816
THR346
N
59.503
63.44
6.598

2817
THR346
CA
58.547
62.387
6.931

2818
THR346
CB
57.641
62.895
8.046

2819
THR346
OG1
56.845
63.966
7.554

2820
THR346
CG2
58.451
63.406
9.231

2821
THR346
C
57.695
61.992
5.732

2822
THR346
O
57.308
60.82
5.624

2823
THR347
N
57.624
62.884
4.756

2824
THR347
CA
56.861
62.628
3.542

2825
THR347
CB
56.594
63.963
2.854

2826
THR347
OG1
55.892
64.8
3.764

2827
THR347
CG2
55.738
63.799
1.603

2828
THR347
C
57.595
61.701
2.579

2829
THR347
O
57.116
60.587
2.334

2830
ASP348
N
58.813
62.056
2.191

2831
ASP348
CA
59.478
61.34
1.1

2832
ASP348
CB
60.322
62.349
0.326

2833
ASP348
CG
59.494
63.58
−0.036

2834
ASP348
OD1
58.651
63.463
−0.913

2835
ASP348
OD2
59.618
64.573
0.671

2836
ASP348
C
60.389
60.221
1.593

2837
ASP348
O
61.026
59.531
0.791

2838
GLU349
N
60.563
60.132
2.9

2839
GLU349
CA
61.417
59.073
3.439

2840
GLU349
CB
62.563
59.668
4.259

2841
GLU349
CG
63.789
60.04
3.415

2842
GLU349
CD
63.561
61.254
2.512

2843
GLU349
OE1
62.904
62.188
2.963

2844
GLU349
OE2
64.113
61.273
1.423

2845
GLU349
C
60.617
58.081
4.273

2846
GLU349
O
61.183
57.063
4.697

2847
GLN350
N
59.313
58.315
4.379

2848
GLN350
CA
58.415
57.475
5.187

2849
GLN350
CB
58.423
56.061
4.621

2850
GLN350
CG
58.036
56.037
3.153

2851
GLN350
CD
58.521
54.741
2.52

2852
GLN350
OE1
57.727
53.957
1.975

2853
GLN350
NE2
59.814
54.509
2.667

2854
GLN350
C
58.862
57.443
6.644

2855
GLN350
O
59.626
56.562
7.059

2856
LEU351
N
58.432
58.437
7.403

2857
LEU351
CA
58.807
58.482
8.825

2858
LEU351
CB
59.121
59.913
9.224

2859
LEU351
CG
60.588
60.116
9.574

2860
LEU351
CD1
60.982
59.146
10.676

2861
LEU351
CD2
61.493
59.96
8.356

2862
LEU351
C
57.697
57.966
9.731

2863
LEU351
O
57.924
57.694
10.915

2864
PHE352
N
56.503
57.877
9.173

2865
PHE352
CA
55.345
57.353
9.902

2866
PHE352
CB
54.837
58.377
10.921

2867
PHE352
CG
54.688
59.82
10.436

2868
PHE352
CD1
53.766
60.151
9.451

2869
PHE352
CE1
53.645
61.467
9.026

2870
PHE352
CZ
54.437
62.455
9.595

2871
PHE352
CE2
55.348
62.128
10.589

2872
PHE352
CD2
55.472
60.812
11.011

2873
PHE352
C
54.248
56.963
8.923

2874
PHE352
O
53.099
56.724
9.312

2875
ARG353
N
54.63
56.865
7.661

2876
ARG353
CA
53.661
56.562
6.608

2877
ARG353
CB
52.87
57.838
6.294

2878
ARG353
CG
51.652
57.607
5.394

2879
ARG353
CD
51.974
57.749
3.91

2880
ARG353
NE
50.811
57.414
3.074

2881
ARG353
CZ
50.799
57.584
1.751

2882
ARG353
NH1
51.842
58.152
1.143

2883
ARG353
NH2
49.724
57.237
1.04

2884
ARG353
C
54.382
56.03
5.374

2885
ARG353
O
55.081
56.779
4.677

2886
CYS354
N
54.256
54.728
5.176

2887
CYS354
CA
54.743
54.07
3.961

2888
CYS354
CB
54.431
52.581
4.074

2889
CYS354
SG
54.646
51.606
2.567

2890
CYS354
C
54.037
54.639
2.737

2891
CYS354
O
52.808
54.766
2.716

2892
GLU355
N
54.818
54.979
1.727

2893
GLU355
CA
54.251
55.537
0.498

2894
GLU355
CB
55.334
56.37
−0.179

2895
GLU355
CG
55.695
57.55
0.726

2896
GLU355
CD
56.902
58.322
0.2

2897
GLU355
OE1
56.733
59.068
−0.754

2898
GLU355
OE2
57.982
58.126
0.744

2899
GLU355
C
53.716
54.409
−0.383

2900
GLU355
O
54.47
53.672
−1.028

2901
LEU356
N
52.398
54.291
−0.371

2902
LEU356
CA
51.706
53.151
−0.987

2903
LEU356
CB
50.222
53.198
−0.632

2904
LEU356
CG
49.906
53.466
0.834

2905
LEU356
CD1
48.395
53.548
1.003

2906
LEU356
CD2
50.484
52.409
1.768

2907
LEU356
C
51.768
53.16
−2.508

2908
LEU356
O
51.848
54.213
−3.149

2909
SER357
N
51.722
51.965
−3.069

2910
SER357
CA
51.506
51.821
−4.511

2911
SER357
CB
51.815
50.395
−4.934

2912
SER357
OG
50.721
49.6
−4.493

2913
SER357
C
50.031
52.07
−4.789

2914
SER357
O
49.215
52.008
−3.862

2915
VAL358
N
49.667
52.128
−6.059

2916
VAL358
CA
48.256
52.34
−6.413

2917
VAL358
CB
48.181
52.647
−7.904

2918
VAL358
CG1
46.738
52.839
−8.359

2919
VAL358
CG2
49.021
53.872
−8.252

2920
VAL358
C
47.409
51.106
−6.098

2921
VAL358
O
46.312
51.241
−5.547

2922
GLU359
N
48.047
49.948
−6.138

2923
GLU359
CA
47.387
48.681
−5.809

2924
GLU359
CB
48.292
47.496
−6.178

2925
GLU359
CG
48.511
47.274
−7.68

2926
GLU359
CD
49.659
48.115
−8.241

2927
GLU359
OE1
50.339
48.749
−7.439

2928
GLU359
OE2
49.679
48.302
−9.447

2929
GLU359
C
47.091
48.602
−4.315

2930
GLU359
O
45.937
48.366
−3.931

2931
LYS360
N
48.052
49.021
−3.504

2932
LYS360
CA
47.85
49.002
−2.054

2933
LYS360
CB
49.21
49.147
−1.387

2934
LYS360
CG
49.128
48.929
0.118

2935
LYS360
CD
50.512
48.968
0.756

2936
LYS360
CE
50.435
48.743
2.262

2937
LYS360
NZ
51.764
48.885
2.881

2938
LY3360
C
46.916
50.117
−1.583

2939
LYS360
O
46.097
49.873
−0.69

2940
SER361
N
46.839
51.197
−2.342

2941
SER361
CA
45.907
52.273
−2

2942
SER361
CB
46.299
53.526
−2.774

2943
SER361
OG
47.621
53.884
−2.401

2944
SER361
C
44.473
51.899
−2.358

2945
SER361
O
43.564
52.149
−1.557

2946
THR362
N
44.318
51.073
−3.379

2947
THR362
CA
42.983
50.644
−3.799

2948
THR362
CB
43.086
50.014
−5.184

2949
THR362
OG1
43.541
51.012
−6.087

2950
THR362
CG2
41.732
49.515
−5.68

2951
THR362
C
42.39
49.636
−2.824

2952
THR362
O
41.261
49.839
−2.358

2953
VAL363
N
43.216
48.736
−2.314

2954
VAL363
CA
42.685
47.755
−1.364

2955
VAL363
CB
43.541
46.488
−1.391

2956
VAL363
CG1
45.012
46.782
−1.145

2957
VAL363
CG2
43.032
45.439
−0.407

2958
VAL363
C
42.578
48.333
0.049

2959
VAL363
O
41.624
47.985
0.758

2960
LEU364
N
43.309
49.401
0.326

2961
LEU364
CA
43.186
50.061
1.629

2962
LEU364
CB
44.437
50.89
1.898

2963
LEU364
CG
45.393
50.244
2.901

2964
LEU364
CD1
45.868
48.859
2.474

2965
LEU364
CD2
46.589
51.153
3.152

2966
LEU364
C
41.958
50.964
1.663

2967
LEU364
O
41.223
50.952
2.66

2968
GLN365
N
41.583
51.481
0.503

2969
GLN365
CA
40.363
52.282
0.403

2970
GLN365
CB
40.404
53.074
−0.899

2971
GLN365
CG
39.306
54.131
−0.963

2972
GLN365
CD
39.646
55.295
−0.035

2973
GLN365
OE1
40.748
55.85
−0.104

2974
GLN365
NE2
38.698
55.663
0.809

2975
GLN365
C
39.131
51.381
0.398

2976
GLN365
O
38.118
51.727
1.02

2977
SER366
N
39.296
50.157
−0.079

2978
SER366
CA
38.203
49.181
−0.04

2979
SER366
CB
38.544
48.025
−0.967

2980
SER366
OG
37.551
47.028
−0.773

2981
SER366
C
37.983
48.632
1.364

2982
SER366
O
36.83
48.505
1.796

2983
GLU367
N
39.054
48.538
2.136

2984
GLU367
CA
38.936
48.114
3.534

2985
GLU367
CB
40.324
47.727
4.037

2986
GLU367
CG
40.864
46.5
3.312

2987
GLU367
CD
42.364
46.363
3.553

2988
GLU367
OE1
43.015
47.397
3.63

2989
GLU367
OE2
42.856
45.244
3.526

2990
GLU367
C
38.379
49.243
4.394

2991
GLU367
O
37.537
48.989
5.263

2992
LEU368
N
38.634
50.472
3.974

2993
LEU368
CA
38.104
51.643
4.672

2994
LEU368
CB
38.827
52.869
4.12

2995
LEU368
CG
38.433
54.137
4.86

2996
LEU368
CO1
38.702
53.986
6.348

2997
LEU368
CD2
39.175
55.347
4.308

2998
LEU368
C
36.601
51.787
4.453

2999
LEU368
O
35.853
51.89
5.435

3000
GLU369
N
36.15
51.502
3.24

3001
GLU369
CA
34.716
51.609
2.948

3002
GLU369
CB
34.467
51.537
1.444

3003
GLU369
CG
35.245
52.579
0.652

3004
GLU369
CD
34.964
53.994
1.145

3005
GLU369
OE1
33.806
54.382
1.149

3006
GLU369
OE2
35.941
54.713
1.315

3007
GLU369
C
33.951
50.465
3.593

3008
GLU369
O
32.907
50.702
4.213

3009
SER370
N
34.595
49.316
3.692

3010
SER370
CA
33.934
48.154
4.273

3011
SER370
CB
34.606
46.911
3.716

3012
SER370
OG
34.433
46.935
2.305

3013
SER370
C
33.947
48.159
5.801

3014
SER370
O
32.996
47.648
6.405

3015
CYS371
N
34.828
48.941
6.407

3016
CYS371
CA
34.771
49.096
7.862

3017
CYS371
CB
36.149
49.437
8.408

3018
CYS371
SG
36.71
48.37
9.751

3019
CYS371
C
33.768
50.179
8.245

3020
CYS371
O
33.097
50.046
9.277

3021
LYS372
N
33.469
51.065
7.307

3022
LYS372
CA
32.377
52.02
7.516

3023
LYS372
CB
32.531
53.174
6.533

3024
LYS372
OG
33.813
53.949
6.804

3025
LYS372
CD
34.021
55.07
5.796

3026
LYS372
CE
35.283
55.86
6.119

3027
LYS372
NZ
35.517
56.919
5.123

3028
LYS372
C
31.029
51.338
7.303

3029
LYS372
O
30.096
51.566
8.083

3030
GLU373
N
31.028
50.308
6.473

3031
GLU373
CA
29.825
49.493
6.285

3032
GLU373
CB
29.989
48.674
5.01

3033
GLU373
CG
30.057
49.582
3.787

3034
GLU373
CD
30.41
48.774
2.541

3035
GLU373
OE1
31.594
48.677
2.237

3036
GLU373
OE2
29.494
48.273
1.906

3037
GLU373
C
29.588
48.563
7.473

3038
GLU373
O
28.439
48.428
7.91

3039
LEU374
N
30.657
48.174
8.15

3040
LEU374
CA
30.506
47.379
9.37

3041
LEU374
CB
31.813
46.664
9.673

3042
LEU374
CG
31.612
45.162
9.838

3043
LEU374
CO1
32.918
44.498
10.253

3044
LEU374
CD2
30.517
44.846
10.85

3045
LEU374
C
30.123
48.257
10.558

3046
LEU374
O
29.314
47.816
11.381

3047
GLN375
N
30.449
49.538
10.493

3048
GLN375
CA
29.968
50.497
11.495

3049
GLN375
CB
30.783
51.776
11.35

3050
GLN375
CG
30.289
52.858
12.301

3051
GLN375
CD
30.87
54.208
11.905

3052
GLN375
OE1
31.523
54.341
10.862

3053
GLN375
NE2
30.607
55.201
12.737

3054
GLN375
C
28.489
50.83
11.28

3055
GLN375
O
27.755
51.059
12.248

3056
GLU376
N
28.017
50.64
10.059

3057
GLU376
CA
26.594
50.819
9.754

3058
GLU376
CB
26.455
51.072
8.258

3059
GLU376
CG
27.144
52.365
7.842

3060
GLU376
CD
27.224
52.44
6.32

3061
GLU376
OE1
26.191
52.286
5.686

3062
GLU376
OE2
28.333
52.56
5.811

3063
GLU376
C
25.761
49.591
10.128

3064
GLU376
O
24.531
49.684
10.207

3065
LEU377
N
26.418
48.472
10.391

3066
LEU377
CA
25.709
47.277
10.855

3067
LEU377
CB
26.354
46.054
10.213

3068
LEU377
CG
26.279
46.11
8.691

3069
LEU377
CD1
27.122
45.007
8.062

3070
LEU377
CD2
24.834
46.039
8.203

3071
LEU377
C
25.82
47.164
12.37

3072
LEU377
O
24.919
46.656
13.049

3073
GLU378
N
26.957
47.605
12.877

3074
GLU378
CA
27.215
47.67
14.316

3075
GLU378
CB
28.193
46.562
14.711

3076
GLU378
CG
27.663
45.153
14.464

3077
GLU378
CD
28.728
44.126
14.849

3078
GLU378
OE1
29.898
44.431
14.673

3079
GLU378
OE2
28.353
43.04
15.278

3080
GLU378
C
27.872
49.003
14.653

3081
GLU378
O
29.107
49.069
14.708

3082
PRO379
N
27.078
49.97
15.091

3083
PRO379
CA
27.594
51.326
15.356

3084
PRO379
CB
26.368
52.177
15.49

3085
PRO379
CG
25.134
51.287
15.512

3086
PRO379
CD
25.629
49.868
15.289

3087
PRO379
C
28.459
51.432
16.618

3088
PRO379
O
29.132
52.447
16.831

3089
GLU380
N
28.463
50.382
17.423

3090
GLU380
CA
29.303
50.319
18.617

3091
GLU380
CB
28.471
49.777
19.771

3092
GLU380
CG
27.321
50.715
20.115

3093
GLU380
CD
26.455
50.095
21.205

3094
GLU380
OE1
26.65
50.437
22.362

3095
GLU380
OE2
25.589
49.307
20.848

3096
GLU380
C
30.534
49.434
18.42

3097
GLU380
O
31.172
49.066
19.413

3098
ASN381
N
30.802
48.991
17.2

3099
ASN381
CA
31.996
48.168
16.992

3100
ASN381
CB
31.838
47.299
15.745

3101
ASN381
CG
33.053
46.383
15.596

3102
ASN381
OD1
34.117
46.832
15.151

3103
ASN381
ND2
32.922
45.147
16.041

3104
ASN381
C
33.225
49.067
16.892

3105
ASN381
O
33.609
49.542
15.814

3106
LYS382
N
33.958
49.089
17.993

3107
LYS382
CA
35.127
49.958
18.129

3108
LYS382
CB
35.398
50.128
19.619

3109
LYS382
CG
35.696
48.803
20.31

3110
LYS382
CD
35.811
48.991
21.816

3111
LYS382
CE
36.287
47.716
22.498

3112
LY3382
NZ
37.641
47.369
22.042

3113
LYS382
C
36.372
49.438
17.408

3114
LYS382
O
37.276
50.232
17.115

3115
TRP383
N
36.296
48.225
16.888

3116
TRP383
CA
37.418
47.665
16.153

3117
TRP383
CB
37.253
46.156
16.11

3118
TRP383
CG
37.381
45.445
17.443

3119
TRP383
CD1
36.452
44.608
18.021

3120
TRP383
NE1
36.947
44.169
19.205

3121
TRP383
CE2
38.171
44.68
19.44

3122
TRP383
CZ2
39.06
44.542
20.495

3123
TRP383
CH2
40.283
45.202
20.458

3124
TRP383
CZ3
40.617
46.003
19.371

3125
TRP383
CE3
39.727
46.154
18.313

3126
TRP383
CD2
38.505
45.498
18.347

3127
TRP383
C
37.439
48.227
14.738

3128
TRP383
O
38.488
48.713
14.299

3129
CYS384
N
36.261
48.433
14.169

3130
CYS384
CA
36.189
49.08
12.859

3131
CYS384
CB
34.873
48.766
12.157

3132
CYS384
SG
35.036
47.735
10.681

3133
CYS384
C
36.341
50.582
12.986

3134
CYS384
O
36.976
51.168
12.109

3135
LEU385
N
36.062
51.139
14.153

3136
LEU385
CA
36.294
52.576
14.347

3137
LEU385
CB
35.661
53.019
15.663

3138
LEU385
CG
34.149
52.822
15.667

3139
LEU385
CD1
33.559
53.159
17.03

3140
LEU385
CD2
33.484
53.651
14.576

3141
LEU385
C
37.792
52.878
14.379

3142
LEU385
O
38.26
53.72
13.599

3143
LEU386
N
38.545
51.992
15.014

3144
LEU386
CA
39.999
52.146
15.073

3145
LEU386
CB
40.512
51.246
16.191

3146
LEU386
CG
42.024
51 .337
16.369

3147
LEU386
CD1
42.466
52.766
16.672

3148
LEU386
CD2
42.488
50.389
17.47

3149
LEU386
C
40.667
51.762
13.753

3150
LEU386
O
41.58
52.469
13.31

3151
THR387
N
40.06
50.848
13.016

3152
THR387
CA
40.623
50.446
11.724

3153
THR387
CB
40.072
49.071
11.37

3154
THR387
OG1
40.515
48.169
12.373

3155
THR387
CG2
40.595
48.567
10.032

3156
THR387
C
40.306
51.458
10.624

3157
THR387
O
41.174
51.714
9.782

3158
1LEA388
N
39.24
52.222
10.803

3159
1LEA388
CA
38.938
53.324
9.888

3160
1LEA388
CB
37.51
53.803
10.143

3161
1LEA388
CG2
37.242
55.138
9.464

3162
1LEA388
CG1
36.492
52.778
9.668

3163
1LEA388
OD1
35.087
53.151
10.126

3164
1LEA388
C
39.924
54.463
10.108

3165
1LEA388
O
40.519
54.94
9.133

3166
1LEA389
N
40.328
54.645
11.356

3167
1LEA389
CA
41.343
55.65
11.682

3168
1LEA389
CB
41.408
55.77
13.2

3169
1LEA389
CG2
42.61
56.595
13.642

3170
1LEA389
CG1
40.115
56.361
13.745

3171
1LEA389
CD1
40.132
56.425
15.267

3172
1LEA389
G
42.711
55.26
11.129

3173
1LEA389
O
43.319
56.064
10.409

3174
LEU390
N
43.03
53.977
11.193

3175
LEU390
CA
44.323
53.499
10.693

3176
LEU390
CB
44.54
52.079
11.202

3177
LEU390
CG
44.637
52.026
12.721

3178
LEU390
CD1
44.618
50.585
13.216

3179
LEU390
CD2
45.87
52.766
13.229

3180
LEU390
C
44.398
53.495
9.168

3181
LEU390
O
45.414
53.933
8.612

3182
LEU391
N
43.278
53.253
8.508

3183
LEU391
CA
43.273
53.26
7.044

3184
LEU391
CB
42.081
52.451
6.555

3185
LEU391
CG
42.263
50.977
6.889

3186
LEU391
CD1
40.962
50.204
6.739

3187
LEU391
CD2
43.372
50.354
6.05

3188
LEU391
C
43.222
54.675
6.483

3189
LEU391
O
43.926
54.95
5.506

3190
MET392
N
42.679
55.608
7.247

3191
MET392
CA
42.705
57.007
6.816

3192
MET392
CB
41.664
57.792
7.603

3193
MET392
CG
40.253
57.411
7.174

3194
MET392
SD
38.92
58.381
7.91

3195
MET392
CE
39.254
58.041
9.65

3196
MET392
C
44.084
57.625
7.019

3197
MET392
O
44.577
58.32
6.119

3198
ARG393
N
44.804
57.127
8.01

3199
ARG393
CA
46.17
57.597
8.246

3200
ARG393
CB
46.538
57.309
9.698

3201
ARG393
CG
45.714
58.177
10.64

3202
ARG393
CD
45.967
59.645
10.332

3203
ARG393
NE
45.148
60.544
11.153

3204
ARG393
CZ
45.574
61.761
11.491

3205
ARG393
NH1
46.814
62.13
11.172

3206
ARG393
NH2
44.801
62.569
12.221

3207
ARG393
C
47.186
56.94
7.312

3208
ARG393
O
48.235
57.534
7.038

3209
ALA394
N
46.824
55.811
6.725

3210
ALA394
CA
47.703
55.167
5.75

3211
ALA394
CB
47.566
53.657
5.895

3212
ALA394
C
47.39
55.575
4.311

3213
ALA394
O
48.242
55.403
3.434

3214
LEU395
N
46.216
56.138
4.075

3215
LEU395
CA
45.86
56.586
2.724

3216
LEU395
CB
44.368
56.359
2.512

3217
LEU395
CG
44.035
54.885
2.33

3218
LEU395
CD1
42.538
54.64
2.471

3219
LEU395
CD2
44.552
54.38
0.989

3220
LEU395
C
46.169
58.062
2.514

3221
LEU395
O
46.704
58.444
1.467

3222
ASP396
N
45.834
58.872
3.504

3223
ASP396
CA
46.112
60.314
3.447

3224
ASP396
CB
45.347
60.952
2.282

3225
ASP396
CG
45.863
62.36
1.974

3226
ASP396
OD1
46.057
63.113
2.925

3227
ASP396
OD2
45.87
62.717
0.807

3228
ASP396
C
45.689
60.964
4.761

3229
ASP396
O
44.6
61.552
4.84

3230
PRO397
N
46.654
61.102
5.656

3231
PRO397
CA
46.372
61.58
7.015

3232
PRO397
CB
47.658
61.374
7.755

3233
PRO397
CG
48.738
60.889
6.802

3234
PRO397
CD
48.059
60.73
5.456

3235
PRO397
C
45.954
63.054
7.088

3236
PRO397
O
45.132
63.411
7.942

3237
LEU398
N
46.326
63.841
6.09

3238
LEU398
CA
45.992
65.267
6.074

3239
LEU398
CB
46.916
65.943
5.072

3240
LEU398
CG
48.375
65.824
5.483

3241
LEU398
CD1
49.292
66.086
4.298

3242
LEU398
CD2
48.695
66.758
6.643

3243
LEU398
C
44.556
65.499
5.632

3244
LEU398
O
43.758
66.073
6.385

3245
LEU399
N
44.18
64.823
4.56

3246
LEU399
CA
42.849
65.006
3.97

3247
LEU399
CB
42.88
64.392
2.574

3248
LEU399
CG
41.55
64.535
1.845

3249
LEU399
CD1
41.2
66.004
1.632

3250
LEU399
CD2
41.588
63.797
0.512

3251
LEU399
C
41.777
64.313
4.801

3252
LEU399
O
40.699
64.872
5.037

3253
TYR400
N
42.171
63.22
5.428

3254
TYR400
CA
41.259
62.481
6.29

3255
TYR400
CB
41.597
61.002
6.199

3256
TYR400
CG
41 .286
60.365
4.846

3257
TYR400
CD1
42.225
59.545
4.237

3258
TYR400
GE1
41.946
58.959
3.01

3259
TYR400
CZ
40.725
59.195
2.396

3260
TYR400
OH
40.441
58.591
1.188

3261
TYR400
CE2
39.783
60.016
3

3262
TYR400
CD2
40.064
60.602
4.228

3263
TYR400
C
41 .306
62.938
7.746

3264
TYR400
O
40.54
62.397
8.551

3265
GLU401
N
42.008
64.023
8.041

3266
GLU401
CA
42.178
64.478
9.43

3267
GLU401
CB
43.059
65.718
9.422

3268
GLU401
CG
43.166
66.335
10.812

3269
GLU401
CD
43.942
67.643
10.732

3270
GLU401
QE1
45.163
67.565
10.687

3271
GLU401
OE2
43.308
68.678
10.596

3272
GLU401
C
40.873
64.854
10.12

3273
GLU401
O
40.642
64.391
11.243

3274
LYS402
N
39.938
65.442
9.39

3275
LYS402
CA
38.681
65.842
10.026

3276
LYS402
CB
37.965
66.845
9.13

3277
LYS402
CG
36.675
67.33
9.782

3278
LYS402
CD
35.949
68.346
8.911

3279
LYS402
CE
34.668
68.828
9.584

3280
LYS402
NZ
33.968
69.81
8.74

3281
LYS402
C
37.774
64.641
10.277

3282
LYS402
O
37.179
64.558
11.359

3283
GLU403
N
37.954
63.602
9.475

3284
GLU403
CA
37.155
62.388
9.619

3285
GLU403
CB
37.187
61.637
8.296

3286
GLU403
CG
36.7
62.503
7.142

3287
GLU403
CD
36.891
61.757
5.825

3288
GLU403
OE1
37.009
60.541
5.874

3289
GLU403
OE2
37.062
62.428
4.817

3290
GLU403
C
37.754
61.503
10.702

3291
GLU403
O
37.013
60.984
11.543

3292
THR404
N
39.062
61.615
10.867

3293
THR404
CA
39.767
60.847
11.89

3294
THR404
CB
41.256
60.844
11.567

3295
THR404
OG1
41.442
60.293
10.271

3296
THR404
CG2
42.024
59.987
12.562

3297
THR404
C
39.56
61.459
13.266

3298
THR404
O
39.419
60.722
14.246

3299
LEU405
N
39.273
62.749
13.297

3300
LEU405
CA
38.948
63.406
14.565

3301
LEU405
CB
39.136
64.913
14.412

3302
LEU405
CG
40.427
65.427
15.055

3303
LEU405
CD1
41.684
64.76
14.501

3304
LEU405
CD2
40.53
66.94
14.91

3305
LEU405
C
37.511
63.103
14.979

3306
LEU405
O
37.271
62.822
16.161

3307
GLN406
N
36.652
62.855
14.001

3308
GLN406
CA
35.27
62.498
14.327

3309
GLN406
CB
34.35
62.666
13.119

3310
GLN406
OG
34.427
64.043
12.464

3311
GLN406
CD
34.233
65.184
13.462

3312
GLN406
OE1
33.285
65.203
14.255

3313
GLN406
NE2
35.166
66.12
13.412

3314
GLN406
C
35.215
61.049
14.788

3315
GLN406
O
34.616
60.769
15.834

3316
TYR407
N
36.07
60.226
14.202

3317
TYR407
CA
36.164
58.824
14.608

3318
TYR407
CB
36.782
58.007
13.48

3319
TYR407
CG
35.786
57.61
12.398

3320
TYR407
CD1
35.772
58.254
11.167

3321
TYR407
CE1
34.855
57.878
10.196

3322
TYR407
CZ
33.956
56.853
10.458

3323
TYR407
OH
33.067
56.448
9.484

3324
TYR407
CE2
33.969
56.206
11.686

3325
TYR407
CD2
34.887
56.584
12.656

3326
TYR407
C
36.958
58.618
15.893

3327
TYR407
O
36.66
57.665
16.617

3328
PHE408
N
37.774
59.582
16.289

3329
PHE408
CA
38.422
59.5
17.6

3330
PHE408
CB
39.641
60.411
17.638

3331
PHE408
CG
40.956
59.677
17.414

3332
PHE408
CD1
41.786
60.022
16.355

3333
PHE408
CE1
42.983
59.345
16.164

3334
PHE408
CZ
43.351
58.325
17.032

3335
PHE408
CE2
42.523
57.982
18.092

3336
PHE408
CD2
41.326
58.659
18.283

3337
PHE408
C
37.463
59.891
18.712

3338
PHE408
O
37.428
59.208
19.742

3339
GLN409
N
36.522
60.768
18.401

3340
GLN409
CA
35.486
61.115
19.377

3341
GLN409
CB
34.801
62.395
18.916

3342
GLN409
CG
35.771
63.57
18.884

3343
GLN409
CD
35.105
64.765
18.212

3344
GLN409
OE1
35.266
65.915
18.638

3345
GLN409
NE2
34.379
64.475
17.147

3346
GLN409
C
34.452
59.998
19.489

3347
GLN409
O
34.075
59.62
20.606

3348
THR410
N
34.228
59.305
18.385

3349
THR410
CA
33.288
58.181
18.384

3350
THR410
CB
32.95
57.837
16.936

3351
THR410
OG1
32.383
58.99
16.327

3352
THR410
CG2
31.934
56.705
16.847

3353
THR410
C
33.891
56.958
19.067

3354
THR410
O
33.246
56.373
19.944

3355
LEU411
N
35.189
56.778
18.897

3356
LEU411
CA
35.89
55.648
19.506

3357
LEU411
CB
37.218
55.515
18.769

3358
LEU411
CG
38.034
54.309
19.206

3359
LEU411
CD1
37.219
53.03
19.101

3360
LEU411
CD2
39.3
54.202
18.368

3361
LEU411
C
36.123
55.867
21

3362
LEU411
O
35.942
54.925
21.781

3363
LYS412
N
36.212
57.124
21.404

3364
LYS412
CA
36.354
57.46
22.822

3365
LYS412
CB
36.878
58.893
22.886

3366
LYS412
CG
37.07
59.396
24.31

3367
LYS412
CD
37.628
60.815
24.317

3368
LYS412
CE
37.835
61.328
25.739

3369
LYS412
NZ
38.358
62.705
25.736

3370
LYS412
C
35.018
57.353
23.558

3371
LYS412
O
34.98
56.877
24.7

3372
ALA413
N
33.93
57.558
22.832

3373
ALA413
CA
32.595
57.425
23.426

3374
ALA413
CB
31.632
58.321
22.655

3375
ALA413
C
32.079
55.986
23.408

3376
ALA413
O
31.189
55.641
24.194

3377
VAL414
N
32.66
55.149
22.563

3378
VAL414
CA
32.315
53.725
22.568

3379
VAL414
CB
32.429
53.189
21.14

3380
VAL414
CG1
32.297
51.672
21.082

3381
VAL414
CG2
31.391
53.838
20.232

3382
VAL414
C
33.236
52.96
23.515

3383
VAL414
O
32.857
51 .926
24.081

3384
ASP415
N
34.409
53.516
23.759

3385
ASP415
CA
35.307
52.919
24.744

3386
ASP415
CB
36.366
52.112
23.995

3387
ASP415
CG
37.098
51.161
24.94

3388
ASP415
OD1
37.234
51.507
26.11

3389
ASP415
OD2
37.609
50.164
24.456

3390
ASP415
C
35.958
53.997
25.612

3391
ASP415
O
37.147
54.301
25.44

3392
PRO416
N
35.279
54.33
26.701

3393
PRO416
CA
35.788
55.333
27.645

3394
PRO416
CB
34.602
55.689
28.488

3395
PRO416
CG
33.483
54.69
28.227

3396
PRO416
CD
33.984
53.779
27.119

3397
PRO416
C
36.94
54.837
28.533

3398
PRO416
O
37.689
55.663
29.066

3399
MET417
N
37.208
53.539
28.531

3400
MET417
CA
38.308
52.997
29.331

3401
MET417
CB
38.027
51.516
29.546

3402
MET417
CG
36.645
51.304
30.152

3403
MET417
5D
36.105
49.583
30.254

3404
MET417
CE
36.11
49.189
28.489

3405
MET417
C
39.618
53.157
28.57

3406
MET417
O
40.664
53.471
29.15

3407
ARG418
N
39.48
53.181
27.255

3408
ARG418
CA
40.607
53.398
26.353

3409
ARG418
CB
40.369
52.58
25.09

3410
ARG418
CG
41.644
51.903
24.606

3411
ARG418
CD
42.063
50.797
25.569

3412
ARG418
NE
41.007
49.775
25.666

3413
ARG418
CZ
40.523
49.319
26.824

3414
ARG418
NH1
41.04
49.747
27.978

3415
ARG418
NH2
39.552
48.403
26.827

3416
ARG418
C
40.725
54.867
25.962

3417
ARG418
O
41.636
55.216
25.202

3418
ALA419
N
39.935
55.729
26.587

3419
ALA419
CA
39.842
57.132
26.168

3420
ALA419
CB
38.795
57.822
27.032

3421
ALA419
C
41.154
57.894
26.284

3422
ALA419
O
41.573
58.501
25.291

3423
THR420
N
41.935
57.597
27.312

3424
THR420
CA
43.225
58.282
27.478

3425
THR420
CB
43.737
58.049
28.897

3426
THR420
OG1
43.951
56.657
29.09

3427
THR420
CG2
42.729
58.522
29.938

3428
THR420
C
44.268
57.808
26.462

3429
THR420
O
44.94
58.659
25.862

3430
TYR421
N
44.133
56.571
26.009

3431
TYR421
CA
45.043
56.039
24.996

3432
TYR421
CB
44.96
54.516
25

3433
TYR421
CG
45.623
53.866
23.788

3434
TYR421
CD1
47.005
53.9
23.646

3435
TYR421
CE1
47.603
53.321
22.534

3436
TYR421
CZ
46.815
52.713
21.565

3437
TYR421
OH
47.405
52.167
20.447

3438
TYR421
CE2
45.435
52.675
21.705

3439
TYR421
CD2
44.839
53.253
22.818

3440
TYR421
C
44.669
56.56
23.616

3441
TYR421
O
45.56
56.964
22.86

3442
LEU422
N
43.39
56.841
23.428

3443
LEU422
CA
42.922
57.4
22.158

3444
LEU422
CB
41.417
57.185
22.071

3445
LEU422
CG
41.083
55.702
22.17

3446
LEU422
CD1
39.586
55.478
22.334

3447
LEU422
OD2
41.638
54.924
20.983

3448
LEU422
C
43.241
58.887
22.067

3449
LEU422
O
43.668
59.347
21.003

3450
ASP423
N
43.354
59.529
23.219

3451
ASP423
CA
43.766
60.934
23.269

3452
ASP423
CB
43.44
61.492
24.652

3453
ASP423
CG
41.951
61.379
24.969

3454
ASP423
OD1
41.156
61.541
24.053

3455
ASP423
OD2
41.633
61.25
26.146

3456
ASP423
C
45.27
61.065
23.035

3457
ASP423
O
45.71
61.971
22.318

3458
ASP424
N
46.012
60.04
23.423

3459
ASP424
CA
47.46
60.028
23.198

3460
ASP424
CB
48.091
58.993
24.128

3461
ASP424
CG
47.868
59.352
25.596

3462
ASP424
OD1
47.843
60.539
25.895

3463
ASP424
OD2
47.81
58.432
26.403

3464
ASP424
C
47.798
59.659
21.755

3465
ASP424
O
48.654
60.307
21.138

3466
LEU425
N
46.965
58.822
21.158

3467
LEU425
CA
47.178
58.392
19.775

3468
LEU425
CB
46.375
57.111
19.573

3469
LEU425
OG
46.664
56.449
18.231

3470
LEU425
CD1
48.144
56.104
18.104

3471
LEU425
CD2
45.808
55.2
18.05

3472
LEU425
C
46.719
59.465
18.79

3473
LEU425
O
47.377
59.687
17.765

3474
ARG426
N
45.777
60.283
19.228

3475
ARG426
CA
45.335
61.422
18.426

3476
ARG426
CB
43.961
61.834
18.932

3477
ARG426
OG
43.405
63.039
18.189

3478
ARG426
CD
42.048
63.42
18.768

3479
ARG426
NE
42.121
63.464
20.239

3480
ARG426
CZ
42.439
64.553
20.942

3481
ARG426
NH1
42.659
65.713
20.32

3482
ARG426
NH2
42.501
64.488
22.274

3483
ARG426
C
46.313
62.587
18.543

3484
ARG426
O
46.562
63.268
17.541

3485
SER427
N
47.051
62.632
19.642

3486
SER427
CA
48.124
63.623
19.782

3487
SER427
CB
48.648
63.604
21.211

3488
SER427
OG
47.599
63.964
22.09

3489
SER427
C
49.28
63.28
18.855

3490
SER427
O
49.718
64.13
18.068

3491
LYS428
N
49.555
61.989
18.763

3492
LYS428
CA
50.604
61.484
17.879

3493
LYS428
CB
50.703
59.984
18.118

3494
LYS428
CG
51.857
59.354
17.353

3495
LYS428
CD
51.883
57.848
17.575

3496
LYS428
CE
51.959
57.519
19.061

3497
LYS428
NZ
51.938
56.066
19.282

3498
LYS428
C
50.271
61.741
16.414

3499
LYS428
O
51.036
62.436
15.731

3500
PHE429
N
49.037
61.453
16.033

3501
PHE429
CA
48.621
61.629
14.639

3502
PHE429
CB
47.283
60.925
14.452

3503
PHE429
CG
47.345
59.403
14.376

3504
PHE429
CD1
46.236
58.65
14.733

3505
PHE429
CE1
46.282
57.265
14.658

3506
PHE429
CZ
47.437
56.63
14.22

3507
PHE429
CE2
48.544
57.384
13.851

3508
PHE429
CD2
48.496
58.77
13.924

3509
PHE429
C
48.473
63.093
14.222

3510
PHE429
O
48.938
63.462
13.135

3511
LEU430
N
48.099
63.954
15.152

3512
LEU430
CA
47.916
65.364
14.809

3513
LEU430
CB
46.953
65.956
15.829

3514
LEU430
CG
46.363
67.28
15.366

3515
LEU430
CD1
45.871
67.181
13.927

3516
LEU430
CD2
45.227
67.696
16.294

3517
LEU430
C
49.251
66.112
14.801

3518
LEU430
O
49.446
67.011
13.97

3519
LEU431
N
50.231
65.557
15.496

3520
LEU431
CA
51.586
66.104
15.444

3521
LEU431
CB
52.335
65.63
16.69

3522
LEU431
CG
53.656
66.362
16.92

3523
LEU431
CD1
53.952
66.49
18.409

3524
LEU431
CD2
54.832
65.726
16.183

3525
LEU431
C
52.276
65.633
14.166

3526
LEU431
O
52.953
66.436
13.511

3527
GLU432
N
51.872
64.47
13.681

3528
GLU432
CA
52.381
63.959
12.403

3529
GLU432
CB
51.895
62.529
12.22

3530
GLU432
CG
52.527
61.594
13.238

3531
GLU432
CD
51.87
60.222
13.152

3532
GLU432
OE1
51.442
59.865
12.064

3533
GLU432
OE2
51.697
59.61
14.197

3534
GLU432
C
51.881
64.799
11.235

3535
GLU432
O
52.702
65.259
10.431

3536
ASN433
N
50.634
65.235
11.317

3537
ASN433
CA
50.093
66.124
10.287

3538
ASN433
CB
48.591
66.227
10.458

3539
ASN433
CG
47.889
65.099
9.726

3540
ASN433
OD1
48.513
64.222
9.115

3541
ASN433
ND2
46.58
65.231
9.688

3542
ASN433
C
50.668
67.53
10.347

3543
ASN433
O
50.95
68.101
9.287

3544
SER434
N
51.084
67.971
11.522

3545
SER434
CA
51.693
69.298
11.625

3546
SER434
CB
51.649
69.751
13.076

3547
SER434
OG
50.284
69.827
13.464

3548
SER434
C
53.135
69.289
11.127

3549
SER434
O
53.557
70.266
10.498

3550
VAL435
N
53.779
68.132
11.169

3551
VAL435
CA
55.123
68.004
10.597

3552
VAL435
CB
55.816
66.803
11.232

3553
VAL435
CG1
57.185
66.563
10.611

3554
VAL435
CG2
55.95
66.986
12.738

3555
VAL435
C
55.056
67.826
9.08

3556
VAL435
O
55.892
68.388
8.359

3557
LEU436
N
53.947
67.286
8.6

3558
LEU436
CA
53.722
67.207
7.153

3559
LEU436
CB
52.506
66.328
6.884

3560
LEU436
CG
52.774
64.867
7.215

3561
LEU436
CD1
51.489
64.048
7.172

3562
LEU436
CD2
53.821
64.28
6.277

3563
LEU436
C
53.473
68.592
6.571

3564
LEU436
O
54.192
68.996
5.649

3565
LYS437
N
52.704
69.4
7.286

3566
LYS437
CA
52.418
70.771
6.84

3567
LYS437
CB
51.28
71.316
7.695

3568
LYS437
CG
50.023
70.468
7.552

3569
LYS437
CD
48.97
70.867
8.58

3570
LYS437
CE
47.756
69.948
8.516

3571
LYS437
NZ
46.775
70.306
9.552

3572
LYS437
C
53.63
71 .688
6.985

3573
LYS437
O
53.894
72.488
6.079

3574
MET438
N
54.495
71.372
7.937

3575
MET438
CA
55.739
72.122
8.121

3576
MET438
CB
56.323
71.717
9.471

3577
MET438
CG
57.636
72.428
9.765

3578
MET438
SD
58.438
71.992
11.324

3579
MET438
CE
58.669
70.223
11.034

3580
MET438
C
56.751
71.823
7.014

3581
MET438
O
57.447
72.741
6.56

3582
GLU439
N
56.641
70.648
6.414

3583
GLU439
CA
57.507
70.292
5.29

3584
GLU439
CR
57.588
68.776
5.211

3585
GLU439
CG
58.283
68.224
6.441

3586
GLU439
CD
58.201
66.706
6.461

3587
GLU439
QE1
57.871
66.112
5.442

3588
GLU439
OE2
58.624
66.14
7.457

3589
GLU439
C
56.973
70.823
3.968

3590
GLU439
O
57.77
71.284
3.144

3591
TYR440
N
55.664
71.001
3.877

3592
TYR440
CA
55.071
71.506
2.63

3593
TYR440
CB
53.63
71.016
2.517

3594
TYR440
OG
53.47
69.497
2.55

3595
TYR440
CO1
54.404
68.674
1.931

3596
TYR440
GE1
54.261
67.294
1.989

3597
TYR440
CZ
53.175
66.742
2.654

3598
TYR440
OH
53.096
65.376
2.822

3599
TYR440
CE2
52.222
67.562
3.241

3600
TYR440
CD2
52.366
68.941
3.183

3601
TYR440
C
55.106
73.032
2.575

3602
TYR440
O
54.901
73.629
1.513

3603
ALA441
N
55.358
73.646
3.719

3604
ALA441
CA
55.625
75.083
3.769

3605
ALA441
CB
54.872
75.677
4.953

3606
ALA441
C
57.119
75.373
3.908

3607
ALA441
O
57.524
76.539
3.806

3608
GLU442
N
57.919
74.313
3.955

3609
GLU442
CA
59.365
74.349
4.261

3610
GLU442
CR
60.23
74.51
2.996

3611
GLU442
CG
59.991
75.764
2.148

3612
GLU442
CD
59.111
75.467
0.934

3613
GLU442
OE1
59.262
76.169
−0.057

3614
GLU442
OE2
58.406
74.467
0.97

3615
GLU442
C
59.715
75.389
5.328

3616
GLU442
O
60.44
76.361
5.079

3617
VAL443
N
59.199
75.161
6.524

3618
VAL443
CA
59.423
76.095
7.631

3619
VAL443
CCB
58.098
76.742
8.02

3620
VAL443
CG1
57.662
77.79
7.003

3621
VAL443
CG2
57.007
75.702
8.238

3622
VAL443
C
60.051
75.414
8.842

3623
VAL443
O
60.146
74.186
8.92

3624
ARG444
N
60.565
76.243
9.737

3625
ARG444
CA
61.135
75.758
11.001

3626
ARG444
CB
62.499
76.408
11.217

3627
ARG444
CG
63.371
76.224
9.977

3628
ARG444
CD
64.806
76.694
10.189

3629
ARG444
NE
65.557
75.752
11.033

3630
ARG444
CZ
66.74
76.044
11.579

3631
ARG444
NH1
67.263
77.262
11.422

3632
ARG444
NH2
67.38
75.133
12.313

3633
ARG444
C
60.197
76.043
12.177

3634
ARG444
O
60.617
76.031
13.344

3635
VAL445
N
58.987
76.468
11.85

3636
VAL445
CA
57.945
76.673
12.86

3637
VAL445
CB
57.195
77.971
12.557

3638
VAL445
CG1
58.147
79.159
12.543

3639
VAL445
CG2
56.444
77.908
11.232

3640
VAL445
C
56.981
75.485
12.87

3641
VAL445
O
56.641
74.929
11.819

3642
LEU446
N
56.597
75.069
14.062

3643
LEU446
CA
55.655
73.954
14.198

3644
LEU446
CB
56.353
72.786
14.884

3645
LEU446
CG
55.487
71.531
14.853

3646
LEU446
CD1
55.189
71.125
13.416

3647
LEU446
CD2
56.153
70.383
15.598

3648
LEU446
C
54.429
74.382
14.999

3649
LEU446
O
54.512
74.717
16.191

3650
HIS447
N
53.294
74.375
14.323

3651
HIS447
CA
52.042
74.804
14.951

3652
HIS447
CB
51.262
75.64
13.948

3653
HIS447
CG
52.022
76.876
13.511

3654
HIS447
ND1
52.232
77.286
12.246

3655
HIS447
CE1
52.958
78.422
12.259

3656
HIS447
NE2
53.213
78.73
13.551

3657
HIS447
CD2
52.643
77.787
14.334

3658
HIS447
C
51.212
73.619
15.429

3659
HIS447
O
50.802
72.749
14.652

3660
LEU448
N
51.055
73.576
16.74

3661
LEU448
CA
50.26
72.565
17.434

3662
LEU448
CB
51.209
71.637
18.18

3663
LEU448
CG
51.959
70.717
17.226

3664
LEU448
CD1
53.12
70.028
17.927

3665
LEU448
CD2
51.008
69.698
16.611

3666
LEU448
C
49.315
73.228
18.434

3667
LEU448
O
48.931
72.614
19.438

3668
ALA449
N
49.046
74.503
18.212

3669
ALA449
CA
48.176
75.268
19.109

3670
ALA449
CB
48.369
76.752
18.841

3671
ALA449
C
46.711
74.916
18.907

3672
ALA449
O
46.262
74.753
17.765

3673
HIS450
N
45.994
74.831
20.018

3674
HIS450
CA
44.56
74.502
20.034

3675
HIS450
CB
43.757
75.577
19.301

3676
HIS450
CG
43.689
76.941
19.957

3677
HIS450
ND1
42.738
77.361
20.813

3678
HIS450
CE1
42.996
78.633
21.178

3679
HIS450
NE2
44.122
79.022
20.538

3680
HIS450
CD2
44.558
77.991
19.778

3681
HIS450
C
44.285
73.169
19.354

3682
HIS450
O
43.405
73.087
18.489

3683
LYS451
N
45.039
72.144
19.713

3684
LYS451
CA
44.853
70.848
19.054

3685
LYS451
CB
46.182
70.387
18.473

3686
LYS451
CG
46.684
71.316
17.376

3687
LYS451
CD
45.718
71.402
16.201

3688
LYS451
CE
46.264
72.329
15.124

3689
LYS451
NZ
47.573
71.854
14.649

3690
LYS451
C
44.329
69.805
20.028

3691
LYS451
O
44.011
68.675
19.636

3692
ASP452
N
44.315
70.19
21.295

3693
ASP452
CA
43.867
69.351
22.414

3694
ASP452
CB
42.432
68.895
22.157

3695
ASP452
CG
41.763
68.503
23.465

3696
ASP452
OD1
42
69.203
24.438

3697
ASP452
OD2
40.966
67.576
23.449

3698
ASP452
C
44.816
68.162
22.596

3699
ASP452
O
44.406
67.053
22.954

3700
LEU453
N
46.099
68.437
22.426

3701
LEU453
CA
47.126
67.396
22.532

3702
LEU453
CB
48.434
67.897
21.934

3703
LEU453
CG
48.301
68.306
20.475

3704
LEU453
CO1
49.619
68.877
19.971

3705
LEU453
CD2
47.857
67.142
19.597

3706
LEU453
C
47.381
67.045
23.985

3707
LEU453
O
47.506
67.937
24.831

3708
THR454
N
47.537
65.761
24.242

3709
THR454
CA
47.783
65.28
25.602

3710
THR454
CR
46.856
64.099
25.882

3711
THR454
OG1
47.061
63.099
24.89

3712
THR454
CG2
45.396
64.522
25.816

3713
THR454
C
49.241
64.868
25.792

3714
THR454
O
49.812
65.054
26.874

3715
VAL455
N
49.867
64.441
24.708

3716
VAL455
CA
51.276
64.027
24.774

3718
VAL455
CG1
50.636
61.756
23.861

3719
VAL455
CG2
52.721
61.979
25.228

3720
VAL455
C
52.035
64.425
23.504

3721
VAL455
O
51.5
64.334
22.392

3722
LEU456
N
53.229
64.965
23.69

3723
LEU456
CA
54.09
65.311
22.553

3724
LEU456
CB
55.107
66.35
23.003

3725
LEU456
OG
54.441
67.656
23.405

3726
LEU456
OD1
55.47
68.63
23.964

3727
LEU456
CD2
53.697
68.269
22.223

3728
LEU456
C
54.835
64.086
22.03

3729
LEU456
O
55.579
63.429
22.766

3730
CYS457
N
54.634
63.798
20.757

3731
CY3457
CA
55.31
62.661
20.125

3732
CYS457
CB
54.251
61.735
19.546

3733
CYS457
SG
53.099
61.052
20.762

3734
CYS457
C
56.279
63.12
19.039

3735
CYS457
O
56.304
64.301
18.679

3736
HIS458
N
57.136
62.196
18.624

3737
HIS458
CA
58.131
62.408
17.551

3738
HIS458
CB
57.409
62.56
16.212

3739
HIS458
CG
56.641
61.337
15.753

3740
HIS458
ND1
57.146
60.28
15.089

3741
HIS458
CE1
56.162
59.389
14.852

3742
HIS458
NE2
55.018
59.896
15.367

3743
HIS458
CD2
55.296
61.098
15.921

3744
HIS458
C
59.014
63.636
17.757

3745
HIS458
O
59.415
64.275
16.775

3746
LEU459
N
59.535
63.79
18.964

3747
LEU459
CA
60.282
65.009
19.3

3748
LEU459
CB
60.256
65.183
20.812

3749
LEU459
CG
58.834
65.391
21 .323

3750
LEU459
CD1
58.787
65.358
22.845

3751
LEU459
CD2
58.241
66.692
20.793

3752
LEU459
C
61.721
64.962
18.796

3753
LEU459
O
62.298
66.004
18.472

3754
GLU460
N
62.158
63.766
18.438

3755
GLU460
CA
63.492
63.579
17.863

3756
GLU460
CB
63.997
62.158
18.141

3757
GLU460
CG
63.548
61.058
17.168

3758
GLU460
CD
62.096
60.619
17.347

3759
GLU460
OE1
61.52
60.948
18.38

3760
GLU460
OE2
61.509
60.243
16.339

3761
GLU460
C
63.539
63.871
16.36

3762
GLU460
O
64.628
63.868
15.779

3763
GLN461
N
62.396
64.153
15.749

3764
GLN461
CA
62.395
64.568
14.346

3765
GLN461
CB
61.121
64.051
13.677

3766
GLN461
CG
60.967
62.534
13.772

3767
GLN461
CD
62.079
61.821
13.005

3768
GLN461
OE1
62.41
62.189
11.872

3769
GLN461
NE2
62.576
60.75
13.598

3770
GLN461
C
62.401
66.092
14.282

3771
GLN461
O
62.903
66.686
13.322

3772
LEU462
N
62.104
66.695
15.421

3773
LEU462
CA
61.88
68.138
15.498

3774
LEU462
CB
60.734
68.368
16.474

3775
LEU462
CG
59.476
67.62
16.044

3776
LEU462
CD1
58.393
67.709
17.112

3777
LEU462
CD2
58.958
68.127
14.701

3778
LEU462
C
63.11
68.937
15.934

3779
LEU462
O
62.951
70.078
16.38

3780
LEU463
N
64.299
68.449
15.607

3781
LEU463
CA
65.56
69.094
16.02

3782
LEU463
CB
66.699
68.213
15.499

3783
LEU463
CG
68.084
68.859
15.598

3784
LEU463
CD1
68.502
69.107
17.041

3785
LEU463
CD2
69.135
68.004
14.9

3786
LEU463
C
65.73
70.508
15.458

3787
LEU463
O
66.175
71.405
16.189

3788
LEU464
N
65.166
70.733
14.279

3789
LEU464
CA
65.273
72.018
13.58

3790
LEU464
CB
65.297
71.738
12.082

3791
LEU464
CG
66.441
70.812
11.691

3792
LEU464
CD1
66.343
70.429
10.221

3793
LEU464
CD2
67.794
71.443
11.994

3794
LEU464
C
64.117
72.977
13.866

3795
LEU464
O
64.02
74.013
13.199

3796
VAL465
N
63.203
72.613
14.749

3797
VAL465
CA
62.09
73.516
15.046

3798
VAL465
CB
60.939
72.724
15.657

3799
VAL465
CG1
59.812
73.638
16.121

3800
VAL465
CG2
60.411
71.698
14.663

3801
VAL465
C
62.554
74.616
15.99

3802
VAL465
O
62.85
74.373
17.164

3803
THR466
N
62.584
75.826
15.461

3804
THR466
CA
63.041
76.984
16.226

3805
THR466
CB
63.764
77.95
15.292

3806
THR466
OG1
62.851
78.394
14.299

3807
THR466
CG2
64.937
77.28
14.589

3808
THR466
C
61.87
77.695
16.888

3809
THR466
O
62.048
78.374
17.91

3810
HIS467
N
60.676
77.462
16.372

3811
HIS467
CA
59.482
78.061
16.976

3812
HIS467
CB
58.976
79.183
16.077

3813
HIS467
CG
60.007
80.268
15.83

3814
HIS467
ND1
60.513
81.111
16.749

3815
HIS467
CE1
61.412
81.926
16.163

3816
HIS467
NE2
61.474
81.591
14.855

3817
HIS467
CD2
60.613
80.573
14.634

3818
HIS467
C
58.401
77.009
17.17

3819
HIS467
O
57.755
76.571
16.209

3820
LEU468
N
58.212
76.615
18.416

3821
LEU468
CA
57.249
75.559
18.735

3822
LEU468
CB
57.956
74.512
19.588

3823
LEU468
CG
57.095
73.282
19.84

3824
LEU468
CD1
56.61
72.671
18.532

3825
LEU468
CD2
57.859
72.248
20.657

3826
LEU468
C
56.048
76.138
19.473

3827
LEU468
O
56.161
76.648
20.596

3828
ASP469
N
54.904
76.068
18.817

3829
ASP469
CA
53.677
76.613
19.393

3830
ASP469
CB
52.998
77.475
18.337

3831
ASP469
OG
51.761
78.159
18.908

3832
ASP469
OD1
51.666
78.263
20.123

3833
ASP469
OD2
50.892
78.489
18.114

3834
ASP469
C
52.753
75.49
19.853

3835
ASP469
O
51.954
74.961
19.076

3836
LEU470
N
52.815
75.224
21.145

3837
LEU470
CA
52.035
74.18
21.815

3838
LEU470
CB
52.951
73.423
22.767

3839
LEU470
CG
54.147
72.799
22.071

3840
LEU470
CD1
55.11
72.226
23.102

3841
LEU470
CD2
53.703
71.727
21.084

3842
LEU470
C
50.929
74.771
22.682

3843
LEU470
O
50.43
74.073
23.574

3844
SER471
N
50.691
76.064
22.558

3845
SER471
CA
49.681
76.727
23.391

3846
SER471
CB
49.627
78.201
23.015

3847
SER471
OG
49.205
78.281
21.661

3848
SER471
C
48.289
76.121
23.23

3849
SER471
O
47.916
75.653
22.148

3850
HIS472
N
47.573
76.091
24.342

3851
HIS472
CA
46.179
75.632
24.401

3852
HIS472
CB
45.31
76.469
23.47

3853
HIS472
CG
45.168
77.919
23.894

3854
HIS472
ND1
44.186
78.428
24.66

3855
HIS472
CE1
44.389
79.751
24.824

3856
HIS472
NE2
45.511
80.081
24.146

3857
HIS472
CD2
46
78.963
23.563

3858
HIS472
C
46.059
74.15
24.076

3859
HIS472
O
45.613
73.764
22.986

3860
ASN473
N
46.572
73.354
24.997

3861
ASN473
CA
46.5
71.89
24.923

3862
ASN473
CB
47.777
71.334
24.291

3863
ASN473
CG
47.782
71.539
22.778

3864
ASN473
OD1
46.778
71.289
22.105

3865
ASN473
ND2
48.906
71.975
22.25

3866
ASN473
C
46.304
71.314
26.327

3867
ASN473
O
46.094
72.054
27.296

3868
ARG474
N
46.329
69.995
26.417

3869
ARG474
CA
46.148
69.308
27.699

3870
ARG474
CB
44.999
68.311
27.603

3871
ARG474
CG
43.67
69.007
27.344

3872
ARG474
CD
42.499
68.06
27.573

3873
ARG474
NE
42.597
66.86
26.73

3874
ARG474
CZ
41 .575
66.021
26.551

3875
ARG474
NH1
40.408
66.253
27.156

3876
ARG474
NH2
41.719
64.947
25.772

3877
ARG474
C
47.41
68.576
28.15

3878
ARG474
O
47.32
67.676
28.994

3879
LEU475
N
48.55
68.945
27.583

3880
LEU475
CA
49.838
68.334
27.944

3881
LEU475
CB
50.949
69.109
27.239

3882
LEU475
OG
50.74
69.225
25.732

3883
LEU475
CD1
51.635
70.307
25.137

3884
LEU475
CD2
50.967
67.894
25.032

3885
LEU475
C
50.054
68.477
29.442

3886
LEU475
O
49.805
69.558
29.982

3887
ARG476
N
50.469
67.411
30.108

3888
ARG476
CA
50.679
67.473
31.567

3889
ARG476
CB
50.319
66.118
32.169

3890
ARG476
CG
48.859
65.738
31.941

3891
ARG476
CD
47.905
66.681
32.666

3892
ARG476
NE
48.198
66.735
34.108

3893
ARG476
CZ
47.448
66.136
35.036

3894
ARG476
NH1
47.778
66.235
36.325

3895
ARG476
NH2
46.364
65.444
34.676

3896
ARG476
C
52.128
67.786
31.931

3897
ARG476
O
52.436
68.26
33.036

3898
THR477
N
53.001
67.589
30.962

3899
THR477
CA
54.429
67.822
31.164

3900
THR477
CB
55.01
66.64
31.944

3901
THR477
OG1
56.419
66.806
32.054

3902
THR477
CG2
54.756
65.309
31.243

3903
THR477
C
55.136
67.94
29.823

3904
THR477
O
54.678
67.383
28.818

3905
LEU478
N
56.181
68.746
29.805

3906
LEU478
CA
57.105
68.751
28.676

3907
LEU478
CB
57.807
70.1
28.61

3908
LEU478
CG
56.811
71.191
28.235

3909
LEU478
CD1
57.427
72.581
28.333

3910
LEU478
CD2
56.245
70.954
26.839

3911
LEU478
C
58.102
67.618
28.882

3912
LEU478
O
58.938
67.657
29.798

3913
PRO479
N
57.987
66.617
28.023

3914
PRO479
CA
58.706
65.348
28.189

3915
PRO479
CB
58.109
64.426
27.167

3916
PRO479
CG
57.115
65.19
26.31

3917
PRO479
CD
57.077
66.597
26.874

3918
PRO479
C
60.195
65.546
27.952

3919
PRO479
O
60.573
66.488
27.251

3920
PRO480
N
61.03
64.668
28.491

3921
PRO480
CA
62.492
64.822
28.366

3922
PRO480
CB
63.073
63.768
29.258

3923
PRO480
CG
61.952
62.923
29.843

3924
PRO480
CD
60.655
63.52
29.324

3925
PRO480
C
63.038
64.685
26.933

3926
PRO480
O
64.095
65.252
26.635

3927
ALA481
N
62.218
64.188
26.016

3928
ALA481
CA
62.581
64.126
24.595

3929
ALA481
CB
61.715
63.072
23.917

3930
ALA481
C
62.422
65.472
23.873

3931
ALA481
O
62.878
65.607
22.731

3932
LEU482
N
61.965
66.494
24.587

3933
LEU482
CA
61.858
67.849
24.036

3934
LEU482
CB
60.922
68.644
24.941

3935
LEU482
OG
60.638
70.043
24.412

3936
LEU482
CD1
59.822
69.977
23.127

3937
LEU482
CD2
59.901
70.869
25.457

3938
LEU482
C
63.233
68.525
23.975

3939
LEU482
O
63.453
69.369
23.098

3940
ALA483
N
64.208
67.91
24.635

3941
ALA483
CA
65.611
68.335
24.546

3942
ALA483
CB
66.366
67.787
25.752

3943
ALA483
C
66.3
67.884
23.249

3944
ALA483
O
67.48
68.185
23.039

3945
ALA484
N
65.571
67.196
22.378

3946
ALA484
CA
66.07
66.89
21.037

3947
ALA484
CB
65.395
65.619
20.535

3948
ALA484
C
65.783
68.042
20.068

3949
ALA484
O
66.313
68.057
18.951

3950
LEU485
N
65.005
69.016
20.515

3951
LEU485
CA
64.757
70.242
19.745

3952
LEU485
CB
63.353
70.788
20.03

3953
LEU485
CG
62.198
70.015
19.394

3954
LEU485
CD1
61.754
68.803
20.21

3955
LEU485
CD2
61.006
70.947
19.212

3956
LEU485
C
65.757
71.308
20.17

3957
LEU485
O
65.375
72.318
20.767

3958
ARG486
N
66.998
71.161
19.738

3959
ARG486
CA
68.063
72.03
20.249

3960
ARG486
CB
69.383
71.283
20.135

3961
ARG486
CG
69.268
69.908
20.783

3962
ARG486
CD
70.612
69.196
20.856

3963
ARG486
NE
71.472
69.773
21.902

3964
ARG486
CZ
72.658
70.339
21.667

3965
ARG486
NH1
73.069
70.535
20.413

3966
ARG486
NH2
73.395
70.785
22.687

3967
ARG486
C
68.152
73.375
19.53

3968
ARG486
O
68.753
74.316
20.068

3969
CYS487
N
67.447
73.5
18.414

3970
CYS487
CA
67.363
74.78
17.702

3971
CYS487
CB
67.248
74.499
16.209

3972
CYS487
SG
68.608
73.545
15.499

3973
CYS487
C
66.159
75.607
18.155

3974
CYS487
O
65.956
76.718
17.649

3975
LEU488
N
65.386
75.07
19.088

3976
LEU488
CA
64.205
75.758
19.613

3977
LEU488
CB
63.524
74.798
20.58

3978
LEU488
CG
62.208
75.339
21.113

3979
LEU488
OD1
61.272
75.661
19.96

3980
LEU488
CD2
61.568
74.334
22.062

3981
LEU488
C
64.603
77.03
20.344

3982
LEU488
O
65.341
76.979
21 .329

3983
GLU489
N
64.125
78.153
19.836

3984
GLU489
CA
64.426
79.46
20.409

3985
GLU489
CB
64.814
80.388
19.268

3986
GLU489
CG
66.055
79.878
18.549

3987
GLU489
CD
66.25
80.642
17.248

3988
GLU489
OE1
65.244
80.885
16.591

3989
GLU489
OE2
67.394
80.786
16.837

3990
GLU489
C
63.211
80.022
21.123

3991
GLU489
O
63.337
80.694
22.157

3992
VAL490
N
62.042
79.715
20.59

3993
VAL490
CA
60.796
80.149
21.232

3994
VAL490
CB
60.09
81.171
20.343

3995
VAL490
CG1
58.719
81.55
20.896

3996
VAL490
CG2
60.943
82.421
20.151

3997
VAL490
C
59.88
78.96
21 .501

3998
VAL490
O
59.407
78.289
20.572

3999
LEU491
N
59.678
78.691
22.779

4000
LEU491
CA
58.761
77.633
23.199

4001
LEU491
CB
59.472
76.723
24.195

40D2
LEU491
CG
58.585
75.567
24.651

4003
LEU491
OD1
58.036
74.783
23.465

4004
LEU491
CD2
59.343
74.641
25.596

4005
LEU491
C
57.516
78.244
23.833

4006
LEU491
O
57.55
78.765
24.956

4007
GLN492
N
56.434
78.204
23.077

4008
GLN492
CA
55.144
78.695
23.56

4009
GLN492
CB
54.456
79.441
22.414

4010
GLN492
CG
52.988
79.785
22.685

4011
GLN492
CD
52.811
80.661
23.922

4012
GLN492
OE1
53.034
80.212
25.051

4013
GLN492
NE2
52.348
81.877
23.698

4014
GLN492
C
54.297
77.519
24.029

4015
GLN492
O
53.707
76.812
23.21

4016
ALA493
N
54.238
77.32
25.332

4017
ALA493
CA
53.495
76.192
25.891

4018
ALA493
CB
54.465
75.248
26.589

4019
ALA493
C
52.405
76.656
26.856

4020
ALA493
O
51.894
75.858
27.656

4021
SER494
N
52.066
77.931
26.779

4022
SER494
CA
51.014
78.512
27.622

4023
SER494
CB
50.852
79.983
27.268

4024
SER494
OG
52.058
80.648
27.622

4025
SER494
C
49.669
77.813
27.464

4026
SER494
O
49.409
77.111
26.476

4027
ASP495
N
48.849
77.984
28.487

4028
ASP495
CA
47.498
77.419
28.563

4029
ASP495
CB
46.611
78.07
27.511

4030
ASP495
OG
46.546
79.577
27.752

4031
ASP495
OD1
45.696
79.991
28.527

4032
ASP495
OD2
47.301
80.289
27.101

4033
ASP495
C
47.556
75.913
28.397

4034
ASP495
O
47.255
75.368
27.325

4035
ASN496
N
48.137
75.292
29.405

4036
ASN496
CA
48.326
73.839
29.425

4037
ASN496
CB
49.661
73.468
28.783

4038
ASN496
CG
49.534
73.059
27.318

4039
ASN496
OD1
49.184
71.912
27.013

4040
ASN496
ND2
49.944
73.957
26.442

4041
ASN496
C
48.339
73.337
30.858

4042
ASN496
O
48.654
74.079
31.796

4043
ALA497
N
48.235
72.026
30.98

4044
ALA497
CA
48.265
71.371
32.292

4045
ALA497
CB
47.429
70.102
32.209

4046
ALA497
C
49.689
71.045
32.759

4047
ALA497
O
49.879
70.412
33.803

4048
1LEA498
N
50.665
71.479
31.974

4049
1LEA498
CA
52.087
71.271
32.253

4050
1LEA498
CB
52.887
71.968
31.159

4051
1LEA498
CG2
54.384
71.81
31.393

4052
1LEA498
CG1
52.511
71.413
29.794

4053
1LEA498
CD1
53.219
72.166
28.676

4054
1LEA498
C
52.511
71.804
33.613

4055
1LEA498
O
52.459
73.011
33.887

4056
GLU499
N
52.842
70.855
34.471

4057
GLU499
CA
53.388
71.137
35.796

4058
GLU499
CB
52.518
70.418
36.822

4059
GLU499
CG
52.157
69.009
36.367

4060
GLU499
CD
51.21
68.36
37.371

4061
GLU499
OE1
50.031
68.681
37.337

4062
GLU499
OE2
51.673
67.503
38.112

4063
GLU499
C
54.845
70.692
35.888

4064
GLU499
O
55.54
70.982
36.869

4065
SER500
N
55.296
69.995
34.858

4066
SER50O
CA
56.692
69.547
34.802

4067
SER500
CB
56.703
68.03
34.895

4068
SER500
OG
57.999
67.589
34.523

4069
SER500
C
57.389
69.998
33.521

4070
SER500
O
56.949
69.678
32.41

4071
LEU501
N
58.53
70.646
33.687

4072
LEU501
CA
59.279
71.207
32.549

4073
LEU501
CB
59.611
72.655
32.889

4074
LEU501
CG
58.354
73.464
33.183

4075
LEU501
CO1
58.7
74.809
33.807

4076
LEU501
CD2
57.506
73.644
31.93

4077
LEU501
C
60.586
70.457
32.293

4078
LEU501
O
61.601
71.081
31.954

4079
ASP502
N
60.513
69.137
32.243

4080
ASP502
CA
61.749
68.338
32.274

4081
ASP502
CB
61.42
66.89
32.626

4082
ASP502
CG
60.866
66.765
34.044

4083
ASP502
OD1
61.01
67.71
34.811

4084
ASP502
OD2
60.208
65.767
34.301

4085
ASP502
C
62.507
68.356
30.953

4086
ASP502
O
63.729
68.541
30.966

4087
GLY503
N
61.778
68.477
29.856

4088
GLY503
CA
62.409
68.487
28.532

4089
GLY503
C
62.806
69.873
28.037

4090
GLY503
O
63.112
70.041
26.853

4091
VAL504
N
62.773
70.853
28.925

4092
VAL504
CA
63.266
72.183
28.588

4093
VAL504
CB
62.384
73.202
29.299

4094
VAL504
CG1
62.736
74.624
28.889

4095
VAL504
CG2
60.913
72.933
29.014

4096
VAL504
C
64.716
72.303
29.055

4097
VAL504
O
65.472
73.164
28.588

4098
THR505
N
65.119
71.341
29.868

4099
THR505
CA
66.477
71.301
30.412

4100
THR505
CB
66.507
70.206
31.477

4101
THR505
OG1
65.481
70.494
32.418

4102
THR505
CG2
67.827
70.125
32.238

4103
THR505
C
67.487
71.029
29.296

4104
THR505
O
67.307
70.116
28.481

4105
ASN506
N
68.575
71.782
29.345

4106
ASN506
CA
69.638
71.783
28.332

4107
ASN506
CB
70.383
70.451
28.36

4108
ASN506
CG
70.893
70.14
29.767

4109
ASN506
OD1
71.343
71.022
30.507

4110
ASN506
ND2
70.741
68.884
30.143

4111
ASN506
C
69.112
72.058
26.927

4112
ASN506
O
69.24
71.221
26.025

4113
LEU507
N
68.481
73.209
26.761

4114
LEU507
CA
68.08
73.652
25.42

4115
LEU507
CB
66.586
73.948
25.365

4116
LEU507
CG
65.771
72.667
25.226

4117
LEU507
OD1
64.283
72.984
25.124

4118
LEU507
CD2
66.222
71.883
23.998

4119
LEU507
C
68.878
74.882
25.017

4120
LEU507
O
68.574
76.005
25.44

4121
PRO508
N
69.789
74.669
24.08

4122
PRO508
CA
70.867
75.63
23.829

4123
PRO508
CB
71.738
74.992
22.792

4124
PRO508
CG
71.19
73.616
22.457

4125
PRO508
CD
69.977
73.414
23.349

4126
PRO508
C
70.347
76.976
23.349

4127
PRO508
O
70.467
77.97
24.076

4128
ARG509
N
69.544
76.932
22.299

4129
ARG509
CA
69.041
78.155
21.673

4130
ARG509
CB
68.834
77.895
20.185

4131
ARG509
CG
70.126
77.504
19.475

4132
ARG509
CD
71.213
78.563
19.64

4133
ARG509
NE
70.76
79.888
19.189

4134
ARG509
CZ
71.43
80.621
18.299

4135
ARG509
NH1
72.545
80.142
17.745

4136
ARG509
NH2
70.974
81.825
17.95

4137
ARG509
C
67.734
78.682
22.262

4138
ARG509
O
67.181
79.628
21.692

4139
LEU510
N
67.259
78.127
23.367

4140
LEU510
CA
65.961
78.558
23.9

4141
LEU510
CB
65.427
77.508
24.863

4142
LEU510
CG
64.004
77.848
25.288

4143
LEU510
CD1
63.077
77.883
24.081

4144
LEU510
CD2
63.489
76.855
26.317

4145
LEU510
C
66.092
79.89
24.619

4146
LEU510
O
66.653
79.959
25.717

4147
GLN511
N
65.528
80.919
24.009

4148
GLN511
CA
65.633
82.285
24.512

4149
GLN511
CB
65.863
83.187
23.306

4150
GLN511
CG
66.983
82.638
22.434

4151
GLN511
CD
67.133
83.451
21.156

4152
GLN511
OE1
66.602
83.086
20.099

4153
GLN511
NE2
67.869
84.543
21.27

4154
GLN511
C
64.35
82.718
25.197

4155
GLN511
O
64.379
83.493
26.166

4156
GLU512
N
63.24
82.213
24.684

4157
GLU512
CA
61.92
82.567
25.219

4158
GLU512
CB
61.133
83.302
24.139

4159
GLU512
CG
61.832
84.579
23.687

4160
GLU512
CD
60.978
85.298
22.648

4161
GLU512
OE1
59.764
85.178
22.73

4162
GLU512
OE2
61.557
85.927
21.773

4163
GLU512
C
61.124
81.339
25.647

4164
GLU512
O
60.82
80.459
24.828

4165
LEU513
N
60.78
81.309
26.922

4166
LEU513
CA
59.912
80.259
27.46

4167
LEU513
CB
60.653
79.566
28.597

4168
LEU513
CG
59.894
78.356
29.126

4169
LEU513
CD1
59.528
77.399
28

4170
LEU513
CD2
60.704
77.635
30.195

4171
LEU513
C
58.598
80.873
27.952

4172
LEU513
O
58.562
81.621
28.942

4173
LEU514
N
57.536
80.58
27.22

4174
LEU514
CA
56.215
81.147
27.51

4175
LEU514
CB
55.621
81.625
26.192

4176
LEU514
CG
56.521
82.643
25.5

4177
LEU514
CD1
56.082
82.886
24.061

4178
LEU514
CD2
56.58
83.952
26.279

4179
LEU514
C
55.291
80.109
28.145

4180
LEU514
O
54.83
79.171
27.482

4181
LEU515
N
55.004
80.318
29.418

4182
LEU515
CA
54.173
79.41
30.216

4183
LEU515
CB
55.067
78.629
31.174

4184
LEU515
CG
56.082
77.739
30.469

4185
LEU515
CD1
57.131
77.248
31.456

4186
LEU515
CD2
55.401
76.57
29.772

4187
LEU515
C
53.178
80.19
31.073

4188
LEU515
O
53.331
80.243
32.3

4189
CYS516
N
52.222
80.833
30.427

4190
CYS516
CA
51.149
81.531
31.139

4191
CYS516
CB
50.745
82.777
30.368

4192
CYS516
SG
51.989
84.078
30.291

4193
CYS516
C
49.938
80.626
31.271

4194
CYS516
O
49.491
80.04
30.277

4195
ASN517
N
49.37
80.603
32.462

4196
ASN517
CA
48.242
79.724
32.794

4197
ASN517
CB
47.002
80.136
32.012

4198
ASN517
CG
46.592
81.54
32.448

4199
ASN517
OD1
46.73
82.51
31.693

4200
ASN517
ND2
46.151
81.643
33.691

4201
ASN517
C
48.611
78.266
32.55

4202
ASN517
O
48.154
77.607
31.603

4203
ASN518
N
49.586
77.85
33.333

4204
ASN518
CA
50.064
76.47
33.374

4205
ASN518
CB
51.481
76.403
32.809

4206
ASN518
CG
51.508
76.636
31.298

4207
ASN518
OD1
51.33
77.758
30.805

4208
ASN518
ND2
51.838
75.577
30.584

4209
ASN518
C
50.051
76.009
34.828

4210
ASN518
O
50.002
76.838
35.745

4211
ARG519
N
50.239
74.72
35.048

4212
ARG519
CA
50.128
74.163
36.408

4213
ARG519
CB
49.533
72.764
36.339

4214
ARG519
CG
48.092
72.818
35.85

4215
ARG519
CD
47.424
71.453
35.94

4216
ARG519
NE
46.05
71.52
35.421

4217
ARG519
CZ
45.238
70.462
35.365

4218
ARG519
NH1
45.655
69.278
35.819

4219
ARG519
NH2
44.005
70.592
34.87

4220
ARG519
C
51.435
74.133
37.206

4221
ARG519
O
51.649
73.204
37.995

4222
LEU520
N
52.29
75.124
37.012

4223
LEU520
CA
53.525
75.223
37.805

4224
LEU520
CB
54.526
76.193
37.164

4225
LEU520
CG
55.264
75.657
35.931

4226
LEU520
CO1
55.652
74.197
36.11

4227
LEU520
CD2
54.496
75.833
34.625

4228
LEU520
C
53.167
75.721
39.205

4229
LEU520
O
52.919
76.918
39.402

4230
GLN521
N
53.133
74.803
40.157

4231
GLN521
CA
52.664
75.127
41.508

4232
GLN521
CB
51.992
73.889
42.088

4233
GLN521
CG
51.458
74.162
43.49

4234
GLN521
CD
51.43
72.869
44.296

4235
GLN521
OE1
52.179
71.928
44.002

4236
GLN521
NE2
50.653
72.88
45.364

4237
GLN521
C
53.789
75.528
42.451

4238
GLN521
O
53.612
76.421
43.286

4239
GLN522
N
54.937
74.891
42.302

4240
GLN522
CA
56.071
75.184
43.184

4241
GLN522
CB
56.408
73.917
43.964

4242
GLN522
CG
55.252
73.516
44.873

4243
GLN522
CD
55.566
72.209
45.588

4244
GLN522
QE1
56.605
72.077
46.244

4245
GLN522
NE2
54.658
71.258
45.452

4246
GLN522
C
57.284
75.65
42.388

4247
GLN522
O
57.639
75.035
41.375

4248
PRO523
N
57.988
76.636
42.926

4249
PRO523
CA
59.095
77.289
42.204

4250
PRO523
CB
59.418
78.507
43.017

4251
PRO523
CG
58.592
78.503
44.293

4252
PRO523
CD
57.696
77.28
44.212

4253
PRO523
C
60.354
76.43
42.01

4254
PRO523
O
61.154
76.728
41.114

4255
ALA524
N
60.403
75.265
42.641

4256
ALA524
CA
61.561
74.374
42.512

4257
ALA524
CB
61.536
73.384
43.671

4258
ALA524
C
61.59
73.608
41.186

4259
ALA524
O
62.675
73.203
40.752

4260
VAL525
N
60.492
73.637
40.441

4261
VAL525
CA
60.462
72.988
39.123

4262
VAL525
CB
59.019
72.595
38.8

4263
VAL525
CG1
58.13
73.818
38.611

4264
VAL525
CG2
58.932
71.688
37.574

4265
VAL525
C
61.048
73.907
38.041

4266
VAL525
O
61.329
73.46
36.923

4267
LEU526
N
61.37
75.136
38.419

4268
LEU526
CA
62.025
76.054
37.492

4269
LEU526
CB
61.62
77.481
37.817

4270
LEU526
CG
60.111
77.685
37.785

4271
LEU526
CD1
59.794
79.115
38.174

4272
LEU526
CD2
59.519
77.381
36.413

4273
LEU526
C
63.539
75.946
37.611

4274
LEU526
O
64.263
76.413
36.723

4275
GLN527
N
64.01
75.219
38.611

4276
GLN527
CA
65.456
75.042
38.776

4277
GLN527
CB
65.743
74.292
40.07

4278
GLN527
CG
67.21
74.447
40.453

4279
GLN527
CD
67.511
75.927
40.674

4280
GLN527
QE1
66.909
76.559
41.55

4281
GLN527
NE2
68.394
76.469
39.851

4282
GLN527
C
66.178
74.348
37.594

4283
GLN527
O
67.216
74.898
37.198

4284
PRO528
N
65.669
73.289
36.954

4285
PRO528
CA
66.335
72.801
35.732

4286
PRO528
CB
65.693
71.483
35.426

4287
PRO528
CG
64.492
71.279
36.327

4288
PRO528
CD
64.489
72.462
37.274

4289
PRO528
C
66.252
73.717
34.499

4290
PRO528
O
66.911
73.417
33.497

4291
LEU529
N
65.597
74.867
34.591

4292
LEU529
CA
65.547
75.81
33.468

4293
LEU529
CB
64.289
76.664
33.556

4294
LEU529
CG
63.017
75.834
33.646

4295
LEU529
CD1
61.809
76.753
33.732

4296
LEU529
CD2
62.873
74.884
32.466

4297
LEU529
C
66.764
76.736
33.458

4298
LEU529
O
67.027
77.39
32.441

4299
ALA530
N
67.604
76.629
34.48

4300
ALA530
CA
68.863
77.389
34.53

4301
ALA530
CB
69.378
77.398
35.964

4302
ALA530
C
69.94
76.796
33.615

4303
ALA530
O
71.003
77.394
33.42

4304
SER531
N
69.634
75.65
33.026

4305
SER531
CA
70.508
75.019
32.037

4306
SER531
CB
70.387
73.514
32.183

4307
SER531
OG
69.087
73.16
31.741

4308
SER531
C
70.136
75.409
30.603

4309
SER531
O
70.537
74.707
29.668

4310
CYS532
N
69.224
76.354
30.437

4311
CYS532
CA
68.935
76.873
29.096

4312
CYS532
CB
67.465
77.265
29.015

4313
CYS532
5G
66.289
75.98
29.486

4314
CYS532
C
69.791
78.111
28.841

4315
CYS532
O
69.453
79.207
29.302

4316
PRO533
N
70.832
77.951
28.037

4317
PRO533
CA
71.903
78.957
27.976

4318
PRO533
CB
73.04
78.269
27.283

4319
PRO533
CG
72.592
76.897
26.815

4320
PRO533
CD
71.167
76.727
27.307

4321
PRO533
C
71.533
80.243
27.232

4322
PRO533
O
72.247
81.244
27.354

4323
ARG534
N
70.419
80.241
26.519

4324
ARG534
CA
69.964
81.447
25.829

4325
ARG534
CB
69.591
81.054
24.409

4326
ARG534
CG
70.392
81.812
23.359

4327
ARG534
CD
71.884
81.554
23.509

4328
ARG534
NE
72.624
82.107
22.367

4329
ARG534
CZ
73.463
81.361
21.649

4330
ARG534
NH1
73.661
80.085
21.984

4331
ARG534
NH2
74.113
81.891
20.612

4332
ARG534
C
68.745
82.076
26.504

4333
ARG534
O
68.219
83.068
25.981

4334
LEU535
N
68.321
81.533
27.638

4335
LEU535
CA
67.025
81.908
28.222

4336
LEU535
CB
66.612
80.841
29.228

4337
LEU535
CG
65.157
81.004
29.655

4338
LEU535
CD1
64.234
80.871
28.45

4339
LEU535
CD2
64.784
79.983
30.724

4340
LEU535
C
67.054
83.266
28.908

4341
LEU535
O
67.527
83.415
30.041

4342
VAL536
N
66.46
84.232
28.232

4343
VAL536
CA
66.372
85.583
28.77

4344
VAL536
CB
66.791
86.567
27.681

4345
VAL536
CG1
66.667
88.01
28.154

4346
VAL536
CG2
68.212
86.283
27.206

4347
VAL536
C
64.946
85.87
29.211

4348
VAL536
O
64.742
86.556
30.221

4349
LEU537
N
63.993
85.238
28.544

4350
LEU537
CA
62.574
85.456
28.847

4351
LEU537
CB
61.856
85.784
27.538

4352
LEU537
CG
60.352
85.99
27.721

4353
LEU537
CD1
60.056
87.149
28.666

4354
LEU537
CD2
59.668
86.221
26.379

4355
LEU537
C
61.93
84.23
29.488

4356
LEU537
O
61.848
83.156
28.876

4357
LEU538
N
61.451
84.422
30.705

4358
LEU538
CA
60.688
83.39
31.411

4359
LEU538
CB
61.486
82.946
32.629

4360
LEU538
CG
60.822
81.78
33.345

4361
LEU538
CD1
60.629
80.599
32.402

4362
LEU538
CD2
61.635
81.365
34.564

4363
LEU538
C
59.342
83.972
31.84

4364
LEU538
O
59.24
84.672
32.855

4365
ASN539
N
58.323
83.69
31.052

4366
ASN539
CA
57.001
84.285
31.278

4367
ASN539
CB
56.517
84.749
29.911

4368
ASN539
CG
55.225
85.551
29.979

4369
ASN539
OD1
54.413
85.485
29.05

4370
ASN539
ND2
55.071
86.332
31.035

4371
ASN539
C
56.046
83.26
31.897

4372
ASN539
O
55.503
82.403
31.196

4373
LEU540
N
55.793
83.418
33.187

4374
LEU540
CA
55.042
82.429
33.977

4375
LEU540
CB
55.913
82.009
35.153

4376
LEU540
OG
57.216
81.363
34.713

4377
LEU540
CD1
58.154
81.221
35.902

4378
LEU540
CD2
56.968
80.014
34.049

4379
LEU540
C
53.742
82.969
34.569

4380
LEU540
O
53.3
82.479
35.615

4381
GLN541
N
53.186
84.012
33.984

4382
GLN541
CA
52.046
84.681
34.62

4383
GLN541
CB
51.853
86.02
33.929

4384
GLN541
CG
53.138
86.811
34.118

4385
GLN541
CD
53.093
88.175
33.452

4386
GLN541
OE1
53.123
88.278
32.22

4387
GLN541
NE2
53.214
89.196
34.28

4388
GLN541
C
50.767
83.845
34.611

4389
GLN541
O
50.437
83.164
33.637

4390
GLY542
N
50.137
83.801
35.773

4391
GLY542
CA
48.872
83.077
35.93

4392
GLY542
C
49.081
81.672
36.486

4393
GLY542
O
48.182
80.827
36.396

4394
ASN543
N
50.275
81.42
36.998

4395
ASN543
CA
50.601
80.101
37.551

4396
ASN543
CB
51.981
79.679
37.047

4397
ASN543
CG
52.046
79.574
35.524

4398
ASN543
OD1
51.046
79.726
34.816

4399
ASN543
ND2
53.233
79.281
35.033

4400
ASN543
C
50.608
80.154
39.078

4401
ASN543
O
50.941
81.192
39.664

4402
PRO544
N
50.294
79.035
39.716

4403
PRO544
CA
50.159
79.004
41.185

4404
PRO544
CB
49.641
77.633
41 .497

4405
PRO544
CG
49.501
76.832
40.21

4406
PRO544
CD
49.912
77.766
39.086

4407
PRO544
C
51.453
79.281
41.97

4408
PRO544
O
51.377
79.897
43.04

4409
LEU545
N
52.605
79.097
41.341

4410
LEU545
CA
53.893
79.392
41.991

4411
LEU545
CB
55.009
78.586
41.313

4412
LEU545
CG
55.737
79.221
40.122

4413
LEU545
CD1
56.836
78.281
39.66

4414
LEU545
CD2
54.853
79.549
38.925

4415
LEU545
C
54.247
80.885
42.028

4416
LEU545
O
55.162
81.275
42.764

4417
GYS546
N
53.418
81.72
41.417

4418
GYS546
CA
53.631
83.167
41.456

4419
GYS546
CB
52.957
83.782
40.239

4420
GYS546
SG
53.492
83.109
38.652

4421
GYS546
C
53.032
83.768
42.723

4422
GYS546
O
53.393
84.884
43.113

4423
GLN547
N
52.306
82.94
43.461

4424
GLN547
CA
51.681
83.352
44.719

4425
GLN547
CB
50.408
82.533
44.926

4426
GLN547
CG
49.503
82.52
43.694

4427
GLN547
CD
49.084
83.929
43.276

4428
GLN547
QE1
49.358
84.352
42.147

4429
GLN547
NE2
48.407
84.623
44.175

4430
GLN547
C
52.599
83.171
45.935

4431
GLN547
O
52.102
83.137
47.068

4432
ALA548
N
53.891
82.981
45.702

4433
ALA548
CA
54.871
82.835
46.787

4434
ALA548
CB
56.191
82.349
46.201

4435
ALA548
C
55.096
84.144
47.545

4436
ALA548
O
54.192
84.98
47.664

4437
VAL549
N
56.285
84.299
48.101

4438
VAL549
CA
56.552
85.483
48.924

4439
VAL549
CB
57.62
85.132
49.959

4440
VAL549
CG1
57.695
86.193
51.056

4441
VAL549
CG2
57.324
83.774
50.585

4442
VAL549
C
57.021
86.625
48.026

4443
VAL549
O
56.219
87.441
47.553

4444
GLYS50
N
58.295
86.588
47.688

4445
GLYS50
CA
58.874
87.57
46.777

4446
GLYS50
C
59.369
86.779
45.584

4447
GLYS50
O
60.574
86.724
45.3

4448
1LEA551
N
58.414
86.324
44.79

4449
1LEA551
CA
58.697
85.317
43.762

4450
1LEA551
OB
57.356
84.768
43.272

4451
1LEA551
CG2
56.499
85.845
42.614

4452
1LEA551
CG1
57.548
83.584
42.336

4453
1LEA551
CD1
58.227
82.428
43.062

4454
1LEA551
C
59.561
85.84
42.607

4455
1LEA551
O
60.407
85.077
42.124

4456
LEU552
N
59.624
87.152
42.437

4457
LEU552
CA
60.486
87.731
41.407

4458
LEU552
CB
60.132
89.204
41.253

4459
LEU552
CG
58.727
89.386
40.693

4460
LEU552
CD1
58.28
90.839
40.788

4461
LEU552
CD2
58.645
88.888
39.256

4462
LEU552
C
61.956
87.596
41.787

4463
LEU552
O
62.713
86.961
41.042

4464
GLU553
N
62.293
87.92
43.027

4465
GLU553
CA
63.704
87.837
43.416

4466
GLU553
CB
64.09
88.895
44.461

4467
GLU553
CG
63.89
88.51
45.931

4468
GLU553
CD
62.455
88.723
46.401

4469
GLU553
OE1
61.698
89.338
45.658

4470
GLU553
OE2
62.11
88.175
47.438

4471
GLU553
C
64.075
86.434
43.886

4472
GLU553
O
65.247
86.066
43.762

4473
GLN554
N
63.092
85.594
44.17

4474
GLN554
CA
63.409
84.214
44.527

4475
GLN554
CB
62.222
83.59
45.254

4476
GLN554
CG
61.966
84.309
46.577

4477
GLN554
CD
60.8
83.682
47.341

4478
GLN554
OE1
59.625
84.018
47.13

4479
GLN554
NE2
61.148
82.835
48.292

4480
GLN554
C
63.754
83.426
43.27

4481
GLN554
O
64.827
82.809
43.218

4482
LEU555
N
63.059
83.73
42.186

4483
LEU555
CA
63.372
83.068
40.919

4484
LEU555
CB
62.16
83.111
40.004

4485
LEU555
CG
61 .027
82.277
40.578

4486
LEU555
CD1
59.804
82.344
39.673

4487
LEU555
CD2
61.471
80.833
40.789

4488
LEU555
C
64.566
83.701
40.223

4489
LEU555
O
65.324
82.973
39.577

4490
ALA556
N
64.891
84.935
40.568

4491
ALA556
CA
66.113
85.545
40.034

4492
ALA556
CB
66.033
87.056
40.227

4493
ALA556
C
67.367
85.009
40.727

4494
ALA556
O
68.398
84.832
40.067

4495
GLU557
N
67.206
84.527
41.951

4496
GLU557
CA
68.324
83.922
42.682

4497
GLU557
CB
68.039
84.044
44.174

4498
GLU557
CG
68.06
85.499
44.622

4499
GLU557
CD
67.376
85.643
45.978

4500
GLU557
OE1
66.545
84.801
46.292

4501
GLU557
OE2
67.612
86.652
46.628

4502
GLU557
C
68.512
82.45
42.327

4503
GLU557
O
69.584
81.888
42.577

4504
LEU558
N
67.506
81.849
41.713

4505
LEU558
CA
67.639
80.461
41.267

4506
LEU558
CB
66.294
79.765
41.445

4507
LEU558
CG
65.833
79.752
42.898

4508
LEU558
CD1
64.424
79.181
43.009

4509
LEU558
CD2
66.803
78.979
43.786

4510
LEU558
C
68.026
80.392
39.796

4511
LEU558
O
68.67
79.428
39.357

4512
LEU559
N
67.62
81.404
39.046

4513
LEU559
CA
67.883
81.457
37.601

4514
LEU559
CB
66.537
81.352
36.881

4515
LEU559
CG
65.673
80.196
37.381

4516
LEU559
CD1
64.234
80.329
36.9

4517
LEU559
CD2
66.249
78.843
36.99

4518
LEU559
C
68.505
82.796
37.192

4519
LEU559
O
67.874
83.526
36.417

4520
PRO560
N
69.796
82.973
37.449

4521
PRO560
CA
70.418
84.31
37.391

4522
PRO560
CB
71.682
84.176
38.183

4523
PRO560
CG
71.94
82.708
38.477

4524
PRO560
CD
70.727
81.957
37.96

4525
PRO560
C
70.742
84.829
35.98

4526
PRO560
O
71 .278
85.933
35.844

4527
SER561
N
70.454
84.047
34.951

4528
SER561
CA
70.725
84.481
33.58

4529
SER561
CB
71.287
83.3
32.803

4530
SER561
OG
72.471
82.879
33.466

4531
SER561
C
69.459
84.993
32.898

4532
SER561
O
69.534
85.686
31.875

4533
VAL562
N
68.317
84.708
33.504

4534
VAL562
CA
67.046
85.165
32.947

4535
VAL562
CB
65.933
84.265
33.467

4536
VAL562
CG1
64.601
84.631
32.828

4537
VAL562
CG2
66.256
82.8
33.2

4538
VAL562
C
66.817
86.608
33.373

4539
VAL562
O
66.612
86.906
34.556

4540
SER563
N
66.813
87.493
32.392

4541
SER563
CA
66.731
88.924
32.682

4542
SER563
CB
67.49
89.663
31.589

4543
SER563
OG
68.805
89.121
31.552

4544
SER563
C
65.286
89.405
32.732

4545
SER563
O
64.981
90.429
33.354

4546
SER564
N
64.397
88.61
32.167

4547
SER564
CA
62.974
88.925
32.211

4548
SER564
CB
62.488
89.148
30.786

4549
SER564
OG
61.107
89.467
30.852

4550
SER564
C
62.192
87.79
32.857

4551
SER564
O
61.62
86.937
32.162

4552
VAL565
N
62.215
87.762
34.179

4553
VAL565
CA
61.421
86.784
34.934

4554
VAL565
CB
62.125
86.463
36.251

4555
VAL565
CG1
61.412
85.333
36.987

4556
VAL565
CG2
63.586
86.092
36.026

4557
VAL565
C
60.043
87.376
35.222

4558
VAL565
O
59.812
87.998
36.266

4559
LEU566
N
59.122
87.141
34.308

4560
LEU566
CA
57.798
87.75
34.408

4561
LEU566
CB
57.323
88.157
33.021

4562
LEU566
CG
58.212
89.226
32.401

4563
LEU566
CD1
57.768
89.527
30.975

4564
LEU566
CD2
58.213
90.498
33.244

4565
LEU566
C
56.795
86.785
35.014

4566
LEU566
O
56.117
86.039
34.295

4567
THR567
N
56.687
86.837
36.329

4568
THR567
CA
55.709
86.012
37.045

4569
THR567
CB
56.393
85.328
38.222

4570
THR567
OG1
56.733
86.313
39.186

4571
THR567
CG2
57.661
84.604
37.791

4572
THR567
C
54.561
86.88
37.553

4573
THR567
O
53.882
86.441
38.47

4574
THR567
OXT
54.277
87.875
36.901

[0440]

15

TABLE 12

Residue/

Atom
Residue
Atom
X
Y
Z

No.
Position
Type
Coord.
Coord.
Coord.

1
MET1
N
25.639
32.902
36.49

2
MET1
CA
26.981
32.307
36.329

3
MET1
CB
27.631
32.812
35.043

4
MET1
CG
27.797
34.332
35.059

5
MET1
SD
28.559
35.081
33.602

6
MET1
CE
27.379
34.546
32.344

7
MET1
C
27.872
32.687
37.507

8
MET1
O
29.046
32.298
37.586

9
GLY2
N
27.289
33.443
38.422

10
GLY2
CA
28.052
34.024
39.53

11
GLY2
C
28.827
35.244
39.024

12
GLY2
O
28.333
36.377
39.024

13
THR3
N
30.035
34.979
38.567

14
THR3
CA
30.902
35.999
37.96

15
THR3
CB
31.984
36.436
38.95

16
THR3
OG1
32.457
35.292
39.638

17
THR3
CG2
31.428
37.396
39.999

18
THR3
C
31.522
35.604
36.595

19
THR3
O
31.389
36.424
35.673

20
PRO4
N
32.202
34.465
36.43

21
PRO4
CA
32.942
34.247
35.182

22
PRO4
CB
33.867
33.101
35.448

23
PRO4
CG
33.544
32.483
36.794

24
PRO4
CD
32.439
33.345
37.367

25
PRO4
C
32.047
33.916
33.997

26
PRO4
O
31.125
33.099
34.091

27
GLN5
N
32.347
34.573
32.891

28
GLN5
CA
31.735
34.265
31.6

29
GLN5
CB
31.439
35.59
30.908

30
GLN5
CG
30.341
35.538
29.846

31
GLN5
CD
30.807
36.449
28.72

32
GLN5
OE1
32.01
36.478
28.417

33
GLN5
NE2
29.886
37.203
28.15

34
GLN5
C
32.772
33.455
30.818

35
GLN5
O
33.19
32.381
31.264

36
LYS6
N
33.151
33.954
29.655

37
LYS6
CA
34.263
33.396
28.891

38
LYS6
CB
33.766
32.99
27.509

39
LYS6
CG
32.679
31.926
27.595

40
LYS6
CD
32.192
31.506
26.214

41
LYS6
CE
31.128
30.416
26.314

42
LYS6
NZ
30.67
30.005
24.975

43
LYS6
C
35.314
34.484
28.772

44
LYS6
O
36.507
34.266
29.012

45
ASP7
N
34.817
35.691
28.567

46
ASP7
CA
35.672
36.867
28.512

47
ASP7
CB
35.499
37.527
27.149

48
ASP7
CG
36.269
38.843
27.06

49
ASP7
OD1
37.47
38.802
26.825

50
ASP7
OD2
35.622
39.878
27.147

51
ASP7
C
35.315
37.833
29.633

52
ASP7
O
36.055
37.941
30.614

53
VAL8
N
34.128
38.409
29.58

54
VAL8
CA
33.82
39.486
30.528

55
VAL8
CB
33.198
40.657
29.767

56
VAL8
CG1
32.082
40.208
28.833

57
VAL8
CG2
32.73
41.768
30.701

58
VAL8
C
32.943
39.027
31.689

59
VAL8
O
31.8
38.589
31.516

60
ILE9
N
33.55
39.055
32.863

61
ILE9
CA
32.847
38.788
34.123

62
ILE9
CB
33.9
38.825
35.231

63
ILE9
CG2
33.334
39.118
36.619

64
ILE9
CG1
34.691
37.53
35.248

65
ILE9
CD1
35.65
37.525
36.426

66
ILE9
C
31.754
39.821
34.383

67
ILE9
O
31.93
41.012
34.101

68
ILE10
N
30.595
39.347
34.81

69
ILE10
CA
29.527
40.263
35.21

70
ILE10
CB
28.201
39.512
35.158

71
ILE10
CG2
27.057
40.376
35.676

72
ILE10
CG1
27.914
39.042
33.738

73
ILE10
CD1
26.564
38.342
33.659

74
ILE10
C
29.798
40.793
36.619

75
ILE10
O
29.82
40.033
37.596

76
LYS11
N
30.081
42.083
36.701

77
LYS11
CA
30.324
42.717
38.001

78
LYS11
CB
30.964
44.083
37.781

79
LYS11
CG
31.214
44.785
39.113

80
LYS11
CD
31.653
46.231
38.918

81
LYS11
CE
31.783
46.946
40.258

82
LYS11
NZ
32.095
48.37
40.067

83
LYS11
C
29.023
42.892
38.782

84
LYS11
O
28.163
43.708
38.433

85
SER12
N
28.886
42.09
39.823

86
SER12
CA
27.739
42.194
40.727

87
SER12
CB
27.424
40.805
41.266

88
SER12
OG
27.184
39.959
40.148

89
SER12
C
28.059
43.148
41.874

90
SER12
O
29.087
43.836
41.853

91
ASP13
N
27.158
43.225
42.841

92
ASP13
CA
27.386
44.063
44.033

93
ASP13
CB
26.047
44.467
44.658

94
ASP13
CG
25.103
43.279
44.868

95
ASP13
OD1
24.338
42.997
43.956

96
ASP13
OD2
25.103
42.732
45.961

97
ASP13
C
28.3
43.365
45.048

98
ASP13
O
27.861
42.738
46.017

99
ALA14
N
29.588
43.499
44.795

100
ALA14
CA
30.628
42.871
45.611

101
ALA14
CB
31.578
42.199
44.623

102
ALA14
C
31.33
43.935
46.463

103
ALA14
O
30.992
45.117
46.327

104
PRO15
N
32.204
43.534
47.382

105
PRO15
CA
32.877
44.504
48.259

106
PRO15
CB
33.846
43.709
49.078

107
PRO15
CG
33.671
42.234
48.764

108
PRO15
CD
32.579
42.152
47.712

109
PRO15
C
33.585
45.613
47.486

110
PRO15
O
34.004
45.445
46.334

111
ASP16
N
33.502
46.806
48.045

112
ASP16
CA
34.174
47.965
47.447

113
ASP16
CB
33.155
48.889
46.77

114
ASP16
CG
31.992
49.3
47.678

115
ASP16
OD1
30.888
49.394
47.163

116
ASP16
OD2
32.21
49.499
48.867

117
ASP16
C
35.017
48.712
48.477

118
ASP16
O
35.681
49.707
48.166

119
THR17
N
34.967
48.235
49.705

120
THR17
CA
35.724
48.867
50.782

121
THR17
CB
34.769
49.09
51.948

122
THR17
OG1
33.657
49.824
51.451

123
THR17
CG2
35.409
49.887
53.08

124
THR17
C
36.867
47.951
51.187

125
THR17
O
36.627
46.785
51.507

126
LEU18
N
38.082
48.474
51.107

127
LEU18
CA
39.308
47.718
51.418

128
LEU18
CB
40.471
48.709
51.364

129
LEU18
CG
41.82
48.074
51.697

130
LEU18
CD1
42.217
47.033
50.659

131
LEU18
CD2
42.904
49.139
51.812

132
LEU18
C
39.263
47.064
52.8

133
LEU18
O
39.369
47.739
53.833

134
LEU19
N
39.174
45.743
52.803

135
LEU19
CA
39.182
44.964
54.049

136
LEU19
CB
38.427
43.665
53.793

137
LEU19
CG
37.009
43.921
53.3

138
LEU19
CD1
36.368
42.634
52.8

139
LEU19
CD2
36.151
44.583
54.373

140
LEU19
C
40.605
44.622
54.476

141
LEU19
O
40.918
43.444
54.689

142
LEU20
N
41.37
45.643
54.827

143
LEU20
CA
42.814
45.489
55.054

144
LEU20
CB
43.401
46.886
55.227

145
LEU20
CG
44.913
46.889
55.046

146
LEU20
CD1
45.263
46.478
53.621

147
LEU20
CD2
45.497
48.263
55.354

148
LEU20
C
43.14
44.648
56.289

149
LEU20
O
44.006
43.765
56.215

150
GLU21
N
42.277
44.717
57.291

151
GLU21
CA
42.482
43.909
58.495

152
GLU21
CB
41.594
44.441
59.612

153
GLU21
CG
41.766
43.635
60.897

154
GLU21
CD
40.796
44.15
61.954

155
GLU21
OE1
40.278
45.239
61.746

156
GLU21
OE2
40.515
43.417
62.891

157
GLU21
C
42.135
42.448
58.242

158
GLU21
O
42.942
41.581
58.595

159
LYS22
N
41.187
42.211
57.351

160
LYS22
CA
40.761
40.843
57.074

161
LYS22
CB
39.388
40.881
56.418

162
LYS22
CG
38.319
41.477
57.323

163
LYS22
CD
36.963
41.438
56.628

164
LYS22
CE
35.864
42.038
57.495

165
LYS22
NZ
34.572
42.015
56.79

166
LYS22
C
41.738
40.149
56.135

167
LYS22
O
41.974
38.943
56.286

168
HIS23
N
42.452
40.925
55.336

169
HIS23
CA
43.46
40.338
54.452

170
HIS23
CB
43.885
41.35
53.393

171
HIS23
CG
42.774
41.931
52.537

172
HIS23
ND1
41.683
41.303
52.059

173
HIS23
CE1
40.942
42.171
51.35

174
HIS23
NE2
41.58
43.362
51.366

175
HIS23
CD2
42.718
43.226
52.087

176
HIS23
C
44.684
39.943
55.263

177
HIS23
O
45.124
38.79
55.164

178
ALA24
N
45.005
40.754
56.261

179
ALA24
CA
46.152
40.463
57.125

180
ALA24
CB
46.493
41.723
57.905

181
ALA24
C
45.859
39.325
58.095

182
ALA24
O
46.68
38.403
58.22

183
ASP25
N
44.609
39.246
58.528

184
ASP25
CA
44.166
38.149
59.391

185
ASP25
CB
42.719
38.383
59.824

186
ASP25
CG
42.57
39.629
60.696

187
ASP25
OD1
43.493
39.926
61.442

188
ASP25
OD2
41.501
40.226
60.65

189
ASP25
C
44.232
36.824
58.647

190
ASP25
O
44.936
35.918
59.11

191
TYR26
N
43.786
36.827
57.4

192
TYR26
CA
43.784
35.606
56.592

193
TYR26
CB
43.004
35.88
55.308

194
TYR26
CG
43.125
34.783
54.252

195
TYR26
CD1
42.393
33.61
54.377

196
TYR26
CE1
42.521
32.608
53.423

197
TYR26
CZ
43.378
32.786
52.346

198
TYR26
OH
43.577
31.757
51.453

199
TYR26
CE2
44.098
33.964
52.208

200
TYR26
CD2
43.969
34.964
53.162

201
TYR26
C
45.189
35.13
56.236

202
TYR26
O
45.471
33.939
56.398

203
ILE27
N
46.108
36.049
55.988

204
ILE27
CA
47.455
35.628
55.591

205
ILE27
CB
48.165
36.79
54.905

206
ILE27
CG2
49.602
36.408
54.568

207
ILE27
CG1
47.432
37.204
53.636

208
ILE27
CD1
47.451
36.085
52.601

209
ILE27
C
48.282
35.137
56.777

210
ILE27
O
48.914
34.077
56.667

211
ALA28
N
48.064
35.71
57.95

212
ALA28
CA
48.816
35.25
59.123

213
ALA28
CB
48.823
36.354
60.171

214
ALA28
C
48.21
33.976
59.709

215
ALA28
O
48.942
33.08
60.15

216
SER29
N
46.918
33.799
59.487

217
SER29
CA
46.236
32.583
59.93

218
SER29
CB
44.776
32.899
60.225

219
SER29
OG
44.145
33.2
58.988

220
SER29
C
46.284
31.469
58.889

221
SER29
O
45.878
30.347
59.206

222
TYR30
N
46.922
31.697
57.75

223
TYR30
CA
46.937
30.681
56.693

224
TYR30
CB
47.36
31.343
55.386

225
TYR30
CG
47.285
30.42
54.174

226
TYR30
CD1
46.057
30.175
53.572

227
TYR30
CE1
45.98
29.33
52.472

228
TYR30
CZ
47.133
28.734
51.98

229
TYR30
OH
47.06
27.902
50.885

230
TYR30
CE2
48.361
28.977
52.578

231
TYR30
CD2
48.436
29.823
53.678

232
TYR30
C
47.877
29.528
57.031

233
TYR30
O
47.524
28.367
56.788

234
GLY31
N
48.872
29.813
57.856

235
GLY31
CA
49.777
28.765
58.34

236
GLY31
C
49.276
28.164
59.654

237
GLY31
O
49.84
27.189
60.161

238
SER32
N
48.206
28.741
60.176

239
SER32
CA
47.602
28.29
61.426

240
SER32
CB
47.293
29.527
62.261

241
SER32
OG
48.479
30.309
62.323

242
SER32
C
46.309
27.514
61.171

243
SER32
O
45.659
27.072
62.127

244
LYS33
N
45.923
27.397
59.909

245
LYS33
CA
44.703
26.669
59.544

246
LYS33
CB
44.376
26.939
58.078

247
LYS33
CG
43.771
28.319
57.858

248
LYS33
CD
43.464
28.547
56.382

249
LYS33
CE
42.648
29.817
56.167

250
LYS33
NZ
43.346
30.996
56.697

251
LYS33
C
44.854
25.167
59.739

252
LYS33
O
44.734
24.647
60.855

253
LYS34
N
44.978
24.471
58.624

254
LYS34
CA
45.114
23.015
58.66

255
LYS34
CB
44.185
22.392
57.628

256
LYS34
CG
42.726
22.508
58.048

257
LYS34
CD
41.807
21.82
57.046

258
LYS34
CE
42.171
20.348
56.869

259
LYS34
NZ
42.041
19.601
58.131

260
LYS34
C
46.54
22.574
58.383

261
LYS34
O
47.288
23.228
57.651

262
ASP35
N
46.871
21.413
58.923

263
ASP35
CA
48.185
20.803
58.688

264
ASP35
CB
48.464
19.864
59.862

265
ASP35
CG
49.801
19.141
59.705

266
ASP35
OD1
49.784
18.021
59.214

267
ASP35
OD2
50.8
19.695
60.138

268
ASP35
C
48.208
20.019
57.373

269
ASP35
O
49.267
19.817
56.772

270
ASP36
N
47.031
19.689
56.869

271
ASP36
CA
46.935
18.925
55.624

272
ASP36
CB
45.951
17.772
55.812

273
ASP36
CG
46.412
16.824
56.919

274
ASP36
OD1
46.944
15.775
56.587

275
ASP36
OD2
46.1
17.11
58.07

276
ASP36
C
46.454
19.827
54.497

277
ASP36
O
47.258
20.556
53.896

278
TYR37
N
45.136
19.855
54.334

279
TYR37
CA
44.437
20.613
53.276

280
TYR37
CB
44.204
22.028
53.813

281
TYR37
CG
42.966
22.75
53.276

282
TYR37
CD1
41.867
22.018
52.844

283
TYR37
CE1
40.747
22.674
52.35

284
TYR37
CZ
40.731
24.061
52.291

285
TYR37
OH
39.63
24.711
51.778

286
TYR37
CE2
41.826
24.796
52.725

287
TYR37
CD2
42.946
24.138
53.219

288
TYR37
C
45.252
20.626
51.978

289
TYR37
O
45.886
19.627
51.618

290
GLU38
N
45.291
21.767
51.315

291
GLU38
CA
46.163
21.911
50.151

292
GLU38
CB
45.486
22.723
49.04

293
GLU38
CG
44.802
24.021
49.477

294
GLU38
CD
45.791
25.093
49.927

295
GLU38
OE1
46.327
25.787
49.078

296
GLU38
OE2
45.998
25.17
51.132

297
GLU38
C
47.53
22.48
50.53

298
GLU38
O
48.36
22.669
49.64

299
TYR39
N
47.822
22.588
51.817

300
TYR39
CA
49.075
23.206
52.252

301
TYR39
CB
48.932
23.577
53.726

302
TYR39
CG
50.053
24.449
54.287

303
TYR39
CD1
49.914
25.831
54.281

304
TYR39
CE1
50.927
26.634
54.788

305
TYR39
CZ
52.075
26.051
55.305

306
TYR39
OH
53.087
26.847
55.795

307
TYR39
CE2
52.214
24.669
55.321

308
TYR39
CD2
51.2
23.868
54.815

309
TYR39
C
50.216
22.213
52.064

310
TYR39
O
51.216
22.548
51.42

311
CYS40
N
49.895
20.947
52.274

312
CYS40
CA
50.872
19.881
52.031

313
CYS40
CB
50.383
18.629
52.751

314
CYS40
SG
51.432
17.165
52.592

315
CYS40
C
51.036
19.587
50.536

316
CYS40
O
52.134
19.226
50.095

317
MET41
N
50.052
19.992
49.748

318
MET41
CA
50.1
19.771
48.303

319
MET41
CB
48.665
19.663
47.806

320
MET41
CG
47.902
18.589
48.571

321
MET41
SD
46.164
18.402
48.116

322
MET41
CE
46.376
18.033
46.359

323
MET41
C
50.798
20.93
47.598

324
MET41
O
51.459
20.729
46.575

325
SER42
N
50.81
22.078
48.255

326
SER42
CA
51.479
23.272
47.74

327
SER42
CB
50.635
24.494
48.076

328
SER42
OG
49.349
24.311
47.497

329
SER42
C
52.884
23.421
48.317

330
SER42
O
53.572
24.41
48.039

331
GLU43
N
53.375
22.364
48.946

332
GLU43
CA
54.723
22.368
49.52

333
GLU43
CB
54.838
21.152
50.436

334
GLU43
CG
56.117
21.155
51.266

335
GLU43
CD
56.092
22.287
52.293

336
GLU43
OE1
57.164
22.666
52.744

337
GLU43
OE2
55.002
22.604
52.747

338
GLU43
C
55.817
22.318
48.444

339
GLU43
O
56.936
22.767
48.708

340
TYR44
N
55.443
22.024
47.205

341
TYR44
CA
56.393
22.079
46.084

342
TYR44
CB
55.927
21.153
44.957

343
TYR44
CG
54.778
21.667
44.085

344
TYR44
CD1
55.054
22.248
42.852

345
TYR44
CE1
54.018
22.717
42.055

346
TYR44
CZ
52.705
22.594
42.488

347
TYR44
OH
51.679
23.093
41.717

348
TYR44
CE2
52.423
21.999
43.709

349
TYR44
CD2
53.461
21.53
44.504

350
TYR44
C
56.566
23.504
45.543

351
TYR44
O
57.341
23.715
44.603

352
LEU45
N
55.823
24.453
46.09

353
LEU45
CA
56.012
25.861
45.762

354
LEU45
CB
54.913
26.321
44.796

355
LEU45
CG
53.481
26.016
45.245

356
LEU45
CD1
52.931
27.067
46.208

357
LEU45
CD2
52.562
25.948
44.032

358
LEU45
C
56.047
26.695
47.037

359
LEU45
O
55.905
27.924
46.97

360
ARG46
N
56.44
26.071
48.139

361
ARG46
CA
56.299
26.696
49.46

362
ARG46
CB
56.501
25.607
50.512

363
ARG46
CG
56.421
26.122
51.948

364
ARG46
CD
55.11
26.844
52.248

365
ARG46
NE
53.936
25.991
52.018

366
ARG46
CZ
52.882
26.412
51.316

367
ARG46
NH1
52.9
27.618
50.744

368
ARG46
NH2
51.828
25.615
51.156

369
ARG46
C
57.258
27.862
49.697

370
ARG46
O
56.849
28.838
50.336

371
MET47
N
58.357
27.913
48.965

372
MET47
CA
59.238
29.082
49.052

373
MET47
CB
60.536
28.757
48.322

374
MET47
CG
61.517
29.916
48.426

375
MET47
SD
61.957
30.378
50.115

376
MET47
CE
62.791
28.852
50.601

377
MET47
C
58.601
30.334
48.436

378
MET47
O
58.631
31.402
49.059

379
SER48
N
57.803
30.148
47.396

380
SER48
CA
57.133
31.289
46.774

381
SER48
CB
56.86
30.972
45.311

382
SER48
OG
58.116
30.786
44.673

383
SER48
C
55.83
31.59
47.505

384
SER48
O
55.477
32.762
47.664

385
GLY49
N
55.289
30.572
48.156

386
GLY49
CA
54.122
30.729
49.03

387
GLY49
C
54.44
31.642
50.209

388
GLY49
O
53.755
32.654
50.421

389
ILE50
N
55.581
31.391
50.832

390
ILE50
CA
56.039
32.211
51.955

391
ILE50
CB
57.212
31.491
52.62

392
ILE50
CG2
57.839
32.354
53.706

393
ILE50
CG1
56.775
30.156
53.211

394
ILE50
CD1
55.746
30.343
54.322

395
ILE50
C
56.467
33.607
51.499

396
ILE50
O
56.145
34.583
52.187

397
TYR51
N
56.915
33.728
50.258

398
TYR51
CA
57.238
35.047
49.708

399
TYR51
CB
57.986
34.871
48.389

400
TYR51
CG
58.101
36.166
47.589

401
TYR51
CD1
58.85
37.227
48.082

402
TYR51
CE1
58.928
38.413
47.364

403
TYR51
CZ
58.257
38.532
46.155

404
TYR51
OH
58.276
39.731
45.477

405
TYR51
CE2
57.518
37.47
45.653

406
TYR51
CD2
57.44
36.285
46.373

407
TYR51
C
55.988
35.895
49.472

408
TYR51
O
55.978
37.062
49.884

409
TRP52
N
54.895
35.273
49.054

410
TRP52
CA
53.652
36.023
48.834

411
TRP52
CB
52.609
35.138
48.154

412
TRP52
CG
53.042
34.527
46.837

413
TRP52
CD1
53.845
35.097
45.873

414
TRP52
NE1
54.022
34.197
44.874

415
TRP52
CE2
53.354
33.054
45.124

416
TRP52
CZ2
53.269
31.845
44.45

417
TRP52
CH2
52.477
30.824
44.96

418
TRP52
CZ3
51.777
31.006
46.15

419
TRP52
CE3
51.874
32.206
46.843

420
TRP52
CD2
52.668
33.224
46.339

421
TRP52
C
53.096
36.487
50.17

422
TRP52
O
52.905
37.696
50.362

423
GLY53
N
53.145
35.584
51.138

424
GLY53
CA
52.709
35.871
52.509

425
GLY53
C
53.46
37.048
53.128

426
GLY53
O
52.844
38.072
53.451

427
LEU54
N
54.78
36.988
53.09

428
LEU54
CA
55.6
38.034
53.71

429
LEU54
CB
57.049
37.572
53.706

430
LEU54
CG
57.232
36.334
54.565

431
LEU54
CD1
58.663
35.833
54.479

432
LEU54
CD2
56.854
36.625
56.007

433
LEU54
C
55.536
39.369
52.979

434
LEU54
O
55.445
40.412
53.64

435
THR55
N
55.363
39.342
51.67

436
THR55
CA
55.323
40.601
50.935

437
THR55
CB
55.593
40.341
49.459

438
THR55
OG1
56.87
39.73
49.354

439
THR55
CG2
55.634
41.644
48.67

440
THR55
C
53.982
41.299
51.11

441
THR55
O
53.987
42.498
51.413

442
VAL56
N
52.906
40.539
51.253

443
VAL56
CA
51.608
41.19
51.44

444
VAL56
CB
50.467
40.277
50.972

445
VAL56
CG1
50.403
38.939
51.695

446
VAL56
CG2
49.121
40.977
51.078

447
VAL56
C
51.427
41.652
52.887

448
VAL56
O
50.965
42.784
53.085

449
MET57
N
52.091
40.987
53.822

450
MET57
CA
52.038
41.442
55.212

451
MET57
CB
52.523
40.335
56.139

452
MET57
CG
51.568
39.149
56.13

453
MET57
SD
49.899
39.469
56.745

454
MET57
CE
50.262
39.707
58.497

455
MET57
C
52.899
42.679
55.401

456
MET57
O
52.426
43.65
56.003

457
ASP58
N
53.989
42.772
54.655

458
ASP58
CA
54.839
43.956
54.766

459
ASP58
CB
56.218
43.653
54.202

460
ASP58
CG
57.167
44.759
54.65

461
ASP58
OD1
56.97
45.248
55.753

462
ASP58
OD2
58.092
45.063
53.912

463
ASP58
C
54.246
45.156
54.031

464
ASP58
O
54.287
46.257
54.589

465
LEU59
N
53.452
44.91
53

466
LEU59
CA
52.771
46.009
52.302

467
LEU59
CB
52.25
45.506
50.959

468
LEU59
CG
53.369
45.239
49.96

469
LEU59
CD1
52.825
44.57
48.703

470
LEU59
CD2
54.102
46.526
49.607

471
LEU59
C
51.594
46.553
53.108

472
LEU59
O
51.255
47.736
52.983

473
MET60
N
51.069
45.742
54.012

474
MET60
CA
50.021
46.2
54.925

475
MET60
CB
49.055
45.044
55.153

476
MET60
CG
48.399
44.625
53.843

477
MET60
SD
47.168
43.309
53.965

478
MET60
CE
48.227
41.986
54.584

479
MET60
C
50.572
46.705
56.264

480
MET60
O
49.784
46.979
57.179

481
GLY61
N
51.891
46.703
56.42

482
GLY61
CA
52.545
47.214
57.638

483
GLY61
C
52.737
46.155
58.726

484
GLY61
O
53.5
46.35
59.68

485
GLN62
N
52.182
44.983
58.481

486
GLN62
CA
52.059
43.944
59.499

487
GLN62
CB
50.598
43.525
59.517

488
GLN62
CG
49.755
44.728
59.924

489
GLN62
CD
48.289
44.513
59.582

490
GLN62
OE1
47.583
43.74
60.239

491
GLN62
NE2
47.83
45.26
58.593

492
GLN62
C
52.983
42.762
59.24

493
GLN62
O
52.645
41.609
59.536

494
LEU63
N
54.229
43.079
58.919

495
LEU63
CA
55.242
42.036
58.699

496
LEU63
CB
56.409
42.643
57.928

497
LEU63
CG
57.451
41.593
57.556

498
LEU63
CD1
56.839
40.503
56.683

499
LEU63
CD2
58.651
42.226
56.86

500
LEU63
C
55.748
41.478
60.033

501
LEU63
O
56.136
40.305
60.106

502
HIS64
N
55.418
42.196
61.097

503
HIS64
CA
55.759
41.82
62.472

504
HIS64
CB
55.662
43.082
63.332

505
HIS64
CG
54.331
43.818
63.248

506
HIS64
ND1
54.087
44.973
62.597

507
HIS64
CE1
52.789
45.306
62.751

508
HIS64
NE2
52.211
44.358
63.523

509
HIS64
CD2
53.151
43.443
63.847

510
HIS64
C
54.848
40.729
63.052

511
HIS64
O
55.036
40.327
64.205

512
ARG65
N
53.862
40.283
62.286

513
ARG65
CA
53.015
39.171
62.716

514
ARG65
CB
51.613
39.387
62.159

515
ARG65
CG
50.974
40.658
62.703

516
ARG65
CD
49.588
40.867
62.105

517
ARG65
NE
48.736
39.69
62.339

518
ARG65
CZ
47.448
39.639
61.992

519
ARG65
NH1
46.868
40.699
61.427

520
ARG65
NH2
46.734
38.536
62.23

521
ARG65
C
53.545
37.831
62.207

522
ARG65
O
53.041
36.775
62.606

523
MET66
N
54.553
37.873
61.351

524
MET66
CA
55.078
36.644
60.75

525
MET66
CB
55.528
36.967
59.334

526
MET66
CG
54.366
37.52
58.515

527
MET66
SD
52.934
36.427
58.341

528
MET66
CE
53.706
35.061
57.443

529
MET66
C
56.223
36.029
61.553

530
MET66
O
56.938
36.709
62.301

531
ASN67
N
56.396
34.731
61.363

532
ASN67
CA
57.419
33.95
62.078

533
ASN67
CB
56.968
32.491
62.088

534
ASN67
CG
55.602
32.344
62.76

535
ASN67
OD1
54.558
32.415
62.102

536
ASN67
ND2
55.637
32.042
64.045

537
ASN67
C
58.79
34.037
61.406

538
ASN67
O
59.329
33.013
60.961

539
ARG68
N
59.44
35.178
61.58

540
ARG68
CA
60.693
35.5
60.876

541
ARG68
CB
61.153
36.87
61.353

542
ARG68
CG
62.48
37.255
60.71

543
ARG68
CD
63.122
38.42
61.448

544
ARG68
NE
63.297
38.068
62.867

545
ARG68
CZ
64.426
37.568
63.379

546
ARG68
NH1
64.456
37.166
64.651

547
ARG68
NH2
65.493
37.383
62.598

548
ARG68
C
61.835
34.516
61.117

549
ARG68
O
62.373
33.979
60.143

550
GLU69
N
62.01
34.073
62.353

551
GLU69
CA
63.126
33.17
62.662

552
GLU69
CB
63.289
33.126
64.177

553
GLU69
CG
64.43
32.206
64.599

554
GLU69
CD
64.48
32.111
66.121

555
GLU69
OE1
65.118
32.963
66.721

556
GLU69
OE2
63.754
31.283
66.654

557
GLU69
C
62.904
31.748
62.138

558
GLU69
O
63.856
31.121
61.657

559
GLU70
N
61.649
31.372
61.96

560
GLU70
CA
61.345
30.023
61.485

561
GLU70
CB
59.984
29.637
62.044

562
GLU70
CG
60.063
29.553
63.564

563
GLU70
CD
58.671
29.616
64.179

564
GLU70
OE1
58.02
28.586
64.258

565
GLU70
OE2
58.276
30.718
64.545

566
GLU70
C
61.347
29.991
59.963

567
GLU70
O
61.813
29.012
59.366

568
ILE71
N
61.122
31.154
59.376

569
ILE71
CA
61.21
31.298
57.926

570
ILE71
CB
60.431
32.55
57.542

571
ILE71
CG2
60.629
32.888
56.069

572
ILE71
CG1
58.954
32.362
57.862

573
ILE71
CD1
58.158
33.637
57.617

574
ILE71
C
62.665
31.422
57.49

575
ILE71
O
63.06
30.787
56.506

576
LEU72
N
63.491
31.955
58.375

577
LEU72
CA
64.928
32.059
58.103

578
LEU72
CB
65.554
32.999
59.131

579
LEU72
CG
65.957
34.352
58.546

580
LEU72
CD1
64.79
35.083
57.889

581
LEU72
CD2
66.588
35.228
59.622

582
LEU72
C
65.598
30.693
58.195

583
LEU72
O
66.353
30.324
57.285

584
ALA73
N
65.113
29.864
59.108

585
ALA73
CA
65.634
28.5
59.226

586
ALA73
CB
65.173
27.918
60.557

587
ALA73
C
65.149
27.611
58.083

588
ALA73
O
65.958
26.872
57.505

589
PHE74
N
63.949
27.887
57.594

590
PHE74
CA
63.408
27.149
56.451

591
PHE74
CB
61.937
27.527
56.291

592
PHE74
CG
61.237
26.906
55.084

593
PHE74
CD1
61.015
25.536
55.034

594
PHE74
CE1
60.377
24.975
53.935

595
PHE74
CZ
59.959
25.784
52.886

596
PHE74
CE2
60.178
27.155
52.937

597
PHE74
CD2
60.817
27.715
54.035

598
PHE74
C
64.165
27.476
55.168

599
PHE74
O
64.663
26.549
54.521

600
ILE75
N
64.508
28.741
54.982

601
ILE75
CA
65.232
29.158
53.775

602
ILE75
CB
65.159
30.676
53.689

603
ILE75
CG2
66.016
31.212
52.551

604
ILE75
CG1
63.722
31.135
53.515

605
ILE75
CD1
63.658
32.651
53.45

606
ILE75
C
66.694
28.721
53.789

607
ILE75
O
67.193
28.237
52.763

608
LYS76
N
67.263
28.61
54.979

609
LYS76
CA
68.647
28.15
55.095

610
LYS76
CB
69.14
28.518
56.489

611
LYS76
CG
70.616
28.191
56.67

612
LYS76
CD
71.106
28.629
58.044

613
LYS76
CE
72.593
28.343
58.213

614
LYS76
NZ
73.067
28.789
59.533

615
LYS76
C
68.747
26.639
54.881

616
LYS76
O
69.69
26.176
54.23

617
SER77
N
67.661
25.939
55.168

618
SER77
CA
67.589
24.495
54.929

619
SER77
CB
66.669
23.893
55.981

620
SER77
OG
67.19
24.24
57.256

621
SER77
C
67.064
24.157
53.53

622
SER77
O
66.946
22.976
53.178

623
CYS78
N
66.704
25.174
52.763

624
CYS78
CA
66.282
24.96
51.383

625
CYS78
CB
65.125
25.89
51.046

626
CYS78
SG
63.546
25.496
51.825

627
CYS78
C
67.413
25.203
50.395

628
CYS78
O
67.296
24.783
49.238

629
GLN79
N
68.482
25.863
50.812

630
GLN79
CA
69.61
26.021
49.888

631
GLN79
CB
70.543
27.143
50.334

632
GLN79
CG
71.732
27.223
49.377

633
GLN79
CD
72.624
28.427
49.635

634
GLN79
OE1
73.014
28.723
50.774

635
GLN79
NE2
72.908
29.13
48.555

636
GLN79
C
70.395
24.72
49.779

637
GLN79
O
70.88
24.178
50.777

638
HIS80
N
70.483
24.21
48.565

639
HIS80
CA
71.26
22.997
48.324

640
HIS80
CB
70.639
22.196
47.183

641
HIS80
CG
69.405
21.404
47.59

642
HIS80
ND1
69.162
20.112
47.303

643
HIS80
CE1
67.982
19.747
47.841

644
HIS80
NE2
67.467
20.825
48.474

645
HIS80
CD2
68.332
21.854
48.325

646
HIS80
C
72.713
23.351
48.04

647
HIS80
O
73.042
24.509
47.757

648
GLU81
N
73.548
22.326
47.956

649
GLU81
CA
75.004
22.519
47.798

650
GLU81
CB
75.712
21.209
48.129

651
GLU81
CG
75.549
20.82
49.595

652
GLU81
CD
76.197
21.864
50.505

653
GLU81
OE1
75.453
22.659
51.062

654
GLU81
OE2
77.393
21.756
50.732

655
GLU81
C
75.453
22.983
46.406

656
GLU81
O
76.638
23.27
46.213

657
CYS82
N
74.526
23.093
45.468

658
CYS82
CA
74.834
23.662
44.155

659
CYS82
CB
74.071
22.89
43.087

660
CYS82
SG
72.273
22.938
43.24

661
CYS82
C
74.455
25.144
44.092

662
CYS82
O
74.459
25.739
43.008

663
GLY83
N
73.977
25.683
45.203

664
GLY83
CA
73.634
27.104
45.265

665
GLY83
C
72.135
27.333
45.248

666
GLY83
O
71.602
28.124
46.041

667
GLY84
N
71.498
26.683
44.289

668
GLY84
CA
70.053
26.769
44.085

669
GLY84
C
69.241
26.441
45.322

670
GLY84
O
69.542
25.515
46.088

671
ILE85
N
68.202
27.232
45.497

672
ILE85
CA
67.308
27.072
46.629

673
ILE85
CB
66.971
28.473
47.123

674
ILE85
CG2
66.144
28.43
48.403

675
ILE85
CG1
68.274
29.233
47.357

676
ILE85
CD1
68.041
30.711
47.635

677
ILE85
C
66.077
26.306
46.165

678
ILE85
O
65.594
26.501
45.04

679
SER86
N
65.767
25.27
46.919

680
SER86
CA
64.601
24.433
46.656

681
SER86
CB
64.751
23.131
47.425

682
SER86
OG
64.727
23.429
48.813

683
SER86
C
63.322
25.123
47.103

684
SER86
O
63.343
26.102
47.857

685
ALA87
N
62.208
24.567
46.659

686
ALA87
CA
60.884
25.1
47.009

687
ALA87
CB
59.902
24.587
45.976

688
ALA87
C
60.403
24.641
48.38

689
ALA87
O
59.413
25.159
48.912

690
SER88
N
61.093
23.642
48.898

691
SER88
CA
60.869
23.084
50.228

692
SER88
CB
59.593
22.255
50.214

693
SER88
OG
59.457
21.603
51.467

694
SER88
C
62.07
22.204
50.522

695
SER88
O
62.657
21.673
49.574

696
ILE89
N
62.447
22.078
51.784

697
ILE89
CA
63.637
21.303
52.175

698
ILE89
CB
63.595
21.164
53.694

699
ILE89
CG2
64.839
20.455
54.22

700
ILE89
CG1
63.454
22.535
54.346

701
ILE89
CD1
63.31
22.421
55.86

702
ILE89
C
63.661
19.916
51.523

703
ILE89
O
62.649
19.204
51.525

704
GLY90
N
64.719
19.663
50.765

705
GLY90
CA
64.898
18.359
50.11

706
GLY90
C
64.479
18.336
48.635

707
GLY90
O
64.821
17.395
47.909

708
HIS91
N
63.726
19.338
48.213

709
HIS91
CA
63.198
19.393
46.841

710
HIS91
CB
61.998
20.342
46.779

711
HIS91
CG
60.687
19.876
47.404

712
HIS91
ND1
60.497
19.209
48.563

713
HIS91
CE1
59.179
18.995
48.748

714
HIS91
NE2
58.526
19.544
47.701

715
HIS91
CD2
59.439
20.093
46.869

716
HIS91
C
64.267
19.88
45.871

717
HIS91
O
65.34
20.322
46.291

718
ASP92
N
63.974
19.799
44.585

719
ASP92
CA
64.925
20.278
43.567

720
ASP92
CB
64.394
19.995
42.159

721
ASP92
CG
64.699
18.567
41.702

722
ASP92
OD1
64.601
17.666
42.524

723
ASP92
OD2
64.959
18.397
40.517

724
ASP92
C
65.189
21.775
43.704

725
ASP92
O
64.275
22.564
43.98

726
PRO93
N
66.465
22.115
43.641

727
PRO93
CA
66.889
23.507
43.494

728
PRO93
CB
68.384
23.466
43.524

729
PRO93
CG
68.846
22.019
43.568

730
PRO93
CD
67.586
21.175
43.579

731
PRO93
C
66.371
24.097
42.186

732
PRO93
O
66.435
23.466
41.122

733
HIS94
N
65.828
25.295
42.293

734
HIS94
CA
65.232
25.945
41.128

735
HIS94
CB
63.742
25.638
41.179

736
HIS94
CG
63.023
25.69
39.85

737
HIS94
ND1
62.769
24.639
39.052

738
HIS94
CE1
62.107
25.06
37.957

739
HIS94
NE2
61.937
26.396
38.069

740
HIS94
CD2
62.491
26.797
39.235

741
HIS94
C
65.467
27.449
41.193

742
HIS94
O
65.287
28.058
42.252

743
LEU95
N
65.691
28.067
40.045

744
LEU95
CA
65.985
29.507
39.993

745
LEU95
CB
66.46
29.808
38.576

746
LEU95
CG
67.029
31.211
38.422

747
LEU95
CD1
68.116
31.481
39.457

748
LEU95
CD2
67.575
31.402
37.013

749
LEU95
C
64.789
30.401
40.352

750
LEU95
O
64.993
31.47
40.936

751
LEU96
N
63.582
29.863
40.274

752
LEU96
CA
62.395
30.616
40.696

753
LEU96
CB
61.168
29.902
40.139

754
LEU96
CG
59.862
30.546
40.589

755
LEU96
CD1
59.724
31.958
40.03

756
LEU96
CD2
58.672
29.689
40.174

757
LEU96
C
62.284
30.678
42.22

758
LEU96
O
62.025
31.751
42.78

759
TYR97
N
62.747
29.629
42.88

760
TYR97
CA
62.669
29.577
44.339

761
TYR97
CB
62.431
28.135
44.759

762
TYR97
CG
61.13
27.578
44.188

763
TYR97
CD1
61.161
26.567
43.235

764
TYR97
CE1
59.976
26.067
42.712

765
TYR97
CZ
58.762
26.579
43.146

766
TYR97
OH
57.586
26.021
42.696

767
TYR97
CE2
58.726
27.593
44.094

768
TYR97
CD2
59.913
28.093
44.615

769
TYR97
C
63.943
30.141
44.95

770
TYR97
O
63.916
30.697
46.055

771
THR98
N
64.964
30.233
44.116

772
THR98
CA
66.181
30.952
44.481

773
THR98
CB
67.272
30.614
43.468

774
THR98
OG1
67.564
29.227
43.573

775
THR98
CG2
68.558
31.379
43.746

776
THR98
C
65.901
32.45
44.478

111
THR98
O
66.176
33.118
45.483

778
LEU99
N
65.101
32.889
43.517

779
LEU99
CA
64.678
34.289
43.466

780
LEU99
CB
63.958
34.543
42.146

781
LEU99
CG
63.39
35.957
42.095

782
LEU99
CD1
64.49
37.003
42.215

783
LEU99
CD2
62.563
36.189
40.836

784
LEU99
C
63.738
34.622
44.618

785
LEU99
O
64.053
35.543
45.381

786
SER100
N
62.825
33.714
44.925

787
SER100
CA
61.867
33.947
46.013

788
SER100
CB
60.834
32.826
46.006

789
SER100
OG
60.151
32.859
44.76

790
SER100
C
62.542
34.001
47.382

791
SER100
O
62.311
34.963
48.125

792
ALA101
N
63.558
33.177
47.588

793
ALA101
CA
64.267
33.192
48.869

794
ALA101
CB
65.054
31.9
49.01

795
ALA101
C
65.217
34.377
48.999

796
ALA101
O
65.276
34.976
50.079

797
VAL102
N
65.722
34.871
47.88

798
VAL102
CA
66.559
36.074
47.913

799
VAL102
CB
67.356
36.16
46.614

800
VAL102
CG1
68.001
37.529
46.427

801
VAL102
CG2
68.409
35.059
46.548

802
VAL102
C
65.708
37.328
48.103

803
VAL102
O
66.104
38.212
48.872

804
GLN103
N
64.458
37.273
47.675

805
GLN103
CA
63.549
38.394
47.906

806
GLN103
CB
62.376
38.267
46.948

807
GLN103
CG
62.841
38.34
45.502

808
GLN103
CD
61.654
38.188
44.562

809
GLN103
OE1
61.201
37.072
44.272

810
GLN103
NE2
61.181
39.323
44.08

811
GLN103
C
63.037
38.409
49.342

812
GLN103
O
62.981
39.486
49.948

813
ILE104
N
62.94
37.239
49.954

814
ILE104
CA
62.553
37.173
51.366

815
ILE104
CB
62.145
35.746
51.702

816
ILE104
CG2
61.878
35.616
53.195

817
ILE104
CG1
60.923
35.313
50.907

818
ILE104
CD1
60.579
33.855
51.189

819
ILE104
C
63.707
37.577
52.279

820
ILE104
O
63.497
38.348
53.224

821
LEU105
N
64.926
37.287
51.855

822
LEU105
CA
66.092
37.695
52.639

823
LEU105
CB
67.258
36.773
52.317

824
LEU105
CG
66.981
35.337
52.746

825
LEU105
CD1
68.155
34.439
52.383

826
LEU105
CD2
66.68
35.242
54.239

827
LEU105
C
66.48
39.149
52.38

828
LEU105
O
67.214
39.741
53.178

829
THR106
N
65.918
39.757
51.351

830
THR106
CA
66.075
41.198
51.177

831
THR106
CB
65.913
41.527
49.696

832
THR106
OG1
66.984
40.913
48.992

833
THR106
CG2
65.982
43.026
49.433

834
THR106
C
65.017
41.928
51.999

835
THR106
O
65.346
42.876
52.723

836
LEU107
N
63.865
41.287
52.128

837
LEU107
CA
62.733
41.856
52.867

838
LEU107
CB
61.511
41.017
52.506

839
LEU107
CG
60.217
41.625
53.024

840
LEU107
CD1
60
42.995
52.401

841
LEU107
CD2
59.037
40.711
52.719

842
LEU107
C
62.949
41.81
54.381

843
LEU107
O
62.571
42.746
55.094

844
TYR108
N
63.632
40.778
54.846

845
TYR108
CA
64.003
40.685
56.263

846
TYR108
CB
63.937
39.224
56.692

847
TYR108
CG
62.548
38.729
57.086

848
TYR108
CD1
62.162
37.427
56.793

849
TYR108
CE1
60.907
36.971
57.177

850
TYR108
CZ
60.041
37.822
57.852

851
TYR108
OH
58.87
37.325
58.382

852
TYR108
CE2
60.417
39.128
58.129

853
TYR108
CD2
61.672
39.582
57.746

854
TYR108
C
65.4
41.226
56.565

855
TYR108
O
65.791
41.261
57.738

856
ASP109
N
66.091
41.717
55.543

857
ASP109
CA
67.51
42.101
55.642

858
ASP109
CB
67.635
43.436
56.369

859
ASP109
CG
69.061
43.959
56.234

860
ASP109
OD1
69.698
43.612
55.249

861
ASP109
OD2
69.506
44.65
57.139

862
ASP109
C
68.305
41.002
56.352

863
ASP109
O
68.882
41.186
57.431

864
SER110
N
68.314
39.848
55.712

865
SER110
CA
68.906
38.639
56.276

866
SER110
CB
67.822
37.86
57.011

867
SER110
OG
67.286
38.693
58.032

868
SER110
C
69.486
37.772
55.168

869
SER110
O
69.478
36.538
55.266

870
ILE111
N
70.163
38.414
54.227

871
ILE111
CA
70.766
37.686
53.099

872
ILE111
CB
71.137
38.684
52.001

873
ILE111
CG2
69.905
39.172
51.249

874
ILE111
CG1
71.921
39.865
52.566

875
ILE111
CD1
72.294
40.859
51.474

876
ILE111
C
72.004
36.881
53.507

877
ILE111
O
72.225
35.809
52.933

878
ASN112
N
72.515
37.178
54.695

879
ASN112
CA
73.7
36.531
55.268

880
ASN112
CB
74.252
37.463
56.345

881
ASN112
CG
74.176
38.93
55.915

882
ASN112
OD1
74.607
39.307
54.818

883
ASN112
ND2
73.6
39.743
56.787

884
ASN112
C
73.374
35.185
55.927

885
ASN112
O
74.259
34.549
56.511

886
VAL113
N
72.109
34.789
55.888

887
VAL113
CA
71.699
33.489
56.425

888
VAL113
CB
70.24
33.614
56.865

889
VAL113
CG1
69.665
32.297
57.378

890
VAL113
CG2
70.095
34.697
57.927

891
VAL113
C
71.859
32.405
55.357

892
VAL113
O
71.957
31.212
55.671

893
ILE114
N
72.005
32.836
54.115

894
ILE114
CA
72.216
31.892
53.021

895
ILE114
CB
70.98
31.96
52.127

896
ILE114
CG2
71.214
32.787
50.863

897
ILE114
CG1
70.51
30.556
51.777

898
ILE114
CD1
69.216
30.587
50.981

899
ILE114
C
73.518
32.233
52.289

900
ILE114
O
74.014
33.362
52.387

901
ASP115
N
74.135
31.239
51.672

902
ASP115
CA
75.386
31.489
50.952

903
ASP115
CB
76.126
30.165
50.768

904
ASP115
CG
77.567
30.411
50.329

905
ASP115
OD1
78.464
30.038
51.068

906
ASP115
OD2
77.743
31.011
49.274

907
ASP115
C
75.088
32.152
49.606

908
ASP115
O
74.808
31.484
48.599

909
VAL116
N
75.373
33.444
49.562

910
VAL116
CA
75.068
34.274
48.392

911
VAL116
CB
75.13
35.733
48.848

912
VAL116
CG1
76.289
35.988
49.807

913
VAL116
CG2
75.168
36.708
47.676

914
VAL116
C
76.003
34.044
47.203

915
VAL116
O
75.519
34.038
46.064

916
ASN117
N
77.187
33.513
47.457

917
ASN117
CA
78.139
33.274
46.369

918
ASN117
CB
79.538
33.235
46.968

919
ASN117
CG
79.834
34.579
47.627

920
ASN117
OD1
79.688
34.745
48.845

921
ASN117
ND2
80.167
35.549
46.793

922
ASN117
C
77.83
31.965
45.658

923
ASN117
O
77.951
31.886
44.429

924
LYS118
N
77.129
31.1
46.371

925
LYS118
CA
76.681
29.834
45.806

926
LYS118
CB
76.4
28.895
46.974

927
LYS118
CG
76.771
27.451
46.66

928
LYS118
CD
78.277
27.271
46.519

929
LYS118
CE
78.997
27.572
47.83

930
LYS118
NZ
78.563
26.65
48.892

931
LYS118
C
75.412
30.063
44.988

932
LYS118
O
75.271
29.492
43.899

933
VAL119
N
74.662
31.09
45.363

934
VAL119
CA
73.474
31.483
44.596

935
VAL119
CB
72.665
32.485
45.415

936
VAL119
CG1
71.565
33.126
44.582

937
VAL119
CG2
72.081
31.859
46.671

938
VAL119
C
73.883
32.145
43.284

939
VAL119
O
73.381
31.756
42.22

940
VAL120
N
74.981
32.885
43.333

941
VAL120
CA
75.52
33.525
42.13

942
VAL120
CB
76.6
34.514
42.562

943
VAL120
CG1
77.342
35.091
41.364

944
VAL120
CG2
76.019
35.629
43.422

945
VAL120
C
76.123
32.505
41.166

946
VAL120
O
75.879
32.597
39.956

947
GLU121
N
76.634
31.409
41.705

948
GLU121
CA
77.197
30.354
40.86

949
GLU121
CB
78.138
29.524
41.719

950
GLU121
CG
79.338
30.365
42.136

951
GLU121
CD
80.1
29.68
43.263

952
GLU121
OE1
79.445
29.111
44.125

953
GLU121
OE2
81.312
29.836
43.308

954
GLU121
C
76.117
29.47
40.24

955
GLU121
O
76.265
29.077
39.075

956
TYR122
N
74.957
29.404
40.875

957
TYR122
CA
73.83
28.679
40.286

958
TYR122
CB
72.786
28.458
41.372

959
TYR122
CG
71.555
27.664
40.941

960
TYR122
CD1
71.688
26.35
40.507

961
TYR122
CE1
70.563
25.625
40.132

962
TYR122
CZ
69.308
26.214
40.198

963
TYR122
OH
68.2
25.524
39.752

964
TYR122
CE2
69.172
27.524
40.64

965
TYR122
CD2
70.297
28.25
41.011

966
TYR122
C
73.215
29.483
39.146

967
TYR122
O
73.021
28.936
38.053

968
VAL123
N
73.202
30.798
39.303

969
VAL123
CA
72.686
31.678
38.249

970
VAL123
CB
72.539
33.078
38.836

971
VAL123
CG1
72.183
34.096
37.763

972
VAL123
CG2
71.514
33.102
39.963

973
VAL123
C
73.631
31.719
37.047

974
VAL123
O
73.186
31.509
35.91

975
LYS124
N
74.922
31.659
37.334

976
LYS124
CA
75.947
31.652
36.285

977
LYS124
CB
77.296
31.814
36.985

978
LYS124
CG
78.472
31.835
36.014

979
LYS124
CD
78.441
33.071
35.126

980
LYS124
CE
79.599
33.084
34.134

981
LYS124
NZ
79.54
34.272
33.267

982
LYS124
C
75.946
30.348
35.485

983
LYS124
O
76.015
30.403
34.25

984
GLY125
N
75.588
29.255
36.144

985
GLY125
CA
75.568
27.929
35.513

986
GLY125
C
74.278
27.623
34.75

987
GLY125
O
74.262
26.719
33.907

988
LEU126
N
73.213
28.354
35.041

989
LEU126
CA
71.959
28.181
34.297

990
LEU126
CB
70.798
28.594
35.186

991
LEU126
CG
70.643
27.665
36.378

992
LEU126
CD1
69.62
28.234
37.345

993
LEU126
CD2
70.258
26.255
35.943

994
LEU126
C
71.92
29.033
33.034

995
LEU126
O
70.995
28.902
32.223

996
GLN127
N
72.896
29.913
32.9

997
GLN127
CA
73.019
30.775
31.726

998
GLN127
CB
74.011
31.846
32.13

999
GLN127
CG
74.282
32.885
31.059

1000
GLN127
CD
75.405
33.739
31.617

1001
GLN127
OE1
75.555
34.921
31.292

1002
GLN127
NE2
76.157
33.127
32.514

1003
GLN127
C
73.565
30.008
30.528

1004
GLN127
O
74.714
29.552
30.537

1005
LYS128
N
72.753
29.908
29.493

1006
LYS128
CA
73.155
29.176
28.29

1007
LYS128
CB
71.918
28.602
27.62

1008
LYS128
CG
71.157
27.714
28.593

1009
LYS128
CD
71.968
26.515
29.07

1010
LYS128
CE
71.18
25.72
30.106

1011
LYS128
NZ
71.954
24.571
30.598

1012
LYS128
C
73.903
30.069
27.313

1013
LYS128
O
73.984
31.291
27.487

1014
GLU129
N
74.282
29.473
26.194

1015
GLU129
CA
75.105
30.16
25.184

1016
GLU129
CB
75.707
29.129
24.225

1017
GLU129
CG
76.667
28.148
24.899

1018
GLU129
CD
76.027
26.768
25.051

1019
GLU129
OE1
74.834
26.729
25.333

1020
GLU129
OE2
76.744
25.786
24.937

1021
GLU129
C
74.322
31.181
24.354

1022
GLU129
O
74.92
31.99
23.639

1023
ASP130
N
73.005
31.165
24.473

1024
ASP130
CA
72.171
32.153
23.789

1025
ASP130
CB
70.988
31.448
23.128

1026
ASP130
CG
70.045
30.863
24.174

1027
ASP130
OD1
69.159
31.593
24.596

1028
ASP130
OD2
70.285
29.745
24.609

1029
ASP130
C
71.678
33.239
24.75

1030
ASP130
O
70.8
34.029
24.386

1031
GLY131
N
72.13
33.195
25.995

1032
GLY131
CA
71.702
34.194
26.98

1033
GLY131
C
70.707
33.639
27.996

1034
GLY131
O
70.881
33.824
29.207

1035
SER132
N
69.681
32.974
27.483

1036
SER132
CA
68.594
32.403
28.296

1037
SER132
CB
67.827
31.415
27.436

1038
SER132
OG
68.718
30.364
27.084

1039
SER132
C
69.058
31.638
29.523

1040
SER132
O
70.073
30.932
29.509

1041
PHE133
N
68.308
31.82
30.594

1042
PHE133
CA
68.565
31.067
31.815

1043
PHE133
CB
68.489
31.997
33.02

1044
PHE133
CG
69.614
33.025
33.105

1045
PHE133
CD1
69.51
34.246
32.45

1046
PHE133
CE1
70.539
35.173
32.533

1047
PHE133
CZ
71.671
34.882
33.278

1048
PHE133
CE2
71.772
33.668
33.944

1049
PHE133
CD2
70.744
32.74
33.858

1050
PHE133
C
67.566
29.931
31.966

1051
PHE133
O
66.417
30.012
31.504

1052
ALA134
N
68.096
28.813
32.425

1053
ALA134
CA
67.276
27.655
32.771

1054
ALA134
CB
68.122
26.395
32.631

1055
ALA134
C
66.767
27.78
34.203

1056
ALA134
O
67.438
28.355
35.065

1057
GLY135
N
65.55
27.319
34.423

1058
GLY135
CA
64.985
27.309
35.777

1059
GLY135
C
65.741
26.306
36.633

1060
GLY135
O
66.395
26.661
37.62

1061
ASP136
N
65.503
25.045
36.341

1062
ASP136
CA
66.294
23.968
36.927

1063
ASP136
CB
65.384
22.791
37.279

1064
ASP136
CG
64.51
22.357
36.1

1065
ASP136
OD1
65.055
22.194
35.012

1066
ASP136
OD2
63.361
22.029
36.349

1067
ASP136
C
67.409
23.546
35.975

1068
ASP136
O
67.361
23.826
34.765

1069
ILE137
N
68.26
22.671
36.488

1070
ILE137
CA
69.451
22.173
35.768

1071
ILE137
CB
70.447
21.562
36.764

1072
ILE137
CG2
70.653
22.509
37.942

1073
ILE137
CG1
70.054
20.167
37.273

1074
ILE137
CD1
69.09
20.17
38.459

1075
ILE137
C
69.173
21.138
34.667

1076
ILE137
O
70.12
20.638
34.051

1077
TRP138
N
67.908
20.886
34.36

1078
TRP138
CA
67.547
19.932
33.313

1079
TRP138
CB
66.201
19.314
33.679

1080
TRP138
CG
66.215
18.583
35.01

1081
TRP138
CD1
65.637
18.992
36.193

1082
TRP138
NE1
65.888
18.055
37.143

1083
TRP138
CE2
66.607
17.034
36.639

1084
TRP138
CZ2
67.107
15.868
37.199

1085
TRP138
CH2
67.829
14.979
36.411

1086
TRP138
CZ3
68.055
15.253
35.067

1087
TRP138
CE3
67.56
16.42
34.498

1088
TRP138
CD2
66.84
17.31
35.279

1089
TRP138
C
67.473
20.603
31.939

1090
TRP138
O
67.276
19.923
30.925

1091
GLY139
N
67.644
21.916
31.908

1092
GLY139
CA
67.69
22.639
30.633

1093
GLY139
C
66.352
23.299
30.342

1094
GLY139
O
65.906
23.383
29.19

1095
GLU140
N
65.754
23.826
31.395

1096
GLU140
CA
64.424
24.442
31.31

1097
GLU140
CB
63.816
24.274
32.693

1098
GLU140
CG
62.367
24.724
32.806

1099
GLU140
CD
62.053
24.741
34.292

1100
GLU140
OE1
63.021
24.737
35.041

1101
GLU140
OE2
60.89
24.746
34.66

1102
GLU140
C
64.52
25.927
30.944

1103
GLU140
O
64.366
26.798
31.809

1104
ILE141
N
64.755
26.186
29.668

1105
ILE141
CA
65.003
27.543
29.15

1106
ILE141
CB
65.631
27.358
27.769

1107
ILE141
CG2
65.662
28.645
26.953

1108
ILE141
CG1
67.032
26.793
27.931

1109
ILE141
CD1
67.837
27.695
28.854

1110
ILE141
C
63.744
28.396
29.044

1111
ILE141
O
62.747
27.967
28.451

1112
ASP142
N
63.791
29.588
29.625

1113
ASP142
CA
62.645
30.501
29.515

1114
ASP142
CB
61.535
29.924
30.394

1115
ASP142
CG
60.164
30.46
30.003

1116
ASP142
OD1
59.82
31.521
30.513

1117
ASP142
OD2
59.499
29.829
29.198

1118
ASP142
C
63.008
31.929
29.953

1119
ASP142
O
63.785
32.125
30.898

1120
THR143
N
62.321
32.912
29.383

1121
THR143
CA
62.517
34.321
29.784

1122
THR143
CB
61.731
35.245
28.858

1123
THR143
OG1
60.354
34.891
28.903

1124
THR143
CG2
62.199
35.159
27.418

1125
THR143
C
62.066
34.637
31.212

1126
THR143
O
62.637
35.541
31.827

1127
ARG144
N
61.245
33.786
31.809

1128
ARG144
CA
60.841
33.994
33.199

1129
ARG144
CB
59.636
33.109
33.485

1130
ARG144
CG
59.134
33.291
34.911

1131
ARG144
CD
57.901
32.438
35.171

1132
ARG144
NE
57.345
32.714
36.504

1133
ARG144
CZ
56.78
31.775
37.265

1134
ARG144
NH1
56.761
30.506
36.852

1135
ARG144
NH2
56.272
32.098
38.456

1136
ARG144
C
61.967
33.621
34.155

1137
ARG144
O
62.222
34.359
35.111

1138
PHE145
N
62.816
32.706
33.72

1139
PHE145
CA
63.935
32.277
34.555

1140
PHE145
CB
64.195
30.805
34.281

1141
PHE145
CG
62.971
29.947
34.584

1142
PHE145
CD1
62.477
29.074
33.624

1143
PHE145
CE1
61.355
28.303
33.898

1144
PHE145
CZ
60.726
28.406
35.132

1145
PHE145
CE2
61.22
29.278
36.093

1146
PHE145
CD2
62.342
30.048
35.82

1147
PHE145
C
65.156
33.134
34.259

1148
PHE145
O
65.986
33.369
35.144

1149
SER146
N
65.095
33.825
33.134

1150
SER146
CA
66.104
34.834
32.831

1151
SER146
CB
66.066
35.125
31.334

1152
SER146
OG
66.328
33.901
30.651

1153
SER146
C
65.823
36.095
33.65

1154
SER146
O
66.753
36.671
34.233

1155
PHE147
N
64.548
36.328
33.922

1156
PHE147
CA
64.134
37.407
34.824

1157
PHE147
CB
62.643
37.65
34.619

1158
PHE147
CG
61.99
38.534
35.677

1159
PHE147
CD1
62.496
39.799
35.949

1160
PHE147
CE1
61.897
40.593
36.917

1161
PHE147
CZ
60.79
40.124
37.612

1162
PHE147
CE2
60.282
38.861
37.34

1163
PHE147
CD2
60.883
38.066
36.373

1164
PHE147
C
64.399
37.052
36.286

1165
PHE147
O
64.882
37.908
37.038

1166
CYS148
N
64.312
35.775
36.62

1167
CYS148
CA
64.647
35.343
37.979

1168
CYS148
CB
64.276
33.875
38.157

1169
CYS148
SG
62.513
33.488
38.089

1170
CYS148
C
66.132
35.521
38.258

1171
CYS148
O
66.481
36.178
39.245

1172
ALA149
N
66.952
35.245
37.259

1173
ALA149
CA
68.397
35.398
37.413

1174
ALA149
CB
69.058
34.739
36.217

1175
ALA149
C
68.842
36.856
37.481

1176
ALA149
O
69.6
37.21
38.395

1177
VAL150
N
68.197
37.721
36.712

1178
VAL150
CA
68.599
39.132
36.723

1179
VAL150
CB
68.159
39.802
35.415

1180
VAL150
CG1
66.648
39.961
35.306

1181
VAL150
CG2
68.816
41.163
35.232

1182
VAL150
C
68.047
39.869
37.948

1183
VAL150
O
68.749
40.732
38.488

1184
ALA151
N
66.984
39.351
38.546

1185
ALA151
CA
66.448
39.971
39.754

1186
ALA151
CB
64.958
39.666
39.842

1187
ALA151
C
67.169
39.454
40.992

1188
ALA151
O
67.467
40.243
41.897

1189
THR152
N
67.693
38.243
40.893

1190
THR152
CA
68.463
37.669
41.996

1191
THR152
CB
68.65
36.174
41.752

1192
THR152
OG1
67.378
35.548
41.833

1193
THR152
CG2
69.535
35.54
42.815

1194
THR152
C
69.82
38.346
42.101

1195
THR152
O
70.14
38.886
43.167

1196
LEU153
N
70.448
38.595
40.962

1197
LEU153
CA
71.746
39.27
40.993

1198
LEU153
CB
72.504
38.977
39.71

1199
LEU153
CG
72.987
37.535
39.663

1200
LEU153
CD1
73.843
37.316
38.425

1201
LEU153
CD2
73.79
37.195
40.914

1202
LEU153
C
71.619
40.777
41.192

1203
LEU153
O
72.527
41.387
41.772

1204
ALA154
N
70.444
41.328
40.937

1205
ALA154
CA
70.215
42.735
41.258

1206
ALA154
CB
68.956
43.207
40.545

1207
ALA154
C
70.05
42.926
42.763

1208
ALA154
O
70.762
43.757
43.34

1209
LEU155
N
69.379
41.983
43.41

1210
LEU155
CA
69.156
42.067
44.862

1211
LEU155
CB
67.967
41.186
45.223

1212
LEU155
CG
66.673
41.709
44.616

1213
LEU155
CD1
65.531
40.726
44.838

1214
LEU155
CD2
66.325
43.08
45.179

1215
LEU155
C
70.361
41.617
45.685

1216
LEU155
O
70.443
41.931
46.877

1217
LEU156
N
71.291
40.914
45.058

1218
LEU156
CA
72.538
40.558
45.742

1219
LEU156
CB
73.006
39.195
45.243

1220
LEU156
CG
72.003
38.095
45.568

1221
LEU156
CD1
72.443
36.77
44.959

1222
LEU156
CD2
71.789
37.956
47.072

1223
LEU156
C
73.642
41.586
45.497

1224
LEU156
O
74.688
41.536
46.155

1225
GLY157
N
73.406
42.508
44.576

1226
GLY157
CA
74.401
43.533
44.247

1227
GLY157
C
75.536
42.957
43.405

1228
GLY157
O
76.683
43.412
43.487

1229
LYS158
N
75.197
42.005
42.553

1230
LYS158
CA
76.21
41.326
41.749

1231
LYS158
CB
76.675
40.088
42.508

1232
LYS158
CG
78.072
39.657
42.076

1233
LYS158
CD
78.556
38.466
42.893

1234
LYS158
CE
80.015
38.142
42.596

1235
LYS158
NZ
80.219
37.876
41.164

1236
LYS158
C
75.618
40.945
40.397

1237
LYS158
O
75.796
39.824
39.9

1238
LEU159
N
75.093
41.952
39.718

1239
LEU159
CA
74.424
41.733
38.428

1240
LEU159
CB
73.543
42.946
38.148

1241
LEU159
CG
72.69
42.746
36.902

1242
LEU159
CD1
71.834
41.493
37.037

1243
LEU159
CD2
71.821
43.968
36.63

1244
LEU159
C
75.42
41.531
37.283

1245
LEU159
O
75.125
40.8
36.33

1246
ASP160
N
76.668
41.886
37.547

1247
ASP160
CA
77.757
41.757
36.571

1248
ASP160
CB
78.823
42.8
36.892

1249
ASP160
CG
78.221
44.203
36.873

1250
ASP160
OD1
78.047
44.733
35.786

1251
ASP160
OD2
77.842
44.67
37.94

1252
ASP160
C
78.404
40.368
36.573

1253
ASP160
O
79.493
40.199
36.014

1254
ALA161
N
77.787
39.411
37.252

1255
ALA161
CA
78.308
38.044
37.271

1256
ALA161
CB
77.81
37.358
38.535

1257
ALA161
C
77.835
37.248
36.058

1258
ALA161
O
78.38
36.179
35.764

1259
ILE162
N
76.823
37.758
35.375

1260
ILE162
CA
76.36
37.14
34.131

1261
ILE162
CB
74.865
36.878
34.241

1262
ILE162
CG2
74.595
35.761
35.243

1263
ILE162
CG1
74.131
38.16
34.626

1264
ILE162
CD1
72.626
37.949
34.743

1265
ILE162
C
76.636
38.061
32.949

1266
ILE162
O
76.975
39.238
33.124

1267
ASN163
N
76.533
37.51
31.753

1268
ASN163
CA
76.664
38.33
30.556

1269
ASN163
CB
77.185
37.504
29.387

1270
ASN163
CG
77.52
38.44
28.227

1271
ASN163
OD1
76.636
39.092
27.656

1272
ASN163
ND2
78.804
38.569
27.95

1273
ASN163
C
75.295
38.909
30.235

1274
ASN163
O
74.505
38.347
29.462

1275
VAL164
N
75.138
40.152
30.651

1276
VAL164
CA
73.85
40.831
30.551

1277
VAL164
CB
73.94
42.094
31.404

1278
VAL164
CG1
72.615
42.845
31.43

1279
VAL164
CG2
74.381
41.757
32.825

1280
VAL164
C
73.486
41.185
29.109

1281
VAL164
O
72.321
40.999
28.746

1282
GLU165
N
74.481
41.284
28.241

1283
GLU165
CA
74.223
41.656
26.848

1284
GLU165
CB
75.555
42.062
26.228

1285
GLU165
CG
75.417
42.42
24.753

1286
GLU165
CD
76.8
42.695
24.171

1287
GLU165
OE1
77.755
42.154
24.714

1288
GLU165
OE2
76.885
43.473
23.232

1289
GLU165
C
73.636
40.492
26.051

1290
GLU165
O
72.663
40.686
25.312

1291
LYS166
N
74.033
39.282
26.408

1292
LYS166
CA
73.547
38.102
25.699

1293
LYS166
CB
74.549
36.975
25.919

1294
LYS166
CG
74.45
35.928
24.818

1295
LYS166
CD
74.854
36.531
23.478

1296
LYS166
CE
74.732
35.522
22.343

1297
LYS166
NZ
73.333
35.112
22.156

1298
LYS166
C
72.179
37.688
26.229

1299
LYS166
O
71.309
37.285
25.447

1300
ALA167
N
71.914
38.042
27.477

1301
ALA167
CA
70.606
37.754
28.066

1302
ALA167
CB
70.746
37.784
29.582

1303
ALA167
C
69.564
38.772
27.603

1304
ALA167
O
68.433
38.385
27.278

1305
ILE168
N
70.023
39.978
27.304

1306
ILE168
CA
69.148
40.998
26.72

1307
ILE168
CB
69.83
42.358
26.837

1308
ILE168
CG2
69.078
43.419
26.046

1309
ILE168
CG1
69.956
42.793
28.29

1310
ILE168
CD1
70.807
44.052
28.402

1311
ILE168
C
68.877
40.691
25.252

1312
ILE168
O
67.725
40.801
24.819

1313
GLU169
N
69.822
40.029
24.603

1314
GLU169
CA
69.627
39.609
23.214

1315
GLU169
CB
70.976
39.156
22.673

1316
GLU169
CG
70.889
38.711
21.219

1317
GLU169
CD
72.274
38.297
20.739

1318
GLU169
OE1
73.239
38.76
21.333

1319
GLU169
OE2
72.347
37.508
19.807

1320
GLU169
C
68.614
38.468
23.107

1321
GLU169
O
67.734
38.523
22.237

1322
PHE170
N
68.572
37.61
24.114

1323
PHE170
CA
67.557
36.557
24.134

1324
PHE170
CB
67.912
35.534
25.204

1325
PHE170
CG
66.845
34.457
25.376

1326
PHE170
CD1
66.655
33.505
24.383

1327
PHE170
CE1
65.681
32.527
24.535

1328
PHE170
CZ
64.891
32.504
25.676

1329
PHE170
CE2
65.075
33.46
26.666

1330
PHE170
CD2
66.05
34.438
26.516

1331
PHE170
C
66.171
37.122
24.427

1332
PHE170
O
65.223
36.796
23.706

1333
VAL171
N
66.095
38.125
25.285

1334
VAL171
CA
64.789
38.709
25.6

1335
VAL171
CB
64.921
39.516
26.887

1336
VAL171
CG1
63.66
40.321
27.181

1337
VAL171
CG2
65.25
38.594
28.054

1338
VAL171
C
64.256
39.581
24.463

1339
VAL171
O
63.072
39.459
24.121

1340
LEU172
N
65.15
40.184
23.695

1341
LEU172
CA
64.711
41
22.558

1342
LEU172
CB
65.819
41.97
22.173

1343
LEU172
CG
66.098
42.971
23.286

1344
LEU172
CD1
67.26
43.881
22.907

1345
LEU172
CD2
64.854
43.785
23.623

1346
LEU172
C
64.339
40.151
21.347

1347
LEU172
O
63.425
40.532
20.605

1348
SER173
N
64.838
38.925
21.293

1349
SER173
CA
64.444
38.006
20.218

1350
SER173
CB
65.569
37.016
19.936

1351
SER173
OG
65.713
36.164
21.062

1352
SER173
C
63.156
37.249
20.559

1353
SER173
O
62.683
36.438
19.755

1354
CYS174
N
62.611
37.493
21.741

1355
CYS174
CA
61.299
36.955
22.098

1356
CYS174
CB
61.309
36.569
23.569

1357
CYS174
SG
62.54
35.332
24.02

1358
CYS174
C
60.183
37.971
21.86

1359
CYS174
O
59.009
37.626
22.047

1360
MET175
N
60.534
39.18
21.442

1361
MET175
CA
59.533
40.231
21.211

1362
MET175
CB
60.266
41.546
20.948

1363
MET175
CG
59.313
42.736
20.87

1364
MET175
SD
60.063
44.323
20.436

1365
MET175
CE
61.269
44.459
21.774

1366
MET175
C
58.637
39.897
20.019

1367
MET175
O
59.108
39.523
18.939

1368
ASN176
N
57.34
39.993
20.247

1369
ASN176
CA
56.355
39.748
19.197

1370
ASN176
CB
55.116
39.118
19.814

1371
ASN176
CG
55.467
37.787
20.466

1372
ASN176
OD1
55.577
37.69
21.691

1373
ASN176
ND2
55.604
36.767
19.641

1374
ASN176
C
55.968
41.045
18.503

1375
ASN176
O
56.294
42.148
18.959

1376
PHE177
N
55.075
40.902
17.537

1377
PHE177
CA
54.623
42.033
16.707

1378
PHE177
CB
54.004
41.477
15.42

1379
PHE177
CG
52.796
40.55
15.594

1380
PHE177
CD1
51.516
41.084
15.682

1381
PHE177
CE1
50.42
40.246
15.84

1382
PHE177
CZ
50.6
38.871
15.9

1383
PHE177
CE2
51.876
38.333
15.794

1384
PHE177
CD2
52.972
39.171
15.636

1385
PHE177
C
53.619
42.956
17.41

1386
PHE177
O
53.224
43.985
16.856

1387
ASP178
N
53.227
42.597
18.622

1388
ASP178
CA
52.327
43.431
19.418

1389
ASP178
CB
51.263
42.542
20.058

1390
ASP178
CG
51.885
41.492
20.978

1391
ASP178
OD1
52.14
41.822
22.128

1392
ASP178
OD2
52.139
40.394
20.5

1393
ASP178
C
53.082
44.215
20.495

1394
ASP178
O
52.456
44.865
21.339

1395
GLY179
N
54.4
44.084
20.535

1396
GLY179
CA
55.183
44.806
21.545

1397
GLY179
C
55.624
43.891
22.687

1398
GLY179
O
56.785
43.926
23.112

1399
GLY180
N
54.685
43.104
23.187

1400
GLY180
CA
54.954
42.16
24.276

1401
GLY180
C
55.894
41.035
23.866

1402
GLY180
O
56.266
40.899
22.695

1403
PHE181
N
56.258
40.23
24.847

1404
PHE181
CA
57.252
39.176
24.641

1405
PHE181
CB
58.408
39.422
25.609

1406
PHE181
CG
59.151
40.756
25.478

1407
PHE181
CD1
58.71
41.886
26.16

1408
PHE181
CE1
59.397
43.086
26.04

1409
PHE181
CZ
60.536
43.157
25.249

1410
PHE181
CE2
60.987
42.026
24.581

1411
PHE181
CD2
60.297
40.826
24.7

1412
PHE181
C
56.675
37.789
24.918

1413
PHE181
O
55.765
37.633
25.747

1414
GLY182
N
57.208
36.805
24.213

1415
GLY182
CA
56.882
35.4
24.477

1416
GLY182
C
57.832
34.795
25.512

1417
GLY182
O
58.746
35.461
26.017

1418
CYS183
N
57.596
33.535
25.843

1419
CYS183
CA
58.412
32.872
26.873

1420
CYS183
CB
57.593
31.755
27.521

1421
CYS183
SG
56.923
30.465
26.445

1422
CYS183
C
59.721
32.336
26.303

1423
CYS183
O
60.746
32.285
26.999

1424
ARG184
N
59.661
31.987
25.029

1425
ARG184
CA
60.821
31.649
24.203

1426
ARG184
CB
60.893
30.131
24.047

1427
ARG184
CG
61.178
29.422
25.366

1428
ARG184
CD
61.162
27.911
25.182

1429
ARG184
NE
59.858
27.476
24.657

1430
ARG184
CZ
59.717
26.79
23.52

1431
ARG184
NH1
60.792
26.458
22.802

1432
ARG184
NH2
58.499
26.439
23.1

1433
ARG184
C
60.573
32.309
22.851

1434
ARG184
O
59.416
32.655
22.578

1435
PRO185
N
61.602
32.503
22.037

1436
PRO185
CA
61.419
33.187
20.751

1437
PRO185
CB
62.78
33.235
20.127

1438
PRO185
CG
63.788
32.59
21.064

1439
PRO185
CD
62.999
32.133
22.28

1440
PRO185
C
60.422
32.446
19.868

1441
PRO185
O
60.53
31.231
19.667

1442
GLY186
N
59.375
33.156
19.482

1443
GLY186
CA
58.321
32.557
18.66

1444
GLY186
C
57.001
32.432
19.422

1445
GLY186
O
55.924
32.504
18.818

1446
SER187
N
57.092
32.285
20.736

1447
SER187
CA
55.898
32.139
21.582

1448
SER187
CB
56.326
31.784
22.998

1449
SER187
OG
57.157
30.632
22.943

1450
SER187
C
55.118
33.445
21.608

1451
SER187
O
55.683
34.502
21.314

1452
GLU188
N
53.83
33.358
21.888

1453
GLU188
CA
52.959
34.543
21.886

1454
GLU188
CB
51.515
34.073
21.752

1455
GLU188
CG
51.31
33.256
20.481

1456
GLU188
CD
49.86
32.788
20.388

1457
GLU188
OE1
49
33.514
20.867

1458
GLU188
OE2
49.646
31.7
19.874

1459
GLU188
C
53.099
35.377
23.159

1460
GLU188
O
53.511
34.866
24.207

1461
SER189
N
52.781
36.656
23.031

1462
SER189
CA
52.765
37.579
24.175

1463
SER189
CB
52.602
39.008
23.67

1464
SER189
OG
53.678
39.334
22.807

1465
SER189
C
51.591
37.318
25.108

1466
SER189
O
50.468
37.041
24.667

1467
HIS190
N
51.866
37.434
26.395

1468
HIS190
CA
50.805
37.41
27.413

1469
HIS190
CB
50.353
35.98
27.709

1470
HIS190
CG
51.355
35.073
28.396

1471
HIS190
ND1
51.303
34.665
29.679

1472
HIS190
CE1
52.36
33.866
29.929

1473
HIS190
NE2
53.068
33.745
28.784

1474
HIS190
CD2
52.453
34.473
27.826

1475
HIS190
C
51.286
38.116
28.677

1476
HIS190
O
52.497
38.204
28.914

1477
ALA191
N
50.343
38.517
29.516

1478
ALA191
CA
50.613
39.311
30.735

1479
ALA191
CB
49.337
39.332
31.565

1480
ALA191
C
51.748
38.813
31.631

1481
ALA191
O
52.654
39.592
31.948

1482
GLY192
N
51.797
37.512
31.876

1483
GLY192
CA
52.849
36.921
32.714

1484
GLY192
C
54.245
37.158
32.145

1485
GLY192
O
55.092
37.772
32.806

1486
GLN193
N
54.386
36.907
30.855

1487
GLN193
CA
55.689
37.027
30.208

1488
GLN193
CB
55.622
36.276
28.895

1489
GLN193
CG
56.84
35.387
28.781

1490
GLN193
CD
56.857
34.42
29.956

1491
GLN193
OE1
55.811
33.94
30.408

1492
GLN193
NE2
58.058
34.043
30.347

1493
GLN193
C
56.074
38.466
29.92

1494
GLN193
O
57.258
38.814
30.005

1495
ILE194
N
55.079
39.327
29.816

1496
ILE194
CA
55.361
40.743
29.636

1497
ILE194
CB
54.12
41.417
29.075

1498
ILE194
CG2
54.309
42.927
28.988

1499
ILE194
CG1
53.811
40.838
27.703

1500
ILE194
CD1
52.583
41.491
27.091

1501
ILE194
C
55.788
41.367
30.957

1502
ILE194
O
56.769
42.116
30.954

1503
TYR195
N
55.318
40.815
32.064

1504
TYR195
CA
55.789
41.27
33.372

1505
TYR195
CB
54.917
40.672
34.47

1506
TYR195
CG
55.355
41.078
35.875

1507
TYR195
CD1
54.944
42.3
36.389

1508
TYR195
CE1
55.35
42.688
37.658

1509
TYR195
CZ
56.166
41.856
38.411

1510
TYR195
OH
56.679
42.313
39.607

1511
TYR195
CE2
56.563
40.625
37.909

1512
TYR195
CD2
56.154
40.235
36.64

1513
TYR195
C
57.23
40.842
33.598

1514
TYR195
O
58.074
41.695
33.904

1515
CYS196
N
57.545
39.625
33.188

1516
CYS196
CA
58.899
39.102
33.375

1517
CYS196
CB
58.895
37.619
33.025

1518
CYS196
SG
57.805
36.595
34.037

1519
CYS196
C
59.924
39.822
32.506

1520
CYS196
O
60.941
40.29
33.032

1521
CYS197
N
59.558
40.132
31.275

1522
CYS197
CA
60.518
40.777
30.382

1523
CYS197
CB
60.163
40.402
28.955

1524
CYS197
SG
60.243
38.631
28.604

1525
CYS197
C
60.584
42.295
30.547

1526
CYS197
O
61.663
42.864
30.343

1527
THR198
N
59.554
42.909
31.11

1528
THR198
CA
59.662
44.339
31.428

1529
THR198
CB
58.291
45.012
31.494

1530
THR198
OG1
57.483
44.352
32.463

1531
THR198
CG2
57.573
44.989
30.149

1532
THR198
C
60.393
44.525
32.751

1533
THR198
O
61.157
45.486
32.895

1534
GLY199
N
60.334
43.512
33.601

1535
GLY199
CA
61.138
43.491
34.818

1536
GLY199
C
62.611
43.372
34.452

1537
GLY199
O
63.409
44.254
34.795

1538
PHE200
N
62.901
42.417
33.581

1539
PHE200
CA
64.263
42.179
33.092

1540
PHE200
CB
64.189
41.043
32.071

1541
PHE200
CG
65.533
40.527
31.557

1542
PHE200
CD1
66.034
39.326
32.039

1543
PHE200
CE1
67.257
38.85
31.587

1544
PHE200
CZ
67.973
39.569
30.641

1545
PHE200
CE2
67.462
40.757
30.138

1546
PHE200
CD2
66.239
41.231
30.59

1547
PHE200
C
64.849
43.42
32.421

1548
PHE200
O
65.894
43.915
32.863

1549
LEU201
N
64.072
44.05
31.554

1550
LEU201
CA
64.576
45.213
30.82

1551
LEU201
CB
63.682
45.451
29.605

1552
LEU201
CG
64.394
45.125
28.29

1553
LEU201
CD1
65.075
43.762
28.297

1554
LEU201
CD2
63.449
45.237
27.101

1555
LEU201
C
64.661
46.473
31.681

1556
LEU201
O
65.585
47.266
31.465

1557
ALA202
N
63.933
46.52
32.785

1558
ALA202
CA
64.053
47.656
33.702

1559
ALA202
CB
62.767
47.785
34.508

1560
ALA202
C
65.242
47.516
34.648

1561
ALA202
O
65.863
48.526
35.006

1562
ILE203
N
65.669
46.286
34.887

1563
ILE203
CA
66.85
46.049
35.726

1564
ILE203
CB
66.762
44.63
36.281

1565
ILE203
CG2
67.979
44.3
37.136

1566
ILE203
CG1
65.493
44.438
37.097

1567
ILE203
CD1
65.345
42.987
37.536

1568
ILE203
C
68.131
46.187
34.908

1569
ILE203
O
69.156
46.662
35.411

1570
THR204
N
68.017
45.915
33.619

1571
THR204
CA
69.161
46.061
32.708

1572
THR204
CB
69.03
45.034
31.592

1573
THR204
OG1
67.834
45.31
30.873

1574
THR204
CG2
68.96
43.614
32.139

1575
THR204
C
69.258
47.449
32.076

1576
THR204
O
70.16
47.681
31.263

1577
SER205
N
68.301
48.315
32.386

1578
SER205
CA
68.222
49.684
31.845

1579
SER205
CB
69.455
50.464
32.281

1580
SER205
OG
69.513
50.396
33.699

1581
SER205
C
68.081
49.72
30.321

1582
SER205
O
68.427
50.718
29.677

1583
GLN206
N
67.332
48.758
29.809

1584
GLN206
CA
67.07
48.622
28.374

1585
GLN206
CB
67.266
47.17
27.965

1586
GLN206
CG
68.734
46.823
27.777

1587
GLN206
CD
69.254
47.459
26.491

1588
GLN206
OE1
70.358
48.013
26.459

1589
GLN206
NE2
68.47
47.32
25.434

1590
GLN206
C
65.651
49.046
28.045

1591
GLN206
O
65.029
48.528
27.107

1592
LEU207
N
65.228
50.118
28.694

1593
LEU207
CA
63.839
50.588
28.601

1594
LEU207
CB
63.534
51.554
29.748

1595
LEU207
CG
63.26
50.884
31.096

1596
LEU207
CD1
62.333
49.683
30.931

1597
LEU207
CD2
64.533
50.49
31.839

1598
LEU207
C
63.575
51.304
27.282

1599
LEU207
O
62.455
51.248
26.765

1600
HIS208
N
64.659
51.681
26.624

1601
HIS208
CA
64.615
52.335
25.316

1602
HIS208
CB
65.927
53.101
25.145

1603
HIS208
CG
67.18
52.29
25.439

1604
HIS208
ND1
67.955
52.373
26.54

1605
HIS208
CE1
68.969
51.489
26.437

1606
HIS208
NE2
68.845
50.859
25.248

1607
HIS208
CD2
67.756
51.348
24.617

1608
HIS208
C
64.434
51.341
24.163

1609
HIS208
O
64.251
51.753
23.013

1610
GLN209
N
64.453
50.052
24.473

1611
GLN209
CA
64.23
49.034
23.452

1612
GLN209
CB
65.088
47.824
23.796

1613
GLN209
CG
65.65
47.163
22.544

1614
GLN209
CD
66.873
47.937
22.066

1615
GLN209
OE1
67.452
48.721
22.829

1616
GLN209
NE2
67.355
47.574
20.89

1617
GLN209
C
62.763
48.605
23.435

1618
GLN209
O
62.319
47.918
22.506

1619
VAL210
N
62.021
49.022
24.45

1620
VAL210
CA
60.607
48.656
24.557

1621
VAL210
CB
60.213
48.716
26.031

1622
VAL210
CG1
58.783
48.233
26.249

1623
VAL210
CG2
61.174
47.912
26.894

1624
VAL210
C
59.73
49.633
23.781

1625
VAL210
O
59.797
50.848
24.002

1626
ASN211
N
58.915
49.109
22.879

1627
ASN211
CA
57.911
49.961
22.237

1628
ASN211
CB
57.444
49.342
20.922

1629
ASN211
CG
56.58
50.333
20.136

1630
ASN211
OD1
55.705
51.015
20.689

1631
ASN211
ND2
56.819
50.378
18.839

1632
ASN211
C
56.735
50.119
23.194

1633
ASN211
O
55.725
49.409
23.091

1634
SER212
N
56.769
51.223
23.922

1635
SER212
CA
55.784
51.476
24.972

1636
SER212
CB
56.35
52.544
25.898

1637
SER212
OG
57.55
52.041
26.472

1638
SER212
C
54.434
51.936
24.433

1639
SER212
O
53.422
51.724
25.103

1640
ASP213
N
54.369
52.304
23.167

1641
ASP213
CA
53.09
52.729
22.603

1642
ASP213
CB
53.356
53.63
21.401

1643
ASP213
CG
54.158
54.857
21.825

1644
ASP213
OD1
53.543
55.798
22.305

1645
ASP213
OD2
55.376
54.818
21.7

1646
ASP213
C
52.282
51.516
22.159

1647
ASP213
O
51.122
51.364
22.564

1648
LEU214
N
52.973
50.544
21.586

1649
LEU214
CA
52.295
49.353
21.072

1650
LEU214
CB
53.175
48.751
19.985

1651
LEU214
CG
52.498
47.59
19.269

1652
LEU214
CD1
51.138
48.001
18.715

1653
LEU214
CD2
53.394
47.056
18.158

1654
LEU214
C
52.052
48.339
22.184

1655
LEU214
O
50.924
47.847
22.324

1656
LEU215
N
52.984
48.277
23.122

1657
LEU215
CA
52.814
47.389
24.273

1658
LEU215
CB
54.181
47.158
24.908

1659
LEU215
CG
54.103
46.281
26.152

1660
LEU215
CD1
53.349
44.985
25.879

1661
LEU215
CD2
55.494
45.992
26.704

1662
LEU215
C
51.847
48.005
25.28

1663
LEU215
O
50.996
47.288
25.819

1664
GLY216
N
51.79
49.326
25.301

1665
GLY216
CA
50.839
50.045
26.145

1666
GLY216
C
49.421
49.817
25.654

1667
GLY216
O
48.555
49.41
26.438

1668
TRP217
N
49.24
49.9
24.346

1669
TRP217
CA
47.928
49.645
23.754

1670
TRP217
CB
47.987
49.982
22.27

1671
TRP217
CG
46.688
49.691
21.55

1672
TRP217
CD1
45.524
50.424
21.625

1673
TRP217
NE1
44.588
49.823
20.849

1674
TRP217
CE2
45.081
48.719
20.257

1675
TRP217
CZ2
44.525
47.781
19.399

1676
TRP217
CH2
45.298
46.719
18.944

1677
TRP217
CZ3
46.624
46.591
19.346

1678
TRP217
CE3
47.189
47.524
20.205

1679
TRP217
CD2
46.421
48.586
20.661

1680
TRP217
C
47.487
48.193
23.933

1681
TRP217
O
46.36
47.973
24.392

1682
TRP218
N
48.418
47.255
23.846

1683
TRP218
CA
48.065
45.847
24.044

1684
TRP218
CB
49.276
44.988
23.689

1685
TRP218
CG
48.974
43.51
23.524

1686
TRP218
CD1
48.616
42.882
22.352

1687
TRP218
NE1
48.432
41.563
22.604

1688
TRP218
CE2
48.65
41.282
23.904

1689
TRP218
CZ2
48.585
40.105
24.633

1690
TRP218
CH2
48.857
40.124
25.995

1691
TRP218
CZ3
49.196
41.314
26.628

1692
TRP218
CE3
49.27
42.498
25.901

1693
TRP218
CD2
48.997
42.485
24.544

1694
TRP218
C
47.658
45.589
25.495

1695
TRP218
O
46.551
45.086
25.727

1696
LEU219
N
48.369
46.205
26.426

1697
LEU219
CA
48.072
46.021
27.85

1698
LEU219
CB
49.247
46.554
28.665

1699
LEU219
CG
50.52
45.735
28.469

1700
LEU219
CD1
51.69
46.373
29.208

1701
LEU219
CD2
50.337
44.289
28.914

1702
LEU219
C
46.795
46.736
28.299

1703
LEU219
O
46.024
46.154
29.074

1704
CYS220
N
46.444
47.845
27.666

1705
CYS220
CA
45.202
48.525
28.052

1706
CYS220
CB
45.288
50.023
27.767

1707
CYS220
SG
45.291
50.544
26.037

1708
CYS220
C
43.982
47.91
27.364

1709
CYS220
O
42.879
47.992
27.916

1710
GLU221
N
44.214
47.072
26.361

1711
GLU221
CA
43.119
46.313
25.745

1712
GLU221
CB
43.508
45.882
24.335

1713
GLU221
CG
43.683
47.065
23.393

1714
GLU221
CD
42.379
47.84
23.23

1715
GLU221
OE1
41.388
47.21
22.895

1716
GLU221
OE2
42.458
49.061
23.216

1717
GLU221
C
42.772
45.064
26.554

1718
GLU221
O
41.756
44.418
26.274

1719
ARG222
N
43.548
44.777
27.59

1720
ARG222
CA
43.252
43.633
28.452

1721
ARG222
CB
44.541
43.198
29.146

1722
ARG222
CG
45.646
42.904
28.136

1723
ARG222
CD
45.292
41.729
27.232

1724
ARG222
NE
45.617
42.034
25.834

1725
ARG222
CZ
44.688
42.163
24.886

1726
ARG222
NH1
43.414
41.876
25.159

1727
ARG222
NH2
45.044
42.487
23.642

1728
ARG222
C
42.201
43.99
29.5

1729
ARG222
O
41.588
43.08
30.076

1730
GLN223
N
41.925
45.275
29.674

1731
GLN223
CA
40.9
45.693
30.633

1732
GLN223
CB
41.158
47.128
31.077

1733
GLN223
CG
40.121
47.56
32.111

1734
GLN223
CD
40.563
48.832
32.823

1735
GLN223
OE1
41.053
49.784
32.2

1736
GLN223
NE2
40.456
48.795
34.138

1737
GLN223
C
39.502
45.573
30.04

1738
GLN223
O
39.087
46.335
29.16

1739
LEU224
N
38.775
44.612
30.574

1740
LEU224
CA
37.399
44.356
30.158

1741
LEU224
CB
37.096
42.908
30.517

1742
LEU224
CG
37.949
41.984
29.664

1743
LEU224
CD1
37.705
40.538
30.048

1744
LEU224
CD2
37.67
42.202
28.18

1745
LEU224
C
36.443
45.309
30.864

1746
LEU224
O
36.812
45.898
31.887

1747
PRO225
N
35.209
45.406
30.378

1748
PRO225
CA
34.2
46.305
30.977

1749
PRO225
CB
33.043
46.286
30.025

1750
PRO225
CG
33.308
45.279
28.919

1751
PRO225
CD
34.695
44.722
29.183

1752
PRO225
C
33.723
45.934
32.396

1753
PRO225
O
32.934
46.678
32.985

1754
SER226
N
34.218
44.835
32.949

1755
SER226
CA
33.978
44.497
34.356

1756
SER226
CB
34.204
43.004
34.54

1757
SER226
OG
35.609
42.78
34.473

1758
SER226
C
34.983
45.195
35.271

1759
SER226
O
34.911
45.044
36.494

1760
GLY227
N
35.986
45.824
34.677

1761
GLY227
CA
37.024
46.493
35.447

1762
GLY227
C
38.35
45.743
35.398

1763
GLY227
O
39.418
46.372
35.4

1764
GLY228
N
38.281
44.429
35.25

1765
GLY228
CA
39.478
43.6
35.389

1766
GLY228
C
40.235
43.358
34.095

1767
GLY228
O
39.674
43.334
32.994

1768
LEU229
N
41.518
43.12
34.281

1769
LEU229
CA
42.45
42.888
33.18

1770
LEU229
CB
43.805
43.518
33.535

1771
LEU229
CG
43.984
45.025
33.28

1772
LEU229
CD1
42.942
45.936
33.919

1773
LEU229
CD2
45.352
45.471
33.769

1774
LEU229
C
42.632
41.384
32.987

1775
LEU229
O
42.696
40.636
33.974

1776
ASN230
N
42.547
40.939
31.745

1777
ASN230
CA
42.849
39.541
31.428

1778
ASN230
CB
41.954
39.013
30.306

1779
ASN230
CG
42.032
39.815
29.01

1780
ASN230
OD1
43.113
40.026
28.45

1781
ASN230
ND2
40.866
40.022
28.429

1782
ASN230
C
44.325
39.382
31.081

1783
ASN230
O
45.112
40.33
31.19

1784
GLY231
N
44.7
38.164
30.732

1785
GLY231
CA
46.107
37.867
30.443

1786
GLY231
C
46.447
38.093
28.978

1787
GLY231
O
47.574
38.476
28.641

1788
ARG232
N
45.506
37.714
28.133

1789
ARG232
CA
45.63
37.864
26.685

1790
ARG232
CB
46.574
36.776
26.164

1791
ARG232
CG
46.11
35.38
26.535

1792
ARG232
CD
47.139
34.331
26.134

1793
ARG232
NE
46.706
32.995
26.569

1794
ARG232
CZ
47.18
32.388
27.659

1795
ARG232
NH1
48.123
32.976
28.399

1796
ARG232
NH2
46.724
31.181
27.999

1797
ARG232
C
44.219
37.785
26.093

1798
ARG232
O
43.295
37.358
26.802

1799
PRO233
N
44.05
38.191
24.84

1800
PRO233
CA
42.715
38.497
24.304

1801
PRO233
CB
42.932
38.832
22.86

1802
PRO233
CG
44.423
38.917
22.585

1803
PRO233
CD
45.105
38.606
23.905

1804
PRO233
C
41.69
37.376
24.456

1805
PRO233
O
42.009
36.184
24.392

1806
GLU234
N
40.484
37.817
24.789

1807
GLU234
CA
39.278
36.977
24.919

1808
GLU234
CB
39.106
36.09
23.687

1809
GLU234
CG
38.852
36.909
22.426

1810
GLU234
CD
38.719
35.987
21.217

1811
GLU234
OE1
39.514
35.064
21.113

1812
GLU234
OE2
37.901
36.298
20.363

1813
GLU234
C
39.259
36.107
26.175

1814
GLU234
O
38.518
35.118
26.213

1815
LYS235
N
39.999
36.501
27.197

1816
LYS235
CA
39.978
35.76
28.459

1817
LYS235
CB
41.407
35.456
28.878

1818
LYS235
CG
42.028
34.359
28.028

1819
LYS235
CD
43.49
34.184
28.404

1820
LYS235
CE
43.668
34.018
29.907

1821
LYS235
NZ
45.096
33.997
30.255

1822
LYS235
C
39.299
36.532
29.579

1823
LYS235
O
39.113
37.754
29.504

1824
LEU236
N
38.936
35.779
30.602

1825
LEU236
CA
38.415
36.328
31.857

1826
LEU236
CB
38.096
35.155
32.777

1827
LEU236
CG
36.878
34.399
32.275

1828
LEU236
CD1
36.694
33.077
33.007

1829
LEU236
CD2
35.642
35.273
32.399

1830
LEU236
C
39.419
37.245
32.543

1831
LEU236
O
40.636
37.032
32.474

1832
PRO237
N
38.892
38.299
33.143

1833
PRO237
CA
39.686
39.157
34.015

1834
PRO237
CB
38.79
40.307
34.339

1835
PRO237
CG
37.388
40.016
33.837

1836
PRO237
CD
37.479
38.673
33.14

1837
PRO237
C
40.077
38.404
35.277

1838
PRO237
O
39.273
37.652
35.835

1839
ASP238
N
41.308
38.598
35.708

1840
ASP238
CA
41.799
37.909
36.908

1841
ASP238
CB
42.324
36.544
36.465

1842
ASP238
CG
42.739
35.677
37.649

1843
ASP238
OD1
43.81
35.932
38.187

1844
ASP238
OD2
42.022
34.735
37.955

1845
ASP238
C
42.903
38.747
37.545

1846
ASP238
O
43.809
39.188
36.83

1847
VAL239
N
42.946
38.816
38.868

1848
VAL239
CA
43.89
39.735
39.531

1849
VAL239
CB
43.523
39.876
41.003

1850
VAL239
CG1
42.254
40.697
41.176

1851
VAL239
CG2
43.398
38.525
41.69

1852
VAL239
C
45.386
39.401
39.409

1853
VAL239
O
46.179
40.347
39.48

1854
CYS240
N
45.776
38.204
38.991

1855
CYS240
CA
47.214
37.99
38.77

1856
CYS240
CB
47.572
36.506
38.842

1857
CYS240
SG
46.878
35.394
37.595

1858
CYS240
C
47.644
38.581
37.428

1859
CYS240
O
48.65
39.299
37.381

1860
TYR241
N
46.71
38.609
36.49

1861
TYR241
CA
46.979
39.173
35.169

1862
TYR241
CB
46.015
38.553
34.168

1863
TYR241
CG
46.153
37.044
33.993

1864
TYR241
CD1
45.052
36.221
34.196

1865
TYR241
CE1
45.174
34.847
34.037

1866
TYR241
CZ
46.397
34.302
33.668

1867
TYR241
OH
46.523
32.937
33.523

1868
TYR241
CE2
47.495
35.123
33.452

1869
TYR241
CD2
47.371
36.496
33.613

1870
TYR241
C
46.755
40.673
35.212

1871
TYR241
O
47.52
41.434
34.607

1872
SER242
N
45.921
41.076
36.155

1873
SER242
CA
45.677
42.492
36.405

1874
SER242
CB
44.526
42.639
37.393

1875
SER242
OG
43.373
42.029
36.826

1876
SER242
C
46.927
43.147
36.971

1877
SER242
O
47.392
44.127
36.379

1878
TRP243
N
47.607
42.472
37.885

1879
TRP243
CA
48.855
43.027
38.414

1880
TRP243
CB
49.265
42.296
39.687

1881
TRP243
CG
50.708
42.579
40.072

1882
TRP243
CD1
51.751
41.68
40.048

1883
TRP243
NE1
52.884
42.322
40.424

1884
TRP243
CE2
52.641
43.616
40.699

1885
TRP243
CZ2
53.461
44.664
41.091

1886
TRP243
CH2
52.917
45.926
41.293

1887
TRP243
CZ3
51.557
46.143
41.103

1888
TRP243
CE3
50.727
45.1
40.71

1889
TRP243
CD2
51.265
43.839
40.506

1890
TRP243
C
50.004
42.943
37.416

1891
TRP243
O
50.725
43.936
37.265

1892
TRP244
N
50.044
41.908
36.594

1893
TRP244
CA
51.157
41.792
35.645

1894
TRP244
CB
51.203
40.369
35.102

1895
TRP244
CG
51.608
39.348
36.148

1896
TRP244
CD1
52.419
39.57
37.238

1897
TRP244
NE1
52.536
38.413
37.934

1898
TRP244
CE2
51.837
37.422
37.35

1899
TRP244
CZ2
51.646
36.088
37.676

1900
TRP244
CH2
50.853
35.286
36.863

1901
TRP244
CZ3
50.252
35.817
35.727

1902
TRP244
CE3
50.436
37.153
35.394

1903
TRP244
CD2
51.227
37.955
36.201

1904
TRP244
C
51.053
42.804
34.507

1905
TRP244
O
52.042
43.492
34.221

1906
VAL245
N
49.834
43.103
34.089

1907
VAL245
CA
49.639
44.115
33.051

1908
VAL245
CB
48.261
43.918
32.429

1909
VAL245
CG1
47.894
45.083
31.523

1910
VAL245
CG2
48.162
42.604
31.669

1911
VAL245
C
49.742
45.526
33.622

1912
VAL245
O
50.425
46.364
33.022

1913
LEU246
N
49.348
45.688
34.876

1914
LEU246
CA
49.403
46.996
35.537

1915
LEU246
CB
48.655
46.866
36.86

1916
LEU246
CG
48.499
48.193
37.587

1917
LEU246
CD1
47.577
49.118
36.803

1918
LEU246
CD2
47.946
47.966
38.989

1919
LEU246
C
50.841
47.405
35.833

1920
LEU246
O
51.265
48.507
35.46

1921
ALA247
N
51.635
46.438
36.256

1922
ALA247
CA
53.027
46.712
36.587

1923
ALA247
CB
53.55
45.571
37.442

1924
ALA247
C
53.889
46.871
35.344

1925
ALA247
O
54.648
47.843
35.288

1926
SER248
N
53.549
46.174
34.27

1927
SER248
CA
54.3
46.342
33.019

1928
SER248
CB
54.031
45.151
32.112

1929
SER248
OG
54.539
43.996
32.76

1930
SER248
C
53.908
47.624
32.29

1931
SER248
O
54.78
48.288
31.717

1932
LEU249
N
52.706
48.101
32.565

1933
LEU249
CA
52.229
49.354
31.989

1934
LEU249
CB
50.715
49.36
32.161

1935
LEU249
CG
50.019
50.297
31.19

1936
LEU249
CD1
50.396
49.964
29.754

1937
LEU249
CD2
48.508
50.232
31.369

1938
LEU249
C
52.865
50.536
32.719

1939
LEU249
O
53.298
51.5
32.073

1940
LYS250
N
53.184
50.324
33.986

1941
LYS250
CA
53.925
51.322
34.759

1942
LYS250
CB
53.729
51.002
36.237

1943
LYS250
CG
54.551
51.917
37.138

1944
LYS250
CD
54.169
53.383
36.975

1945
LYS250
CE
55.018
54.266
37.88

1946
LYS250
NZ
54.875
53.855
39.285

1947
LYS250
C
55.416
51.308
34.419

1948
LYS250
O
55.999
52.383
34.231

1949
ILE251
N
55.937
50.144
34.059

1950
ILE251
CA
57.351
50.027
33.678

1951
ILE251
CB
57.722
48.542
33.671

1952
ILE251
CG2
59.112
48.315
33.084

1953
ILE251
CG1
57.649
47.952
35.073

1954
ILE251
CD1
57.92
46.453
35.062

1955
ILE251
C
57.637
50.636
32.305

1956
ILE251
O
58.722
51.194
32.092

1957
ILE252
N
56.634
50.665
31.442

1958
ILE252
CA
56.806
51.297
30.134

1959
ILE252
CB
56.091
50.466
29.076

1960
ILE252
CG2
56.634
49.043
29.069

1961
ILE252
CG1
54.587
50.449
29.292

1962
ILE252
CD1
53.904
49.556
28.268

1963
ILE252
C
56.322
52.75
30.099

1964
ILE252
O
56.389
53.383
29.039

1965
GLY253
N
55.821
53.259
31.217

1966
GLY253
CA
55.406
54.668
31.309

1967
GLY253
C
53.93
54.91
30.992

1968
GLY253
O
53.345
55.905
31.441

1969
ARG254
N
53.295
53.919
30.389

1970
ARG254
CA
51.939
54.061
29.845

1971
ARG254
CB
51.82
53.177
28.614

1972
ARG254
CG
52.849
53.56
27.564

1973
ARG254
CD
52.656
54.994
27.085

1974
ARG254
NE
53.692
55.354
26.108

1975
ARG254
CZ
54.796
56.032
26.431

1976
ARG254
NH1
54.983
56.449
27.686

1977
ARG254
NH2
55.701
56.314
25.493

1978
ARG254
C
50.841
53.683
30.83

1979
ARG254
O
49.722
53.365
30.405

1980
LEU255
N
51.079
53.903
32.115

1981
LEU255
CA
50.122
53.489
33.152

1982
LEU255
CB
50.802
53.587
34.513

1983
LEU255
CG
49.936
52.955
35.595

1984
LEU255
CD1
49.734
51.475
35.306

1985
LEU255
CD2
50.531
53.15
36.985

1986
LEU255
C
48.867
54.366
33.154

1987
LEU255
O
47.778
53.872
33.466

1988
HIS256
N
48.975
55.508
32.495

1989
HIS256
CA
47.874
56.46
32.333

1990
HIS256
CB
48.494
57.805
31.953

1991
HIS256
CG
49.486
57.746
30.8

1992
HIS256
ND1
50.829
57.847
30.882

1993
HIS256
CE1
51.362
57.745
29.648

1994
HIS256
NE2
50.343
57.592
28.773

1995
HIS256
CD2
49.183
57.603
29.466

1996
HIS256
C
46.842
56.041
31.275

1997
HIS256
O
45.869
56.77
31.054

1998
TRP257
N
47.066
54.919
30.604

1999
TRP257
CA
46.067
54.392
29.674

2000
TRP257
CB
46.761
53.764
28.469

2001
TRP257
CG
47.306
54.766
27.47

2002
TRP257
CD1
46.924
56.082
27.333

2003
TRP257
NE1
47.642
56.637
26.324

2004
TRP257
CE2
48.48
55.74
25.772

2005
TRP257
CZ2
49.39
55.819
24.728

2006
TRP257
CH2
50.126
54.697
24.367

2007
TRP257
CZ3
49.955
53.496
25.049

2008
TRP257
CE3
49.048
53.408
26.099

2009
TRP257
CD2
48.312
54.525
26.462

2010
TRP257
C
45.151
53.359
30.331

2011
TRP257
O
44.166
52.939
29.711

2012
ILE258
N
45.453
52.953
31.554

2013
ILE258
CA
44.57
51.994
32.227

2014
ILE258
CB
45.409
51.032
33.077

2015
ILE258
CG2
45.788
51.633
34.426

2016
ILE258
CG1
44.685
49.707
33.293

2017
ILE258
CD1
44.452
48.992
31.966

2018
ILE258
C
43.54
52.751
33.07

2019
ILE258
O
43.832
53.818
33.626

2020
ASP259
N
42.31
52.269
33.073

2021
ASP259
CA
41.296
52.89
33.924

2022
ASP259
CB
39.902
52.613
33.369

2023
ASP259
CG
38.872
53.465
34.104

2024
ASP259
OD1
38.67
53.204
35.286

2025
ASP259
OD2
38.451
54.462
33.54

2026
ASP259
C
41.443
52.338
35.338

2027
ASP259
O
40.881
51.287
35.69

2028
ARG260
N
42.021
53.168
36.19

2029
ARG260
CA
42.351
52.748
37.552

2030
ARG260
CB
43.276
53.793
38.159

2031
ARG260
CG
44.569
53.928
37.366

2032
ARG260
CD
45.47
54.977
38.003

2033
ARG260
NE
46.75
55.115
37.29

2034
ARG260
CZ
47.088
56.219
36.619

2035
ARG260
NH1
46.202
57.205
36.465

2036
ARG260
NH2
48.289
56.31
36.047

2037
ARG260
C
41.142
52.58
38.465

2038
ARG260
O
41.143
51.627
39.247

2039
GLU261
N
40.031
53.234
38.159

2040
GLU261
CA
38.859
53.123
39.035

2041
GLU261
CB
37.947
54.322
38.809

2042
GLU261
CG
38.639
55.636
39.157

2043
GLU261
CD
39.093
55.636
40.615

2044
GLU261
OE1
38.24
55.783
41.478

2045
GLU261
OE2
40.292
55.525
40.828

2046
GLU261
C
38.077
51.84
38.776

2047
GLU261
O
37.568
51.229
39.725

2048
LYS262
N
38.165
51.33
37.56

2049
LYS262
CA
37.495
50.07
37.25

2050
LYS262
CB
37.232
49.999
35.753

2051
LYS262
CG
36.219
51.042
35.306

2052
LYS262
CD
35.952
50.925
33.811

2053
LYS262
CE
34.942
51.964
33.342

2054
LYS262
NZ
34.685
51.829
31.899

2055
LYS262
C
38.345
48.882
37.675

2056
LYS262
O
37.803
47.93
38.248

2057
LEU263
N
39.657
49.056
37.657

2058
LEU263
CA
40.531
47.962
38.078

2059
LEU263
CB
41.932
48.188
37.524

2060
LEU263
CG
42.86
47.037
37.897

2061
LEU263
CD1
42.278
45.694
37.466

2062
LEU263
CD2
44.25
47.24
37.308

2063
LEU263
C
40.569
47.888
39.597

2064
LEU263
O
40.441
46.793
40.158

2065
ARG264
N
40.405
49.04
40.224

2066
ARG264
CA
40.317
49.093
41.677

2067
ARG264
CB
40.356
50.545
42.134

2068
ARG264
CG
40.062
50.619
43.623

2069
ARG264
CD
40.165
52.03
44.185

2070
ARG264
NE
39.734
52.023
45.593

2071
ARG264
CZ
40.534
51.731
46.622

2072
ARG264
NH1
41.846
51.572
46.43

2073
ARG264
NH2
40.033
51.697
47.859

2074
ARG264
C
39.038
48.438
42.173

2075
ARG264
O
39.139
47.511
42.982

2076
ASN265
N
37.93
48.661
41.482

2077
ASN265
CA
36.668
48.048
41.908

2078
ASN265
CB
35.492
48.829
41.333

2079
ASN265
CG
35.129
49.997
42.251

2080
ASN265
OD1
34.476
49.808
43.284

2081
ASN265
ND2
35.572
51.187
41.881

2082
ASN265
C
36.563
46.569
41.541

2083
ASN265
O
35.943
45.818
42.304

2084
PHE266
N
37.365
46.109
40.595

2085
PHE266
CA
37.423
44.671
40.328

2086
PHE266
CB
38.068
44.45
38.968

2087
PHE266
CG
38.268
42.98
38.61

2088
PHE266
CD1
37.201
42.234
38.127

2089
PHE266
CE1
37.381
40.897
37.8

2090
PHE266
CZ
38.628
40.306
37.956

2091
PHE266
CE2
39.697
41.052
38.434

2092
PHE266
CD2
39.517
42.39
38.76

2093
PHE266
C
38.242
43.951
41.396

2094
PHE266
O
37.817
42.898
41.886

2095
ILE267
N
39.251
44.628
41.918

2096
ILE267
CA
40.071
44.044
42.98

2097
ILE267
CB
41.414
44.766
42.98

2098
ILE267
CG2
42.315
44.234
44.081

2099
ILE267
CG1
42.111
44.612
41.634

2100
ILE267
CD1
43.459
45.326
41.627

2101
ILE267
C
39.382
44.166
44.343

2102
ILE267
O
39.485
43.249
45.169

2103
LEU268
N
38.482
45.13
44.461

2104
LEU268
CA
37.645
45.245
45.66

2105
LEU268
CB
36.966
46.612
45.659

2106
LEU268
CG
37.939
47.78
45.775

2107
LEU268
CD1
37.249
49.097
45.444

2108
LEU268
CD2
38.594
47.851
47.148

2109
LEU268
C
36.57
44.159
45.664

2110
LEU268
O
36.359
43.513
46.698

2111
ALA269
N
36.14
43.775
44.471

2112
ALA269
CA
35.165
42.694
44.301

2113
ALA269
CB
34.566
42.827
42.904

2114
ALA269
C
35.763
41.294
44.457

2115
ALA269
O
35.019
40.313
44.579

2116
CYS270
N
37.082
41.206
44.522

2117
CYS270
CA
37.739
39.927
44.785

2118
CYS270
CB
39.056
39.868
44.02

2119
CYS270
SG
38.912
39.869
42.22

2120
CYS270
C
38.009
39.71
46.273

2121
CYS270
O
38.47
38.622
46.642

2122
GLN271
N
37.717
40.696
47.108

2123
GLN271
CA
37.932
40.538
48.552

2124
GLN271
CB
37.871
41.908
49.217

2125
GLN271
CG
38.867
42.853
48.569

2126
GLN271
CD
38.911
44.207
49.266

2127
GLN271
OE1
38.288
44.432
50.309

2128
GLN271
NE2
39.785
45.05
48.748

2129
GLN271
C
36.856
39.657
49.168

2130
GLN271
O
35.669
39.793
48.851

2131
ASP272
N
37.265
38.715
49.995

2132
ASP272
CA
36.256
37.952
50.724

2133
ASP272
CB
36.746
36.522
50.939

2134
ASP272
CG
35.623
35.521
51.191

2135
ASP272
OD1
34.541
35.956
51.577

2136
ASP272
OD2
35.795
34.375
50.796

2137
ASP272
C
36.002
38.671
52.044

2138
ASP272
O
36.919
39.144
52.725

2139
GLU273
N
34.728
38.834
52.355

2140
GLU273
CA
34.356
39.462
53.622

2141
GLU273
CB
32.971
40.076
53.462

2142
GLU273
CG
33.01
41.15
52.379

2143
GLU273
CD
31.612
41.669
52.066

2144
GLU273
OE1
30.702
40.852
52.075

2145
GLU273
OE2
31.509
42.82
51.666

2146
GLU273
C
34.394
38.415
54.729

2147
GLU273
O
34.71
38.717
55.885

2148
GLU274
N
34.236
37.167
54.323

2149
GLU274
CA
34.507
36.046
55.219

2150
GLU274
CB
33.689
34.837
54.776

2151
GLU274
CG
32.196
35.146
54.719

2152
GLU274
CD
31.661
35.505
56.103

2153
GLU274
OE1
32.124
34.911
57.067

2154
GLU274
OE2
30.793
36.364
56.165

2155
GLU274
C
35.992
35.729
55.111

2156
GLU274
O
36.461
35.35
54.032

2157
THR275
N
36.687
35.867
56.231

2158
THR275
CA
38.156
35.712
56.348

2159
THR275
CB
38.529
34.268
56.721

2160
THR275
OG1
39.945
34.189
56.84

2161
THR275
CG2
38.069
33.195
55.735

2162
THR275
C
38.951
36.227
55.137

2163
THR275
O
39.538
35.458
54.366

2164
GLY276
N
38.914
37.546
54.999

2165
GLY276
CA
39.692
38.336
54.025

2166
GLY276
C
40.156
37.662
52.742

2167
GLY276
O
39.373
37.067
51.998

2168
GLY277
N
41.436
37.839
52.464

2169
GLY277
CA
42.047
37.342
51.224

2170
GLY277
C
41.424
37.88
49.931

2171
GLY277
O
40.34
38.48
49.91

2172
PHE278
N
42.177
37.697
48.861

2173
PHE278
CA
41.684
37.991
47.511

2174
PHE278
CB
42.632
38.924
46.773

2175
PHE278
CG
42.68
40.37
47.25

2176
PHE278
CD1
43.555
40.752
48.257

2177
PHE278
CE1
43.605
42.074
48.671

2178
PHE278
CZ
42.784
43.019
48.074

2179
PHE278
CE2
41.911
42.638
47.066

2180
PHE278
CD2
41.858
41.314
46.652

2181
PHE278
C
41.549
36.711
46.696

2182
PHE278
O
42.362
35.781
46.812

2183
ALA279
N
40.448
36.649
45.972

2184
ALA279
CA
40.16
35.56
45.04

2185
ALA279
CB
38.649
35.45
44.917

2186
ALA279
C
40.757
35.863
43.672

2187
ALA279
O
41.172
36.997
43.409

2188
ASP280
N
40.806
34.858
42.814

2189
ASP280
CA
41.357
35.064
41.465

2190
ASP280
CB
41.688
33.711
40.811

2191
ASP280
CG
40.527
32.72
40.702

2192
ASP280
OD1
40.202
32.1
41.707

2193
ASP280
OD2
39.935
32.652
39.636

2194
ASP280
C
40.414
35.918
40.612

2195
ASP280
O
40.849
36.882
39.961

2196
ARG281
N
39.133
35.599
40.695

2197
ARG281
CA
38.051
36.411
40.148

2198
ARG281
CB
37.463
35.679
38.942

2199
ARG281
CG
38.52
35.426
37.875

2200
ARG281
CD
37.938
34.729
36.654

2201
ARG281
NE
37.351
33.434
37.02

2202
ARG281
CZ
37.887
32.27
36.655

2203
ARG281
NH1
39.006
32.249
35.925

2204
ARG281
NH2
37.305
31.124
37.016

2205
ARG281
C
37.013
36.544
41.261

2206
ARG281
O
37.01
35.706
42.175

2207
PRO282
N
36.16
37.557
41.196

2208
PRO282
CA
35.226
37.842
42.294

2209
PRO282
CB
34.381
38.98
41.808

2210
PRO282
CG
34.908
39.464
40.468

2211
PRO282
CD
36.076
38.556
40.128

2212
PRO282
C
34.373
36.63
42.651

2213
PRO282
O
34.098
35.785
41.793

2214
GLY283
N
34.206
36.415
43.945

2215
GLY283
CA
33.38
35.295
44.423

2216
GLY283
C
34.154
34
44.702

2217
GLY283
O
33.731
33.201
45.546

2218
ASP284
N
35.241
33.777
43.976

2219
ASP284
CA
36.042
32.554
44.128

2220
ASP284
CB
37.148
32.535
43.081

2221
ASP284
CG
36.594
32.578
41.663

2222
ASP284
OD1
35.6
31.912
41.415

2223
ASP284
OD2
37.296
33.125
40.824

2224
ASP284
C
36.71
32.456
45.493

2225
ASP284
O
36.668
33.383
46.312

2226
MET285
N
37.282
31.289
45.735

2227
MET285
CA
38.07
31.065
46.947

2228
MET285
CB
38.543
29.617
46.972

2229
MET285
CG
37.371
28.643
46.987

2230
MET285
SD
37.825
26.894
47.02

2231
MET285
CE
38.777
26.876
48.557

2232
MET285
C
39.279
31.991
46.965

2233
MET285
O
39.856
32.312
45.919

2234
VAL286
N
39.565
32.506
48.146

2235
VAL286
CA
40.704
33.405
48.327

2236
VAL286
CB
40.371
34.354
49.467

2237
VAL286
CG1
39.192
35.22
49.058

2238
VAL286
CG2
40.054
33.601
50.754

2239
VAL286
C
41.993
32.639
48.597

2240
VAL286
O
41.972
31.514
49.111

2241
ASP287
N
43.099
33.213
48.155

2242
ASP287
CA
44.407
32.565
48.34

2243
ASP287
CB
44.591
31.524
47.23

2244
ASP287
CG
44.683
32.182
45.858

2245
ASP287
OD1
43.695
32.19
45.14

2246
ASP287
OD2
45.759
32.684
45.55

2247
ASP287
C
45.538
33.598
48.324

2248
ASP287
O
45.434
34.605
47.616

2249
PRO288
N
46.658
33.292
48.968

2250
PRO288
CA
47.727
34.292
49.169

2251
PRO288
CB
48.708
33.634
50.091

2252
PRO288
CG
48.253
32.217
50.394

2253
PRO288
CD
46.928
32.036
49.676

2254
PRO288
C
48.45
34.773
47.899

2255
PRO288
O
48.891
35.927
47.875

2256
PHE289
N
48.353
34.028
46.808

2257
PHE289
CA
48.962
34.433
45.535

2258
PHE289
CB
48.838
33.229
44.603

2259
PHE289
CG
49.372
33.374
43.18

2260
PHE289
CD1
50.734
33.506
42.951

2261
PHE289
CE1
51.216
33.612
41.653

2262
PHE289
CZ
50.334
33.586
40.581

2263
PHE289
CE2
48.971
33.455
40.808

2264
PHE289
CD2
48.491
33.347
42.107

2265
PHE289
C
48.213
35.631
44.958

2266
PHE289
O
48.783
36.722
44.821

2267
HIS290
N
46.896
35.508
44.968

2268
HIS290
CA
46.032
36.582
44.483

2269
HIS290
CB
44.721
35.971
44.008

2270
HIS290
CG
44.899
35.089
42.79

2271
HIS290
ND1
44.744
33.754
42.729

2272
HIS290
CE1
44.997
33.33
41.475

2273
HIS290
NE2
45.304
34.417
40.733

2274
HIS290
CD2
45.248
35.508
41.529

2275
HIS290
C
45.769
37.636
45.552

2276
HIS290
O
45.434
38.774
45.213

2277
THR291
N
46.122
37.341
46.791

2278
THR291
CA
46.007
38.343
47.849

2279
THR291
CB
45.971
37.653
49.206

2280
THR291
OG1
44.836
36.799
49.22

2281
THR291
CG2
45.816
38.659
50.342

2282
THR291
C
47.175
39.316
47.782

2283
THR291
O
46.955
40.533
47.85

2284
LEU292
N
48.32
38.814
47.348

2285
LEU292
CA
49.477
39.68
47.138

2286
LEU292
CB
50.719
38.808
46.976

2287
LEU292
CG
51.947
39.635
46.603

2288
LEU292
CD1
52.224
40.72
47.635

2289
LEU292
CD2
53.174
38.751
46.412

2290
LEU292
C
49.282
40.532
45.891

2291
LEU292
O
49.485
41.751
45.959

2292
PHE293
N
48.634
39.974
44.882

2293
PHE293
CA
48.42
40.743
43.652

2294
PHE293
CB
48.223
39.776
42.494

2295
PHE293
CG
49.469
38.952
42.185

2296
PHE293
CD1
49.341
37.654
41.715

2297
PHE293
CE1
50.475
36.906
41.432

2298
PHE293
CZ
51.737
37.45
41.623

2299
PHE293
CE2
51.867
38.748
42.096

2300
PHE293
CD2
50.733
39.498
42.375

2301
PHE293
C
47.239
41.705
43.76

2302
PHE293
O
47.279
42.781
43.154

2303
GLY294
N
46.34
41.442
44.692

2304
GLY294
CA
45.253
42.374
44.981

2305
GLY294
C
45.783
43.59
45.73

2306
GLY294
O
45.597
44.73
45.283

2307
ILE295
N
46.596
43.329
46.741

2308
ILE295
CA
47.18
44.399
47.558

2309
ILE295
CB
47.809
43.728
48.777

2310
ILE295
CG2
48.766
44.652
49.516

2311
ILE295
CG1
46.732
43.22
49.727

2312
ILE295
CD1
45.906
44.365
50.302

2313
ILE295
C
48.216
45.228
46.793

2314
ILE295
O
48.145
46.465
46.831

2315
ALA296
N
48.97
44.586
45.915

2316
ALA296
CA
49.948
45.312
45.1

2317
ALA296
CB
50.926
44.304
44.509

2318
ALA296
C
49.266
46.088
43.977

2319
ALA296
O
49.598
47.259
43.747

2320
GLY297
N
48.18
45.526
43.471

2321
GLY297
CA
47.353
46.187
42.462

2322
GLY297
C
46.775
47.481
43.011

2323
GLY297
O
47.107
48.557
42.5

2324
LEU298
N
46.138
47.395
44.169

2325
LEU298
CA
45.531
48.579
44.788

2326
LEU298
CB
44.743
48.153
46.02

2327
LEU298
CG
43.52
47.325
45.651

2328
LEU298
CD1
42.813
46.814
46.9

2329
LEU298
CD2
42.56
48.126
44.78

2330
LEU298
C
46.561
49.624
45.204

2331
LEU298
O
46.345
50.808
44.907

2332
SER299
N
47.742
49.205
45.629

2333
SER299
CA
48.766
50.182
46.009

2334
SER299
CB
49.912
49.465
46.705

2335
SER299
OG
50.832
50.461
47.127

2336
SER299
C
49.321
50.932
44.801

2337
SER299
O
49.404
52.165
44.859

2338
LEU300
N
49.395
50.264
43.658

2339
LEU300
CA
49.879
50.912
42.431

2340
LEU300
CB
50.432
49.827
41.507

2341
LEU300
CG
51.271
50.412
40.372

2342
LEU300
CD1
52.473
51.167
40.927

2343
LEU300
CD2
51.731
49.328
39.405

2344
LEU300
C
48.765
51.696
41.719

2345
LEU300
O
49.046
52.546
40.865

2346
LEU301
N
47.525
51.479
42.134

2347
LEU301
CA
46.394
52.268
41.63

2348
LEU301
CB
45.132
51.411
41.668

2349
LEU301
CG
45.205
50.246
40.691

2350
LEU301
CD1
44.053
49.275
40.911

2351
LEU301
CD2
45.24
50.733
39.249

2352
LEU301
C
46.152
53.53
42.459

2353
LEU301
O
45.396
54.41
42.03

2354
GLY302
N
46.785
53.624
43.618

2355
GLY302
CA
46.681
54.846
44.422

2356
GLY302
C
46.209
54.599
45.854

2357
GLY302
O
45.822
55.543
46.557

2358
GLU303
N
46.208
53.348
46.281

2359
GLU303
CA
45.812
53.052
47.661

2360
GLU303
CB
45.241
51.636
47.745

2361
GLU303
CG
44.821
51.216
49.155

2362
GLU303
CD
43.859
52.219
49.782

2363
GLU303
OE1
42.661
51.998
49.714

2364
GLU303
OE2
44.356
53.158
50.394

2365
GLU303
C
46.999
53.24
48.603

2366
GLU303
O
47.681
52.273
48.962

2367
GLU304
N
46.991
54.409
49.227

2368
GLU304
CA
48.064
54.869
50.124

2369
GLU304
CB
47.977
56.388
50.206

2370
GLU304
CG
46.613
56.843
50.713

2371
GLU304
CD
46.537
58.367
50.721

2372
GLU304
OE1
45.729
58.888
51.476

2373
GLU304
OE2
47.203
58.968
49.891

2374
GLU304
C
48.035
54.281
51.541

2375
GLU304
O
48.833
54.698
52.386

2376
GLN305
N
47.101
53.384
51.819

2377
GLN305
CA
47.142
52.624
53.073

2378
GLN305
CB
45.746
52.098
53.385

2379
GLN305
CG
44.735
53.217
53.596

2380
GLN305
CD
43.349
52.609
53.788

2381
GLN305
OE1
43.183
51.628
54.52

2382
GLN305
NE2
42.386
53.146
53.06

2383
GLN305
C
48.084
51.431
52.921

2384
GLN305
O
48.559
50.864
53.911

2385
ILE306
N
48.364
51.083
51.676

2386
ILE306
CA
49.302
50.013
51.367

2387
ILE306
CB
48.686
49.172
50.254

2388
ILE306
CG2
49.573
47.983
49.912

2389
ILE306
CG1
47.295
48.69
50.648

2390
ILE306
CD1
46.632
47.932
49.505

2391
ILE306
C
50.613
50.629
50.892

2392
ILE306
O
50.611
51.5
50.013

2393
LYS307
N
51.713
50.165
51.464

2394
LYS307
CA
53.043
50.639
51.069

2395
LYS307
CB
54.093
49.846
51.84

2396
LYS307
CG
53.949
50.058
53.341

2397
LYS307
CD
55.022
49.301
54.111

2398
LYS307
CE
54.863
49.495
55.614

2399
LYS307
NZ
55.865
48.715
56.357

2400
LYS307
C
53.25
50.45
49.571

2401
LYS307
O
52.791
49.458
48.991

2402
PRO308
N
53.893
51.429
48.953

2403
PRO308
CA
54.059
51.432
47.498

2404
PRO308
CB
54.815
52.685
47.183

2405
PRO308
CG
55.073
53.451
48.472

2406
PRO308
CD
54.442
52.631
49.585

2407
PRO308
C
54.81
50.192
47.042

2408
PRO308
O
55.782
49.77
47.681

2409
VAL309
N
54.282
49.559
46.012

2410
VAL309
CA
54.893
48.337
45.496

2411
VAL309
CB
53.782
47.31
45.292

2412
VAL309
CG1
52.667
47.871
44.419

2413
VAL309
CG2
54.304
45.985
44.746

2414
VAL309
C
55.665
48.611
44.206

2415
VAL309
O
55.172
49.255
43.272

2416
ASN310
N
56.909
48.172
44.214

2417
ASN310
CA
57.79
48.283
43.055

2418
ASN310
CB
59.194
47.942
43.547

2419
ASN310
CG
60.216
47.897
42.416

2420
ASN310
OD1
60.203
46.971
41.591

2421
ASN310
ND2
61.119
48.86
42.422

2422
ASN310
C
57.346
47.311
41.971

2423
ASN310
O
57.44
46.09
42.155

2424
PRO311
N
57.077
47.85
40.791

2425
PRO311
CA
56.422
47.09
39.715

2426
PRO311
CB
55.968
48.131
38.738

2427
PRO311
CG
56.518
49.487
39.146

2428
PRO311
CD
57.241
49.269
40.462

2429
PRO311
C
57.309
46.056
39.004

2430
PRO311
O
56.789
45.237
38.241

2431
VAL312
N
58.594
46.018
39.316

2432
VAL312
CA
59.491
45.052
38.691

2433
VAL312
CB
60.82
45.762
38.461

2434
VAL312
CG1
61.908
44.807
37.99

2435
VAL312
CG2
60.654
46.924
37.492

2436
VAL312
C
59.706
43.835
39.586

2437
VAL312
O
59.618
42.693
39.12

2438
PHE313
N
59.864
44.081
40.877

2439
PHE313
CA
60.187
42.992
41.809

2440
PHE313
CB
61.265
43.476
42.774

2441
PHE313
CG
62.615
43.798
42.139

2442
PHE313
CD1
62.982
45.117
41.902

2443
PHE313
CE1
64.213
45.403
41.327

2444
PHE313
CZ
65.081
44.37
40.998

2445
PHE313
CE2
64.72
43.053
41.247

2446
PHE313
CD2
63.488
42.767
41.82

2447
PHE313
C
58.995
42.51
42.631

2448
PHE313
O
59.098
41.472
43.297

2449
CYS314
N
57.912
43.273
42.599

2450
CYS314
CA
56.711
43.024
43.418

2451
CYS314
CB
56.06
41.705
43.004

2452
CYS314
SG
54.437
41.355
43.723

2453
CYS314
C
57.073
43.027
44.906

2454
CYS314
O
56.716
42.124
45.668

2455
MET315
N
57.829
44.043
45.29

2456
MET315
CA
58.271
44.201
46.681

2457
MET315
CB
59.775
43.939
46.766

2458
MET315
CG
60.14
42.489
46.474

2459
MET315
SD
61.893
42.094
46.663

2460
MET315
CE
62.08
42.498
48.415

2461
MET315
C
57.978
45.62
47.146

2462
MET315
O
57.768
46.501
46.306

2463
PRO316
N
57.888
45.833
48.449

2464
PRO316
CA
57.776
47.198
48.967

2465
PRO316
CB
57.767
47.065
50.457

2466
PRO316
CG
57.833
45.59
50.822

2467
PRO316
CD
57.939
44.827
49.513

2468
PRO316
C
58.921
48.081
48.478

2469
PRO316
O
60.109
47.752
48.616

2470
GLU317
N
58.537
49.273
48.054

2471
GLU317
CA
59.458
50.231
47.437

2472
GLU317
CB
58.656
51.47
47.055

2473
GLU317
CG
59.399
52.336
46.045

2474
GLU317
CD
59.31
51.675
44.678

2475
GLU317
OE1
58.257
51.118
44.404

2476
GLU317
OE2
60.271
51.741
43.921

2477
GLU317
C
60.562
50.662
48.391

2478
GLU317
O
61.735
50.555
48.021

2479
GLU318
N
60.232
50.779
49.669

2480
GLU318
CA
61.221
51.22
50.659

2481
GLU318
CB
60.482
51.685
51.911

2482
GLU318
CG
59.622
50.584
52.522

2483
GLU318
CD
58.833
51.135
53.706

2484
GLU318
OE1
58.506
50.346
54.58

2485
GLU318
OE2
58.427
52.284
53.618

2486
GLU318
C
62.265
50.155
51.021

2487
GLU318
O
63.376
50.528
51.412

2488
VAL319
N
62.031
48.904
50.652

2489
VAL319
CA
63.021
47.866
50.927

2490
VAL319
CB
62.3
46.53
51.068

2491
VAL319
CG1
63.288
45.382
51.243

2492
VAL319
CG2
61.314
46.574
52.228

2493
VAL319
C
64.019
47.81
49.78

2494
VAL319
O
65.232
47.726
50.015

2495
LEU320
N
63.543
48.196
48.607

2496
LEU320
CA
64.409
48.232
47.431

2497
LEU320
CB
63.552
48.006
46.197

2498
LEU320
CG
62.901
46.633
46.277

2499
LEU320
CD1
61.914
46.423
45.144

2500
LEU320
CD2
63.951
45.529
46.28

2501
LEU320
C
65.161
49.554
47.358

2502
LEU320
O
66.308
49.585
46.895

2503
GLN321
N
64.645
50.546
48.062

2504
GLN321
CA
65.392
51.787
48.265

2505
GLN321
CB
64.432
52.844
48.791

2506
GLN321
CG
63.324
53.166
47.799

2507
GLN321
CD
62.241
53.956
48.524

2508
GLN321
OE1
61.048
53.849
48.211

2509
GLN321
NE2
62.662
54.652
49.565

2510
GLN321
C
66.498
51.591
49.299

2511
GLN321
O
67.619
52.064
49.084

2512
ARG322
N
66.259
50.719
50.266

2513
ARG322
CA
67.257
50.455
51.309

2514
ARG322
CB
66.561
49.715
52.446

2515
ARG322
CG
67.543
49.308
53.538

2516
ARG322
CD
66.855
48.523
54.649

2517
ARG322
NE
67.832
48.089
55.66

2518
ARG322
CZ
67.913
48.623
56.881

2519
ARG322
NH1
67.07
49.591
57.245

2520
ARG322
NH2
68.831
48.179
57.742

2521
ARG322
C
68.423
49.612
50.793

2522
ARG322
O
69.581
49.875
51.139

2523
VAL323
N
68.141
48.714
49.861

2524
VAL323
CA
69.218
47.926
49.251

2525
VAL323
CB
68.723
46.508
48.984

2526
VAL323
CG1
68.421
45.787
50.293

2527
VAL323
CG2
67.505
46.492
48.07

2528
VAL323
C
69.771
48.564
47.973

2529
VAL323
O
70.749
48.053
47.413

2530
ASN324
N
69.228
49.717
47.604

2531
ASN324
CA
69.642
50.478
46.413

2532
ASN324
CB
71.082
50.964
46.579

2533
ASN324
CG
71.19
51.955
47.736

2534
ASN324
OD1
70.782
53.116
47.613

2535
ASN324
ND2
71.809
51.509
48.818

2536
ASN324
C
69.498
49.667
45.13

2537
ASN324
O
70.41
49.614
44.296

2538
VAL325
N
68.321
49.093
44.951

2539
VAL325
CA
68.017
48.324
43.742

2540
VAL325
CB
67.85
46.841
44.078

2541
VAL325
CG1
67.643
46.023
42.809

2542
VAL325
CG2
69.065
46.3
44.823

2543
VAL325
C
66.752
48.894
43.107

2544
VAL325
O
65.658
48.32
43.17

2545
GLN326
N
66.921
50.071
42.53

2546
GLN326
CA
65.801
50.776
41.899

2547
GLN326
CB
65.739
52.189
42.474

2548
GLN326
CG
65.343
52.191
43.948

2549
GLN326
CD
63.876
51.794
44.104

2550
GLN326
OE1
63.514
51.013
44.992

2551
GLN326
NE2
63.04
52.375
43.261

2552
GLN326
C
65.941
50.843
40.381

2553
GLN326
O
66.745
51.617
39.85

2554
PRO327
N
65.116
50.063
39.702

2555
PRO327
CA
65.046
50.094
38.238

2556
PRO327
CB
64.162
48.944
37.87

2557
PRO327
CG
63.557
48.354
39.133

2558
PRO327
CD
64.142
49.142
40.289

2559
PRO327
C
64.466
51.413
37.732

2560
PRO327
O
63.543
51.978
38.334

2561
GLU328
N
65.004
51.89
36.624

2562
GLU328
CA
64.529
53.157
36.052

2563
GLU328
CB
65.71
53.912
35.454

2564
GLU328
CG
65.288
55.275
34.91

2565
GLU328
CD
66.489
55.969
34.28

2566
GLU328
OE1
67.6
55.584
34.621

2567
GLU328
OE2
66.282
56.888
33.5

2568
GLU328
C
63.491
52.908
34.966

2569
GLU328
O
63.842
52.713
33.8

2570
LEU329
N
62.228
53.029
35.338

2571
LEU329
CA
61.119
52.793
34.399

2572
LEU329
CB
59.807
52.832
35.175

2573
LEU329
CG
59.845
51.956
36.426

2574
LEU329
CD1
58.562
52.115
37.232

2575
LEU329
CD2
60.092
50.487
36.099

2576
LEU329
C
61.092
53.866
33.31

2577
LEU329
O
61.756
54.903
33.446

2578
VAL330
N
60.407
53.582
32.214

2579
VAL330
CA
60.291
54.567
31.129

2580
VAL330
CB
59.554
53.943
29.945

2581
VAL330
CG1
59.371
54.932
28.796

2582
VAL330
CG2
60.245
52.685
29.442

2583
VAL330
C
59.51
55.78
31.621

2584
VAL330
O
58.394
55.649
32.139

2585
SER331
N
60.135
56.939
31.528

2586
SER331
CA
59.479
58.179
31.939

2587
SER331
CB
60.269
58.798
33.082

2588
SER331
OG
59.633
60.024
33.412

2589
SER331
C
59.404
59.166
30.781

2590
SER331
O
60.341
59.197
29.998

2591
SER331
OXT
58.428
59.902
30.728

[0441]

	Number	Date	Country
	60476722	Jun 2003	US
	60401604	Aug 2002	US

Modulators of RabGGT and methods of use thereof

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Parent Case Info

Provisional Applications (2)