NOVEL METHODS OF GENERATING ANTIBODIES

Abstract

The invention describes a method of generating antibodies to a mixture of peptidogenic proteins wherein the peptidogenic protein has altered conformational dynamics as compared to a starting protein and wherein the peptidogenic protein has a similar conformation to the starting protein. The peptidogenic proteins can be used to induce an immune response, which can lead to the generation of antibodies and/or can be used to vaccinate a mammal.

Description

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 16, 2016, is named Combined_SA_01_PCT_ST25_V2.txt and is 10,883,263 bytes in size.

INTRODUCTION

Methods for making antibodies have been around for over 100 years and are routinely used by the skilled artisan. See, for example, Morrison et al., Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985). Improved methods for generating antibodies have extended these initial methods and have been used to generate many of the therapeutic antibodies now being sold commercially. For example, technologies such as phage display and transgenic mice, that is, mice containing the human immunoglobulin genes, have been used to generate fully human antibodies. However, certain antigens continue to challenge a researcher's ability to raise antibodies even when using the most current techniques.

To induce a cell-mediated immune response within the human body, foreign proteins are broken down into smaller peptides, usually between 8-24 amino acids in length, and are bound to MHC molecules, for display on the surface of antigen presenting cells. The MHC-bound peptides are presented to T-cells to trigger a cell mediated immune response.

The three-dimensional (3D) structure of proteins has been implicated as a factor in proteolytic processing and presentation of epitopes (see, Carmicle et al., Molecular Immunology (2007) vol. 44: 1159-1168). Moreover, Ohkuri et al. (see, Okhuri et al., J. Immunol., (2010), vol. 185: 4199-4205) agreed that conformational stability of a protein is an immunologically dominant factor. However, there is no consensus regarding exactly how the 3D structure affects the immune response.

Delamarre et al. (see, Delamarre et al., JEM, (2006), vol 203: 2049-2055) found that less digestible forms of proteins that were less susceptible to digestion via lysosomal proteolysis were more immunogenic, and therefore, concluded that increasing protein stability improved the immune response. For example, Delamarre et al. showed that the immunogenicity of protein antigens can be improved by reducing susceptibility to proteolysis. Similarly, Mirano-Bascos et al. (see, Mirano-Bascos et al., J. of Virology, (2010), vol. 84: 3303-3311) mutated cysteine residues to prevent each of three disulfide bonds from forming, and determined that the CD4+ T-cell response was broadly reduced for all three variants. Mirano-Bascos et al. similarly concluded that global destabilization of the 3-D structure of a protein reduced antigenic presentation and led to a suppressed immune response. In other studies, such as for example, Nguyen et al., Vaccine, (2015), vol. 33: 2887-2896, outer domain disulfide bonds were deleted with the expectation that such deletions would improve antigenic presentation. Instead, a typical pattern of epitope dominance was observed and the authors concluded that it may not be possible to generate a substantially stronger immune response.

Other groups similarly conclude that protein stabilization is needed for an immune response. For example, Deressa et al., (see, Deressa et al., PLOS, (2014), vol. 9: 1-12) concluded that even minor modifications in the amino acid sequence of an antigen caused fundamental quantitative and qualitative changes in the immune response. Likewise, Porta et al. (see, Porta et al., PLOS, (2013), vol. 9: 1-8) reported that stability is needed for inducing an immune response. Other groups such as Thomas (see, Thomas et al., Human Vaccines & Immunotherapeutics, (2013), vol. 9:744-752) similarly concluded that increasing thermal stability for peptides elicited a better immune response.

In contrast, other groups such as So (see, So et al., Immunology, (2001), vol. 104: 259-268) report conflicting results. So et al. investigated the effect of crosslinking (e.g., removing cross-links and adding crosslinks) on the magnitude of in vivo T-cell responses and found that removing such crosslinks led to better antigen processing and an improved immune response. Similarly, Thai et al., J. Biol. Chem. (2004) vol. 279: 50257-50266) reported mutating surface accessible residues to decrease stability and increase conformational dynamics to increase the immunogenicity of the protein antigen. Thai et al. is also directed towards administration of single antigens.

There is no consensus on whether removing or adding crosslinks improves or inhibits antigen processing. Accordingly, it is unclear in the art as to whether increasing or decreasing protein stability would lead to an improved immune response comprising a broad, diverse array of antibodies.

Thus, there continues to be a need to develop new and improved methods of generating antibodies which can provide a different and broader repertoire of antibodies than previously obtained.

SUMMARY OF THE INVENTION

This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject.

As described herein, the invention is directed towards a method of triggering an immune response wherein said method comprises designing a mixture of peptidogenic proteins derived from a starting protein, wherein the peptidogenic proteins have altered conformational dynamics as compared to the starting protein and wherein the peptidogenic proteins are similar in conformation to the starting protein, introducing the peptidogenic proteins to an animal and generating an immune response. The peptidogenic proteins can be introduced into the animals directly (by, for instance, inoculation or immunization) or can be expressed in vivo by polynucleotides that have been introduced into the animal and which encode the peptidogenic proteins. Upon expression of these peptidogenic proteins, the immune response is triggered to generate antibodies both to the peptidogenic proteins and to the original starting protein.

In preferred embodiments, the conformational dynamics of a starting protein are preferably altered by altering the thermodynamic stability of the starting protein. In further preferred embodiments, the conformational dynamics of the starting protein are altered by replacing at least one non-surface amino acid residue of a starting protein to modify the peptidogenicity of the protein. Methods of altering conformational dynamics include, but are not limited to, examining a model of the 3-D structure (experimental or predicted based on homology) of the starting protein, identifying non-surface amino acid residues of the starting protein and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic protein, and/or by comparing the pattern of conserved amino acid homology across proteins orthologous to the starting protein from different species to provisionally identify non-surface amino acid residues of the starting protein (e.g., conserved hydrophobic residues) and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic protein. Other methods of predicting or empirically discovering non-surface (i.e., buried) amino acid residues can also be used. These methods also include using bioinformatics tools that predict secondary structures and/or identify disordered regions of a starting protein to identify at least one non-surface amino acid residue within these structures or ordered regions for replacement, and replacing the at least one non-surface amino acid residue to generate the peptidogenic protein (see, e.g., Cheng et al., Nucleic Acids Res (2005) 33:W72-6; Huang et al. (2014), DisMeta: A Meta Server for Construct Design and Optimization In Chen editor, Structural Genomics, Humana Press pp. 3-16). In some embodiments, substitutions in disordered regions are avoided. For example, disorder predictors could be used to identify ordered/structured regions in order to select ordered regions in which to make mutations (Id.). Still other methods include using biochemical experiments to identify core residues, such as through alanine scanning of hydrophobic residues or comparable methods, to identify at least one non-surface amino acid residue within these structures or regions for replacement, and replacing the at least one non-surface amino acid residue to generate the peptidogenic protein. Accordingly, in some embodiments, residues for replacement can be identified based on known structures, and in other embodiments, residues for replacement can be identified based on conserved hydrophobic residues.

In preferred embodiments a non-surface amino acid residue is replaced with a smaller amino acid residue. In further preferred embodiments, the smaller amino acid is an alanine or glycine. In other preferred embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids are replaced in the starting protein. In still other preferred embodiments, at least 10 amino acids, at least 20 amino acids, at least 30 amino acids, at least 40 amino acids, or at least 50 amino acids are replaced in the starting protein. In still other preferred embodiments, multiple amino acid replacements are distributed across a mixture of proteins. For example, in one embodiment, to mutate 10 different residues, the starting protein is mutated 10 different times to generate 10 different peptidogenic proteins, each with a single amino acid replacement. Each of the ten proteins are mixed together to inoculate the animal. In some cases, wild type starting protein, i.e. the protein with no mutations, is part of the mixture. In further preferred embodiments, at least one disulfide bond is eliminated in the starting protein, such as, for example, replacing the cysteines with alanines, serines, and/or glycines, etc. In further preferred embodiments, both cysteines involved in the formation of the at least one disulfide bond in the starting protein are replaced with alanines, serines, and/or glycines, or preferably with alanines or glycines, etc. In further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, leucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid or asparagine with glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (h) at least one glutamic acid or glutamine with aspartic acid, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, glutamine, asparagine, leucine, or isoleucine; or (l) at least one alanine with a glycine; or (m) at least one residue with a non-natural amino acid; and/or (n) any of the above combinations.

In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. A combinatorial approach may be used to determine optimal substitutions to increase peptidogenicity.

In preferred embodiments, the change in conformational dynamics of the peptidogenic protein is measured by a change in melting temperature as compared to the starting protein and/or by measuring a change in Gibbs free energy of stabilization. Preferred methods of measuring Gibbs free energy include, but are not limited to, denaturant modulated equilibrium unfolding. Preferred denaturants are urea and/or guanidinium hydrochloride. Alternatively, changes in conformational dynamics can be assayed by detecting a change in a proteolytic sensitivity assay, such as, for example, by measuring digestion with cathepsins and/or other proteases and then analyzing the mixture by mass spectrometry (MS) or sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE).

In preferred embodiments, determining whether peptidogenic proteins have a similar conformation to the starting protein can be measured by a cross-reacting antibody that binds to a 3D conformational epitope (often a discontinuous epitope) on both the peptidogenic proteins and the starting protein. Methods for measuring antibody binding include, but are not limited to an immunoprecipitation assay, surface plasma resonance, isothermal titration calorimetry, oblique-incidence reflective difference (OI-RD), western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and/or protein A immunoassays.

In further preferred embodiments, a test for measuring cross-reactivity is by a binding assay. In further preferred embodiment, the antibody binding (including a cross-reacting antibody) to a peptidogenic protein has a dissociation constant (KD) of less than or equal to 10⁻⁹M, of less than or equal to 10⁻⁸M, less than or equal to 10⁻⁷M, and/or less than or equal to 10⁻⁶M.

In preferred embodiments, the starting protein is selected from an envelope glycoprotein of the human immunodeficiency virus (HIV), HIV gp120, HIV gp41, HIV gp160, an ebola antigen, a hepatitis C virus (HCV) antigen, a hepatitis B virus (HBV) antigen, a Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) antigen, a Zika virus antigen, an influenza virus antigen, a viral antigen, a malaria antigen, a bacterial antigen, a parasitic antigen, an allergen, a venom, a toxin, or a tumor-associated antigen, a transmembrane domain protein, an ion channel protein, and/or a G-protein coupled receptor.

In further preferred embodiments, the tumor associated antigen is selected from MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, GAGE-I, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I, RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I, SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocyte differentiation antigens, p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase, Melan-A, MART-1, gp100, gp75, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml-RAR alpha fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, NA-88, SP17, and TRP2-Int2, (MART-I), E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, alpha-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS, tyrosinase related proteins, TRP-1, TRP-2, and cytomegalovirus phosphoprotein 65 (pp65).

In another preferred embodiment, the peptidogenic protein is a protein that is part of a complex. For example, buried interfacial residues may be targeted for amino acid substitution, in e.g., proteins such as gp120, which is an envelope glycoprotein that forms a trimeric complex and is involved in HIV infection.

In a preferred embodiment, the mixture of polynucleotides encoding the peptidogenic proteins can be synthesized in vitro. The polynucleotides can also preferably comprise either DNA or mRNA. In preferred embodiments, the polynucleotides are in vitro transcribed (IVT) mRNA. The mRNA, including the IVT mRNA, can further comprise a poly(A) tail and/or a 5′ cap. In another preferred embodiment, the mRNA can be translated in vitro to produce the peptidogenic proteins, including by use of coupled in vitro transcription/translation (IVTT).

The mixture of polynucleotides can comprise sequences encoding different peptidogenic proteins derived from either the same starting protein or from multiple starting proteins. In further preferred embodiments, the polynucleotides can be associated with a targeting component that targets the polynucleotides to a cell or organ. Alternatively, the polynucleotides can be unassociated with a targeting component. The polynucleotides encoding the peptidogenic proteins may also comprise a vector sequence.

Mixtures of these polynucleotides as well as animals (genetically modified or not genetically modified) expressing mixtures of polynucleotides are also contemplated. In preferred embodiments, the animal is a mammal and in further preferred embodiments, the mammal is a human, a mouse, a rabbit, a llama, or a cow.

In further preferred embodiments, the method induces an immune response. The immune response can occur in vivo, ex vivo and/or in vitro.

The polynucleotides encoding the peptidogenic proteins, including, but not limited to mixtures of polynucleotides, can be delivered to the animal by injection. In preferred embodiments, the injection occurs in the muscle of the animal. The delivery of the polynucleotides to the animal can be used for vaccination purposes, in research, or antibody development.

In further preferred embodiments, the antibody produced by the described methods is recovered and isolated. In preferred embodiments, the antibody is a fully human antibody, a chimeric antibody, a single-chain antibody, a camelid antibody, a humanized antibody, a polyclonal antibody or a monoclonal antibody. In preferred embodiments, the polyclonal antibody is further fractionated into single, isolated antibody species. In other preferred embodiments, the produced antibody is affinity matured, such as, for example, by phage display, yeast display, ribosome display or by a panning technique.

Also contemplated are polynucleotides that encode the antibodies produced by the methods described herein. These antibody encoding polynucleotides can also comprise a heterologous promoter and/or a vector sequence.

The peptidogenic proteins and/or the mixtures of polynucleotides encoding the peptidogenic proteins can also be used to vaccinate a mammal. In preferred embodiments, the vaccine is a cancer vaccine, an HIV vaccine, an HCV vaccine, an HBV vaccine, an influenza virus vaccine, a MERS-CoV vaccine, a Zika vaccine, a malaria vaccine, and/or an ebola virus vaccine comprising the peptidogenic proteins.

In further preferred embodiments, the invention is a method of processing a peptidogenic protein wherein the method comprises introducing to an antigen presenting cell a peptidogenic protein, wherein the peptidogenic protein has altered conformational dynamics as compared to a starting protein and wherein the peptidogenic protein has a similar conformation to the starting protein; and permitting the antigen presenting cell to process and display T cell epitopes derived from the peptidogenic protein.

In preferred embodiments, the antigen presenting cell is a dendritic cell, a B cell, a monocyte or a macrophage. In further preferred embodiments, the method is carried out in vitro or ex vivo. In further preferred embodiments, the antigen presenting cell is transfected with a polynucleotide encoding the peptidogenic protein(s) and/or placed in contact with the peptidogenic protein(s). In further preferred embodiments the antigen presenting cell undergoes phagocytosis or pinocytosis of the peptidogenic protein(s) or polynucleotide(s).

DETAILED DESCRIPTION OF THE INVENTION

Overview

We describe herein a novel method of generating an immune response, including enhancing the generation of antibodies by using a protein's “peptidogenic potential” via altering the conformational dynamics of a starting protein while maintaining that protein's 3-D conformation. These peptidogenic proteins can then be used to mount an immune response, used as a vaccine and/or to generate antibodies.

Thus, the invention is directed to a method of triggering an immune response wherein said method comprises designing a mixture of peptidogenic proteins derived from a starting protein, wherein the peptidogenic proteins have altered conformational dynamics as compared to the starting protein and wherein the peptidogenic proteins are similar in conformation to the starting protein, introducing the peptidogenic proteins to an animal and generating an immune response. The peptidogenic proteins can be introduced into the animals directly (by, for instance, inoculation or immunization) or can be expressed in vivo by polynucleotides that have been introduced into the animal and which encode the peptidogenic proteins. Upon expression of these peptidogenic proteins, the immune response is triggered to generate antibodies preferably to both the peptidogenic proteins and to the original starting protein.

Introduction of the polynucleotides can occur, for example, by either directly or after first performing ex vivo transfection of dendritic cells. Additionally, polynucleotides encoding the peptidogenic proteins can be generated and introduced into an animal. The peptidogenic proteins can then be produced in the animal to generate antibodies to the peptidogenic proteins. The methods described herein have the potential to profoundly impact the immunogenicity of proteins. Preferred biophysical and biochemical properties that are altered in the protein, include, but are not limited to conformational dynamics of a protein, the thermodynamic stability, MHC-II binding, and/or the protease susceptibility of the starting protein. The methods described herein can also be used to simultaneously produce cross-reacting antibodies to different peptidogenic proteins (either derived from the same or different starting proteins) which has the potential to profoundly change the way in which antibodies are currently being generated as the repertoire of antibodies that can be obtained by a single injection in an animal has the potential to streamline antibody development and vaccination efficacy.

We have recognized that the conformational dynamics of a protein are critical for the ability of the protein to mount an immune response. The propensity of an antigen to efficiently yield peptide fragments in vivo after immunization we have termed “peptidogenicity.” Having the ability to alter the conformational dynamics of a starting protein to design a mixture of peptidogenic proteins which can be administered directly as a protein mixture or simultaneously expressed in an animal by a mixture of polynucleotides has the potential to generate a broad repertoire of antibodies with a single injection in a cost effective manner.

Thus, as disclosed herein, immunizing an animal with a mixture of peptidogenic proteins can robustly stimulate the immune system, generating stronger and/or better immune responses when placed in contact with an antigen presenting cell.

The immunization with a mixture (or combinatorial cocktail) of peptidogenic proteins is advantageous due to the complexity of the proteolytic attack on the protein antigen(s) that produces the peptides. For example, providing multiple different peptidogenic proteins having different amino acid sequences creates an environment where the “tuning mutation(s)” optimal for the production of a given peptide (T cell epitope) in the right time frame may be different from the mutations optimal for production of another peptide. For example, some cells, such as dendritic cells, mediate T-cell responses during an activation phase. If these cells are presented with antigens outside of this activation window (e.g., before or after activation) then a T-cell response may not be triggered. Thus, T-cells need to be presented with antigens at the appropriate time, which is governed by rates of protein degradation (e.g., proteolysis) in the antigen presenting cell, to trigger an immune response. By giving the antigens as mixtures, a multiplicity of different peptidogenic proteins can be endocytosed by a single cell, which theoretically maximizes the diversity of the peptides produced and displayed by that cell. Alternatively, by giving the antigens as mixtures, a multiplicity of different peptidogenic proteins can be endocytosed by multiple cells, which theoretically maximizes the diversity of the peptides produced and displayed by these cells. Additionally, the peptidogenic proteins having increased conformational dynamics may lead to an improved MHC class II binding which is expected to maximize the immune response. For example, for proteins that are relatively non-immunogenic and/or are not good vaccine components because of being too stable, and thus protease degradation is inhibited and subsequent peptide presentation is thereby impoverished resulting in attenuation of the immune response in adaptive immunity, such proteins could be altered as described herein to generate a mixture of peptidogenic proteins with altered conformational dynamics while maintaining a similar conformation as compared to the starting protein.

In preferred embodiments, a starting protein, also referred to as a test starting protein, can be systematically mutated to alter the thermodynamic stability of the starting protein, without significantly altering the three-dimensional structure of the corresponding folded protein, to generate peptidogenic proteins having increased peptidogenicity while displaying essentially the same 3D (conformational) surface epitopes as the starting protein.

Thus, increasing the immunogenicity of a starting protein by altering its conformational dynamics to produce numerous peptidogenic proteins which can then be simultaneously introduced into an animal will generate a robust immune response and has the potential to raise a broader repertoire of polyclonal antibodies which can be further fractionated (for example, by molecularly cloning via their respective encoding mRNAs) into single isolated species.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art, such as in the arts of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry. Standard techniques are used for molecular biology, genetic and biochemical methods (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Ausubel et al., Short Protocols in Molecular Biology (1999) 4^th ed., John Wiley & Sons, Inc.), which are incorporated herein by reference.

As used herein, “peptidogenicity” refers to the propensity of a protein to efficiently yield a robust set of diverse peptides which can be used to yield an immune response. Various assays exist for measuring peptidogenicity (see, for example, So et al., FIGS. 2c-d; Thai et al., FIG. 7c-f; and Delamarre et al., FIGS. 1b-c, 4b-c and 5a-b).

As used herein, a “peptidogenic protein” refers to a mutated protein that has been modified in its amino acid sequence to alter its conformational dynamics as compared to the starting protein sequence while maintaining a similar conformation to the starting protein.

As used herein, “non-surface residues” are residues that are not surface accessible with regard to the 3D structure of a protein, e.g., residues that are buried within the interior of the 3D structure of the native protein. In preferred embodiments, “non-surface” residues are defined by the method of Lee and Richards (see, e.g., Lee B et al., J. Mol. Biol. (1971); 55(3):379-IN4. doi:http://dx.doi.org/10.1016/0022-2836(71)90324-X.), where the relative solvent accessibility of the residue in the native protein is less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 5%, or 0%, or by the same method where the difference between the absolute solvent accessible surface area and the surface area in the fully extended Ala-X-Ala tripeptide (see, e.g., Gready J E et al., Protein Science. (1997); 6(5):983-98. doi: 10.1002/pro.5560060504.) is greater than 40 Ų, greater than 50 Ų, greater than 60 Ų, greater than 70 Ų, greater than 80 Ų, greater than 90 Ų, greater than 100 Ų, greater than 110 Ų, or greater than 120 Ų. In further preferred embodiments, “non-surface” residues are defined as residues with a solvent accessible surface area of less than 10 Ų, less than 5 Ų, less than 2.5 Ų, or less than 1 Ų, as calculated by a structural analysis software package familiar to those skilled in the art (e.g. UCSF Chimera (see, e.g., Pettersen E F et al., J. Comput. Chem. (2004); 25(13):1605-12. Epub 2004 Jul. 21.), PyMol (see, e.g., Schrodinger, LLC. The PyMOL Molecular Graphics System, Version 1.8. 2015.), etc.

As used herein, a “starting protein” or “test starting protein” refers to the amino acid sequence of the “original” or “reference” protein that is used to derive the peptidogenic protein. In some examples, the “starting protein” can be a peptidogenic protein that has been further modified.

As used herein, an “immune response” refers to the humoral immune response and/or the cell-mediated immune response that is triggered by an antigen presenting cell after processing a protein. In the humoral immune response, B lymphocytes produce antibodies that react with native, unprocessed antigens. These antigen-antibody reactions may in some cases involve cell-surface antigens that activate the complement cascade, which causes the lysis of cells bearing those antigens. In the cell-mediated immune response, T lymphocytes mobilize macrophages in the presence of processed peptide antigens recognized as foreign. Activated T lymphocytes can also attack cells bearing foreign antigens directly.

As used herein, an “antigen presenting cell” refers to a cell that can break down (“process”) a protein into peptides and present the peptides, in conjunction with the MHC allele, preferably major HLA complex class I or class II molecules, on the cell surface. Examples of antigen presenting cells include, but are not limited to dendritic cells, macrophages, B cells, and monocytes.

As used herein, “conformational dynamics” is defined as the phenomena related conformational changes and flexibility of a protein structure in the spatial arrangement of atoms or groups of atoms with respect to each other in a protein molecule. Conformational dynamics include “breathing” motions and involve the vibration, bending, twisting, rotation, and other allowed modes of movement of the atoms joined by the covalent bonds in the protein molecule, governed by intrinsic restoring forces but modulated by non-covalent interactions such as hydrogen bonds, van der Waals forces, and electrostatic interactions. These motions can subtly change the geometry of the protein on a sub-picosecond timescale and can result in a vast diversity of conformational states on a time-scale of microseconds to milliseconds. Conformational molecular dynamics of proteins is often studied using computer simulations. See, for example, Shaw et al (2010) Science 330, 341. Also as used herein, the conformational dynamics of a starting protein can be altered by chemical modifications, amino acid substitutions, and other mutations such as deletions, insertion, truncations, or any combination thereof, etc. By stating that the conformational dynamics of the peptidogenic protein is varied with regard to the wild type protein, it is meant that the one or more amino acid substitutions of the peptidogenic protein results in altered conformational dynamics as compared to the wild type protein.

As used herein, “thermodynamic stability” is defined in terms of a chemical system where no or minimal energy is either released or consumed, and thus no or minimal changes in thermal energy are present and the system is in its lowest energy state under a given set of experimental conditions. Also as used herein, a “decrease in thermodynamic stability” or “decreased thermodynamic stability” means that the parameters pertaining to thermodynamic stability of the peptidogenic protein are attenuated as compared to those of the starting protein measured under the same conditions, and this decrease can be achieved in the peptidogenic protein by, but not limited to, alterations to the molecular structure of the starting protein via chemical modifications, amino acid substitutions, and other genetic mutations. Methods of measuring a decrease in thermodynamic stability are known in the art and described herein, and include protocols incorporating the measurement of parameters such as melting temperature and urea- or guanidinium hydrochloride-induced equilibrium unfolding (denaturation). These parameters are typically arrived at by monitoring the protein unfolding reaction as a function temperature or denaturant concentration under conditions of equilibrium or quasi-equilibrium. Methods for monitoring the unfolding reaction by measuring the concentration of the unfolded state relative to that of the folded state include, but are not limited to, UV absorption, fluorescence, and circular dichroism. This approach allows the calculation of a stabilization free energy (Gibbs free energy) of the mutant protein relative to the stabilization free energy of the starting protein measured under the same conditions. The difference in free energy is typically denoted by ΔΔG=ΔG_mutant−ΔG_{standard(e.g., wt)}, where ΔG_mutant and ΔG_{standard(e.g., wt)} are the stabilization free energies of the mutant and “standard” (e.g., wt or wild type) proteins, respectively, and MG is the difference. ΔΔG>0 indicates a mutant protein that is less stable than the standard protein, and ΔΔG<0 indicates a mutant protein that is more stable than the standard protein.

As used herein, a peptidogenic protein has a “similar conformation” to a starting protein if the 3-D structure is sufficiently maintained after mutating non-surface residues of the protein (and, consequently, potentially modifying its overall conformational dynamics) to allow for an antibody to cross react with both the peptidogenic protein and the starting protein. “Cross-reactivity” can be measured by a binding assay as described herein or as is well known in the art and is measured as a “binding affinity” which is based on dissociation constants (K_D), off rates (k_off), and/or on rates (k_on). The peptidogenic protein does not need to have an identical 3-D structure as the starting protein; just a sufficiently similar structure displaying similar 3D conformational epitopes (including discontinuous epitopes), that will allow for an antibody to recognize both proteins, even though the binding affinities may be nonidentical.

In the present invention, the term “antibody,” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds the peptidogenic protein and/or the starting protein. As such, the term antibody encompasses not only whole antibody molecules, but also antibody fragments as well as variants (including derivatives such as fusion proteins) of antibodies and antibody fragments. Examples of molecules which are described by the term “antibody” in this application include, but are not limited to: single chain Fvs (scFvs), Fab fragments, Fab′ fragments, F(ab′)₂, disulfide linked Fvs (sdFvs), Fvs, and fragments comprising or alternatively consisting of, either a VL or a VH domain. The term “single chain Fv” or “scFv” as used herein refers to a polypeptide comprising a VL domain of an antibody linked to a VH domain of an antibody. See Carter (2006) Nature Rev. Immunol. 6:243.

Additionally, antibodies of the invention include, but are not limited to, monoclonal, multi-specific, bi-specific, human, humanized, mouse, or chimeric antibodies, single chain antibodies, camelid antibodies, Fab fragments, F(ab′) fragments, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), domain antibodies and epitope-binding fragments of any of the above. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.

Most preferably, the antibodies are human antibodies. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries and xenomice or other organisms that have been genetically engineered to produce human antibodies. For a detailed discussion of a few of the technologies for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598; and Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995).

Human antibodies or “humanized” chimeric monoclonal antibodies can be produced using techniques described herein or otherwise known in the art. For example, methods for producing chimeric antibodies are known in the art. See, for review the following references: Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).

The antibodies of the present invention may be monovalent, bivalent, trivalent or multivalent. For example, monovalent scFvs can be multimerized either chemically or by association with another protein or substance. A scFv that is fused to a hexahistidine tag or a Flag tag can be multimerized using Ni-NTA agarose (Qiagen) or using anti-Flag antibodies (Stratagene, Inc.).

The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for the peptidogenic protein, for more than one peptidogenic protein, for the starting protein, or they may be specific for both the peptidogenic protein and/or the starting protein and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et. al., J. Immunol. 148:1547-1553 (1992).

The term “fragment” as used herein refers to a polypeptide comprising an amino acid sequence of at least 5 amino acid residues, at least 10 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, at least 25 amino acid residues, at least 30 amino acid residues, at least 35 amino acid residues, at least 40 amino acid residues, at least 45 amino acid residues, at least 50 amino acid residues, at least 60 amino residues, at least 70 amino acid residues, at least 80 amino acid residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 125 amino acid residues, at least 150 amino acid residues, at least 175 amino acid residues, at least 200 amino acid residues, or at least 250 amino acid residues, of the amino acid sequence of the peptidogenic protein or starting protein. In some embodiments, a fragment may also refer to a polypeptide comprising an amino acid sequence of about 8 to 24 amino acid residues, or about 5 to 30 amino acid residues.

The term “fusion protein” as used herein refers to a polypeptide that comprises, or alternatively consists of, an amino acid sequence of the peptidogenic protein, the starting protein, and/or the antibody raised against the peptidogenic protein and an amino acid sequence of one or more heterologous peptides and/or polypeptides. For vaccine applications, the heterologous polypeptide sequence fused to the peptidogenic protein is preferably from a viral protein.

The term “host cell” as used herein refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences or developmental steps that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.

A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar chemical nature (e.g., size, charge, steric features [e.g., beta-branched vs. non-beta-branched], polarity [hydrophilic vs. hydrophobic], aromatic vs. non-aromatic, etc.). Whether or not a particular substitution is deemed “conservative” may also depend on the structural context in the folded protein in which a substitution occurs. Amino acid side chains may be chemically similar in one respect but chemically dissimilar in another, and the context may determine which of these properties dominates in terms of how “conservative” (i.e., least disruptive) that particular substitution is. Families of amino acid residues having chemically similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Some side chains have a hybrid character that is pH-dependent in physiologically relevant pH ranges. For example, histidine (pKa˜6) becomes more positively-charged (basic) below pH 6, and polar but substantially uncharged at pH 7.5 and above. Cysteine (pKa˜8.5) is substantially uncharged (and not particularly polar) below pH 8, but negatively charged (and acidic) at pH 9. The tyrosine phenolic side chain is also partially ionized and negatively charged at higher pH. Moreover, the local electrostatic environment (context) of the rest of the protein can shift these effective pH values substantially. Moreover, an acidic protein cysteine thiolate side chain can react, via thiol-disulfide exchange involving an intermediary disulfide-containing compound such as oxidized glutathione, with another protein cysteine thiol to form an intramolecular disulfide bond; such bonds are highly hydrophobic (non-polar). Additionally, both naturally occurring and/or non-naturally occurring amino acids can be used in the peptidogenic proteins.

Mutations can be introduced in a site-directed fashion or randomly along all or part of the coding sequence. Libraries of mutants can be designed to introduce a single amino acid substitution, two amino acid substitutions, three amino acid substitutions, four amino acid substitutions, and so forth, up to nineteen amino acid substitutions at a given residue site. In still other embodiments, libraries of mutants can be designed to introduce more than nineteen amino acid substitutions (including natural and non-natural amino acids) at a given residue site. In addition, libraries can be combinatorially designed to simultaneously produce multiple mutations at two sites, three sites, four sites, and so on. Following mutagenesis, the encoded protein may routinely be expressed and the conformational dynamics of the encoded protein and/or peptidogenicity can be determined using techniques described herein or by routinely modifying techniques known in the art. The resultant mutant proteins can be screened and evaluated for altered thermodynamic stability or for peptidogenicity or for similar conformation to the starting protein. Alternatively, the expressed protein “output” from the designed library can be used to immunize an animal without prior screening for protein properties.

As used herein, the “patient” or “subject suitable for treatment” may be a mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon, rhesus macaque), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon), or a human. In other embodiments, non-human mammals, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g. murine, primate, porcine, canine, camels, llamas, or rabbits) may be employed.

Other aspects and embodiments of the invention provide the aspects and embodiments described herein with the term “comprising” replaced by the term “consisting of” and the aspects and embodiments described above with the term “comprising” replaced by the term “consisting essentially of”.

As used herein, “and/or” is to be taken as specific disclosure of each of the two or more specified features or components with or without the others. For example “A, B and/or C” is to be taken as specific disclosure of each (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C and (vii) A and B and C, just as if each is set out individually.

Methods of Altering the Conformational Dynamics of a Protein

A peptidogenic protein can be generated using standard molecular biology mutagenesis techniques well known in the art. For example, the peptidogenic protein can be generated by random mutagenesis as is well known in the art, such as, for example, by error-prone PCR, random nucleotide insertion or deletion or other methods prior to recombination.

To generate the peptidogenic protein, protein engineering may be employed. Recombinant DNA technology known to those skilled in the art can be used to create peptidogenic proteins including single or multiple amino acid substitutions, deletions, insertions, or fusion proteins. Such peptidogenic proteins may be screened for those that have altered conformational dynamics while maintaining a similar conformation to the starting protein as described herein.

For example, to increase the conformational dynamics of the peptidogenic protein, the following table, Table 1, shows the average change in Gibbs free energy for exemplary amino acid substitutions in a range of proteins, derived from Tables 1 and 2 of Loladze et al., J. Mol. Biol. 320, 343-357 (2002) [note: this paper uses a non-standard convention when expressing Gibbs free energies between mutant and wild type proteins, namely using negative values to indicate destabilization (ΔΔG=ΔG(mutant)−ΔG(WT)); the standard convention is that positive changes indicate destabilization (ΔΔG=ΔG(WT)−ΔG(mutant), see paragraph 0040 above)]. For example, Val and Leu (and the other larger non-polar amino acid residues) can be substituted with smaller ones such as Ala, Thr, Asn, and/or Gly. In addition, the buried site of Glu in the native protein structure, can be substituted with Leu, Val, Asn, Thr, Ser, Ala, and/or Gly. The types of single site amino acid substitutions shown generally have little impact on the overall conformation of the starting protein.

TABLE 1
Amino Acid Substitution Average Gibbs Free Energy difference
(multiple positions in  between mutant and wild type at core
various proteins)       residues within a protein ΔΔG (kJ/mol)
Val −> Ala              −12.1(±3.3)
Val −> Thr              −11.3(±3.7)
Val −> Asn              −21.5(±1.0)
Leu −> Ala              −14.2(±4.2)

Another illustrative paper describing destabilizing mutations in the core of a protein that increase conformational dynamics is Kim et al (1993) Protein Sci. 2:588-596. In this work, the authors show that the mutations Phe22->Ala (2.1 kcal/mol), Tyr23->Ala (7.0 kcal/mol), Tyr35->Gly (5.7 kcal/mol), Asn43->Gly (6.0 kcal/mol), and Phe45->Ala (7.2 kcal/mol) destabilize bovine pancreatic trypsin inhibitor (BPTI) at pH 3.5 by the respective amounts shown in parentheses, without seriously disrupting the overall 3D structure of BPTI.

In addition, genetic deletions, insertions, inversions, repeats, and type substitutions selected according to general rules known in the art should have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et at., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main approaches for studying the tolerance of an amino acid sequence to change. The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or screens to identify sequences that maintain functionality.

As the authors state, these studies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at a certain position of the protein. For example, most buried amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Other such phenotypically silent substitutions are described in Bowie, J. U. et al., supra, and the references cited therein. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu and Ile; interchange of the hydroxyl-bearing residues, Ser and Thr; exchange of the acidic residues, Asp and Glu; substitution between the sidechain amide-bearing residues, Asn and Gln; exchange of the basic amino acids, Lys and Arg; and replacements among the aromatic residues, Phe and Tyr.

In preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, isoleucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, isoleucine; or (h) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, leucine, isoleucine, or glutamine; or (l) at least one alanine with a glycine or proline; or (m) at least one asparagine with a glycine, alanine, serine, threonine, glutamine, aspartic acid, or glutamic acid; or (n) at least one glutamine with a glycine, alanine, serine, threonine, asparagine, aspartic acid, glutamic acid, or histidine; or (o) at least one glycine with an alanine or proline; or (p) at least one residue with a non-natural amino acid; or (q) any combination of (a)-(p). In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. In some embodiments, hydrophobic resides are targeted for replacement.

Amino acids in the starting protein that are essential for function, conformation, and/or structure and positioned on the protein surface vs. internal can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, Science 244: 1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for those having altered conformational dynamics while maintaining a similar conformation to the starting protein.

In an additional embodiment, the amino acid sequence of the starting protein has one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or 50 amino acids) replaced with the substituted amino acids as described above (either conservative or non-conservative substitutions) to produce the peptidogenic protein. For example, substitutions in positions not involving a starting protein's activity and/or internal to the protein structure can be readily made. Sites that are critical for ligand-receptor binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); and de Vos et al. Science 255:306-312 (1992)).

Recombinant DNA technology that employs combinatorial mutagenesis and synthetic DNA synthesis approaches known to those skilled in the art can also be used to create a peptidogenic protein including single or multiple amino acid substitutions, deletions, additions or fusion proteins. Such modified polypeptides may be then screened for altered conformational dynamics while maintaining a similar conformation as the starting protein.

Thus, a peptidogenic protein can be made where one or more amino acid residues are deleted, added, or substituted to generate peptidogenic proteins having altered conformation dynamics. For example, residues in the hydrophobic “core” of the protein can be substituted with non-polar residues having smaller side chains (supra) in order to create cavities in the core and disrupt the packing, and cysteine residues can be deleted or substituted with other amino acid residues in order to eliminate disulfide bridges (which are often found in protein cores). In some embodiments, at least one disulfide bond is eliminated in the starting protein, such as, for example, replacing the cysteines with alanines, serines, and/or glycines, etc. In further preferred embodiments, both cysteines involved in the formation of the at least one disulfide bond are replaced with alanines, serines, and/or glycines, or preferably with alanines or glycines, etc.

The peptidogenic proteins are preferably provided in an isolated form, and preferably are substantially purified. Additionally, the peptidogenic proteins would display a stable 3D conformational epitope for B-cell activation while synthesized peptides (such as by chemical synthesis) can be co-administered, which could optimize the epitopes for MHC-II presentation. Alternatively, the peptidogenic proteins and peptides can be expressed by a mixture of polynucleotides. In still other embodiments, peptidogenic proteins can be combined with a wild type starting protein and synthetic peptide(s) to elicit an immune response.

In some embodiments, the rate of polypeptide degradation may be adjusted in order to produce an optimal mix of peptides, and in the right time frame, to allow maximal diversity of the displayed peptides on the antigen presenting cells.

Immunization with mixtures (such as combinatorial cocktails) of antigens is advantageous due to the complexity of the proteolytic attack on the protein antigen(s) that produce the peptides for display. Thus, the “tuning mutation(s)” optimal for the production of a given peptide (T cell epitope) in the right time frame may be different from the mutations optimal for production of another peptide. By giving the antigens as mixtures, a multiplicity of different mutant proteins may be endocytosed by a single cell or multiple cells, which maximizes the diversity of the peptides produced and displayed by that cell.

Combinatorial immunization, in which subjects are immunized with two or more distinct antigens that have the same overall surface features (i.e. cross-reacting B-cell epitopes) but with different conformational dynamics, enriches the diversity of T-cell epitopes. This combinatorial approach, which includes hundreds or even thousands of different immunogens in a single inoculation (both protein-based and nucleotide-based) may vastly increase the B-cell epitope repertoire, since every molecule in the mix can contribute to one or more unique T-cell epitopes while maintaining a wild type-like conformation. In some aspects, because the wild-type configuration is maintained, the B-cell epitope repertoire is biased towards the most stable (and presumably wild type-like) molecules in the ensemble.

Peptidogenic Protein has a Similar Conformation as a Starting Protein

The operational test of whether the peptidogenic protein has a “similar conformation to the starting protein” is whether or not a cross-reacting antibody, especially an antibody that recognizes a conformational (3D) epitope, specifically binds to both the peptidogenic protein and the starting protein. In the present invention “cross-reactivity” or a “cross-reacting antibody” is defined in terms of “binding affinity” which can be measured based on dissociation constant (K_D), off rate (k_off), and/or on rate (k_on).

For example, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at a dissociation constant or K_D less than or equal to 5×10⁻⁶ M, 10⁻⁶ M, 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, or 10⁻⁸ M. Even more preferably, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at a dissociation constant K_D less than or equal to 5×10⁻⁹M, 10⁻⁹M, 5×10⁻¹⁰M, 10⁻¹⁰ M, 5×10⁻¹¹M, 10⁻¹¹ M, 5×10⁻¹²M, 10⁻¹²M, 5×10⁻¹³ M, 10⁻¹³ M, 5×10⁻¹⁴M, or 10⁻¹⁴ M. The invention encompasses a dissociation constant or K_D for the peptidogenic protein and/or the starting protein that is within any one of the ranges that are between each of the individual recited values. Additionally, it is specifically contemplated that the K_D for the antibody that binds to a peptidogenic protein may not be identical to its K_D with respect to the starting protein, and in preferred embodiments, the K_D for the antibody that hinds to the peptidogenic protein is less than the K_D for its binding to the starting protein. It is understood that, operationally, K_D in this case refers to the functional affinity of the antibody for the antigen. Functional or “apparent” affinity may be enhanced in multivalent antibodies that contain multiple interacting sites (e.g., Fab arms) that can bind to the antigen (“avidity effect”).

Additionally, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein with an off rate (k_off) of less than or equal to 5×10⁻² sec⁻¹, 10⁻² sec⁻¹, 5×10⁻³ sec⁻¹ or 10⁻³ sec⁻¹. More preferably, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at off rate (k_off) of less than or equal to 5×10⁻⁴ sec⁻¹, 10⁻¹ sec⁻¹, 5×10⁻⁵ sec⁻¹, or 10⁻⁵ sec⁻¹, 5×10⁻¹ sec⁻¹, 10⁻⁶ sec⁻¹, 5×10⁻⁷ sec⁻¹ or 10⁻⁷ sec⁻¹. The invention encompasses an off rate (k_off) for the peptidogenic protein and/or the starting protein that is within any one of the ranges that are between each of the individual recited values. Additionally, it is specifically contemplated that the k_off of the antibody for the peptiflogenic protein may not be identical to the k_off of the starting protein, and in preferred embodiments, the (k_off) for the binding of the antibody to the peptidogenic protein is greater than the (k_off) for the binding of the antibody to the starting protein.

Assays to test for the cross-reactivity are described herein or are known in the art. For example, binding assays may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Pat. No. 5,223,409), on spores (e.g., U.S. Pat. Nos. 5,571,698; 5,403,484; and 5,223,409), on plasmids (e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869 (1992)) or on phage (e.g., Scott and Smith, Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310 (1991)). Examples of such assays are described further below in the Examples.

Use of the Peptidogenic Protein to Generate Antibodies

The peptidogenic protein can be used to generate antibodies by methods well known by the skilled artisan, such as, for example, methods described in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914 (1985); and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with a peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein described herein.

Animals such as rabbits, rats, mice, llamas, camels, and/or cows can be immunized with the peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein. For instance, intraperitoneal and/or intradermal injection of emulsions containing about 100 micrograms of a peptidogenic protein or carrier protein and Freund's adjuvant or any other adjuvant known for stimulating an immune response may be used. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptidogenic protein antibody which can be detected, for example, by ELISA assay using free peptidogenic protein adsorbed, directly or indirectly (e.g., via a biotinylated AviTag), to a solid surface. The titer of anti-peptidogenic protein antibodies in serum from an immunized animal may be increased by selection of anti-peptidogenic protein antibodies, for instance, by adsorption to the peptidogenic protein on a solid support and elution of the selected antibodies according to methods well known in the art. Such selections could also be done using the starting protein.

Additionally, antibodies generated by the disclosed methods can be affinity matured using display technology, such as for example, phage display, yeast display or ribosome display. In one example, single chain antibody molecules (“scFvs”) displayed on the surface of phage particles are screened to identify those scFvs that immunospecifically bind to the peptidogenic protein and/or the starting protein. The present invention encompasses both scFvs and portions thereof that are identified to immunospecifically bind to the peptidogenic protein and/or the starting protein. Such scFvs can routinely be “converted” to immunoglobulin molecules by inserting, for example, the nucleotide sequences encoding the VH and/or VL domains of the scFv into an expression vector containing the constant domain sequences and engineered to direct the expression of the immunoglobulin molecule.

Recombinant expression of an antibody raised using the peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein of the invention (including scFvs and other molecules comprising, or alternatively consisting of, antibody fragments or variants thereof (e.g., a heavy or light chain of an antibody of the invention or a portion thereof or a single chain antibody of the invention)), requires construction of an expression vector(s) containing a polynucleotide that encodes the antibody or fragment or variant thereof. Once a polynucleotide encoding an antibody molecule (e.g., a whole antibody, a heavy or light chain of an antibody, or variant or portion thereof (preferably, but not necessarily, containing the heavy or light chain variable domain)), of the invention has been obtained, the vector(s) for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing an antibody by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences (as well as the coding sequences for the peptidogenic protein) and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding either the peptidogenic protein or an antibody raised to the peptidogenic protein (e.g., a whole antibody, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody, or a portion thereof, or a heavy or light chain CDR, a single chain Fv, or fragments or variants thereof), operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy chain, the entire light chain, or both the entire heavy and light chains.

The expression vector(s) can be transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce either the peptidogenic protein or the antibody that has been raised against a peptidogenic protein. Thus, the invention includes host cells containing polynucleotide(s) encoding the peptidogenic protein or an antibody raised against the peptidogenic protein (e.g., whole antibody, a heavy or light chain thereof, or portion thereof, or a single chain antibody of the invention, or a fragment or variant thereof), operably linked to a heterologous promoter. In preferred embodiments, for the expression of entire antibody molecules, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to express the peptidogenic protein or the antibody raised to the peptidogenic protein. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected, with the appropriate nucleotide coding sequences, express the peptidogenic protein or the antibody raised to the peptidogenic protein. These include, but are not limited to, microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, are used for the expression of either the peptidogenic protein or a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).

In bacterial systems, a number of expression vectors may be advantageously selected depending upon the intended use. For example, when a large quantity of a protein (whether a peptidogenic protein or an antibody raised against the peptidogenic protein) is to be produced, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., EMBO 1. 2:1791 (1983)), in which the coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or Factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) may be used as a vector to express a peptidogenic protein or an antibody raised against the peptidogenic protein. The virus grows in Spodoptera frugiperda cells. Coding sequences may be cloned individually into non-essential regions (for example, the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example, the polyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination.

Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the peptidogenic protein or an antibody raised against the peptidogenic protein in infected hosts (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 8 1:355-359 (1984)).

Specific initiation signals may also be required for efficient translation of inserted coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., Methods in Enzymol. 153:51-544 (1987)).

In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed, to this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERY, BHK, Hela, COS, NSO, MDCK, 293, 3T3, W138, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT2O and T47D, and normal mammary gland cell line such as, for example, CRL7O3O and HsS78Bst.

For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the peptidogenic protein or an antibody raised against the peptidogenic protein may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with a polynucleotide controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign polynucleotide, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the peptidogenic protein or an antibody raised against the peptidogenic protein.

A number of selection systems may be used, including but not limited to, the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthineguanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:8 17 (1980)) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 (Goldspiel et al., Clinical Pharmacy, 12: 488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62: 191-217 (1993); TIB TECH 11(5):155-2 15 (May; 1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example; in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, N Y (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, N.Y. (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981).

The expression levels of a peptidogenic protein or an antibody raised against the peptidogenic protein can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York, 1987)). When a marker in the vector system expressing a peptidogenic protein or an antibody raised against the peptidogenic protein is amplifiable, an increase in the level of inhibitor present in the host cell culture will increase the number of copies of the marker gene. Since the amplified region is associated with the coding sequence, production of the peptidogenic protein or an antibody raised against the peptidogenic protein will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).

Other elements that can be included in vector sequences include heterologous signal peptides (secretion signals), membrane anchoring sequences, introns, alternative splice sites, translation start and stop signals, inteins, biotinylation sites and other sites promoting post-translational modifications, purification tags, sequences encoding fusions to other proteins or peptides, separate coding regions separated by internal ribosome reentry sites, sequences encoding “marker” proteins that, for example, confer selectability (e.g., antibiotic resistance) or sortability (e.g., fluorescence), modified nucleotides, and other known polynucleotide cis-acting features not limited to these examples.

In the case of antibodies, the host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain is preferably placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2 197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA or synthetic DNA sequences.

Once a peptidogenic protein or an antibody raised against the peptidogenic protein has been produced by recombinant expression, it may be purified by any method known in the art for purification of a protein, for example, by chromatography (e.g., ion exchange, affinity (particularly by Protein A affinity and immunoaffinity for the specific antigen), and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, a peptidogenic protein or an antibody raised against the peptidogenic protein may be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

In one example, the peptidogenic protein or the antibody raised to the peptidogenic protein described herein may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof), or albumin (including but not limited to recombinant human albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998), resulting in chimeric polypeptides. Such fusion proteins may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fe fragments (see, e.g., PCT Publications WO 96/22024 and WO 99/04813). IgG Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion disulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J. Biochem., 270:3958-3964 (1995). Nucleic acids encoding the peptidogenic protein or antibodies described herein can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin (“HA”) tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix-binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.

Vaccination

A mixture of peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins can be used to vaccinate an animal. This vaccination may lead to the raising of antibodies to the peptidogenic proteins. A subject suitable for treatment as described above may be a mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon, rhesus macaque), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon), or a human. In some preferred embodiments, the subject is a human. In other embodiments, non-human mammals, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g. murine, primate, porcine, canine, or rabbit animals) may be employed.

In some embodiments, the peptidogenic proteins are chimeric fusion proteins, e.g., a viral protein that has been fused to another protein, that are used for vaccines.

A vaccination strategy can be based on repetitive administration of the peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins to the subject as described herein to enable the development of memory B cells and memory T cells against the peptidogenic protein. Vaccination can be conducted either prophylactically or therapeutically. The peptidogenic proteins can be derived from either the same starting protein or from multiple starting proteins. While prophylactic vaccination strategies aim to stimulate the subject's immune system in developing preventive adaptive immunity to a pathogen, the goal of therapeutic vaccination strategy is conducted after the disease has been already established or to improve a clinical situation, present in the subject.

Proteolytic processing involves antigens such as peptidogenic proteins being processed in Antigen Presenting Cells after endocytosis and fusion of the endosome with a lysosome. The endosome then merges with an exocytic vesicle from the Golgi apparatus containing class II MHC molecules, to which the resultant peptides bind. The MHC-peptide complex then trafficks to the plasma membrane where the antigen is available for display to CD4⁺ T cells. Any limitation of the proteolytic processing of the peptidogenic proteins could promote a narrowing of the diversity of the peptide products, which would give the class II MHC molecules fewer options among which to select stable binding partners, and this could exacerbate the phenomenon of immunodominant determinants Heightened immunodominance would in turn increase the proportion of non-responders in the population, because immune responsiveness is governed by the genetics of class II MHC alleles. Hence, vaccines using a mixture of peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins described herein should increase the variety of antigen peptides resulting from intra-endosomal proteolytic processing and therefore would be expected to increase the effectiveness of the vaccine.

Introduction into Animals Polynucleotides Encoding Peptidogenic Proteins

Polynucleotides encoding the peptidogenic proteins can also be directly introduced into animals. See, for example, U.S. Pat. Nos. 5,676,954; 6,875,748; 5,661,133; Sahin et al., Nat Rev Drug Discov, 2014 October; 13(10):759-80; Kariko et al., Mol Ther, 2008 November; 16(11):1833-40; Kariko et al., Nucleic Acid Res, 2011, November; 39(21):e142; U.S. Pat. No. 6,511,832. In one example, polynucleotides, such as a DNA sequences encoding a mixture of peptidogenic proteins are directly injected into a host animal and the polynucleotides enter into the nucleus to be transcribed to mRNA in order to produce the peptidogenic proteins.

Similarly, the polynucleotides can also be mRNA sequences, such as an in vitro transcribed mRNA (IVT mRNA). Essentially, synthetic mRNAs can be engineered to express peptidogenic proteins, and ideally, the mRNA is translated in the cell's cytoplasm without entering the nucleus. In the cytoplasm, the mRNA is decoded by ribosomes and is translated into the peptidogenic proteins.

In either method, the peptidogenic proteins are then processed and used to generate antibodies, much like immunization with a protein. The polynucleotides encoding the peptidogenic proteins can be synthesized using the genetic codon degeneracy and standard DNA synthesis techniques. Mixtures of different polynucleotides encoding the same peptidogenic protein, different peptidogenic proteins derived from the same starting protein, and/or different peptidogenic proteins derived from different starting proteins can be used.

Mammals that can be used to raise antibodies, include but are not limited to rabbits, rats, mice, llamas, and/or cows. The polynucleotides disclosed herein can be injected into the animals via intramuscular, intradermal, intranasal, subcutaneous, intravenous, intratracheal, and intrathecal deliveries. This method of raising antibodies allows for the concurrent production of many species of antibodies as compared to conventional methodology, substantially increasing the repertoire of antibodies produced.

Formulations

A pharmaceutical composition may comprise the peptidogenic proteins described herein, polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein along with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art. Suitable materials will be sterile and pyrogen-free, with a suitable isotonicity and stability. Examples include sterile saline (e.g. 0.9% NaCl), water, dextrose, glycerol, ethanol or the like or combinations thereof. Such materials should be non-toxic and should not interfere with the efficacy of the active compound. The precise nature of the carrier or other material will depend on the route of administration, which may be by bolus, infusion, injection or any other suitable route, as discussed below. The composition may further contain auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like. Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

In some embodiments, the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins or an antibody raised to the peptidogenic protein may be provided in a lyophilized form for reconstitution prior to administration. For example, lyophilized reagents may be re-constituted in sterile water and mixed with saline prior to administration to a subject.

Additionally, “cocktails” of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are specifically contemplated. For example, a mixture of different peptidogenic proteins or polynucleotides encoding different peptidogenic proteins derived from the same starting protein can be used to mount an immune response. Alternatively, a mixture of different peptidogenic proteins or polynucleotides encoding different peptidogenic proteins derived from different starting materials may also be used to mount an immune response.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.

Optionally, other therapeutic or prophylactic agents may be included in a pharmaceutical composition or formulation.

Treatment may be any treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition or delay of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, cure or remission (whether partial or total) of the condition, preventing, delaying, abating or arresting one or more symptoms and/or signs of the condition or prolonging survival of a subject or patient beyond that expected in the absence of treatment.

Treatment as a prophylactic measure (i.e. prophylaxis) is also included. For example, a subject susceptible to or at risk of the occurrence or re-occurrence of the disease may be treated as described herein. Such treatment may prevent or delay the occurrence or re-occurrence of the disease in the subject.

The term “therapeutically-effective amount” as used herein, pertains to that amount of the peptidogenic protein or an antibody raised to the peptidogenic protein which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.

It will be appreciated that appropriate dosages of the peptidogenic protein or an antibody raised to the peptidogenic protein can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the administration. The selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the active compound, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of peptidogenic protein, polynucleotide encoding the peptidogenic protein, or an antibody raised to the peptidogenic protein and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve concentrations of the active compound at a site of therapy without causing substantial harmful or deleterious side-effects.

In general, a suitable dose of the peptidogenic protein or an antibody raised to the peptidogenic protein is in the range of about 100 μg to about 250 mg per kilogram body weight of the subject per day. Where the peptidogenic protein or an antibody raised to the peptidogenic protein is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals). Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the physician.

By “simultaneous” administration, it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered to the subject in a single dose by the same route of administration.

By “separate” administration, it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered to the subject by two different routes of administration which occur at the same time. This may occur for example where one agent is administered by infusion or parenterally and the other is given orally during the course of the infusion or parenteral administration.

By “sequential” it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered at different points in time, provided that the activity of the first administered agent is present and ongoing in the subject at the time the second agent is administered. Preferably, a sequential dose will occur such that the second of the two agents is administered within 48 hours, preferably within 24 hours, such as within 12, 6, 4, 2 or 1 hour(s) of the first agent.

Multiple doses of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins and/or an antibody raised to the peptidogenic protein may be administered. For example 2, 3, 4, 5 or more than 5 doses may be administered after administration of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein. The administration of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein may continue for sustained periods of time after initial administration. For example treatment with the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein may be continued for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month or at least 2 months. Treatment with the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein may be continued for as long as is necessary to achieve a therapeutic response.

The peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein and compositions comprising these molecules may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); and parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly. Usually administration will be by the intravenous route, although other routes such as intraperitoneal, subcutaneous, transdermal, oral, nasal, intramuscular or other convenient routes are not excluded.

The pharmaceutical compositions comprising the peptidogenic protein, the polynucleotides encoding the peptidogenic proteins or an antibody raised to the peptidogenic protein may be formulated in suitable dosage unit formulations appropriate for the intended route of administration.

Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the active compound in the solution is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml, from about 1 μg/ml to about 10 mg/ml, from about 10 μg/ml to about 1 mg/ml, from about 1 mg/ml to about 20 mg/ml, from about 10 mg/ml to about 120 mg/ml, or any other concentration suitable for administration of biological drugs (e.g., proteins, antibodies, etc.). The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.

Compositions comprising the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins and/or an antibody raised to the peptidogenic protein may be prepared in the form of a concentrate for subsequent dilution, or may be in the form of divided doses ready for administration. Alternatively, the reagents may be provided separately within a kit, for mixing prior to administration to a human or animal subject.

The peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the individual circumstances. For example, peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein as described herein may be administered in combination with one or more additional active compounds.

Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.

It is to be understood that the application discloses all combinations of any of the above aspects and embodiments described above with each other, unless the context demands otherwise. Similarly, the application discloses all combinations of the preferred and/or optional features either singly or together with any of the other aspects, unless the context demands otherwise.

Modifications of the above embodiments, further embodiments and modifications thereof will be apparent to the skilled person on reading this disclosure, and as such these are within the scope of the present invention. All documents and sequence database entries mentioned in this specification are incorporated herein by reference in their entirety for all purposes. The invention is further described below, with reference to the following examples.

EXAMPLES

Example 1: Generating Peptidogenic Antigens

To generate peptidogenic proteins, a starting protein can be modified at its core residues (e.g., one or more mutations) to alter its conformational dynamics. Multiple different peptidogenic proteins can be designed and expressed to immunize animals, such as rabbits, to generate a polyclonal antibody response. Alternatively, polynucleotides encoding the peptidogenic proteins can be directly administered to the animals to generate the peptidogenic proteins in vivo. The response will be monitored by two complementary and mutually reinforcing methods (Georgiou et al, 2014; FIG. 2): (a) purifying B cells from the blood, spleen, and bone marrow of immunized animals, isolating cDNA from mRNA encoding the variable regions of the heavy and light chains, and analyzing this repertoire via deep DNA sequencing; and (b) immunoaffinity purifying from immune sera polyclonal Fab or (Fab′)2 fragments using antigen attached to a solid support, digesting the eluted Fab/(Fab′)2s with proteases, and sequencing the resultant peptides using LC/MS/MS.

Specifically, challenging test animals (rabbits) with a variety of peptidogenic proteins (or polynucleotides encoding the peptidogenic proteins) where the conformation is similar to the starting protein, but the conformational dynamics of the peptidogenic protein is varied, can be performed. Using next-generation DNA sequencing technology, the humoral response in the animal can be comprehensively characterized Immunoglobulin V-regions from B lymphocytes can be cloned and subjected to massively parallel deep sequencing (5-8). In conjunction with this, polyclonal antibodies from the same test animal can be purified by immunoaffinity chromatography, then protease-digested and subjected to LC-MS/MS to determine the peptide sequences (9, 10). Comparisons of these two datasets illuminate the repertoire of individual antibodies comprising the polyclonal response (9).

For example, small mammalian proteins that have been extremely well-characterized biophysically can be used as test antigens. Preferred examples, include, but are not limited to bovine pancreatic trypsin inhibitor and/or Alzheimer's amyloid precursor protein Kunitz domain. Alternatively, antigens relevant to unmet vaccine needs, such as for example, P. falciparum sporozoite antigens can also be generated and tested in this method. Additionally, optimization (or re-optimization) of synthetic vaccines with respect to conformational dynamics of the component proteins (perhaps replacing a single component with a combinatory cocktail of several versions of the same antigen with different core destabilizing mutations) can also be generated. Testing these new vaccines in clinical trials could involve monitoring of the vaccinated individuals using similar DNA sequence analyses of blood-derived B-cell V-region repertoires and proteomic characterization of immunoaffinity-purified polyclonal antibody peptides, similar to the procedures described above.

Other preferred examples of antigens that can be used according to embodiments of the invention described herein, include, but are not limited to antigens or antigens derived from, malarial polypeptides such as thrombospondin-related adhesive protein (TRAP) and/or apical membrane antigen 1 (AMA1), human immunodeficiency virus (HIV) gp120 and gp41, hepatitis C (HCV) envelope glycoproteins E1 and E2, Middle East respiratory syndrome coronavirus (MERS-CoV) Spike glycoprotein, human influenza virus hemagglutinin (HA) and neuraminidase, hepatitis B virus (HBV) capsid core, as well as antigens from related viruses that infect apes, monkeys, birds, pigs, camels, and other animals.

In preferred embodiments, any one of the P. falciparum protein antigens listed in the following Table 2 can be used as a starting protein to derive the peptidogenic protein. Additionally, multiple antigens listed in Table 2 can be used as the starting proteins to derive multiple different peptidogenic proteins to be used as a vaccine, generate an immune response, including the raising of antibodies.

TABLE 2
							Predicted
			Predicted SP				SP
	Predicted		Cleavage		Predicted		Cleavage
Gene	Size	Paralogs	Site	Gene	Size	Paralogs	Site
MAL13P1.225	157		23/24	PFI0880C	396		25/26
PF13_0203	158		22/23	PF11_0251	421		22/23
PF11_0164	195	PFC0795C	21/22	PFC0065C	437	PF08_0022,	31/32
						PF14_0015
PFL0375W	209		16/17	PFC0925W	492		30/31
PFI1270W	217		20/21	MAL13P1.121	565		34/35
PF10_0104	223		22/23	PF13_0133	590		33/34
PF13_0128	230		18/19	PFL2015W	676		27/28
PF11_0058	233		35/36	PFD0440W	693		25/26
PFA0490W	234		29/30	PFC0330W	699		26/27
PF07_0087	244		26/27	PFD0430C	840		24/25
PFB0570W	250		21/22	PF14_0462	851	PFC0550W	28/29
PF13_0180	258	PFL0740C	19/20	PF07_0100	1032		35/36
PF11_0065	282		23/24	MAL7P1.23	1183		30/31
PF14_0678	287		21/22	PFL1835W	1188		26/27
PF13_0125	292		19/20	PF07_0047	1229	PFF0940C	35/36
PF13_0141	316	PFF0895W	20/21	PF14_0250	1320		28/29
PF14_0117	327	PFI1775W,	22/23	PFE0905W	1379		24/25
		PFL2530W
PF11_0098	343		26/27	PFA0180W	1472		31/32
PF14_0660	358		23/24	PFL1210W	1696		25/26
PFD0240C	378		20/21	PF14_0363	1922		26/27
PFE0080C	398		21/22	PFB0400W	2508		34/35
PFA0660W	402	PFB0090C,	34/35	PFI0920C	577		26/27
		PFB0595W,
		PFE0055C
PF11_0352	423		23/24	PF14_0094	768		22/23
PF11_0055	424		21/22	PFA0125C	1567		26/27
PFB0475C	446		22/23	PF10_0372	120		25/26
PF11_0302	452		21/22	PFL2315C	137		28/29
PFA0210C	466		23/24	MAL13P1.271	181		36/37
PF07_0089	467		16/17	MAL7P1.31	236		20/21
PF14_0060	475		16/17	PF10_0317	263	PF14_0653	35/36
MAL8P1.17	483		24/25	PF07_0070	322		19/20
MAL7P1.77	522		23/24	MAL7P1.64	357		28/29
PF11_0099	540		33/34	PFI0935W	370		21/22
PF07_0068	546		22/23	PFA0160C	434		22/23
PF13_0201	574		25/26	PFB0465C	457		27/28
PF07_0094	579		17/18	PF10_0208	627		23/24
PF07_0006	594	MAL8P1.143	22/23	PFB0760W	686		25/26
PFL0770W	618	PF07_0073	20/21	MAL13P1.206	687		26/27
PFI1645C	642	PF13_0262	18/19	PF14_0541	717		15/16
PF14_0166	674		25/26	PFL0790W	870		21/22
PFE0815W	681		24/25	PFL2410W	1039		24/25
PF11_0174	700		27/28	PF14_0440	1191		23/24
PFE0475W	722	PFB0525W	21/22	PF11_0333	1503		25/26
PF11_0074	743		17/18	PF10_0242	1541		20/21
PFL1385C	743		23/24	PFC0590C	1816		20/21
PF14_0102	782		22/23	PF14_0342	1898		27/28
PF11_0212	791		20/21	MAL7P1.92	2543	PFI0550W	22/23
PF07_0129	811		21/22	PF14_0593	1357		18/19
PFL2570W	816		22/23	MAL13P1.49	144		24/25
PFL1070C	821		28/29	MAL13P1.172	260		26/27
PFB0695C	888		32/33	PF08_0006	272		19/20
PF11_0175	906	PF08_0063	26/27	PFD1035W	328		37/38
MAL13P1.22	912		15/16	PF11_0052	336		24/25
PFL0035C	926		27/28	MAL13P1.79	383		19/20
PFI0685W	955		18/19	PF10_0295	426		23/24
PFD0425W	984		21/22	PFL1745C	459		22/23
PF14_0293	992		24/25	PF14_0677	467		24/25
PF14_0344	993		20/21	PFL0600W	558		23/24
PFL0560C	1024		20/21	PF08_0108	573	PF14_0281	26/27
PF07_0035	1248		20/21	PF08_0081	577		18/19
PFL1675C	1256		21/22	PF14_0620	858		25/26
PFC0435W	1294		19/20	PFE0710W	867		21/22
PFI1445W	1364		19/20	PF11_0270	1013		20/21
PF13_0354	1408		23/24	MAL7P1.149	1051		19/20
PFC0110W	1416	MAL7P1.229,	24/25	PFC0810C	1119		22/23
		PFA0125C,
		PFD1155W
PFC0120W	1417		24/25	PF14_0249	1169		25/26
PF08_0078	1419		20/21	PF13_0116	1258		19/20
PF14_0614	1502		16/17	MAL13P1.60	1260		25/26
PF14_0051	1515		26/27	PF11_0246	1336		23/24
PF11_0076	1988		22/23	PFL2505C	2215		21/22
MAL13P1.262	2006		21/22	PFB0405W	3135		20/21
PFC0640W	2114		26/27	PF11_0256	608		17/18
PFL2520W	2792	MAL13P1.176,	24/25	PF08_0047	613		28/29
		PF13_0198
PFC0282W	116		23/24	PFC0835C	440		22/23
PF08_0004	137		25/26	PFI0605C	446		20/21
PF11_0224	162		22/23	PF10_0127	499		16/17
PF13_0272	208		22/23	PF11_0344	622		24/25
MAL13P1.171	211		20/21	PF10_0130	628		25/26
PFE1340W	214		27/28	PFL2395C	639	PF14_0428	28/29
PF14_0369	235		20/21	PF08_0008	738		21/22
PF14_0178	259		22/23	PF14_0201	966		22/23
PFL0870W	352		24/25	PFI1475W	1720		19/20
PFC0210C	397		18/19	PF13_0182	1838		26/27
PFI0500W	432		28/29	PF14_0495	2189		20/21
PF11_0069	276		25/26	PF13_0277	2068		22/23
PFD0355C	286		32/33

To alter the conformational dynamics of a starting protein, the following changes in Gibbs Free Energy, shown in Table 3 below, can be considered:

TABLE 3
Amino Acid Substitution Average Gibbs Free Energy difference
(multiple positions in  between mutant and wild type at core
various proteins)       residues within a protein ΔΔG (kJ/mol)
Val −> Ala              −12.1(±3.3)
Val −> Thr              −11.3(±3.7)
Val −> Asn              −21.5(±1.0)
Leu −> Ala              −14.2(±4.2)

As discussed in Loladze et al (J. Mol. Biol. 320, 343-357 (2002)), the following amino acid substitutions can decrease the thermodynamic stability (e.g., reflected in the Gibbs free energy) and alter the conformational dynamics of a starting protein. For example, Val and Leu (and other larger non-polar amino acid residues) can be substituted with smaller ones such as Ala, Thr, Asn, and/or Gly. In addition, the buried site of Glu in the starting protein, can be substituted with Leu, Val, Asn, Thr, Ser, Ala, and/or Gly. These single site amino acid substitutions are expected to generate peptidogenic proteins with lower stability but a similar conformation to the starting protein.

Alternatively, the conformational dynamics of the starting protein is altered by replacing (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, leucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid or asparagine with glycine, serine, threonine, alanine, valine, leucine, isoleucine; or (h) at least one glutamic acid or glutamine with aspartic acid, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, glutamine, asparagine, leucine, or isoleucine; or (l) at least one alanine with a glycine; or (m) at least one residue with a non-natural amino acid; and/or (n) any of the above combinations.

In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. A combinatorial approach may be used to determine optimal substitutions to increase immunogenicity.

Example 2: Peptidogenic Proteins of Bovine Pancreatic Trypsin Inhibitor

Bovine pancreatic trypsin inhibitor (BPTI) is an extremely well-characterized small protein, on which there is a substantial body of literature describing its folding, structure, activity, thermodynamic properties, expression properties, and protease specificities (15). Our own lab was the first to express recombinant BPTI and engineer its properties using site-directed mutagenesis (16, 17). Wild type BPTI has three disulfide bonds, cross-linking disulfides 14-38, 30-51, and 5-55; the 14-38 disulfide is on the surface, and the other two disulfides are deeply buried in the hydrophobic core of the protein. Mutations of any one of these disulfides by replacing the two disulfide cysteines with alanine residues destabilizes the BPTI molecule (18). All possible combinations of disulfide bond mutants of BPTI have been made by ourselves and by others, and all are markedly destabilizing. Importantly, where it has been examined, for all combinations of mutants of BPTI that knock out one or two native disulfide bonds, the protein nevertheless maintains a similar three-dimensional structure and trypsin inhibitor activity comparable to wild type BPTI (19-22) Therefore, despite stability differences manifested by Tms ranging from >100° C. to <40° C., the wild type molecule and its disulfide mutants all display similar, if not virtually identical 3D conformational epitopes. For example, at 40° C. the mutant protein would be almost 50% unfolded at body temperature, and at >100° C. (higher than the boiling point of water) the wild type protein is among the most thermostable proteins known.

TABLE 4
Mutants of BPTI that knock out one or more of the native disulfide
bonds or core residues while preserving 3D structure
BPTI variant  Sequence
wild type     RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA
              KRNNF KSAED CMRTC GGA (SEQ ID NO.: 919)
[C14A C38A]   RPDFC LEPPY TGPAK ARIIR YFYNA KAGLC QTFVY GGARA
              KRNNF KSAED CMRTC GGA (SEQ ID NO.: 920)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A          KRNNF KSAED CMRTC GGA (SEQ ID NO.: 921)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YAYNA KAGLC QTFVY GGARA
K15A, F22A    KRNNF KSAED CMRTC GGA (SEQ ID NO.: 922)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFANA KAGLC QTFVY GGARA
K15A, Y23A    KRNNF KSAED CMRTC GGA (SEQ ID NO.: 923)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A, N43G    KRGNF KSAED CMRTC GGA (SEQ ID NO.: 924)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A, F45A    KRNNA KSAED CMRTC GGA (SEQ ID NO.: 925)

For our immunological experiments with BPTI, since we are interested in protease digestion and peptide generation in vivo from the antigen, we will make the BPTI mutants described in Table 4. Mutated residues are underlined, cysteine residues are shown in bold. These consist of wild type BPTI with the surface disulfides 14-38 mutated to alanine, which has been shown to confer increased stability to reducing agents. The BPTI mutants will also be made in the [Lys15→Ala] background. The Lys15-Ala mutation ablates the P1 residue side chain and reduces BPTI's affinity towards trypsin and other proteases by as much as 107-fold, rendering it essentially inactive as a protease inhibitor (23). Additional mutations within the core of the protein (e.g. F22A, Y23A, N43G, F45A) serve to destabilize the protein and alter conformational dynamics to varying degrees while still maintaining a 3D structure comparable to wild type BPTI. This table is intended to be non-limiting with respect to present invention embodiments.

Analogous mutations can be made in the Alzheimer's amyloid precursor protein Kunitz inhibitor (APP-KI), which is a human protease inhibitor homologous to BPTI. APP-KI has a relatively low isoelectric point (pI) and so, unlike BPTI, it should be electrostatically nearly neutral in charge at lysosomal pH. Like BPTI, APP-KI has previously been expressed and characterized in terms of folding, activity, and 3D structure, and it has three disulfide bonds precisely homologous to those found in BPTI.

We will express the mutants both with and without flanking tag sequences. Tags we have used to vary solubility include the calmodulin binding peptide (CBP) tag, which is highly soluble, to the TrpLE tag, which is highly insoluble (24). In a particularly favored construct, however, we use a tripartite tag: AviTag-hexaHis-TEV protease cleavage site. This tag confers intermediate solubility, can by biotinylated using the BirA biotin ligase (25), allows binding to a HisTrap column for purification and/or on-column refolding (Campbell and Anderson, in preparation), and can be cleaved off the antigen if necessary. The antigen can be used to immunize animals either without the tag (i.e., after TEV cleavage) or with the tag intact followed by subtractive depletion of anti-tag antibodies (S. Blackshaw and D. Eichinger, personal communication).

Example 3: Preferred Targets of the Present Invention

As used herein a “Target” is a specifically selected protein disclosed in Table 5 that can be modified to have an improved peptidogenicity as described herein. Column 1 lists the SEQ ID NO. corresponding to the sequence provided in the Sequence Listing. Column 2 lists the “Protein Name” of each Target and Column 3 provides the “UniProt Reference Number” which is a unique “cataloging” number (UniProt Reference Numbers provide a mapping of a proteome to a reference genome assembly, e.g., as produced by the Genome Reference Consortium (GRC)) used in the art that provides publicly known and established descriptions of both the function, expression and sequence information for each Target listed in Column 2. This public information (retrieved from the UniProt database (http://www.uniprot.org) on Aug. 10, 2016) including the sequence information corresponding to each Target, is herein incorporated by reference in its entirety. The Sequence Listing and Table 5 describes the positions of the specific residues in each target protein where mutations can be made to generate the corresponding peptidogenic proteins along with the specific amino acids that can be substituted at each position. In preferred embodiments, multiple substitutions can be made in each target protein at the recited positions in the Sequence Listing and as shown in Table 5. In further preferred embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the residues listed in the Sequence Listing and/or Table 5 for each target protein, in any combination, can be changed in the respective starting Target proteins listed in Column 2 using the amino acid specified in the Sequence Listing and/or as described in the last two paragraphs of Example 1. By spreading the mutations over multiple positions and/or target proteins, and by mixing these mutated molecules together, an immunization cocktail can be created.

TABLE 5
TARGETS
			Exemplified Sites of Mutations to Generate Peptidogenic Protein
SEQ ID NO.	Protein Name/Strain	UniProt ID No.	(Each position can be substituted alone or in any combination with any of the other listed amino acid positions.)
1	Hemagglutinin [Cleaved into: Hemagglutinin	A4GCL9	V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, I74, A75, W77, L78, L79, C84, L87, W93,
	HA1 chain; Hemagglutinin HA2 chain]/strain		Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A151, A152, C153, H155, L165, L166, W167, L168, L178, V190,
	A/USA: Phila/1935 H1N1		L191, V192, L193, W194, V196, H197, H198, Y209, Y215, V216, V218, V219, Y223, M244, Y246, Y247, L250, L251,
			I257, F259, A261, L265, I266, A267, Y270, A271, F272, A273, L274, F278, I282, I283, C292, C296, A302, I303, H313,
			I317, V324, L329, M331, V332, A349, M361, Y366, A388, I389, A440, L452, V459, L462, V466, L470, C481, H486,
			C488, C492, M493
2	Proprotein convertase subtilisin/kexin	A8T655	V80, A95, L98, A102, F122, V124, A134, I143
	type 9 (EC 3.4.21.—)
3	Plasminogen (EC 3.4.21.7)	B2R7F8	Y193, W209, C234, W244, C245, F246, C257, I259
4	cDNA FLJ60453, highly similar to	B4DEZ9	V80, L98, A102, F122, V124, A134, I143
	Proprotein convertase subtilisin/kexin
	type 9 (EC 3.4.21.—)
5	Receptor protein-tyrosine kinase	B4DTR1	V474, I476, A495, I512, C513, V521, L530, V534, L546, L547, W549, C550, I553, A554, M557, L560, L565, V566,
	(EC 2.7.10.1)		H567, L570, A571, A572, V575, V577, V583, I585, A591, A614, F623, V629, W630, Y632, V634, V636, L639, M640,
			I655, L659, I670, V675, M679, C682, W683, F693, F700, M703, V711
6	Interleukin-4	D4HNR6	L31, I34, L38, C48, C70, A72, A73, L76, C89, H100, L107, L110, L114, A118, L133, F136, L140, M144
7	Cell wall-binding repeat protein/NAP07	D5RWT1	F32, F51, F53, F73, A74, F104, F124, A129, A132, F143, F164, A165, F195, F215, A220, A223, F237
8	Insulin, isoform 2	F8WCM5	L35, A38, L39
9	Fusion glycoprotein F0	G8EJ09	L204, I206, I214, S215, I233, V247, M251, L257, I261, M274, I280, V281, Y299, V301, L303, C313, C333, C343, V349,
			F352, V365, F366, C367, C382, A412, I413, V414, C416, C422, A424, V442, V450
10	TcdA	I6YE93	F2585, A2593, F2604, F2625, A2626, F2656, F2676, A2681, A2684, F2698
11	Spike glycoprotein/isolate	K9N5Q8	C30, F40, W44, I48, A53, Y58, Y64, I67, L74, Y85, F101, Y105, F112, V117, I120, A123, A124, I132, Y144, V153, L169,
	United Kingdom/H123990006/2012 (HCoV-EMC)		V170, L172, C176, A182, Y184, C185, C195, F232, C237, F239, Y243, W253, F254, I256, V263, L265, M278, F279,
			A282, I290, Y292, Y293, I300, A309, A312, F313, Y314, Y316, L318, V329, A336, C339, L347, C349, Y351, F354,
			V360, Y361, F366, A368, C383, F404, C407, Y409, L411, L414, L415, L417, V420, F423, C425, A434, C437, Y438, F446,
			A461, I464, F467, Y469, C478, A482, Y497, C503, I573, Y577, V584, C585, C603, Y606, V616, F617, C620, V631,
			Y632, Y648, Y649, C650, C654, V655, V657, V659, V661, I662, Y663, A671, L673, V677, C679, L697, L707, V711, C713,
			V724, C727, L729, L731, L735, C736, A737, V770, I782, F786, I795, V802, C806, V810, C811, C817, L821, Y824,
			F827, C828, L835, L893, L894, F895, V898, Y909, C912, L923, C925, V934, L935, Y947, W960, A968, F972, Y978, V989,
			L990, I997, F1001, A1004, A1007, F1012, A1018, V1026, A1030, A1032, L1033, L1036, L1040, F1044, A1046, I1047,
			A1049, I1054, L1058, A1065, I1067, L1070, I1071, L1075, L1078, A1080, L1086, V1103, C1106, V1107, F1116,
			C1117, I1123, V1127, A1130, L1134, F1136, Y1141, L1155, C1156, A1166, Y1171, F1172, W1184, Y1192, I1197,
			V1209, Y1211, L1223, L1260, L1262, M1266, L1276, Y1280, I1281, C1320, C1323, C1327
12	Serine/threonine-protein kinase Sgk1	O00141	A115, V126, F158, F166, L172, F174, V175, L184, A199, Y202, A203, A204, I206, A207, A209, L210, L223, I228, L230,
	(EC 2.7.11.1)		I236, L238, A265, V278, W280, W281, C282, L283, A285, V286, L287, M290, A324, L327, L328, L331, I349, F355,
			L363
13	AP-4 complex subunit mu-1	O00189	V187, L189, V191, L195, I199, V210, I214, L216, M226, I228, L230, F234, V250, L270, V281, M282, Y284, L286, F296,
			L311, V313, L315, L317, C319, A327, V330, L332, L334, L347, W363, L365, V368, M380, A405, L407, F409, L411,
			L419, Y449
14	Toll-like receptor 4	O00206	Y38, C40, L59, L61, L69, F74, F77, L80, L83, L85, C88, I90, I93, A97, Y98, L101, L104, L107, L109, I114, A121, F122,
			L125, L128, L131, A133, L141, I146, L149, L152, L155, V157, A158, I162, F165, L167, F171, L174, L177, L180, L182,
			I187, I190, L195, V197, L198, L203, L206, L208, L210, M215, I218, A222, F223, I226, L228, L231, L233, M243, C246,
			I247, L253, V255, L258, L260, F272, A276, L277, L280, F288, L290, Y296, L297, I300, L303, F304, L307, V310, F313,
			L315, V318, I320, V323, F326, F330, W332, L335, L337, C340, F342, L348, L350, L353, L356, F358, G363, L372, L375,
			L378, L380, L385, F387, C390, C391, F396, L401, L404, L406, I412, M414, F418, L421, L424, L427, F429, M437, V442,
			F443, L446, L449, I450, L452, I454, V461, I466, F467, L470, L473, L476, M478, F483, L488, F492, L495, L498, L501,
			L503, C506, L508, A515, F516, L519, L522, V524, L525, M527, F532, F533, L535, Y540, L543, L546, L549, Y551, I556,
			L571, L574, L576, F581, F590, L591, I594, L600, M607, V620
15	Tumor necrosis factor receptor superfamily	O00220	C132
	member 10A
16	Agouti-related protein	O00253	C94, C119
17	Tubby-related protein 1	O00294	V295, C307, L309, L326, L337, I352, I367, L370, V381, F382, L403, A404, A405, V406, V423, I424, I425, I437, L446,
			L461, I493, V503, L504, F506, F514, L516, Y518, L522, C523, A524, L525, A527, F528, A529, I530, A531, L532, L539
18	Tumor necrosis factor receptor superfamily	O00300	C41, C44, C65, C124
	member 11B
19	Krev interaction trapped protein 1	O00522	A10, V12, A13, V14, I15, Y28, Y33, I35, L36, L37, L54, I68, V72, A108, L110, I112, V113, L135, L152, M156, L157,
			L160, L164, I174, L292, H293, A296, L304, A323, I325, H326, A328, C329, A336, L340, C346, A362, A363, I370, V371,
			L374, C396, A407, I424, V434, V444, I447, I463, I465, W487, L491, L508, I522, A527, I528, I530, L531, A535, L539,
			A546, L551, I552, L554, A555, L557, L558, L559, H571, I584, V585, L590, A594, I601, Y605, L621, F625, L626, C629,
			I632, V658, V660, V662, L667, H668, L669, L670, F697, I699, V710, A715, V718, L722, L725
20	C-C motif chemokine 21	O00585	L63, F64, C75, A76, V83
21	Lysosomal alpha-mannosidase	O00754	A241, Y306
22	Receptor-type tyrosine-protein phosphatase T	O14522	F74, M75, V77, A88, L90, L92, H101, F105, L120, V122, V124, V135, A149, L151, A152, I153, Y161, V163, F165, I177,
			A178, V179, V184, F211, C213, L227, A250, V252, Y265, C267, V268, I269, V277, A281, L305, I307, V325, I358, L362,
			L403, L405, C417, V424, L449, I458, L460, L462, L464, I502, I504, Y519, I521, F553, Y562, F564, I566, A568, V578
23	Tumor necrosis factor receptor superfamily	O14763	C81, C139
	member 10B
24	Tripeptidyl-peptidase 1	O14773	L49, F51, A52, L61, V65, L80, L82, V85, A86, V89, V99, A105, F119, C122, L124, I126, A129, L133, F138, V150, Y157,
			L159, V167, F169, V170, L173, V200, Y209, A226, C227, A228, F230, L240, F243, V277, Y279, L280, M281, A283,
			A285, I287, F304, L305, W307, L308, V320, H321, V323, Y336, I337, V340, L344, A347, A348, A349, L355, F356, A363,
			F378, A380, V385, V388, F397, V404, V426, A448, V452, A453, A454, L455, Y459, V461, V462, V471, A476, V480,
			F481, I484, L485, L487, I488, V518, H523, C526, F536, V545, L556, L560
25	Tumor necrosis factor ligand superfamily	O14788	L168, I170, L184, L206, V208, Y214, L216, A218, I220, F222, L238, V240, V242, L283, I289, I291, V293, A310
	member 11
26	Growth/differentiation factor 8	O14793	C281, C282, C372, C374
27	Ras-related protein M-Ras	O14807	L11, Y14, L16, V17, V18, V19, V24, L29, F33, V39, I56, A61, I62, L63, V65, L66, A69, M77, M82, F88, L89, I90, V91, Y92,
			V94, V103, F106, I110, V113, F119, M121, I122, L123, V124, A125, I136, A145, A157, V164, A167, F168, L171, V172
28	Tumor necrosis factor	O14836	C89, C100, A101
	receptor superfamily member 13B
29	Interferon regulatory factor 6	O14896	W449
30	Natural cytotoxicity triggering receptor 3	O14931	A35, L37, C39, A49, F56, H89, A91, I95, V98, I105, Y106, C108, V110, V112, L125
31	Peripheral plasma membrane protein CASK	O14936	F8, C15, V26, C29, V40, V45, F48, L59, L69, I74, L77, L87, M89, V90, F91, L99, C100, I103, Y113, A118, M122, I125,
			L126, A128, L129, C132, I137, I138, H139, V142, C146, V147, L148, L149, V158, L160, A166, A187, V191, V202,
			W203, C205, V207, I208, L209, F210, I211, L212, L213, F227, I230, W242, A249, L252, V253, M256, V267, A270,
			W275, L276, L295, A310, V312
32	Cyclin-G-associated kinase	O14976	L40, V42, A57, L68, L71, I82, L92, I98, I107, L122, L130, C145, V148, L149, I151, F152, C156, A158, V159, M162,
	(EC 2.7.11.1)		H171, L179, L181, I187, L189, F192, I198, I246, L249, L253, L256, F288, I292, M295, V309, L313, A317, I328,
			F525, V640
33	Synapsin-3	O14994	L94, L95, V96, I97, W104, F126, C139, V141, I162, L163, V164, V181, V192, L211, F223, V226, V246, V247, V261,
			F267, V273, V274, A281, I295, A304, Y305, W335, V336, C339, I348, C349, A350, V351, A353, I363, M371, M385,
			A386, V389
34	Spectrin beta chain, non-erythrocytic 2	015020	F63, W66, V67, L71, L81, L85, L91, L92, L94, L95, V119, A122, L123, L126, L133, I141, V142, L152, V153, I156, I157,
			I162, I165, L182, C186, V198, F201, W205, A210, F211, A213, I214, V215, L228, H234, L237, A240, F241, A244, L253,
			L254, V259, I269, I270, Y272, V273, A274, Y276, Y277, L2225, A2238, V2246, C2248, L2250, L2255, F2257, L2278,
			V2295, F2296, L2298, F2308, A2310, W2319, V2323, A2326
35	Niemann-Pick C1 protein	O15118	W27, V59, C63, L73, C74, C75, L80, L94, C97, C100, L104, L107, C113, L121, V141, L144, Y146, V148, F152, A153,
			M156, A159, C160, V163, A172, L173, C177, W189, I190, F194, C227, C243, L408, I410, F431, L435, V443, L444, L446,
			I450, V462, L464, I467, C479, I481, V484, L485, Y487, F488, L495, A507, H510, H512, C516, C533, V541, L545,
			V546, L547, A558, L561, I563, F565, V567, A580, W583, F587, L649, L656, A659, L720, L724, V727, F763, A1035,
			F1100, A1124, M1138, M1228
36	Laminin subunit alpha-5	O15230	L273
37	Phosphomannomutase 2	O15305	L8, C9, L10, F11, L17, M28, F31, L32, L35, I41, V43, V44, V52, L56, V60, Y64, V67, F68, L73, A75, I87, L99, C103,
			M126, L127, V129, I132, F144, F157, L161, I178, F180, V182, C192, L193, V196, F206, F207, I220, C241
38	Phosphatidylinositol 3,4,5-	O15357	A31, L34, L35, F44, L45, V46, A55, L58, C59, V60, I71, V81, V87, L98, I99, Y102, L113, V117, I424, V426, F427, I428,
	trisphosphate 5-phosphatase		W431, I466, V468, F469, L489, I508, V510, A511, V512, L513, V514, A543, V544, V546, F548, F550, F555, F557, C560,
	2 (EC 3.1.3.86)		H601, F603, F605, L608, Y610, I619, L631, L637, V646, F657, W688, C689, I692, L693, Y707, C709, I713, V721, F722,
			V727, M1201, L1205, L1217, L1228, L1236, V1241, L1250
39	Eukaryotic translation	O15372	V36, V39, V45, L67, I78
	initiation factor 3 subunit H
40	Neural cell adhesion molecule 2	O15394	L32, F40, C42, A44, W53, L78, I80, A83, C93, A95, V107, A132, V134, C136, I173, I176, Y184, C186, V190, I201, V203,
			V205, A220, A222, F230, C232, W244, L266, V268, I271, Y279, C281, A283, A294, L296, I304, L320, C322, W334,
			F343, I354, L365, I367, V370, Y378, C380, A382, M393, I418, I420, C422, V424, W434, L460, I462, Y473, C475, A477,
			Y488, A493, A512, V514, F516, Y530, V532, L556, I567, V569, A570, A571, L611, I613, A621, V628, L653, L656,
			V664, I666, A668
41	Toll-like receptor 3	O15455	A35, C37, I53, L56, L58, L63, L66, F71, Y74, L77, L80, V82, I87, L98, L101, V103, L104, L106, L111, F119, L125, L128,
			L130, I135, F143, L149, L152, L154, L164, L170, L173, L176, L178, I183, L186, L191, I193, F194, L199, L202, L204,
			I209, C216, F217, L223, L226, L228, V231, L241, C242, L245, I250, L253, L255, L260, F268, L269, L271, L276, L279,
			L281, L286, V289, F294, L297, L300, F303, L305, I310, L313, L318, L321, V324, L327, L329, F351, L354, L357, L360,
			M362, F375, L378, L381, L384, L386, L396, F401, L404, L409, H410, L412, L414, I419, I422, A426, F427, L430, L433,
			L436, L438, L440, I443, L447, W452, L455, I458, I461, L463, L469, L471, F476, V479, L482, L485, L487, V490,
			L492, V495, F502, L505, L508, L511, L513, I521, M525, L526, L529, L532, L535, L537, L542, L545, W546, F557, L558,
			L561, L564, L567, L569, F574, F582, L585, L588, I591, L593, L595, L598, L601, F606, L612, L615, L617, I622, V625,
			A633, F634, L640, M642, F647, I654, F657, Y675, V688
42	Fibroblast growth factor 10	O15520	L82, L90, I92, L111, I113, V123, A125, L132, A133, M134, C150, L152, Y164, M176, V178, A179, L180, A199, F201
43	Leucine-rich repeat transmembrane protein	O43155	I75, L100, I121, L129, L132, L135, L138, L140, I159, L161, L163, L164, L166, L185, A193, L203, L206, L209, V211,
	FLRT2		L215, L216, F235, I237, L254, L257, L259, L278, L281, L288, L291, F296, L299, L305, I318, L325
44	Kunitz-type protease inhibitor 2	O43291	C84, C133, C179
45	Desert hedgehog protein	O43323	A59, V67, A95, M99, C103, V107, L110, A111, V114, L123, V125, W129, L140, H141, A146, L147, I149, Y159, L161,
			L162, A163, A166, V174, V182, V184, V186, A188, V194
46	Glutamate receptor ionotropic, delta-2	O43424	V445, V446, F453, V454, F470, V474, L475, L478, A491, L508, V509, A517, I519, I521, L524, V534, V547, L548, L549,
			L562, L671, Y679, M708, I712, V732, A738, F739, V740, V745, L746, F758, Y770, I772, A773, L774, F784, I788, M797
47	Tumor necrosis factor ligand superfamily	O43557	A96, L98, L112, A132, L133, V135, Y141, I143, V147, L149, I162, H164, L166, L180, V215, V216, V217, L224, F235
	member 14
48	Carbonic anhydrase 12 (EC 4.2.1.1)	O43570	W43, I58, L60, Y79, L89, V96, L98, M104, I106, L118, L120, H121, W122, H133, A142, L144, H145, I146, H148, A160,
			A168, L170, A171, V172, L173, I174, Y183, I186, L190, V193, V202, I207, L210, C230, V234, W236, V238, F239,
			I245, L250, L251, L253, A256, L257, M270, V285
49	Alpha-actinin-4	O43707	F56, W59, C60, L64, F78, L82, L84, L87, L88, V112, A115, L116, I119, L126, A131, I134, V135, L143, M145, I146, I149,
			I150, A154, I155, I158, L169, C173, V185, F188, W192, A197, F198, A200, L201, I202, L215, V221, L224, A227, F228,
			A231, M240, A243, I246, A256, I257, M258, Y260, V261, F264, Y265, A274, A415, F418, A422, L436, I449, I473,
			L480, V491, I498, L505, L516, H530, Y533, A537, M544, I563, L577, I587, A594, L605, I619, V626, L637, M679, I719,
			I743, M815, I880
50	EGF-like repeat and discoidin I-like domain-	O43854	C59, C116, C154, M325, W351, A356, A366, W367, L378, V380, V388, I391, A396, V405, Y408, L410, A411, Y422,
	containing protein 3		A453, I456, I458, I467, L469, L473
51	Tolloid-like protein 1 (EC 3.4.24.—)	O43897	A148, A149, W157, I162, F178, A181, W185, V191, I203, F205, I226, V238, V239, L242, V245, I246, F248, H250,
			H252, V261, I268, F276, I296, M297, H298, I313, A340
52	Peroxisome biogenesis factor 1	O43933	V19, V108, I155
53	Kalirin (EC 2.7.11.1)	O60229	L2148
54	Cubilin (460 kDa receptor)	O60494	Y952, I962, I970, L1020, F1024, I1037, Y1068, C1074, Y1076, I1086, L1095, L1107, I1109, F1143, F1154, A1156,
			C1191, W1193, L1195, A1202, F1203, M1255, F1270, A1272, V1281, L1291, C1306, W1308, V1318, V1368, L1370, F1382
55	Gremlin-1	O60565	C178
56	Toll-like receptor 5	O60602	L72, L75, L94, L97, A114, L121, L124, L144, L147, I157, L169, I175, F177, I182, L190, L314, L317, L338, L341,
			L359, V362, I365, A425, V447, L450, L475, V497, L507, L531, L553, I555
57	ATP-binding cassette sub-family C member 9	O60706	M702, I703, V704, C709, L714, L715, A717, I718
58	Voltage-dependent L-type calcium channel	O60840	A252, A700, I707, A1015, V1082, A1095, Y1120, A1372, M1389
	subunit alpha-1F
59	Matrix metalloproteinase-20	O60882	L45, Y49, L75, L81, L122, I126, V138, A141, V142, A145, L146, A148, W149, V153, L155, A165, I167, I169, F171,
			A190, F193, F205, W211, L220, F221, V223, A224, A225, F228, A231, L232, L234, A242, L243, M244, Y245, Y250,
			L258, V263, I266, L269
60	Low-density lipoprotein receptor-related	O75197	L35, L36, F37, A38, V43, L62, A65, A67, V68, V77, Y78, W79, V82, A86, I87, L113, L122, Y123, W124, I132, V134,
	protein 5		M165, Y166, W167, I176, A179, M181, V190, A212, I219, A242, L250, W252, I260, H261, I284, V286, L309, L311,
			L312, C321, C323, L344, L345, L346, A347, I355, L357, A375, Y388, W389, A396, I397, L430, Y431, W432, I440, V442,
			M473, Y474, W475, I484, A487, L489, L517, W519, I530, L545, I568, L588, M589, C605, L615, C616, F617, C627,
			I1274, C1323
61	Core histone macro-H2A.1	O75367	A19, F23, V25, M28, I32, H36, V43, A45, V47, Y48, M49, A50, A51, V52, L53, L56, I60, L61, A64, A67, A68, V76, H80,
			I81, L83, V85, L91, V98, A101, L197, L199, I200, I204, L207, A208, F210, A214, I215, I216, I223, L233, F241, V245,
			L255, A258, A270, V273, I274, H275, C276, L290, V294, C297, L298, A301, I309, A310, F311, I314, A326, A327, I330,
			L331, A333, I334, F338, I346, V349, F351, Y362, M366
62	Filamin-B	O75369	F22, C26, L30, I37, L40, L44, L50, I51, L53, L54, V80, V82, A83, L84, F86, L87, I92, I102, I110, L111, L113, V114,
			L117, I118, I123, L145, W148, I149, I153, F161, W165, A170, L171, A173, L174, V175, A179, C183, A198, A201, M202,
			A205, L209, V211, V214, I215, I220, V230, M231, Y233, L234, F237, A257, A275, V279, A284, V291, V317, H327, V329,
			V331, F333, I338, V345, V1043, F1061, I1063, A1068, V1097, Y1099, Y1107, V1109, I1111, I1118, A1125, I1127,
			V1136, A1138, V1156, A1161, A1170, V1192, Y1194, Y1202, L1204, M1206, Y1208, V1220, I1231, V1243, F1251,
			V1253, I1270, Y1290, V1292, Y1294, H1302, V1304, V1306, V1320, V1331, A1341, F1349, V1351, A1356, A1385,
			Y1387, Y1395, V1397, I1399, I1406, V1413, V1424, V1435, V1445, A1450, V1459, V1481, V1493, V1495, Y1497,
			I1502, V1509, V1511, V1520, V1532, A1534, F1540, I1542, A1544, A1547, I1556, V1578, Y1580, Y1588, I1590,
			V1592, Y1594, I1599, I1606, A1608, A1614, C1617, F1636, V1638, A1643, V1648, V1652, I1674, A1678, Y1684,
			I1686, V1688, I1695, V1702, A1704, V1755, V1764, V1784, V1786, H1796, M1798, I1800, I1807, V1824, F1842,
			I1844, V1878, Y1880, Y1888, I1890, V1892, A1906, I1908, I1964, F1966, H1974, V1976, I1978, V1994, A2002,
			A2005, F2023, V2025, V2059, Y2061, Y2069, V2071, F2075, V2087, I2089, V2133, H2153, V2155, H2165, V2167,
			V2169, V2185, V2196, F2214, I2216, V2250, Y2252, A2254, Y2260, V2262, I2264, I2271, V2278, V2280, I2281,
			A2287, L2290, L2300, I2310, L2312, A2315, I2319, V2323, V2345, H2355, I2357, V2359, F2361, V2373, V2387,
			L2394, F2405, I2407, A2412, V2440, Y2442, Y2450, I2452, V2454, Y2456, I2462, A2469, A2512, V2515, A2525,
			V2535, C2537, V2571, V2575, V2585, W2587, I2592, V2599
63	Vacuolar protein sorting-associated protein	O75436	F42, V48, V52, H65, I68, I70, F72, V73, I76, L101, F111, V114, V126, L128, Y130, F131, L132, V134, V151, M166,
	26A		L174, I176, F178, Y180, Y185, I191, I195, M207, L209, L211, A231, I246, I248, L250, L252, F268, V270, Y272, L274,
			L276, L278, I292
64	Low-density lipoprotein receptor-related	O75581	L23, L24, Y25, A26, L31, V34, V47, L50, A53, A55, V56, F58, V59, I65, Y66, W67, V70, A74, I75, V90, V91, L94, L100,
	protein 6		C102, L109, Y110, W111, I119, V121, L128, M152, Y153, W154, I163, A166, M168, I177, L189, L196, Y197, W198,
			A199, I206, A218, V219, L224, A229, L232, L237, Y238, W239, I247, L248, A249, C250, I271, A273, L296, C297,
			L298, M299, C308, C310, L317, L331, L332, L333, A334, L339, I342, L344, A362, Y375, W376, A383, I384, A414, L417,
			Y418, W419, I427, V429, L453, M460, Y461, W462, I471, A474, A475, L476, V485, A496, I504, W506, M517, I532,
			W547, I555, L575, M576, C592, L602, C603, L604, C614, L634, L635, F636, I642, I645, A664, A666, I676, Y677, I686,
			A689, V700, V712, L719, Y720, W721, A722, I729, V731, L755, M762, W764, I773, A776, A777, M778, V787, A793,
			I798, L805, W807, I815, A829, L832, I845, W847, I855, A858, I869, V876, V881, C893, L903, C904, A906, L936, L937,
			F938, I944, L959, V967, A969, L979, Y980, W981, I982, I989, A992, Y1027, I1028, Y1029, C1032, I1038, V1040,
			V1051, L1052, A1061, V1062, M1071, Y1072, F1073, I1083, A1086, A1087, L1088, L1116, F1117, W1118, A1119,
			I1126, L1157, W1159, I1160, I1167, L1188, C1207, I1217, C1218, L1219, C1313
65	Oral-facial-digital syndrome 1 protein	O75665	M834, H851, V852, A854, A858
66	Protein XRP2	O75695	V57, F62, I64, C67, C70, I72, I74, F75, V81, I83, C86, C89, I91, F92, L93, V96, V100, F102, C105, C108, C110, L112,
			A113, C114, F117, V119, C122, L125, V127, L129, C131, I137, I143, F145, F148, W150, Y152, L155, F157, F159, A162,
			F167, W171, L189, V195, V199, L207, V221, C236, L237, V238, V239, A248, A250, L253, M257, V270, A277, V280,
			A285, V297, A299, L300, F302, A307, V308, C311, A333, F340, A344
67	Gap junction beta-3 protein	O75712	L25, A39, W44, F51, C60, C64, W77, V84, I92, L135, L149, C164, V167, C176, M191, C198
68	Isocitrate dehydrogenase [NADP]	O75874	V10, V11, M13, M18, I21, I22, W23, L25, I26, L30, I31, V35, L39, L44, I46, A60, A61, A63, I64, V69, V71, C73, A74, I76,
	cytoplasmic		I99, I102, V107, F108, I112, I113, C114, I117, W124, I128, I129, I130, H133, A134, A179, I189, F192, A193, F197,
			M199, A200, L207, L209, F223, I226, F227, F239, I244, M254, A258, F265, I266, W267, A268, C269, V281, A282, Y285,
			M290, M291, L295, V296, C297, V303, A305, A307, A308, I330, A331, I333, F334, A335, W336, L340, A344, L352,
			A353, F355, A356, A358, L359, V362, I367, F371, M372, L376, A377, A378, F397, M398, L401, L405
69	Tumor necrosis factor ligand superfamily	O75888	L219, L225
	member 13
70	Dysferlin	O75923	L2, V86
71	Multiple PDZ domain protein	O75970	M129, A130, F138, L140, I165, V167, A176, I188, L189, A190, I191, L196, A205, V216, L218, V219, I220, A221, I258,
			L260, V279, A290, I302, L303, I305, L310, V318, V329, L331, I333, A334, V378, L380, I405, V407, A415, V416, I422,
			I428, V431, L436, A444, V455, L457, L459, L703, I728, I730, I738, A739, L745, L751, V754, L759, A767, A774, V779,
			I781, V783, V1152, L1154, L1162, I1185, I1187, A1196, L1202, I1208, V1209, V1211, L1216, A1219, A1224, V1235,
			F1237, V1239, I1337, L1353, A1365, V1375, F1376, I1377, A1386, L1398, L1399, I1401, L1406, A1414, A1421,
			V1425, I1427, I1428, F1429, I1430, A1435, I1630, I1632, I1654, I1656, A1664, A1665, I1677, V1680, L1685, A1693,
			V1704, L1706, L1708, I1726, L1728, V1749, A1760, I1772, V1788, V1799, V1803, I1890, I1892, A1901, I1916, A1929,
			I1940, M1942, V1944, I1988, L1990, L1997, I2014, V2016, A2025, I2037, V2040, L2045, A2053, L2057, V2064,
			L2066, V2068
72	Nebulette	O76041	A961, F975, I981, V996, L1005
73	Bestrophin-1	O76090	V90, V158, F248
74	Serine/threonine-protein kinase 10	O94804	A53, A62, A64, I82, I84, A86, C88, I93, V94, L106, I108, M109, V118, I121, M122, L125, L129, I134, V136, V137, C138,
	(EC 2.7.11.1)		M141, L142, A144, L145, L148, H155, L158, A160, V163, L164, M165, L167, I171, L173, F176, V178, A180, A200, A218,
			I220, L223, L227, I228, M230, V245, L246, I249, F267, F270, A274, L275, A285, L288, F293, V294, L303, L306, V307
75	Tumor necrosis factor ligand superfamily	O95150	A97, L99, L117, M132, L139, I141, Y147, I149, V153, F155, A168, I177, V179, V180, I181, I212, L220, L226, V228,
	member 15		V230, V236, F245, F246, A248
76	Interleukin-18 receptor accessory protein	O95256	L165, I173, C175, W191, C221, A236, V238, C273, A275, F277, W289, V326, F335, C337, V339, V350, L352
77	Bile salt export pump (ATP- binding cassette	O95342	A452, L453, V454, A464, L467, I468
	sub-family B member 11)
78	Tumor necrosis factor receptor superfamily	O95407	C49, C52, C91, C132
	member 6B
79	Apolipoprotein M	O95445	F49, I50, A51, A53, A54, I69, V70, L145, L146
80	Gap junction beta-6 protein	O95452	I25, A39, W44, F51, C60, C64, H73, W77, V84, A92, I140, F154, C169, I171, C180, M195, C202
81	Follistatin-related protein 3	O95633	V37, W39, A70, V134, C135, C146, L148, L159, C195, C211
82	Interleukin-33	O95760	A124, L126, I134, V159, L160, L161, M183, V184, L186, L194, A196, V203, A216, F217, F218, V219, C227, F230,
			C232, I240, L247, A248, F265
83	EGF-containing fibulin-like extracellular	O95967	C71, C109, C162, C241, C281
	matrix protein 2
84	Cytochrome b5	P00167	I17, L28, I29, L30, V34, L41, L51, A55, L84
85	L-lactate dehydrogenase A chain	P00338	I23, V25, V26, V28, A34, C35, A36, I39, L40, M41, A45, L48, A49, L50, V51, L58, L91, V92, I93, I94, L109, V110, V114,
			F117, F119, I120, I121, V124, C131, L133, L134, I135, V136, V140, I142, L143, V146, A147, V158, I159, C163, F170,
			M174, C185, V189, L190, V198, V200, M204, V206, L218, V230, V234, V256, A257, L259, A260, I263, V273, I277,
			I283, V287, F288, L289, V291, C293, L295, L316, A320, L323
86	NADH-cytochrome b5 reductase 3	P00387	L45, L47, F60, F62, L71, L73, I79, L81, V106, L108, V109, I110, M127, L131, F142, L149, F157, V175, M177, I178,
			A179, I184, M187, L188, V190, I191, I194, C204, L206, L207, F208, I216, L217, L218, L222, F233, Y237, L239, I258,
			L270, V271, L272, M273, C284, L288
87	Cytochrome c oxidase subunit 2	P00403	I83, I97, W106, Y108, V142, L144, I150, M152, I154, H161, W163, A164, V165, L168, A174, F184, M207, I209, V210,
			L211
88	Phenylalanine-4-hydroxylase	P00439	A34, I35, L37, F39, V51, F55, F79, F80, L83, L91, I94, L98, A104, L109, W120, I125, L128, F131, A132, A165, W187,
			V190, F191, L194, A202, C203, Y206, L213, F219, I224, L227, V230, F233, L234, F240, L255, L258, A259, F260, V262,
			F263, C265, Y268, I269, I283, C284, L287, L288, H290, V291, L293, F294, F299, A300, F302, I306, A309, L311, A313,
			I318, L321, A322, I324, F327, V329, L333, I340, A342, Y343, A345, L347, L348, L354, C357, A373, L385, Y386, Y387,
			A389, A395, V399, F402, A403, I406, F410, I421, L424, I432, A434
89	Superoxide dismutase	P00441	A5, C7, L9, V15, I18, I19, F21, V30, V32, I36, L39, H44, F46, H47, V48, H49, A61, H64, H72, H81, V82, L85, V88, A90,
	[Cu—Zn] (EC 1.15.1.1)		A96, V98, V104, I105, L107, I113, I114, L118, V119, V120, H121, A141, A146, C147, I150
90	Coagulation factor VIII	P00451	L26, A28, L90, L91, I95, I105, L107, V115, L117, A119, A131, V147, Y155, W157, Y177, L191, I192, A194, L196, V197,
			C198, L217, F218, A219, F221, H251, V253, Y256, V272, W274, V276, I277, I288, F295, I307, A315, L319, C329,
			M339, A341, V343, V345, I405, A406, A407, Y414, A415, L431, Y442, V445, F447, I467, L472, L480, I482, F484, Y492,
			I494, L517, Y530, W532, Y552, L566, I567, L570, L571, I572, C573, L594, F595, F598, Y605, M633, I636, V640,
			V648, W656, I658, V670, F677, L689, V697, M699, M701, L709, C711, M721, A723, L725, I1719, A1720, A1721, V1752,
			V1753, F1754, H1774, L1775, L1777, L1778, I1782, A1784, I1790, V1792, F1794, Y1802, F1804, V1826, W1836,
			V1838, M1842, C1851, A1853, Y1856, H1867, L1870, I1871, L1874, L1875, V1876, C1877, V1892, F1895, A1896,
			L1897, F1899, F1902, F1937, H1938, A1939, I1940, L1948, L1951, M1953, A1954, I1959, W1961, Y1962, L1963,
			L1964, H1973, I1975, F1977, F1982, L1997, V2005, V2017, C2019, M2029, F2033, V2035, M2046, A2066, A2070,
			A2080, W2081, I2099, I2100, H2101, A2108, I2117, F2120, I2122, Y2124, Y2134, F2145, I2163, I2164, A2165,
			L2181, L2185, M2186, C2188, C2193, M2199, I2209, A2220, W2222, A2227, A2237, W2238, L2249, V2251, F2253,
			V2259, V2262, V2267, M2274, V2276, F2279, I2281, F2302, L2316, L2325, I2327, I2336, A2337, L2338, M2340,
			V2342, A2347
91	Coagulation factor XIII A chain	P00488	L46, H65, Y70, L75, I76, V77, F83, V85, I87, F89, F100, V102, Y104, V105, I106, V120, A133, V136, V143, L145, I147,
			V155, F158, Y161, V162, A163, Y182, I183, L184, F185, V194, L196, Y205, V206, I213, F214, W226, I235, C239,
			V242, M243, L250, V259, M266, V275, L276, A292, W293, I299, Y303, V310, C315, W316, V317, F318, A319, V321, F322,
			L326, C328, L329, I331, A333, V336, Y339, A342, L349, I353, L355, Y373, H374, C375, W376, A379, M381, F390,
			A395, V396, C410, A413, A417, I418, H420, H422, A429, V432, F433, A434, V436, L440, I441, Y442, I461, I465, V466,
			Y482, L493, A498, V519, M521, F523, F534, L536, I538, F540, I550, A552, Y553, L554, A556, I558, Y561, V576,
			L578, I590, Y595, L605, H606, F607, F608, V609, A611, I613, V619, L620, L628, V642, M647, V649, V651, F653,
			L661, V664, V666, L668, I684, C696, L706, I707, A708, M710, L715, H717, V718, V724
92	Hypoxanthine-guanine	P00492	V35, I37, I42, L49, A50, V53, M57, I62, V63, A64, L65, C66, L68, F74, F75, L78, L79, I82, I93, I100, L125, V130, L131,
	phosphoribosyltransferase		I132, V133, I137, M143, L146, L149, V150, V160, A161, L163, L164, F181, I183, V188, V189, Y191, A192, F199,
			L202, V205, C206, V207
93	Tyrosine-protein kinase	P00519	L88, C100, A102, V111, W127, A137, L141, F149, L150, V151, I163, L165, A179, L198, V199, H202, L213, A217, I242,
	ABLI (EC 2.7.10.2)		V268, V270, F283, L284, A287, V289, M290, I293, L298, L301, V304, C305, Y312, I313, I314, L323, L327, V335,
			V339, L340, M343, A344, I347, A350, M351, L354, I360, H361, L364, A365, A366, C369, V371, V377, V379, F382,
			L384, F401, A407, L411, V422, W423, F425, V427, L428, L429, Y440, V448, L452, M458, C464, M472, C475, W476,
			F486, I489, F493
94	Epidermal growth factor	P00533	L41, F55, C58, V61, L65, I67, V70, L79, I82, V85, Y88, V89, L90, I91, A92, V96, I99, L101, L104, I106, I107, A118,
	receptor (EC 2.7.10.1)		L119, A120, V121, L132, L135, M137, L140, I143, A147, V148, F150, L156, V159, I167, V168, C199, W200, C223, C236,
			A237, A238, C240, C260, V300, V301, C326, C337, I340, F345, I351, I356, F359, C362, I365, L369, I371, V374, A375,
			L392, L395, V398, I401, L405, L406, I407, L417, A419, F420, L423, I426, L438, A439, V440, V441, L443, I445, L448,
			L450, L453, I456, V461, I463, L469, C470, Y471, A472, I475, L480, C499, C510, C515, W516, C571, C624
95	Adenylate kinase	P00568	L5, I10, F12, V13, V14, C25, I28, I60, L73, L76, M80, F90, L91, I92, Y95, F105, I109, L114, L115, L116, V118, M125,
	isoenzyme 1		I146, V160, Y164, V173, V186
96	Prothrombin (EC 3.4.21.5)	P00734	Y87, C90, A93, L100, C103, A109, Y116, C129, C157, W168, C169, Y170, C181, I183, A242, C262, V272, W273, C274,
			Y285, C286, V295, F324, F329, C336, L355, I364, V365, A370, M374, W377, V379, M380, L381, F382, L390, C391,
			A393, L395, I396, W400, V401, L402, A404, A405, H406, C407, L408, L409, L422, L423, V424, I426, L444, H450, I463,
			A464, L465, M466, L468, V472, I478, H479, V481, C482, L483, A489, L492, L493, A495, V501, W504, L507, L523,
			V525, V526, L528, I530, V531, C536, I544, M548, F549, C550, A551, A563, C564, F572, V573, M574, W582, M585,
			I587, V588, C594, Y600, F602, Y603, H605, V606, F607, L609, W612, I613, V616, I617
97	Coagulation factor IX (EC	P00740	C128, V132, V227, A233, V242, V243, L244, I256, V257, I262, V263, A265, A266, I275, V277, V278, A279, I316,
	3.4.21.22)		A317, L318, L319, L321, V331, V353, W356, L369, V374, C382, F395, C396, A397, H415, V416, L425, I428, I443,
			Y444, V447, Y450, V451, I454
98	Coagulation factor X (EC	P00742	C121, C136, I235, V236, C241, C246, A250, L251, L252, I253, C261, I265, L266, I271, L272, A274, A275, C277,
	3.4.21.6)		V286, V288, V302, I309, H311, I323, A324, V325, L326, L328, V338, A341, C342, A349, L353, G359, V361, F364,
			L377, M379, L380, V382, C390, L392, M402, C404, A405, H423, V424, F432, V433, I436, A444, I451, Y452, V455,
			F458, W461, I462
99	Complement factor D (EC	P00746	I26, L27, M40, A41, V43, C51, V54, L55, V61, L62, A64, C67, V78, L80, L115, L116, L117, L118, L120, L126, L133,
	3.4.21.46)		C148, V150, A151, W153, V169, L171, C179, I189, L193, C195, A196, C204, L212, L218, V221, V222, C229, Y238,
			V241, I248
100	Plasminogen (EC 3.4.21.7)	P00747	A31, C49, C53, C61, A63, F64, C73, M76, Y111, W127, C152, W163, C164, Y165, C176, I178, M186, Y193, W209,
	[Cleaved into: Plasmin		H217, Y219, C234, W244, C245, F246, C257, I259, Y283, C296, W299, L319, C324, W334, C335, H336, C347, I349,
	heavy chain A; Activation		Y385, C398, W401, H407, H409, L421, C426, W436, C437, F438, C449, L451, Y489, C502, W505, H513, C531, W542,
	peptide; Angiostatin;		C543, Y544, C555, V557, C577, V581, W594, V596, L598, C607, L611, V617, L618, A620, C623, Y633, V635, I636,
	Plasmin heavy chain A,		L637, V654, I666, A667, L668, L669, L671, V681, I682, A684, C685, C699, I701, W704, L716, A719, L721, V723,
	short form; Plasmin light		C729, L735, L744, C745, A746, H748, L764, V765, C766, Y772, L774, V777, A785, V792, Y793, V794, V796, F799,
	chain B]		V800, I803
101	Coagulation factor XII (EC	P00748	C135, V158, C161, C163, C209, A388, A389, A398, L401, L408, A410, A411, L414, V425, L427, L462, A463, L464,
	3.4.21.38)		L465, L467, V482, C500, A503, W505, C532, C548, A549, L567, V568, C569, L580, I583, V598, V602, I609
102	Complement factor B (EC	P00751	L58, A96, C103, Y121, I127, C145, C158, C165, V177, V187, C205, M223, V230, A231, F234, L235, I242, M269, I271,
	3.4.21.47)		Y272, L273, V274, L275, I281, F286, A289, C292, L293, I297, V300, Y309, L311, V312, Y314, A315, V322, V324,
			V335, L339, I342, A358, L359, V362, V383, I384, I385, L386, M387, L391, V401, I405, L409, I411, Y426, V427, F428,
			V430, I439, A443, H451, F453, V455, M458, L461, V464, F465, M468, V481, W495, A497, I499, V501, C511, M512,
			A514, V515, V516, F520, V521, L522, A524, A525, C527, F528, V530, V539, V541, I569, V577, A578, L579, I580,
			L582, C596, C599, A606, L607, L622, I628, A630, L631, F632, V633, V645, I647, C656, A660, A663, V669, V675, V676,
			F680, L681, C682, C695, L703, I704, V705, F711, I712, V714, V716, V721, A738, F741, H742, I743, L745, V748,
			L752, L756, L761, L764
103	Renin (EC 3.4.23.15)	P00797	I90, I92, F99, V101, V102, F103, V110, W111, V112, C117, A123, C124, F130, V154, I162, I163, V165, V170, M173,
			F174, M180, V193, V194, M196, F198, I209, F210, I213, V218, V223, F224, F226, Y227, Y228, I242, I262, V266,
			W267, I269, M271, V274, L288, A289, V291, I298, I305, L308, M309, V322, V323, C325, L331, I334, F336, L338, Y343,
			L345, Y350, F352, C362, L364, A365, I366, A380, L381, A383, F385, I386, Y390, F393, I400, F402, A403
104	Carbonic anhydrase 2 (EC	P00918	W16, V31, I33, Y51, I59, A65, F66, V68, F70, A77, V78, L79, Y88, L90, F93, H94, F95, H96, W97, H107, A115, A116,
	4.2.1.1)		L118, H119, L120, V121, H122, W123, A133, V134, L140, A141, V142, L143, I145, F146, L147, V149, L156, V159,
			V160, V162, L163, I166, F175, F178, L183, L184, L188, Y190, W191, Y193, L197, L202, L203, C205, V206, W208,
			I209, V210, L211, I215, V217, V222, F225, L228, F230, M240, L250, I255, A257
105	Argininosuccinate synthase	P00966	V7, V8, L9, C19, I20, L21, W23, L24, V31, I32, A33, Y34, L35, A51, V64, F68, V69, F72, I73, I77, L89, L93, A94, C97,
	(EC 6.3.4.5)		A99, I105, A106, Y113, C132, A143, F150, Y163, A164, L185, M186, H187, Y190, L195, L206, L223, I225, F227, V235,
			V238, L250, F251, L254, V257, A258, H261, V263, V269, I281, A286, I289, L290, A293, H294, I297, F317, A318, V321,
			Y322, C331, I338, V345, V349, V351, V353
106	Serine protease inhibitor	P00995	V46, C47, L60, C61, I71, I73
	Kazal-type 1
107	Antithrombin-III	P01008	M49, A75, V80, L83, A86, F90, A91, F94, Y95, L98, I108, F109, L110, L113, I115, A118, F119, A120, M121, A126, C127,
			L131, L134, M135, V137, F138, F140, I143, I151, H152, F153, F154, F155, A156, L158, L162, A166, A175, L178, F179,
			V197, A200, F207, I218, V222, I230, I234, A238, L242, V244, L245, V246, L247, V248, I251, F253, W257, F261,
			F271, A281, M283, M284, V301, L302, L304, F306, I311, M313, V314, L315, I316, L317, V327, L331, L343, L348,
			V349, V350, M352, I357, L363, L367, L372, L375, L383, I386, A388, L394, V396, A399, H401, A403, L405, V407,
			A414, A415, A416, A419, V420, V421, I422, A423, F434, A436, F440, L441, V442, F443, I444, V447, I453, F454,
			M455, V458, A459
108	Alpha-1-antitrypsin	P01009	F47, I50, L54, F57, A58, F59, L61, Y62, L65, I74, F75, F76, V79, I81, A82, A84, F85, A86, M87, L88, I100, L101, L104,
			F106, I111, I116, F120, L123, L124, L127, L134, L142, F143, L144, F154, V158, L161, Y162, V169, F171, A177, I181,
			V185, I193, V197, V205, F206, A207, L208, V209, I212, F213, F214, W218, F222, V224, F232, V234, V242, M244, M245,
			F251, I253, L259, V263, L264, M266, Y268, A272, A274, I275, F276, F277, L278, L284, L287, L291, I295, F299,
			L300, A308, L310, H311, L312, I317, L323, L327, L330, I332, V335, A340, L342, V345, L351, L353, A356, V357,
			H358, A360, V361, L362, I364, A371, A372, A374, M375, F376, L377, A379, I380, V388, F390, F394, V395, F396,
			L397, M398, L407, F408, M409, V412, V413
109	Angiotensinogen	P01019	V44, A103, V106, L109, A110, L113, F115, I117, Y118, V133, L134, A138, V139, F140, L143, A144, L146, L158, L16
			2, V164, L175, V180, L181, A183, L184, A186, V187, L191, V192, L203, L205, V208, V209, V211, F212, L217, L219,
			F223, L227, Y230, F241, A247, M255, V258, L276, A277, F278, Y281, V282, F284, M288, F291, F300, V310, L313,
			V331, V334, A340, C341, L342, L343, L344, I345, V356, F361, I377, L379, M381, L384, L392, L395, L396, I404, L405,
			L409, L411, L414, V424, I428, F430, L432, L456, F460, L461, A463, V464, A469, A471, L472, H473, F474, L475, V478
110	Complement C3	P01024	M25, I28, I29, L34, M42, L44, A46, H47, V55, V57, V59, L76, V86, F88, I90, V106, V108, A110, F112, V117, V121, L122,
			V123, Y129, I138, Y139, V145, Y147, I149, F150, V152, V163, V165, I167, V188, L189, W204, I206, A208, Y210,
			F222, V224, F232, Y243, I245, L251, V253, I255, A257, V265, A269, V271, F273, I275, L284, I293, V300, L302, L319,
			L324, V326, A328, V330, I346, I348, I355, F364, M368, F370, L372, V374, V376, A384, V387, V389, L400, A407,
			L409, I422, V424, A443, Y446, Y455, L456, L465, V473, F475, I487, Y490, L493, I494, I521, I526, F529, L531, V532,
			A533, Y534, Y535, L537, V546, V547, A548, V555, I585, A591, V593, V596, A597, V602, I616, W617, V620, V638, F639,
			A642, L644, F646, C693, C694, M698, M703, V723, F724, C727, C728, I731, W802, A806, V825, F829, L833, V839,
			V840, V845, I847, A849, L851, L860, V862, V864, L866, A871, C873, A876, I888, V896, Y898, V899, I900, V901, V910,
			V912, A914, A915, V916, V925, L929, V931, L947, I962, V971, I980, L982, V987, M990, A994, V995, A997, L1000,
			L1003, C1010, M1015, I1016, M1018, V1022, I1023, A1024, V1025, Y1027, L1028, A1045, I1049, L1057, A1058,
			F1059, A1065, F1066, A1067, A1068, F1069, A1073, L1078, A1080, Y1081, V1082, V1083, V1085, F1086, L1088,
			A1089, V1090, L1100, C1101, A1103, V1104, L1107, V1117, F1118, V1124, H1126, M1129, M1141, A1142, A1145,
			F1146, V1147, L1148, I1149, L1151, A1154, C1158, V1162, L1165, A1172, L1176, Y1180, L1183, Y1187, V1189,
			A1190, I1191, A1192, A1195, L1196, A1197, L1202, F1210, W1220, L1227, Y1228, V1230, A1232, Y1235, A1236,
			L1237, L1238, A1239, L1240, L1241, V1249, V1252, V1253, L1256, Y1266, A1271, F1273, M1274, V1275, F1276,
			A1278, L1279, A1280, Y1282, L1292, L1294, V1296, L1298, I1311, F1330, V1332, A1334, L1342, V1344, Y1348,
			A1350, F1361, L1386, I1388, C1389, I1402, L1403, I1405, M1407, M1408, F1411, A1412, L1418, L1421, I1429,
			L1444, I1446, Y1447, V1451, A1460, F1461, V1463, L1471, A1476, V1477, V1479, A1481, Y1482, Y1483, C1489,
			Y1493, C1518, A1536, Y1543, V1544, Y1545, L1549, F1558, Y1561, M1563, I1565, F1584, C1590, Y1602, L1603,
			M1604, W1605, Y1620, L1649, F1652
111	Complement C5	P01031	V24, I25, A27, F31, V33, A35, I39, V40, I41, F50, A52, I54, I56, V71, L73, L85, I87, V102, V106, M117, L126, Y135,
			V141, V143, V145, Y146, L148, L161, F163, I183, I190, W199, I201, A203, Y205, F217, V219, I238, F246, I248, I250,
			A252, V260, A263, V265, I267, F269, I271, M283, L292, F301, V307, L310, L323, I325, V327, V329, Y347, L363, I371,
			V373, V375, V388, L390, A418, V428, L431, F433, V435, A448, A454, Y457, L465, I484, V486, Y499, L502, I503, I526,
			M534, L540, L541, V542, Y543, Y544, L554, V555, L561, I563, V573, V588, L590, M592, V600, A601, L602, A603,
			A604, V605, A608, V609, L620, A643, V645, F646, A649, L651, F653, I683, A687, V695, C698, C699, C711, C724,
			I725, A727, F728, C731, C732, V734, A735, V780, W797, I799, V802, I804, C810, V819, V823, V833, I839, L841, V845,
			Y846, C856, V888, V896, V900, L901, I910, F912, L914, L927, L944, V968, L977, V979, V984, I987, L988, A1008,
			A1010, L1012, V1015, F1019, Y1020, V1021, Y1024, L1025, L1049, V1068, W1077, L1078, A1080, F1081, A1082, L1083,
			V1089, L1104, L1107, I1127, L1142, Y1143, A1146, F1147, V1149, I1150, I1152, A1155, C1159, I1164, A1167,
			L1168, A1171, L1175, F1186, L1188, A1189, I1190, A1192, Y1193, A1194, F1205, I1208, F1227, W1228, A1245,
			V1248, A1252, Y1253, A1254, L1255, L1256, L1259, V1267, V1270, I1271, W1273, L1274, F1284, I1291, A1293, I1294,
			L1297, L1303, L1309, M1311, I1313, V1315, M1328, F1333, V1340, L1346, V1348, A1357, V1359, V1361, V1365,
			I1402, A1404, A1406, Y1408, H1421, A1422, V1423, M1424, I1426, L1439, L1442, F1450, V1460, L1462, I1467,
			V1475, F1477, I1479, A1491, F1493, V1495, Y1498, H1499, C1505, V1519, A1545, A1552, I1557, Y1559, A1560,
			Y1561, V1563, Y1577, A1579, L1581, A1590, I1598, F1600, A1609, Y1617, L1618, I1619, M1620, A1624, Y1637,
			I1645, C1657, F1660, L1664, F1667
112	Complement C5a	P01032	C22, C47, A50, C55
	anaphylatoxin
113	Cystatin-C	P01034	V49, A52, A56, L90, V92, L94, G95, C109, C123, F125, I127
114	GTPase NRas	P01111	Y4, L6, V7, V8, V9, A11, V14, L19, L23, V29, V44, I46, C51, L52, L53, I55, L56, A59, M67, M72, F78, L79, C80, V81,
			F82, A83, I84, F90, I93, L95, Y96, I100, V103, V109, M111, V112, L113, V114, L120, V125, A130, A134, A146, V152,
			A155, F156, L159, V160, I163, M168
115	Platelet-derived growth	P01127	V127, V153, V170, L172
	factor subunit B
116	Low-density lipoprotein	P01130	I40, V45, C52, I83, C95, C116, I122, C134, C155, I161, A166, C173, C204, C222, C318, C338, C352, C377, Y400, L401,
	receptor		F402, F403, V409, M412, L414, I423, A431, L432, V436, I441, W443, I451, A480, V481, I488, Y489, W490, V498,
			V500, A501, M531, Y532, W533, I542, L547, V556, L575, W577, V578, I585, L605, L611, A612, V618, F619, W620,
			A627, I628, A631, A643, L646, C667, C677, C681, L682, C698
117	Transforming growth factor	P01137	L258, C293, C294, V295, F302, C326, L340, A341, L364, I366, C387, C389
	beta-1
118	Beta-nerve growth factor	P01138	C136, V157, V159, V163, C189, A210, A218, A219, I223, I225
119	Vasopressin-neurophysin 2-	P01185	C44, C52, I57, C58, C59, C65, A72, C75, C92, C98, A99, A100, C104, C105, C110
	copeptin
120	Somatotropin	P01241	F36, A39, A43, L46, L49, A50, Y54, F70, C79, I84, L99, L101, L102, I104, L106, L107, L108, I109, W112, V116, L119,
			F123, A131, V136, L140, L143, I147, L150, Y186, L189, F192, M196, V199, F202, L203, V206
121	Insulin [Cleaved into:	P01308	L35, A38, L39, I91, C95, L105, C109
	Insulin B chain; Insulin A
	chain]
122	Insulin-like growth factor II	P01344	L37, L41, F52, I66, C70, C75, L80, Y83, C84, A85
123	Lymphotoxin-alpha	P01374	A65, L67, I68, L94, L99, V101, Y107, V109, V113, F115, L131, H133, V135, L181, V198, F200, A202
124	Tumor necrosis factor	P01375	A90, V92, A94, A98, L105, V117, L124, V125, V126, L131, Y132, L133, I134, V138, F140, C145, V150, L152, H154,
			I156, A160, L202, L208, A210, V226, F228, I230
125	Interferon gamma	P01579	Y6, I7, F10, C13, I14, A31, L34, A40, F52, L56, I67, M68, I72, V73, Y76, F77, L79, F80, I89, V93, I96, M100, F104, F105,
			F115, A132, I133, L136, M140, L158
126	Interleukin-1 alpha	P01583	I135, L136, A163, F166, A170, Y171, A178, V182, I183, Y192, I214, L221, F223, F234, I244, A245, V252, L254, F264
127	Interleukin-1 beta	P01584	C124, L126, L134, V135, L142, A144, V156, F158, M160, V163, V174, A175, L176, L178, L185, C187, M211, F215,
			V216, F217, L226, F228, I238, F262
128	Erythropoietin	P01588	L39, A46, A49, C56, C60, L62, V68, A87, V90, L94, L97, A100, L118, V122, A125, L129, L132, L136, A141, A145,
			A162, L168, F169, F175, L176, L180, Y183
129	Interleukin-2 receptor	P01589	A38, L47, C67, C80, C125, V143, V148, Y150, C168
	subunit alpha
130	T-cell surface glycoprotein	P01730	L39, C41, A43, F51, W53, I61, L62, L69, L76, A80, W87, F92, L94, I95, I96, L99, Y107, C109, V111, V118, L120, L121,
	CD4		V122, F123, L134, L139, L141, L143, V153, C155, L169, V171, L174, W182, C184, V186, I199, V201, V219, F221,
			F223, L238, F254, V261, M274, L282, L284, A287, A292, L297, L299, L308, V312, L314, V315, V316, M317, L326,
			C328, V330, L340, L342, V358, W368, C370, L372
131	Ig epsilon chain C region	P01854	I131, L133, C135, V137, W149, L178, W185, Y191, C193, V195, I237, C239, V241, V251, V280, L284, Y297, C299,
			V301, L310, V326, L343, C345, I347, F350, I355, V357, W359, V386, L390, V392, F403, C405, A407, V408, H409,
			A412, V418, V424
132	HLA class I	P01889	M29, Y31, Y33, F46, V52, F57, V58, F60, A73, W75, I76, Y83, Y91, A95, L102, L105, L119, M122, C125, V127, Y140,
	histocompatibility antigen,		Y142, Y147, I148, L150, L154, W157, A163, A164, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
	B-7 alpha chain		L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, V285, H287
133	HLA class II	P01903	F47, M48, F49, F57, V59, A77, A81, A84, A86, I88, L130, I131, C132, I134, F137, W146, F173, L176, L179, Y186,
	histocompatibility antigen,		C188, V190, H192
	DR alpha chain
134	HLA class II	P01906	H50, F58, V60, I78, A85, M89, L131, I132, C133, V135, I138, W147, I174, L177, L180, Y187, C189, V191, H193
	histocompatibility antigen,
	DQ alpha 2 chain
135	HLA class II	P01909	H50, F58, V60, A84, I88, L130, C132, V134, I137, W146, I173, L176, L179, Y186, C188, V190, H192
	histocompatibility antigen,
	DQ alpha 1 chain
136	HLA class II	P01911	F36, L37, F46, F47, V53, F55, L56, Y59, V67, F69, F76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145,
	histocompatibility antigen,		C146, V148, F151, W160, M171, L190, V199, Y200, C202, V204
	DRB1-15 beta chain
137	HLA class II	P01912	F36, L37, F46, F47, V53, Y55, L56, Y59, V67, F69, F76, W90, L97, C108, V120, V128, L138, L143, L144, V145, C146,
	histocompatibility antigen,		V148, F151, W160, V171, L190, V199, Y200, C202, V204
	DRB1-3 chain
138	HLA class II	P01920	F39, V40, F49, V56, Y58, V59, Y62, A70, F72, Y79, W93, L100, C111, L123, V131, L141, L146, L147, V148, C149,
	histocompatibility antigen,		V151, F154, W163, V174, L193, V202, Y203, C205, V207
	DQ beta 1 chain
139	Collagen alpha-1(I) chain	P02452	C63
	(Alpha-1 type I collagen)
140	Collagen alpha-1(II) chain	P02458	C57
	(Alpha-1 type II collagen)
	[Cleaved into: Collagen
	alpha-1(II) chain;
	Chondrocalcin]
141	Collagen alpha-1 (III) chain	P02461	C55, C1262, L1265, V1279, I1290, C1294, I1303, V1310, V1326, F1328, A1364, I1368, Y1370, A1377, L1390,
			L1392, F1400, C1417, F1429, Y1431, L1439, I1441, I1444, A1445, V1458, V1463, F1465
142	Collagen alpha-1 (IV) chain	P02462	V1448, L1474, Y1475, L1487, Y1521, W1522, L1523, I1545, C1548, A1549, V1550, C1551, A1553, F1583, H1586,
	[Cleaved into: Arresten]		C1604, F1613, I1614, C1616, C1622, C1662, V1664, C1665, M1666
143	Alpha-crystallin A chain	P02489	L75, V77, V94, I96, V124, L129, L139, F141
144	Apolipoprotein A-I	P02647	V35, L38, A39, Y42, L46, Y53, F57, L106, V117, L138, Y139, L198
145	Apolipoprotein E	P02649	W44, A47, F51, L55, V58, V65, L69, L70, V74, L78, M86, L89, L96, L100, A109, L111, L115, A117, A118, L122, M126,
			V129, C130, L133, Y136, L144, L151, V153, L155, A156, L159, L162, L166, L173, L177, Y180, A194, L247, L270, V298
146	Fibrinogen alpha chain	P02671	I675, Y692, W708, L714, L724, V726, L728, A738, Y740, V744, Y751, L753, A762, A765, H780, F785, C799, A800,
	[Cleaved into:		W807, Y809, A815, L817, V841, W843, L853, V856, M858
	Fibrinopeptide A;
	Fibrinogen alpha chain]
147	Fibrinogen beta chain	P02675	C241, I244, M254, Y255, I257, V268, C270, W279, I282, F292, Y299, C316, Y322, W323, I329, L340, L341, I342,
	[Cleaved into:		M344, A354, H355, Y356, F359, V361, Y368, V372, A379, A382, L383, A387, H400, F405, C424, W432, W433, Y434,
	Fibrinopeptide B;		A439, A440, Y447, Y452, V465, V466, W467, M477, M480, M482
	Fibrinogen beta chain]
148	Fibrinogen gamma chain	P02679	C179, I182, Y193, I195, V206, C208, V219, F220, Y237, W253, I259, I262, Y270, A271, L272, V274, L276, A286, Y288,
			A289, F291, V293, Y300, L302, F307, A312, A315, F316, F321, H333, F338, F348, C352, A353, W360, W361, M362,
			H366, A367, H369, L370, Y375, Y380, Y389, I393, I394, W395, M405, M410, I412, I413, L418, H427, A431
149	Acetylcholine receptor	P02708	V153, L154, A167, V177, V201, I203
	subunit alpha
150	Band 3 anion transport	P02730	M435, C479
	protein
151	Protein AMBP [Cleaved	P02760	C287, A304, C333
	into: Alpha-1-microglobulin
152	Transthyretin	P02766	L32, V34, V36, A45, V48, V50, V52, L75, L78, F84, I88, Y89, V91, I93, Y98, W99, A111, A117, I127, A128, A129, L130,
			L131
153	Serum albumin	P02768	V31, A32, F43, A45, L46, V47, L48, I49, A50, F51, A52, Y54, L55, C58, H63, L66, V70, A74, C77, C86, L93, L98, A102,
			M111, C114, F126, C148, F151, L163, A167, F173, A175, L178, F181, A182, A188, F189, C192, L202, L209, A215,
			C224, A225, F235, A239, A241, F247, A250, A253, V255, L258, V259, V265, C270, L274, L275, C277, A285, I295, L299,
			C302, V317, F333, V334, V339, Y343, F354, A359, V367, L369, L370, L371, L373, Y377, L381, C384, Y394, V397, F401,
			V405, C416, F427, L431, L432, V439, V442, L447, V448, V450, L454, V457, C461, A473, V480, L481, L484, V486,
			H488, V497, C500, F512, F531, A535, I537, A552, L553, V554, L556, V557, A563, L568, V571, F575, F578, V579,
			C582, F592, L607, L609
154	Ferritin light chain	P02792	V13, A15, V17, L20, V21, Y24, A27, Y31, L34, Y37, F38, V48, F51, F52, L55, A56, Y63, L66, L67, M69, W90, A96,
			M97, A99, A100, M101, L107, L111, L112, L114, L126, L130, F134, M145, L149, L152, F167
155	Capsid protein/genotype D	P03147	F9, L15, L19, F23, F24, A36, Y38, A54, L55, C61, W71, W102, F103, L108, F110, V120, F122, W125, A131, Y132,
	subtype adw (isolate United		A137, I139, L140
	Kingdom/adyw/1979)
	(HBV-D)
156	Estrogen receptor	P03372	C185, V187, C188, V199, C202, C205, F209, C227, I229, C237, A239, C240, L242, C245, M250, A307, M315, L319,
			A322, M342, L345, L349, L354, M357, I358, W360, A361, V364, F367, V376, L378, L379, A382, W383, I389, L391,
			V392, L402, A405, L408, L410, V418, F425, F435, F445, V446, C447, L448, I452, L453, L454, V458, H474, I475,
			V478, I482, L486, M490, L507, I510, I514, M517, M522, M528, L540, L544
157	Fusion glycoprotein F0/strain A2	P03420	F32, C37, A39, V40, A47, L48, V56, I57, I59, V76, I79, L83, A89, V90, L93, L158, V164, L171, V187, L188, L195, I199,
			L203, C212, I214, V220, F223, L230, I233, F237, V247, M251, L252, L257, L260, I261, M264, I266, M274, I280, V281,
			I288, S290, I291, L297, A298, Y299, V300, V301, L303, Y306, C313, C322, I332, C333, L334, Y342, C343, V349, F351,
			F352, V365, F366, C367, I379, L381, C382, C393, I395, I407, L410, A412, I413, V414, C416, C422, A424, V442, M447,
			V450, V459, I475, Y478, A490, V495
158	Hemagglutinin [Cleaved	P03441	A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94, C97,
	into: Hemagglutinin HA1		Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180, V182,
	chain; Hemagglutinin HA2		H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, I242, L243, I245, L251, I252, A253, F258, I274, C281,
	chain]/strain		I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
	A/Bangkok/1/1979 H3N2		I478, I481, A495
159	Hemagglutinin [Cleaved	P03446	I20, C21, I22, V33, V43, L58, C59, L69, C72, L74, I78, L79, Y95, I96, V97, L118, F122, C150, M163, L166, I188, V189,
	into: Hemagglutinin HA1		F190, W192, I194, Y207, V216, M242, Y244, L249, V255, I257, L263, I264, A265, C294, L327, A347, Y364, A386, L460,
	chain; Hemagglutinin HA2		L468, H484, C486, C490
	chain]/strain
	A/Duck/Alberta/60/1976
	H12N5
160	Hemagglutinin [Cleaved	P03448	A8, I19, I21, V42, L48, L49, F57, C58, L66, L68, C71, I73, W76, I77, L78, C83, L86, W92, Y94, I95, V96, Y107, L117,
	into: Hemagglutinin HA1		L120, I121, V127, F133, C151, Y153, L163, L164, W165, I166, I177, I189, L190, Y191, F192, W193, V195, H196, H197,
	chain; Hemagglutinin HA2		Y208, V215, M217, I243, Y245, I249, L250, L256, V258, L264, I265, A266, Y269, A270, F271, F273, A281, C292, C296,
	chain]/strain		V302, L303, I317, V324, L329, L331, A332, A349, M361, Y366, A388, V389, A440, L452, V459, L462, V466, L470,
	A/Shearwater/Australia/1972		C481, H486, C488, C492, M493
	H6N5
161	Hemagglutinin [Cleaved	P03456	I19, C20, I21, V32, V42, Y57, C58, L68, C71, I73, I77, Y78, Y94, I95, V96, L117, F121, C149, I162, L165, I188, I189,
	into: Hemagglutinin HA1		F190, L191, W192, I194, Y207, V216, M242, Y244, L249, L255, I257, L263, I264, A265, C295, A348, Y365, A387, L461,
	chain; Hemagglutinin HA2		L469, H485, C487, C491, A509
	chain]/strain
	A/Turkey/Ontario/6118/1968
	H8N4
162	Hemagglutinin [Cleaved	P03457	L10, I21, C22, I23, V34, V44, L51, L59, C60, L68, L70, C73, I75, I79, Y80, Y96, I97, V98, L119, F123, C151, M159, L162,
	into: Hemagglutinin HA1		A174, I184, L185, F186, M187, W188, I190, Y203, V212, I238, Y240, L245, L251, I253, L259, I260, A261, C290,
	chain; Hemagglutinin HA2		H304, L323, A343, Y360, A382, L456, L464, H480, C482, C486
	chain]/strain
	A/Turkey/Wisconsin/1/1966
	H9N2
163	Neuraminidase (EC	P03471	W87, I94, F97, I106, I114, V116, Y121, V122, C124, F132, A133, L134, L140, L158, L159, C175, A177, C183, L190,
	3.2.1.18)/strain		V192, C193, V194, A201, A203, F205, Y207, L223, C230, V231, C232, V239, V240, M241, I254, L255, F256, I257,
	A/Memphis/1/1971 H3N2		V275, C278, C280, Y281, Y284, V287, C289, I290, C291, V302, V303, I305, Y316, V317, C318, L321, V322, V349, W352,
			A353, F354, V360, W361, M362, Y374, F377, V379, I397, V398, I409, F410, I418, C421, F422, Y423, V424, L426, V436,
			W438, I443, V444, V445, F446, I464
164	Neuraminidase (EC	P03472	L88, I95, A106, V107, V115, V117, Y122, V123, C125, F132, Y133, A134, L135, L159, I160, W162, C177, I178, C185,
	3.2.1.18)/strain		M192, I194, C195, I196, A203, A205, V206, I207, Y209, A221, L225, C232, V233, C234, C239, V241, V242, F243, I256,
	A/Tern/Australia/G70C/1975		Y257, Y258, F259, H276, I277, C280, C282, Y283, I289, C291, C293, V304, I305, I307, Y318, I319, C320, V323, L324,
	H11N9		V350, F353, Y355, W362, L363, I369, Y375, M377, L378, V380, A383, I397, V398, F410, M411, Y420, A422, C423,
			F424, Y425, V426, L428, V438, I445, V446, M448, C449, A464
165	Neuraminidase (EC	P03474	F92, I114, I115, F119, V120, A121, F130, L132, L156, V159, A175, A176, A181, C182, I191, V193, A200, L201, V202,
	3.2.1.18)/strain B/Lee/1940		I204, I221, L222, I232, C236, Y237, L238, M239, I240, A245, F253, L254, I256, I265, H273, C277, I287, C289, A290,
			C291, A298, F302, V303, L305, I314, L323, I333, H354, W364, M377, L379, M400, V401, F411, C424, I425, I427, M429,
			V430, H431, H439, A441, A442, A444, I445, Y446, L448, L454, L455
166	Neuraminidase (EC	P03476	F94, I106, V116, Y121, V122, C124, F132, A133, L134, L158, F161, C176, C184, M191, V193, C194, M195, A202, A204,
	3.2.1.18)/strain		I206, Y208, L224, C231, C233, V240, A241, V242, V255, Y256, W257, I258, L277, C280, C282, I286, V288, C290,
	A/Turkey/Oregon/1971		I291, C292, W303, M304, I306, Y316, V317, C318, H322, V348, F351, F353, W360, L361, F373, I375, V378, L396,
	H7N3		V397, F409, I410, F417, F421, Y422, V423, L425, V436, I443, V444, F446, I464
167	Neuraminidase (EC	P03477	I105, V113, V115, F120, I121, F131, F132, L133, L157, C160, A177, W178, A180, A182, C183, L190, L192, I194, A201,
	3.2.1.18)/strain		V202, A203, L205, M223, V231, C232, Y238, L240, I241, A250, Y252, I254, I257, I262, H274, F275, C278, C280, Y281,
	A/Turkey/Ontario/6118/1968		V287, C289, V290, C291, I303, F305, I313, C317, I320, F321, F350, F352, Y354, V358, W359, I360, F372, M374,
	H8N4		V375, V382, I394, I395, F407, C422, F423, W424, V425, M427, W438, I444, F446
168	Neuraminidase (EC	P03478	I98, I106, V108, F113, V114, F124, F125, L126, L150, V153, W171, A173, A175, C176, M183, I185, V187, A194, Y195,
	3.2.1.18)/strain		A196, I198, L216, V224, C225, I226, Y231, V233, M234, A243, Y245, I247, V255, H267, I268, C271, C273, Y274,
	A/Shearwater/Australia/1972		M277, V280, C282, V283, C284, L296, F298, C310, I313, F346, F348, V354, W355, A356, I360, F368, V370, L371, I378,
	H6N5		I384, V390, L391, F403, I415, C418, F419, W420, L421, M423, W435, F443
169	NADH-ubiquinone	P03886	Y43, A50, A52, M53, F56
	oxidoreductase chain 1 (EC
	1.6.5.3)
170	Angiogenin (EC 3.1.27.—)	P03950	F33, C50, I53, M54, C63, I66, F69, I70, H71, I77, A79, I80, L93, V102, C105, C116, Y118, V127, V128, V129, P136,
			L139
171	Coagulation factor XI	P03951	F30, C46, C50, C56, L57, L58, F59, C76, L78, M120, A130, C136, C140, F148, F149, C165, L167, A220, V225, C226,
			C230, C236, F238, F239, C255, L257, A274, C283, V289, F301, C317, C321, C327, F329, F330, A337, C346, I366, I388,
			W401, V403, L405, C416, I420, I421, I426, L427, A429, A430, V444, Y445, V463, I481, A482, L483, L484, L486,
			V490, C500, C514, V516, W519, A535, I537, C545, Y549, I554, C560, A561, A570, L579, C581, V586, H588, L589, V590,
			I592, V607, Y608, V611, V612, Y614, I618
172	Catalase (EC 1.11.1.6)	P04040	A76, A79, A81, F85, V87, I91, A97, V99, F100, I109, A110, V111, F113, A117, F132, V134, F136, W143, L145, I152,
			F153, F154, I155, I159, F164, W183, W186, L193, V196, F200, I205, H209, M212, L222, V230, C232, F234, Y236, A250,
			L265, F266, A268, W277, F279, I281, M284, A289, F294, L299, V313, L316, V317, L318, V329, I332, A333, I343,
			L351, L355, V375, V443, Y447, L459, C460, I463, A464, L467, A478, V479, F482, V485, Y489, I493, L496, L497
173	RAF proto-oncogene	P04049	I58, V60, L62, V72, L78, C81, L82, L86, A97, V98, A118, L126, V128, C152, C165, C176, V180, C184, V372, I405, V420,
	serine/threonine-protein		I446, A449, A453, M456, L459, H466, M469, L476, V482, I484, F487, A513, V516, V531, Y534, V537, L538, M542,
	kinase (EC 2.7.11.1)		M581, V585, C588, F599, I606
174	Glucosylceramidase (EC	P04062	V54, C55, C57, F76, L108, F120, A123, M124, A127, A128, A129, I132, A139, L142, L143, L144, Y147, F148, I153,
	3.2.1.45)		Y155, I157, I158, V160, M162, A163, C165, F167, A175, L183, L199, I200, A203, L213, L214, A215, L224, H245,
			W248, A249, Y251, F252, F255, L256, Y259, L264, A268, V269, A271, C287, L288, F290, F298, I299, L303, L318, M319,
			L320, A331, V334, A340, I347, A348, V349, H350, A357, L363, L375, F376, A377, A380, C381, V382, W396, Y402, I406,
			I407, V414, W417, L422, A423, L424, V437, I441, I442, V443, F450, M455, F456, H458, L459, H461, F462, I466,
			V473, A485, V486, A487, L488, A495, V496, V497, V498, V499, L500, L509, I511, L519, I528, H529, Y531, W533
175	Vitamin K-dependent	P04070	C105, C131, L212, V227, V228, L229, A240, V241, L242, V248, L249, A251, C254, V263, L265, L280, I300, A301,
	protein C (EC 3.4.21.69)		L302, L303, V339, I363, I365, C373, A388, M406, A408, V417, L419, V434, Y435, V438, I445, I449
176	Cystatin-B	P04080	A20, V23, L27, F54, I55, V57, V65, H66, L67, V69, L82
177	Trefoil factor 1	P04155	C51, C57, C68, F69
178	Major prion protein	P04156	I139, Y150, Y157, V161, Y163, F175, V176, C179, V180, I182, I184, M205, M206, V209, V210, M213, C214
179	Superoxide dismutase [Mn],	P04179	L38, I42, I46, M47, H50, H54, H55, V59, L62, A72, I82, L88, H98, F101, W102, L105, L117, A120, I121, F131, L135,
	mitochondrial (EC 1.15.1.1)		W147, W149, L150, C164, L170, L179, L180, I182, V184, W185, A188, Y189, Y200, L201, I204, V207, I208, W210,
			V213, Y217
180	Phosphatidylcholine-sterol	P04180	V49, I50, L51, V52, L60, A62, A117, V133, V149, L152, V163, A165, A166, Y168, L184, V188, M191, V199, F200, L201,
	acyltransferase (EC 2.3.1.43)		I202, L206, C208, L209, H210, L211, L212, F214, L215, F230, I231, A235, I241, M244, A248, I261, F289, I290, F305,
			F306, L309, L328, V333, V335, C337, L338, Y339, V372, A373, C380, W383, L396, M404, V405, I414, L418
181	HLA class II	P04233	C213, V253
	histocompatibility antigen
	gamma chain
182	T-cell surface glycoprotein	P04234	V33, V35, C37, Y71
	CD3 delta chain
183	von Willebrand factor	P04275	V815, C827, C829, C849, C851, C1272, L1276, L1278, V1279, F1280, L1281, L1282, F1293, L1296, F1299, V1300,
			M1303, M1304, L1307, V1314, V1316, A1317, V1318, V1319, Y1321, I1329, L1340, A1344, V1347, A1355, V1360,
			L1361, F1369, A1377, I1380, L1382, L1383, L1384, M1385, A1386, F1397, V1401, L1404, I1410, V1411, I1412,
			V1414, I1416, A1420, I1425, I1428, F1438, L1440, V1443, L1446, I1453, V1454, L1457, L1497, V1499, A1500,
			F1501, V1502, L1503, F1514, F1520, M1521, V1524, I1525, M1528, I1535, V1537, V1539, L1540, Y1542, Y1550,
			I1561, V1565, A1581, L1582, L1585, A1600, V1604, Y1605, M1606, V1607, V1625, V1626, I1628, V1630, I1642,
			L1657, A1661, V1665, L1666, C1670, L1690, V1692, I1693, L1694, L1695, L1696, F1707, F1713, A1714, F1717,
			I1718, A1721, V1732, L1733, Y1735, V1743, L1754, V1758, M1761, I1770, A1773, L1774, A1777, L1781, A1795,
			V1796, V1797, I1798, L1799, V1800, V1808, A1812, A1815, V1822, I1825, I1827, L1836, L1839, L1857, V1861,
			L1871, C2724, L2786, C2804
184	Argininosuccinate lyase	P04424	L34, V39, A44, Y45, L49, I63, L67, V70, I88, H89, A91, L96, A104, L107, V118, L121, M125, C129, L132, L136, W137,
			L139, I140, M143, V144, A147, F155, L161, W169, I173, L174, A177, L180, L187, V190, I194, L197, L199, L216,
			L220, F222, A232, F238, V239, A240, F242, L243, W245, A246, C249, M250, L253, M256, A257, L260, F268, F270,
			V271, L273, L293, I296, V303, L310, L325, A331, V332, V335, M339, L343, A346, V349, I350, L353, M360, A363,
			M368, L369, L373, A374, Y375, L377, A387, A390, A394, A398, L405, L413, F420, V424, V434, A444, V448
185	HLA class II	P04440	Y36, A46, F47, F53, L54, Y57, A65, F67, F74, W88, L95, V101, C106, L118, V126, L136, L141, L142, V143, C144,
	histocompatibility antigen,		V146, F149, W158, V169, V186, L188, V197, Y198, C200, V202
	DP beta 1 chain
186	Envelope glycoprotein	P04578	A55, V65, A70, M95, V101, M104, I108, W112, V120, C131, I154, I165, L193, H216, A221, A224, I225, G235, C239,
	gp160/group M subtype B		V242, I251, L259, L260, V270, I284, I285, V286, L288, V292, I294, C296, M326, C331, I333, W338, L342, I345, A346,
	(isolate HXB2) (HIV-1)		L349, I359, I360, F361, H374, F376, C378, F383, C385, L390, F391, L416, C418, I423, I424, V430, A433, M434, I449,
			L452, L453, L454, I467, F468, W479, L483, Y486, V489, I491, V505, I548, V549, L555, L556, A558, I559, A561, L565,
			L566, V570, I573, L576, I580, L602, A607, I635, I642, W666, W680, M687, I688, V698
187	Receptor tyrosine-protein	P04626	H42, M45, L46, Y50, C53, V56, L60, L62, L65, F73, L74, I77, V80, Y83, V84, L85, I86, A87, V91, V94, L96, L99, I101,
	kinase erbB-2 (EC 2.7.10.1)		V102, A113, L114, A115, V116, L137, L140, L142, L145, I148, V153, I155, L161, C162, Y163, I172, F173, C204, W205,
			C227, C240, A241, A242, L304, C331, L345, A355, V356, I361, F364, C367, I370, L374, A375, F376, L397, F400, L403,
			I406, L410, I412, L422, F425, L428, V430, I431, A440, L443, L445, L448, I450, L453, L455, L461, L465, A466,
			L467, I468, H469, L474, C475, F476, V477, L494, C504, C520, W521, C540, C576
188	High affinity nerve growth	P04629	L103, A110, L117, L122, L138, C215, L249, L251, V254, L258, C265, A267, V282, C300, I301, L346, L348, L361,
	factor receptor (EC 2.7.10.1)		A363, A376
189	Hemagglutinin [Cleaved	P04661	I19, C20, I21, V32, V42, V49, F57, C58, I60, I66, L68, C71, F73, A74, W76, I77, L78, C83, L86, W92, Y94, I95, V96,
	into: Hemagglutinin HA1		Y107, L117, F121, V124, F127, F133, A149, C151, F153, M163, V164, L166, I176, V188, L189, I190, V191, W192, I194,
	chain; Hemagglutinin HA2		H195, H196, Y207, V214, V216, Y221, M242, F244, Y245, I248, V249, I255, F257, F263, L264, A265, Y268, A269, F270,
	chain]/strain		I272, L280, C294, H308, H311, I315, L327, A347, Y364, A386, L460, L468, H484, C486, C490
	A/Duck/England/1/1956
	H11N6
190	Heat shock protein beta-1	P04792	V6, F8, L10, V97, L99, V101, A105, V118, I120, V148, L163, V165, A167
191	Cytochrome b-245 heavy	P04839	A394, V398, V404, M405, L406, V407, V413, F416, I419, V423, L436, F441, Y442, F454, L458, F473, F520, I532,
	chain (EC 1.—.—.—)		V534, F535, L546
192	Insulin-like growth factor I	P05019	L58, A61, L62, F73, I91, C95, C100, L105, Y108, C109, A110
193	Fructose-bisphosphate	P05062	L16, I19, A20, I23, V24, I30, L31, A32, A33, M40, L44, F59, I62, L63, F64, V66, I70, I74, V77, I78, L79, L84, F94, I97,
	aldolase B (EC 4.1.2.13)		L98, V104, V105, I107, L109, L131, C135, Y138, V143, F145, W148, A150, L152, L162, A163, I164, A168, A170, L171,
			A172, Y174, A175, C178, L183, V184, I186, V187, C202, V209, L210, V213, A216, L217, L228, L229, V234, Y244,
			A250, A252, V254, A256, L257, V261, V265, I268, C269, F270, A280, L282, L284, I287, L298, F300, Y302, A305, L306,
			A308, A310, A313, W314, F328, M329, A332, A334, A338, L357
194	Amyloid beta A4 protein	P05067	I34, A35, L41, M43, Y72, C73, V85, I94, W97, C117, C133, W150, A154, C158, C174, F179, V182, F184, V185, C186,
			C291, C316, C337, V375, L442, L453, Y476, A479, V490, L494, Y497, V498, A500, A523, I537, L548, A555, I558,
			I666, V669, H684, L688, V689
195	Arginase-1 (EC 3.5.3.1)	P05089	I8, I10, I11, A13, F15, V24, V30, L31, L36, L40, V67, V73, A76, L80, A81, V84, A85, V87, L95, V96, L97, H101, L103,
			A104, I105, I108, H111, H115, L118, V120, I121, W122, V123, A125, I129, L140, V145, L148, L149, L152, I169, A171,
			I174, V175, Y176, I177, L179, L190, F198, V211, M212, L219, I227, H228, L229, F231, V233, L236, A243, L252, I260,
			I264, L273, I275, M276, V278, V293, A296, I299, A302, C303, F304
196	Aldehyde dehydrogenase,	P05091	C36, I39, F40, A48, F54, V68, A69, V76, A79, V80, A82, A83, A85, W93, L104, L105, L108, A109, L111, I112, Y118,
	mitochondrial (EC 1.2.1.3)		L119, A120, A121, L122, L125, L139, V142, L143, C145, L146, Y149, A150, A153, V178, C179, L189, L190, M191,
			A193, L196, A199, L200, A201, V205, V206, V207, M208, V210, L216, A218, L219, Y220, V221, A222, L224, I225, A228,
			V234, V235, I237, V238, A245, I249, A250, V255, V258, A259, I270, A273, A274, I293, I294, A303, A307, H308, A310,
			L311, F312, F313, C318, C319, C320, A321, F326, V327, F335, A343, I370, Y373, I374, F397, I398, V402, F403,
			V406, I412, A413, I417, V421, M422, I424, L425, F427, I430, V433, V434, L444, A445, A446, A447, V448, F449, L459,
			A478, F482, L494, L499, Y502
197	Integrin beta-3	P05106	C31, C39, C42, L43, C49, A50, W51, C52, C64, L70, C75, V109, I114, L116, L118, F126, I128, V130, V133, V138, I140,
			Y141, Y142, L143, M144, L146, M150, I157, L160, L164, A165, M168, I177, F179, A181, F182, V183, Y190, Y192, A198,
			C203, C210, Y216, L220, L222, F229, V233, F249, A251, I252, M253, A255, C258, I262, L271, L272, V273, F274, I291,
			M313, Y315, M321, L325, L332, I333, F334, A335, V336, Y344, I351, L359, V366, I370, A373, Y374, V381, L383, L392,
			A398, C400, I406, L409, C412, L415, V421, F423, I425, A427, V429, F440, I442, L451, V453, V455, C461, C474,
			C497, C499, C512, C521, C547, C562, C584, C593, C601, C624, V641, C661, C681, C689, V691, F693, L705
198	Integrin beta-2	P05107	C25, V30, C33, C36, I37, C43, W45, C46, C62, L68, C73, L98, V103, L105, L107, A113, F115, V117, F119, I127, L129,
			Y130, Y131, L132, M133, L135, M139, V146, L149, L153, L154, A156, L157, I166, F168, F171, V172, F179, V180,
			C191, C198, F204, F217, V221, I226, L237, A239, M240, M241, V243, A244, C246, I250, V255, L258, L259, V260, F261,
			A262, I278, Y293, Y301, L307, L311, I316, I319, F320, A321, V322, Y330, L333, I337, A341, L345, V352, I356, A359,
			V367, L369, L378, Y382, C400, V403, I409, F411, V413, V415, A417, F426, I428, A430, V437, V439, V441, C445,
			C459, C467, C481, C483, C497, C506, C534, C549, C557, A572, C573, C582, C590, C612, A629, C662, V672, Y674,
			I687, V689
199	Interleukin-4	P05112	L31, I34, L38, L41, C48, I56, F69, C70, A72, A73, V75, L76, C89, H100, L103, L107, L110, L114, A118, L133, F136,
			L137, L140, M144
200	Interleukin-5	P05113	V84, L87, L91
201	Plasminogen activator	P05121	V31, A32, A35, F38, V40, V42, F43, V46, A47, V55, V56, F57, Y60, V62, A63, V65, L66, A67, M68, L69, L71, I81, M85,
	inhibitor 1		I89, M94, A95, L101, L105, I114, A119, I120, F121, V122, L128, F132, F136, F140, V144, V147, F149, A155, I159,
			V163, I171, L174, L175, V180, L186, V187, L188, V189, A191, L192, F194, W198, F202, L211, F212, M224, M225, F231,
			Y244, I246, L247, L249, Y251, L256, M258, F259, I260, A261, A262, L270, L273, L277, A279, I282, W285, L296, V297,
			L298, F301, V307, L309, L313, L316, M318, M321, F329, L332, L338, V340, A343, L344, V347, I349, V351, A358,
			A363, V364, I365, V366, A368, M377, F381, L382, F383, V384, V385, H387, V393, L394, F395, M396, V399, M400
202	Protein kinase C gamma	P05129	L120, V386, A461, I476, W538, L544
	type
203	Plasma protease C1 inhibitor	P05155	L142, A145, F149, L153, Y154, A168, F169, I174, A175, L177, L178, L193, L197, F213, V218, I224, F225, L230,
			F236, I262, V266, I274, L278, L281, V288, L290, A292, I293, L295, F313, M325, Y330, A333, A342, V344, L347,
			L353, L355, V356, M370, L374, L386, M409, M413, L430, M441, H443, L447, L449, V454, A456, A457, A458, A459,
			A461, L478, F479, V480, L481, F488, V490, F491, M492
204	Complement factor I (EC	P05156	C33, V74, A76, C86, F100, V129, I140, A150, V152, A153, C154, A163, C181, L182, V184, C186, L193, A210, C214,
	3.4.21.45)		C229, C241, C247, L254, C256, C266, I357, C365, I368, I375, L376, A378, A379, L382, I430, A431, L432, I433, A452,
			C467, L491, M508, C510, A511, L529, V530, C531, V540, W541, V543, V558, V562
205	Alkaline phosphatase, tissue-	P05186	L46, A51, V54, I55, M56, F57, L58, A69, A70, L87, M89, A96, A111, A114, A116, Y117, L118, A123, V128, V130, I150,
	nonspecific isozyme		L151, A154, V161, I163, V164, V169, A172, A179, A182, M192, A196, I204, A205, L208, M209, I215, V217, I218,
			M219, M226, L252, V253, W256, I269, L275, L278, V283, L286, L287, L289, F290, M295, M312, V315, A316, L320,
			F327, F328, L329, L330, V331, I336, H340, A345, A348, L349, A352, V353, M355, A358, I359, A362, L372, V374,
			V375, A377, H379, I395, A412, I413, V459, V461, A468, L471, V480, V483, M484, A485, A487, I490
206	Interleukin-6	P05231	I53, I57, I60, I64, L67, A86, L92, C111, I115, I116, L119, F122, V124, Y125, L126, Y128, L129, A140, V143, L150,
			I151, L154, I164, L179, M189, I194, L195, F198, F201, L202, A208
207	60S acidic ribosomal protein	P05386	A8, C9, A13, L16, I28, I32, F47
	P1
208	T-cell surface glycoprotein	P05540	A222, F224, F226, L239, F255, V262, L283, I285, A293, L298, L300, V311, L313, V314, V315, M316, L326, C328,
	CD4		V330, L340, L342, I358, W368, C370
209	Integrin beta-1	P05556	C27, A32, C38, I39, C45, C64, I114, L119, L121, L123, F131, L133, I143, L145, Y146, Y147, L148, M149, L151, M155,
			V162, L169, M173, I182, F184, F187, V188, Y195, I196, C213, Y219, F232, V236, F252, A254, I255, M256, V258, A259,
			C261, I265, V270, L273, L274, V275, F276, I293, Y316, L322, L326, I331, I334, F335, A336, V337, Y345, L348, I352,
			L360, V367, I371, I372, V382, L384, C415, I418, F426, I428, I430, I445, V454, V456, L458
210	Gag-Pol polyprotein/group	P05961	L8, W16, I19, L21, Y29, V34, A37, L41, L50, L51, C57, I60, L61, L64, L75, L78, V82, A83, L85, Y86, C87, V88, I94, A100,
	M subtype B (isolate MN)		I104, W158, V161, V162, F167, V171, I172, F175, A182, L187, M190, L191, V194, A199, A200, L204, I208, A212, I239,
	(HIV-1)		A240, W252, V261, Y265, I269, L273, I276, V277, I285, F296, Y299, V300, F303, Y304, L307, A309, L325, C333,
			L337, M350, C353, C395, A405, C416, L499, I507, I509, A516, L518, V526, L527, M530, V550, Y553, I556, I558, I560,
			C561, A565, V569, L570, V571, I578, I579, L583, L584, L591, V603, I624, A626, L627, I630, C631, I640, I643, V653,
			F654, A655, I656, L667, V668, F670, L673, V683, A691, L693, V699, V701, L702, V704, A707, Y708, F709, V711,
			L713, F717, A722, F723, I725, I728, Y737, Y739, V741, L742, W746, A751, I752, F753, M757, I760, L761, F764, L780,
			Y781, V782, L786, H791, I795, L798, H801, L802, L803, F807, F820, W822, M823, Y825, L827, W832, V834, L839,
			W845, V847, I850, L853, L857, A860, I863, Y864, I867, L872, L876, L888, A892, L896, A897, L903, L918, I919, A920,
			V922, W930, Y932, I934, L942, A948, A953, V958, L961, A964, V965, I968, I973, V974, F982, L984, I986, W991,
			W994, W995, A1001, W1003, I1004, W1007, V1016, W1019, I1027, F1033, V1035, A1039, A1048, Y1050, L1062, L1072,
			A1074, I1075, H1076, L1077, A1078, L1079, V1086, I1088, V1089, A1095, I1099, V1111, I1114, I1115, L1118,
			V1124, L1126, V1141, V1145, A1161, M1175, A1186, W1214, V1225, I1226, L1227, A1229, V1230, H1231, I1237,
			F1253, L1254, L1257, A1258, V1279, C1283, L1311, I1314, A1328, V1329, A1332, V1333, I1344, A1349, I1353,
			A1358, I1361, V1378
211	Collagen alpha-2	P05997	C64
212	T-cell surface glycoprotein	P06127	F33, A35, C44, L48, V50, L52, V59, C60, W64, A77, V80, C81, L90, L92, I105, I106, C107, F114, C125, L128, L130,
	CD5		C132, L133, V289, V291, L300, C301, W312, V315, C316, C321, C350, C360, V365
213	Insulin receptor	P06213	L29, C35, I40, L47, L50, C53, V55, I56, L60, M65, L81, M83, I84, L88, L90, V93, L99, L102, F103, L106, V108, I109,
			A119, L120, I122, M125, L128, L131, L133, L136, V144, I146, L152, I163, L164, C186, C209, W210, C223, C228, C235,
			C239, C252, A254, F275, W278, C286, V305, L326, I348, A354, L357, C360, I363, L367, I369, I371, L381, L385, I388,
			I391, Y394, L395, I397, L406, F408, F409, L412, I415, F427, A429, L435, L438, W439, L446, I448, L453, F455, H456,
			L461, I466, M469, I512, L514, W516, L532, A537, M580, I591, V593, A608, I638, L640, V657, I809, I820, L822, A824,
			C825, V867, H868, V886, V900, C911, V923, I925, A927, F942, V944
214	Tyrosine-protein kinase Lck	P06239	V66, L88, A100, I111, A137, L141, F151, L152, I153, L165, V167, I183, I193, L205, Y209, L216, L220, V240, L245,
	(EC 2.7.10.2)		L247, V270, V272, L275, F285, A289, L295, L300, L303, A305, V306, V307, I312, I314, I315, L324, L328, L341, L342,
			M344, A345, I348, A349, M352, I355, I361, H362, L365, A367, A368, I370, V372, C378, I380, A381, F383, A386, A408,
			A411, F417, V423, W424, F426, I428, L429, L430, I433, V449, L453, C465, L469, M473, C476, W477, F487, L490,
			V493, L494
215	Alpha-galactosidase A (EC	P06280	W44, H46, C63, I64, L68, F69, M72, A73, M76, W81, Y86, L89, C90, I91, C94, W95, M96, L120, A121, V124, L129, L131,
	3.2.1.22)		I133, Y134, A135, V137, Y152, A156, F159, V164, L167, F169, L180, Y184, M187, A190, V199, Y200, C202, I219,
			C223, H225, W226, I232, I239, I242, L243, I253, W262, M267, L268, V269, I270, V281, M284, A285, L286, W287, A288,
			I289, M290, A291, A292, L294, M296, A307, L311, V316, I319, F337, V339, W340, A348, A350, V351, A352, M353,
			I354, I367, V369, L372, A377, C378, A381, C382, I384, L403, I407, V413, L414, L415, L417
216	HLA class II	P06340	H50, F58, V60, A78, A87, I89, L131, I132, C133, V135, I138, W147, F174, L177, V180, Y187, C189, V191, H193
	histocompatibility antigen,
	DO alpha chain
217	Gelsolin	P06396	F59, I70, W71, V73, L78, V81, L85, F89, A94, Y95, V96, I97, L98, V101, L112, H113, W115, A127, A128, L135, A143,
			F157, A173, L189, F190, V192, V198, A200, F210, C215, F216, I217, L218, L220, I224, W227, L238, A240, V243,
			I247, G254, G264, M270, L271, P276, A279, L280, A282, G283, A292, A298, L300, V303, M310, A316, F321, A322, L326,
			C331, F332, I333, L334, I342, F343, V344, A358, L359, A362, F365, I366, V377, V379, L380, F389, F392, A434, M439,
			I449, I452, F468, Y474, I475, I476, Y478, Y480, I489, I490, W493, V526, H534, L535, L538, F539, M544, I545, I546,
			L565, F566, V568, A578, L588, A593, F594, V595, L596, A602, L604, W605, A610, A618, L621, L622, V632, F641,
			A644, L645, L657, L669, A671, C672, V680, L693, A694, V698, M699, L700, L701, V707, F708, V709, W710, A723,
			L724, A727, I744, V747, F756
218	Complement C2 (EC	P06681	L47, A82, C89, Y107, V113, C144, C151, A160, V173, C191, I462, M573, V697
	3.4.21.43)
219	Complement C5	P06684	A691, C703, C728, A731, C735, C736, A739
220	Glycogen phosphorylase,	P06737	I16, V25, L28, F32, L36, F54, A55, L56, A57, V60, L64, V83, Y84, Y85, L86, L88, F90, L96, M100, I101, L105, A108,
	liver form (EC 2.4.1.1)		C109, I113, L118, L123, L132, L137, L140, A141, A142, C143, F144, L145, M148, A149, L151, L153, A154, A155,
			Y156, Y158, I160, Y162, V201, F203, V222, A224, V239, M242, L244, W245, A247, A273, I276, L280, L294, Y298, F299,
			V300, V301, A302, A303, L305, I308, I309, F317, F327, F330, V334, A335, I336, L338, A344, L345, A346, I347, L350,
			M351, F354, I357, L360, A365, L368, F373, A374, Y375, V380, W388, L392, V393, L396, L397, H400, I403, I404, I407,
			I415, L418, M429, L431, I432, I440, M442, A443, L445, C446, I447, A452, V453, V456, A457, I459, H460, V464, F469,
			F472, L475, I487, W492, L493, L494, A501, L503, I504, Y512, V513, L516, L519, L522, H523, F531, L532, V538,
			L544, F546, L550, M563, F564, V566, I571, Y574, L578, L579, C581, L582, H583, V584, I585, I591, V604, I605, I606,
			A610, A611, M616, A617, I620, I621, L623, I624, V627, V630, V631, M636, V637, L641, V643, I644, L646, V651, L653,
			A654, V657, I658, A660, L663, I667, A670, M680, F682, M683, L684, A687, L688, I690, A696, M700, A701, F712,
			A729, L736, L739, V742, I743, I746, F759, I762, L766, F772, F775, Y778, Y781, V782, C784, V788, Y792, V802,
			L803, I806, A807, F812, I818, Y821, A822, W826
221	Glucose-6-phosphate	P06744	A2, L4, F10, L13, W16, L26, F40, I51, V53, Y55, L59, V60, V64, M67, L68, L71, A72, V77, A79, A80, M84, A97, V98, L99,
	isomerase		H100, V101, A102, L103, I111, V118, V125, M129, F132, C133, V136, I149, V152, I153, I155, M166, V167, A170,
			L171, V184, I192, L205, F206, I207, I208, A209, F213, A222, A225, F229, A233, A238, V239, H242, F243, V244,
			A245, L246, V253, F256, I258, F264, F266, W269, V270, Y274, L276, W277, A279, I280, L282, I284, A285, L286, F293,
			L296, L297, A300, M303, F307, L312, A316, V318, L319, L320, A321, L322, L323, I325, W326, A337, M338, L339,
			Y341, L345, F348, F352, V379, Y392, I395, C404, F406, L407, I408, F429, L436, M437, A445, L463, I477, F479, L482,
			M486, L487, A489, L490, V491, A492, M493, Y494, H496, I498, F499, V500, I503, I504, W505
222	Tumor necrosis factor	P06804	A93, V95, L127, V137, V141, F143, L154, H156, V158, C179, L204, L210, A212, F230, V232
223	Beta-hexosaminidase	P06865	W24, Y37, V60, L61, A64, L90, V94, L95, V96, V97, Y116, L118, I120, C125, L127, V132, W133, A135, L136, L139, F142,
	subunit alpha (EC 3.2.1.52)		I156, I161, H169, L172, L173, L174, L181, I186, L190, V192, M193, L198, V200, F201, H202, W203, H204, L205,
			V206, F211, F216, L221, Y234, V239, V242, A246, I251, V253, L254, A255, F257, L264, W266, L273, V290, F300,
			M301, F304, F305, V308, F312, L317, H318, L319, F326, W329, I335, M339, L351, F354, Y355, I356, L359, L360, V363,
			Y366, V371, V372, W373, V376, I389, V391, V398, Y400, L404, V407, A414, L415, L416, W420, L422, F434, Y435,
			A457, C458, M459, L469, L473, W474, A477, A479, V480, A481, L484, W485, A496, L500, F503, L507, V519
224	Thrombomodulin	P07204	C369, C388, C390, C413, C439, C464
225	Vitamin K-dependent	P07225	C212, C241, C265, C267
	protein S
226	Prostate-specific antigen	P07288	I25, V40, V42, V53, L54, V55, V60, L61, A63, A64, C66, I73, L75, F90, V92, L121, L123, L124, L126, L132, A135, V136,
			C152, A154, F165, V174, L176, C184, C198, A199, L217, C219, L223, I226, L242, Y243, V246
227	Cathepsin D (EC 3.4.23.5)	P07339	L71, I83, I85, F92, V94, V95, W104, V105, C117, Y123, L147, V156, F179, F190, F195, I198, L199, M201, V214, F215,
	[Cleaved into: Cathepsin D		L218, F229, A268, W270, V272, L274, V277, V279, L285, A292, V294, M301, V308, L311, A317, I327, I338, L340,
	light chain; Cathepsin D		L342, L349, Y354, F370, L382, L385, V388, F389, I390, Y394, V396, F397, V404, F406, A407
	heavy chain]
228	Trypsin-1 (EC 3.4.21.4)	P07477	I24, V39, L41, L52, W57, V58, V59, A61, C64, I69, V71, L73, V80, L81, F87, I88, I108, M109, L110, I111, L113, I119,
			V123, I126, L128, C139, I141, W144, C160, A163, C171, A173, Y175, F184, C185, V186, V204, C206, L210, V213, V214,
			V228, Y229, V232, Y235, V236, I239
229	Decorin	P07585	V65, C67, V75, L86, L88, I93, I96, F101, L107, L110, L112, I117, A124, F125, L128, L131, L134, L136, L144, L152,
			L155, A157, I162, V165, F170, L173, M176, I179, L181, L186, A195, F196, M199, L202, I205, I207, A208, I212, I215,
			L223, L226, L228, I233, V236, L241, L244, L247, L250, L252, I257, L265, L271, L274, L276, L281, L288, I294, V297,
			L299, I304, F312, C313, Y324, V327, L329, A352
230	Prosaposin	P07602	C66, V69, V70, A73, I86, L90, C94, V110, I117, L118, V131, C132, C230, C265, C271, V317, C318, L321, V325, I338,
			M345, C346, C357, V360, I368, L369, V381, C382, V411, C412, L415, V416, L419, I432, L436, C451, F454, L462, L466,
			M470, V475, C476, A481
231	Beta-hexosaminidase	P07686	A55, W57, L70, C91, L93, L94, A97, V124, L127, V129, I131, A139, Y149, L151, V153, A158, L160, A162, V165, W166,
	subunit beta (EC 3.2.1.52)		A168, L169, L172, F175, I189, I194, H202, I205, L206, I207, L214, I219, L223, A225, M226, F228, F231, V233, L234,
			H235, W236, H237, I238, V239, F244, I249, L254, Y266, V271, V274, A278, I283, L286, F289, L296, W298, L305,
			I322, L333, F336, F337, I340, F344, I349, H350, L351, F358, W361, I367, M371, L383, F386, Y387, I388, V391, L392,
			I395, I398, I403, V404, W405, V421, V423, Y429, L433, V436, V443, I444, L445, W449, L451, Y463, Y464, A486, C487,
			L502, W503, A506, A508, V509, L513, W514, A525, L529, H532, M536, I541, A548
232	Uromodulin	P07911	C106, C315, V357, F369, A424
233	Proto-oncogene tyrosine-	P07949	Y30, F31, Y36, L40, V42, L50, V53, L68, L72, L80, I86, L95, L97, L109, V121, L123, V125, A143, V145, F147, C166,
	protein kinase receptor Ret		F174, F185, C197, V223, L229, L239, A241, V242, C243, V245, F258, V260, V262, Y263, A269, Y314, F329, L358, L372
	(EC 2.7.10.1)
234	Fumarate hydratase,	P07954	V62, A70, V92, I93, A95, F96, I98, L99, A102, A103, A104, V106, A117, A119, I120, A123, A124, V127, L138, V140,
	mitochondrial		V153, V156, I157, A161, I162, V175, V181, F191, A194, M195, H196, I197, A198, A199, A200, V203, L207, L211, L214,
			L218, A220, F225, I228, I229, I231, V240, L242, L244, F248, Y251, V255, A258, I262, M266, I269, L272, A273, A274,
			A278, F289, V293, A294, V297, L303, A308, L315, A317, H318, A320, L321, L324, M328, A332, L335, I338, A339,
			I342, L356, L358, C377, M380, V383, A384, V387, M388, V392, V394, V407, M411, M412, I413, V416, L417, A420,
			L422, L423, F430, C434, V435, V436, I438, A440, I445, M449, L455, L459, A468, I471, A475, L482, A486, L492,
			F497
235	Gap junction beta-1 protein	P08034	F51, C60, C64, H73, C168, V170, C179
236	Rhodopsin	P08100	V11, Y26, W35, F103, C110, L112, I179, C185
237	Beta-microseminoprotein	P08118	C38, C57, C60, C62, I67, C84, V97
238	Annexin A6	P08133	A26, L29, A32, M33, I43, L44, I47, V58, Y62, L70, I71, L74, L85, I86, V87, L89, M90, A98, I101, A104, I105, C114, L115,
			I116, I118, L119, M127, L130, A133, Y134, L142, I146, I147, M157, L158, V159, L162, V177, V181, L184, A187, F199,
			I200, I202, L203, L211, V214, F215, Y218, I226, I230, L241, M242, L243, A244, V245, V246, C248, I249, F256, A257,
			L260, A263, M264, L274, I275, I277, M278, V279, L284, M286, L287, I289, I292, F293, L301, I305, L317, L318, L320,
			V338, A339, W343, V357, A369, L372, A375, M376, I386, I387, I390, I401, F405, L413, M414, L417, L428, I429,
			L432, M433, Y439, A441, W44, A447, M448, A457, L458, I461, L462, A463, I470, I473, A476, Y477, L485, L489, I500,
			L501, A505, A519, A523, V525, A526, I529, L530, I532, F547, M548, I550, L551, L559, V562, F563, F566, V574, I578,
			A589, F590, A592, I593, V594, V597, L602, F604, A605, L608, M612, L622, I625, M626, I632, L634, L635, I637,
			F641, L649, I653, A664, L665, L666, L668, C669
239	Multidrug resistance protein	P08183	A58, M75, L107, M111, Y118, V125, A129, F135, C137, A139, A140, I144, I147, F151, F152, A154, I155, M156, I160,
	1 (EC 3.6.3.44)		L171, L175, V179, I182, I186, A198, V206, L214, I218, A233, A250, A254, V257, A260, V264, A266, F267, Y277, L281,
			A284, A292, A301, A302, A308, A311, A313, F314, L332, V334, F335, V338, A348, A358, A362, I365, I369, I375,
			L392, V397, L410, L413, V417, V423, A424, L425, V426, C431, L439, M440, V451, I458, I461, V463, L466, I470, V473,
			L479, F480, I484, I488, I500, V504, A507, A509, I513, V524, I539, A540, I541, A542, A544, I551, L553, L554, A557,
			V569, A572, L573, A576, I583, I585, V592, I598, A599, F601, L615, Y622, I700, C717, A718, I735, I736, L754, L758,
			F759, L762, A780, L784, L788, V792, F793, M796, L797, L818, A822, V825, A828, A834, A841, L857, A897, A900,
			I901, F904, V907, F916, A935, C956, A961, L976, V977, F983, A1001, A1005, H1007, I1008, V1035, F1037, V1040,
			F1042, L1053, L1056, V1060, L1066, A1067, L1068, V1069, V1079, L1082, L1083, V1094, I1101, L1104, V1106, L1109,
			L1113, V1116, F1123, A1128, I1131, I1145, A1148, A1149, A1152, I1154, Y1165, V1169, A1185, I1186, A1187,
			L1190, L1198, L1199, V1214, A1217, C1227, I1228, I1230, I1237, I1243, V1244, V1245, L1260, Y1267
240	Mineralocorticoid receptor	P08235	C603, V605, V617, C620, C623, F627, A630, C645, I647, A657, C658, C663, M668, L742, A752, L765, L769, L772,
			M777, W783, A784, L787, F790, L801, W806, L809, F812, L814, L827, A830, L833, F835, C849, I855, F859, L862,
			L864, F866, Y869, I871, M872, V874, L875, L876, L877, L878, F892, M895, L903, V907, L924, L927, L928, M931,
			F943, V954, L960, I964
241	Beta-glucuronidase (EC	P08236	W45, F47, L68, V99, W100, Y101, V119, V120, I123, A130, V132, L147, I168, I170, A171, I172, L176, F208, Y211,
	3.2.1.31)		L214, V218, L220, V244, L258, V260, L262, V282, W288, L303, V305, L307, A309, V324, F336, I338, F345, H346, V348,
			L373, L376, A378, A380, F381, Y386, Y388, M395, V402, V403, I404, C407, L412, H426, M430, V433, A442, V444,
			M445, W446, V448, A449, A459, L463, M465, V466, V479, V482, A493, V498, I517, L521, F525, I536, I537, Y541,
			A543, Y561, L565, L566, Y569, L573, V581, L585, I586, F589, F592, V601, I608, F609, A618, A619, L622, Y626
242	ATP-dependent 6-	P08237	I18, A19, V20, L21, A27, M30, A32, A33, V34, A36, V37, V38, A46, V48, V51, L58, V59, V73, L77, A101, A102, L105,
	phosphofructokinase, muscle		L113, C114, V115, I116, L122, F128, L135, V159, L161, V162, I165, F169, I176, A181, I185, M186, V189, A196, F203,
	type		V204, L205, V207, C212, L215, A216, L217, F229, I230, L243, C244, L247, I260, I261, V262, A263, A266, I279, V283,
			V284, V293, L296, A307, L312, A320, V321, L324, L325, A333, V335, V336, L348, V358, A370, A389, A404, V405,
			M406, V408, A412, A413, M415, A417, A418, V419, V423, V433, L434, V435, V436, F440, V456, I481, V494, I495,
			I496, A501, Y502, L506, C519, F522, V523, V524, I525, A527, V533, V540, A542, A545, C550, C553, A560, V567,
			F568, I569, I570, C577, L580, A581, A584, L586, A587, I595, L605, V609, L612, M616, L624, V625, L626, I640,
			Y644, A676, M679, A683, M684, M687, I691, A702, V710, L711, V723, L726, W742, L745
243	Neutrophil elastase (EC	P08246	I30, V45, L47, A57, L59, V65, M66, A68, A69, V72, A73, A79, V80, V82, L84, I118, V119, I120, L121, V133, A153, M154,
	3.4.21.37)		W156, A166, L172, V174, C187, L206, V207, C208, I212, I215, A216, C223, A231, F232, A233, V235, I242
244	72 kDa type IV collagenase	P08253	A50, L54, C60, L74, M77, L83, I124, L135, V140, A143, F144, A147, F148, W151, L157, A167, I169, I171, F173, F184,
	(EC 3.4.24.24)		A192, F195, F207, L212, W213, V221, V223, Y225, G226, A228, C233, F235, F237, C247, W258, C259, C274, A286,
			C291, F295, C305, W316, C317, C332, A347, C349, F353, F355, W374, C375, A376, A379, Y381, W387, C390, L397,
			F398, V400, A401, A402, F405, H407, A408, M409, L411, A419, L420, M421, A422, Y427, L433, I441, L444, I478,
			A479, I485, F487, F488, I493, W494, A522, V523, Y524, A526, V533, F534, F535, Y543, L556, V568, A570, A571,
			F572, I582, F583, I606, L617, A619, V620, V621, F631, F632, L640, W657
245	Neuraminidase (EC	P08326	I104, V112, V114, F119, V120, F130, F131, L132, L156, V159, A176, W177, A179, A181, C182, M189, V191, V193,
	3.2.1.18)/strain		A200, V201, A202, V204, L222, C231, I232, Y237, V239, M240, A249, Y251, I253, A256, I261, H273, I274, C277,
	A/Equine/Kentucky/1/1981		C279, Y280, V286, C288, V289, C290, L302, I304, C316, I319, F349, F351, V357, W358, A359, I363, F371, I373, I374,
			I393, I394, L397, F406, L418, C421, F422, W423, V424, M426, W437, I443, M445
246	Neprilysin (EC 3.4.24.11)	P08473	A66, L69, F83, A87, C88, L118, L122, A132, A136, A138, L139, L157, L158, I164, W167, V169, W174, A184, A187,
			I188, A189, L191, I201, L203, I217, H218, I219, Y231, A244, Y245, F248, M249, V252, A253, I256, M273, V276,
			L279, I283, A284, A286, M303, L305, A306, I308, L314, I316, W323, F326, I330, M331, I336, V344, V345, V346,
			A348, Y351, L352, L355, L359, L367, M371, W373, I376, V380, L383, Y387, F394, C411, A412, V415, M419, A422, V423,
			Y427, V440, I444, I447, V450, F451, L455, A463, A469, A473, A475, L493, Y497, L500, A539, I553, V554, F555, F564,
			F565, L573, I578, M580, I582, I586, F590, F615, M622, Y626, A634, I649, A650, A658, A661, Y662, L685, F686, F687,
			L688, F690, A691, V693, C695, A703, I719, L723, F729, C735, M741, V749
247	Integrin alpha-IIb	P08514	L34, Y42, F50, L54, H57, I66, V67, V68, A70, V84, C87, L115, L124, V128, I135, V136, A137, C138, A139, W144,
			V146, A153, V158, C161, L163, A164, A172, Y174, C198, A200, L212, V213, L214, A216, L225, L226, A227, A229,
			V231, I234, L243, V247, Y284, V285, V286, A288, W291, A297, V298, I300, L301, F320, A325, V329, L337, L338, V339,
			A341, A354, V356, V359, Y360, L361, L378, F387, A392, L394, L397, I405, A406, V407, A408, V420, V422, L438,
			A447, F448, Y463, L466, I467, V468, A470, V476, A477, V478, Y479, A481, V485, I518, V522, L535, A537, L539, L541,
			V552, A581, I596, L598, L600, C633, L662, L664, A675, A681, V682, A688, A693, V715, V716, M724, M734, V736,
			F750, L752, I754, A775, Y815, L817, V825, L828, I832, V919, C921, M926, V934, L940, L945, L955, A959, V982,
			L986
248	Apolipoprotein	P08519	C4145, W4148, C4173, C4184
249	Pleckstrin	P08567	V26, V27, L28, I33, F35, I48, V68, F69, I71, H79, F81, W92, I96, I100, M133, I140, C155, F156, V161, I162, L165, A181,
			L184, L190, A200, F209, A215, Y217, F219, L251, F266, L268, A273, L275, H276, I290, L292, L314, F315, I317, L327,
			A329, W338, I342, A345
250	Collagen alpha-2	P08572	L1492, L1518, Y1519, L1531, Y1565, W1566, L1567, I1587, C1590, V1592, C1593, A1595, F1625, H1628, A1630,
			C1646, F1655, I1656, C1658, C1665, C1705, V1707, C1708, M1709
251	Receptor-type tyrosine-	P08575	C226, F246, A248, V279, I281, L295, V297, V301, I319, L321, F340, C365, I369, I408, W410, F420, L422, L444, L455,
	protein phosphatase C (EC		L457, A459, A463, M499, V501, L518, V520, F537, F550, A552, F554
	3.1.3.48)
252	Hepatocyte growth factor	P08581	A48, I62, F63, L64, A66, I70, Y71, V72, L73, L78, L130, I131, C133, C141, H144, I154, I161, C175, V176, V177, I193,
	receptor		F195, F196, V197, I214, V216, L219, I235, V237, Y245, I259, Y260, F261, L262, I278, I279, F281, L288, Y291, M294,
			L296, C298, I299, L300, F314, I316, L317, A319, L329, A330, I341, F343, G344, V345, F346, A347, A354, A361, M362,
			C363, F365, I367, V370, V383, L386, H388, F389, L424, L429, F430, L439, I442, I452, A453, L455, F462, V465, V467,
			H476, V477, V486, L503, V504, I505, I510, I513, L515, L518, C520, C529, C541, C561, A573, L581, I583, F588, V603,
			L622, C624, I638, I640, F652, I659
253	Complement factor H	P08603	C21, A48, Y50, V62, C66, C80, V108, A110, C129, C141, V144, C146, V174, F176, M190, C192, C205, Y227, F233,
			Y235, A249, C251, C325, V347, Y355, I372, C389, F391, L394, V414, L422, V429, C431, Y467, A473, C494, C505,
			L532, I551, C553, C569, Y587, L593, F595, V609, C611, L636, V655, Y657, I671, C673, C684, Y709, V715, F717, I731,
			C733, C744, C753, L761, F771, I777, C792, C870, I876, C915, C926, V942, V955, A971, C973, C984, C1048, Y1067,
			V1073, V1089, C1109, I1120, V1134, Y1136, C1138, L1144, I1150, C1152, C1167, I1169, M1174, I1179, L1181, L1189,
			V1197, F1199, C1218, L1223, C1228
254	Genome polyprotein	P08617	W91, V106, V107, L110, V117, L121, A127, F129, I131, V135, L147, I148, A150, M151, V152, V202, I207, V209, L213,
	[Cleaved into: Protein		V227, A229, F231, A306, V326, Y329, F331, L346, A347, C350, W356, L360, L376, C379, V418, A443, I444, I448,
	VP0/genotype IB (isolate		Y450, C451, V465, L471, F600, Y628, V644, V702, I722, Y727, L734, C738, L841, F869, L880, I907, I911, F914, L953,
	HM175) (HHAV) (Human		L954, I962, V1528, V1533, F1535, V1537, M1548, A1550, L1551, V1553, L1558, L1559, V1560, F1576, F1578, V1604,
	hepatitis A virus (isolate		V1605, L1606, M1607, V1609, I1618, I1623, A1631, A1636, L1638, V1639, L1654, V1676, A1679, W1680, M1690,
	Human/Australia/		A1694, L1695, V1696, I1706, L1707, I1709, A1712, L1718, V1719, A1720, L1722, V1723
	HM175/1976))
255	40S ribosomal protein S17	P08708	V9, A13, I17, C35, I50, A51, V54, I61
256	Coagulation factor VII (EC	P08709	C141, I213, C219, V228, L229, L230, L242, V248, V249, A251, A252, L264, A266, L268, V285, V288, I289, Y294,
	3.4.21.21)		I303, A304, L305, L306, V318, L321, L333, V341, W344, A354, V362, C370, M387, F388, C389, A390, H408, A409,
			H411, L418, I421, V422, V436, Y437, V440, Y443, I444, W446, L447, L450, A463
257	Interleukin-6 receptor	P08887	L45, C47, V50, V58, W60, V86, Y94, C96, V130, C132, L148, L149, V150, C176, L178, Y188, V190, M192, V194, L234,
	subunit alpha		V236, L251, F253, L255, Y257, A259, V270, L273, I279, A282, H288, V290, L292, A294
258	Dihydropteridine reductase	P09417	V13, L14, V15, C26, V27, F30, V37, A38, V40, V67, V71, V80, A82, I83, L84, C85, M107, L121, A122, L131, L132,
	(EC 1.5.1.34)		L134, A153, V157, H158, C161, A176, A177, I178, A179, V180, L181, L208, F212, L227, I228, V230
259	Fructose-1,6-bisphosphatase	P09467	L14, F17, V18, L34, L38, A41, V42, I45, A52, L74, V82, L86, A91, C93, V94, L95, V96, V106, V115, V116, C117, F118,
	1		L121, V133, I136, F137, I139, Y140, A153, A162, A163, Y165, A166, L174, V175, L176, A177, V182, C184, F185,
			F194, A223, V224, Y227, V250, V253, L257, I262, F263, L264, L278, L279, Y280, C282, M285, A286, Y287, V288,
			M289, A292, A296, V303, L304, I311, A315, V317, I318, L319, V325, F328, V331
260	Macrophage colony-	P09603	C39, I43, L51, L54, F69, V70, L75, C80, A85, V89, M93, L112, L115, L119, C122, C134, L145, V149, V152, F153,
	stimulating factor 1		L160, F167, C171
261	Platelet-derived growth	P09619	L52, C54, V60, W62, L85, L90, C100, Y117, I118, F119, V120, I147, C149, V151, L160, C190, V225, I231, L233,
	factor receptor beta		C235, V237, L265, L276, I278, Y289, C291, V293, I308
262	Pro-cathepsin H [Cleaved	P09668	V240, V279
	into: Cathepsin H mini
	chain; Cathepsin H (EC
	3.4.22.16); Cathepsin H
	heavy chain; Cathepsin H
	light chain]
263	Ubiquitin carboxyl-terminal	P09936	M12, L13, V16, L17, L20, V22, A23, V42, C47, A48, L49, L50, L51, L52, F53, I67, M82, I86, L95, I96, H97, A98, V99,
	hydrolase isozyme L1		L114, F117, L118, A130, F133, I139, A142, H143, V146, A147, F160, H161, F162, I163, L164, F165, L172, Y173, L175,
			M179, L193, L194, A197, A198, C201, V212, V217, A218, L219, C220
264	Leukotriene A-4 hydrolase	P09960	C8, V16, C17, L22, V28, L35, A39, L41, V43, L53, L55, V65, I67, M87, I89, A94, L95, I103, I105, F107, A115, L116,
			L119, Y131, L132, F133, C136, A138, C141, A143, L145, C147, V153, Y157, A159, V161, V163, L167, A169, L170,
			A173, F192, I198, C200, Y201, L202, A204, V206, V207, V221, V228, F235, M241, L242, A245, L248, L259, L260, V261,
			L262, F266, C275, L276, F278, V279, L283, I294, A295, I298, H300, W302, V307, W312, W316, L317, H321, Y324, L325,
			H328, I329, A343, L344, L350, L366, L370, V382, F388, A389, L390, L391, F392, L394, L397, L398, F404, F407, L408,
			Y411, V412, I420, W425, L429, L440, W448, C469, W476, F487, F503, L504, I518, M521, F527, I535, W539, L540,
			L542, C543, I544, A551, L554, A555, A559, F567, L571, F572, L575, A585, Y589, H597, L603, V604
265	Complement C4-A	P0C0L4	L24, L25, F26, V31, L37, V39, V41, L43, V52, V56, L76, L87, A94, L110, V111, A112, I130, L132, I149, Y150, V156,
			Y158, V160, A162, I174, V176, V178, I215, A217, F219, F231, V233, F241, I252, I266, A268, I271, V276, A280, V282,
			L286, L305, F319, V340, A341, A343, I345, L378, A382, L386, V390, V403, V405, A407, V409, V431, I433, I435, L444,
			A450, V462, L473, L491, M508, L510, V529, V533, F541, F543, V544, A545, F546, Y547, V560, A564, L633, V646,
			F647, L652, F654, I687, C703, A720, C735, A739, F833, L835, L837, L855, L863, V865, V867, V889, V897, V901, V913,
			V914, A915, V927, L931, V945, L948, V978, V980, A994, L995, V1000, A1001, M1015, I1016, L1018, A1019, A1023,
			A1024, Y1027, L1028, A1045, I1049, I1056, Y1066, A1067, A1068, W1077, L1078, A1080, V1082, L1083, V1085,
			L1086, A1089, L1107, F1117, L1132, V1139, A1140, L1141, A1143, F1144, V1145, I1147, A1148, L1149, V1168,
			A1175, L1179, A1192, A1193, A1194, I1195, A1197, A1199, L1200, A1205, L1210, A1213, L1217, W1230, I1262,
			A1266, Y1267, A1268, L1269, H1271, A1282, A1285, L1289, V1306, I1307, A1308, A1311, L1327, V1329, L1331,
			L1358, I1366, V1368, L1378, Y1384, L1501, V1512, V1522, L1524, F1538, A1540, L1578, A1617, Y1625, F1627,
			V1629, F1643, I1647, F1667, V1669, Y1683, L1684, I1685, M1686, Y1701
266	Complement C4-B	P0C0L5	L43, I149, I271, L305, V409, L510, A564, L652, I1366
267	Serum amyloid A-1 protein	P0DJI8	M35, A38, F54, A56, A62, A72, A73, A99, A100
268	Serum amyloid A-2 protein	P0DJI9	A72, A99
269	Transcriptional activator	P10071	C548, L563, C578
	GLI3
270	HLA class I	P10321	M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, V76, Y83, Y91, A95, L102, L105, L119, M122, C125, L127, Y142,
	histocompatibility antigen,		Y147, I148, L150, L154, W157, A163, A164, A176, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
	Cw-7 alpha chain		L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, M285, H287
271	Hemagglutinin [Cleaved	P10448	A50, L61, C62, C65, L71, A74, L75, C80, A87, V89, V91, C102, I112, L115, L119, A135, Y143, I145, C151, F161,
	into: Hemagglutinin HA1		M164, A165, W166, A167, V168, V180, V182, I193, V195, W196, H199, M206, Y210, F218, I251, V253, I266, Y268, I272,
	chain; Hemagglutinin HA2		L273, L274, V278, A281, I288, C300, L301, H302, A385, A511
	chain]/strain B/Bonn/1943
272	Lysosomal protective	P10619	L54, H61, L62, H63, Y64, W65, F66, V67, V78, V79, L80, W81, L82, L91, L94, L95, H98, F101, W117, A121, V123, L124,
	protein (EC 3.4.16.5)		Y125, V132, F134, V149, A156, L157, F160, F164, Y167, L172, F173, L174, Y179, A180, I182, Y183, I184, L187,
			A188, V189, V191, L202, V204, L208, L218, V219, A222, L236, F248, C256, L260, V263, V267, V297, V298, M327,
			A337, Y340, L341, V346, L350, W359, C362, V366, Y370, M377, Y381, L382, L384, L385, L393, L394, Y395, M401,
			F411, V412, W426, V428, V441, I447, A448, F449, L450, I452, A455, H457, V459, A466, A467, M470, F471, F474
273	Mast/stem cell growth factor	P10721	I54, L56, C58, W66, Y95, C97, I107, V109, V111, F118, V134, C136, I170, I172, V175, L184, C186, V188, F200, L202,
	receptor Kit		V213, F229, V231, C233, I235, W246, A273, L275, A280, F288, C290, A292, V325, L333, V335, Y337, A339, W348,
			Y362, V374, L377, L382, Y390, F392, V394, F405, V407, V409, C428, A430, A431, W440, V473, V474, V489, C491,
			A493
274	60 kDa heat shock protein,	P10809	A36, M40, V44, L47, A48, V51, V80, A81, A95, V98, V101, A102, A116, V118, L119, A120, I123, A124, I140, V144,
	mitochondrial		A147, V148, A150, V151, L155, V162, I168, V171, A172, A176, I182, I186, A189, M190, F219, F228, C237, A242,
			V244, L245, L246, I251, I257, V258, A260, L271, V272, I273, I274, A275, V278, A282, L286, V297, V298, A299, V300,
			A302, L313, M316, A317, A319, V324, F325, L342, V345, V348, I349, V350, L357, L358, I371, I374, A395, L397, V401,
			A402, V403, L404, V406, V421, A424, A427, A430, A431, V437, L438, C442, A443, L444, L445, C447, I465, I467, I468,
			L472, A476, A480, I490, V491, I494, A507, M513, I519, A528, L529, A532, A533, A536, L539
275	Thyroid hormone receptor	P10828	C107, V109, A114, C124, C127, F131, C151, I153, C164, F166, C169, M174, V225, A228, H229, L246, A268, F269,
	beta		I280, V283, F286, A287, L290, F293, L304, C308, C309, I312, L315, A318, L328, A335, V336, V349, F354, A371, L372,
			L373, A375, L377, L378, M379, I392, F399, A402, F403, L421, V425, L428, I431, A436, F439, M442, C446, L456
276	Growth hormone receptor	P10912	F64, C66, L84, C112, F114, Y125, I127, L129, C140, V143, V147, L160, A169, I171, V173, M188, L194, V217, L220,
			V228, V230, V249
211	78 kDa glucose-regulated	P11021	V30, V31, I33, L35, C41, V42, V44, I53, Y65, V66, A67, F68, A80, V92, L98, I99, V108, V119, Y127, I128, V130, A141,
	protein		I145, A147, L150, M153, A157, A159, V165, A168, V169, V170, V172, A174, A183, A187, A191, L193, V195, M196,
			A204, A205, A206, I207, A208, L211, I220, L221, V222, F223, L225, F230, V232, L234, L235, I237, F242, V244,
			V245, A246, L253, F258, V262, M263, F266, I267, Y270, V278, A284, V285, L288, V292, A295, L299, A305, I307, I309,
			Y313, F318, L322, F327, L334, F335, M339, V342, V345, L346, I356, I359, V360, L361, V362, I371, V375, F379, A393,
			V394, A395, A398, A399, V400, A402, L422, I426, I437, F451, V461, I463, V465, Y466, I487, I497, V499, F501, L509,
			V511, A513, V542, L565, Y568, A569, L572, M594, A597, V598, L605, F616, L623, V627
278	Hemagglutinin [Cleaved	P11132	V5, I19, C20, I21, A25, V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71, V73, A74, W76, L77, L78, C83, F86, W92,
	into: Hemagglutinin HA1		Y94, I95, V96, Y107, L117, L120, L121, F127, I133, A150, C151, Y153, V163, V164, W165, L166, I176, L188, L189,
	chain; Hemagglutinin HA2		I190, L191, W192, I194, H195, H196, A201, Y207, Y213, V214, V216, L221, M242, F244, F245, I248, L249, I255, F257,
	chain]/strain		F263, I264, A265, Y268, A269, Y270, I272, I280, M281, C290, C294, A300, I301, H308, H311, I315, V322, L327, L329,
	A/Duck/Ireland/113/1983		A330, A349, M361, Y366, A388, I389, A440, L452, V459, L462, V466, L470, C481, H486, C488, C492, M493, A510
	H5N8
279	Solute carrier family 2,	P11166	I40, Y44, W65, I297, F298
	facilitated glucose
	transporter member 1
280	Solute carrier family 2,	P11168	L10, A17, Y26, V30, I31, I38, Y42, W97, V101, F104, M128, A131, A139, M142, I154, Y164, C165, L171, V172, M174,
	facilitated glucose		Y175, I176, I179, W218, L221, L222, A229, L234, L236, L246, A256, L260, L263, M276, L294, I304, V306, A307,
	transporter member 2		L310, I322, Y325, I329, F330, V360, F369, M373, M376, C379, A380, M383, A403, I404, F407, V408, I418, M422,
			V423, A424, F427, A435, A439, V465, F466, L473, I495
281	Pyruvate dehydrogenase E1	P11177	A38, I39, M43, L47, V53, L55, V60, A61, I82, A93, I95, A96, A100, I107, C108, F110, F113, A119, V123, A127, V140,
	component subunit beta,		I142, F144, F162, A163, Y166, V174, V175, A183, L186, I187, A190, V197, V198, V199, L200, Y206, F212, A216,
	mitochondrial		I225, I237, V239, V240, V246, A252, A253, L256, C263, V265, I266, M268, I279, V283, L289, V290, I305, I309, A314,
			I337, I349, I353
282	Integrin alpha-M	P11215	F27, F34, V46, V47, V48, A50, L63, C66, A84, M87, L89, L102, L103, A104, C105, C123, F124, I151, A152, F153, L154,
			I155, I161, M169, F172, V173, V176, M177, L180, F187, L189, M190, Y192, F200, F202, F205, V215, A228, I231,
			V234, L238, I252, L253, V254, V255, I256, V271, I272, A275, V280, I281, V284, I285, V287, A290, F291, L300, I303,
			A304, F313, V315, F318, A320, L321, L328, I332, F333, L365, L366, V378, I390, M399, L404, I411, L419, V420, L421,
			A423, V432, A433, M434, F435, V464, V466, L474, V475, L476, I477, A479, V491, V493, C494, L509, F520, L527,
			V530, V538, A539, I540, A542, A551, V552, Y553, L554, F555, I571, A572, L580, F583, L601, V603, A605, V609, L612,
			V617, L618, V631, V657, I670, V674, L680, A689, F691, L714, L716, L718, I729, L731, L733, L748, F764, L792,
			V794, F800, V802, V804, V806, V818, F820, F822, C864, I881, F883, A889, L895, L897, A899, V925, M951, H953, Y955,
			V957, L965, I967, L969, F971, V973, L977, I982, W983, L1014, V1020, A1025, C1027, C1032, F1037, I1039, F1043,
			A1045, L1047, L1051, W1055, L1064, I1066, A1070, I1072, V1097
283	Glycogen phosphorylase,	P11217	V16, V25, L28, L36, F54, A55, A57, V60, L64, I83, Y84, Y85, L86, L88, F90, L96, M100, V101, L105, A108, C109, L118,
	muscle form (EC 2.4.1.1)		L123, L132, L137, L140, A141, A142, C143, F144, M148, A149, L151, L153, A154, A155, Y156, Y158, I160, Y162,
			V201, F203, V222, A224, V238, V239, M242, L244, W245, A247, A273, I276, L280, L294, Y298, F299, V300, V301,
			A302, A303, L305, I308, I309, F317, F327, F330, V334, I336, L338, L345, A346, I347, L350, M351, L354, L357,
			M360, A365, V368, C373, A374, Y375, V380, W388, L392, L393, L396, L397, H400, I403, I404, I407, F411, V415, A418,
			M429, L431, V432, I440, M442, A443, L445, C446, I447, A448, A452, V453, V456, A457, I459, H460, L464, F469, F472,
			L475, I487, W492, L493, V494, A501, V503, I504, F512, I513, L516, L519, L522, L523, F531, I532, V538, L544, F546,
			L550, L563, F564, I566, I571, Y574, L578, L579, C581, L582, H583, V584, I585, I591, V604, M605, I606, A610, A611,
			M616, A617, I620, I621, L623, V624, A626, I627, V630, V631, A636, V637, L641, V643, L646, L653, A654, V657, I658,
			A660, A661, L663, I667, A670, M680, F682, M683, L684, A687, L688, I690, A696, M700, A701, F712, A729, I736,
			L739, V742, I743, L746, F759, I762, M765, L766, F772, F775, Y778, Y781, I782, C784, V788, Y792, V802, I803, I806,
			A807, F812, I818, A819, Y821, A822, W826
284	Spike glycoprotein/strain	P11224	I16, V44, L79, V87, Y96, I104, A106, V108, L111, A121, I128, F132, V140, I148, A150, V152, C153, I157, C158, C165,
	A59 (MHV-A59) (Murine		F202, H205, A215, F226, Y240, V241, F244, I245, C246, Y258, Y268, L269, F270, I292, V319, C354, F385, F393, V395,
	hepatitis virus)		L411, A414, Y416, Y429, A468, C471, V474, C479, C481, A482, A499, A529, I534, I549, F550, A551, L585, F594,
			F619, A641, L652, C658, V661, C682, C706, C775, C780, C786, V800, L876, Y891, V900, V906, I912, A931, V952,
			I956, A980, A994, I998, I1030, A1039, L1046, I1047, A1053, L1054, L1067, A1072, A1075, V1079, I1099, V1103,
			Y1111, F1112, I1113, H1114
285	Acetylcholine receptor	P11230	W141, C151, Y157, C165, V329
	subunit beta
286	Ras-related protein Ral-A	P11233	H15, V17, I18, M19, V20, V25, L30, F34, V55, L57, V62, I64, I66, L67, A70, I78, F83, F89, L90, C91, V92, F93, I95,
			F101, F107, I111, V114, V120, F122, L123, L124, V125, L131, V137, A142, A146, A158, V164, V167, F168, L171, M172,
			I175, M180
287	Medium-chain specific acyl-	P11310	A27, A52, F55, A56, I60, A65, I78, A81, M87, I91, C106, L107, I108, L112, A113, C116, V119, A122, M131, I133, Y145,
	CoA dehydrogenase,		L146, M149, C156, A157, C159, I172, I185, I192, W200, Y201, F202, L203, L204, A205, A215, A218, F219, F222, I223,
	mitochondrial		V224, I233, C244, I250, F252, V255, V257, L263, V272, A273, A276, V283, V284, A285, A286, A288, V289, L291,
			A292, A295, A299, A303, M326, V330, A333, M335, A340, A341, A354, A357, A361, A365, L368, A369, A372, V387,
			A394, Y397
288	Fibroblast growth factor	P11362	L51, L53, C55, V86, V88, C101, F114, V174, F176, C178, I215, M217, V220, Y228, C230, V232, F275, C277, C341,
	receptor 1		A343, L356
289	Glucose-6-phosphate 1-	P11413	I33, F34, I35, I36, M37, A39, A44, I48, I52, W53, L55, I67, V68, Y70, A71, F88, F101, Y118, L121, M125, A134, L137,
	dehydrogenase		F138, Y139, L140, Y147, V150, I154, C158, I167, I168, I196, Y197, I199, Y202, M207, I230, C232, V233, L235,
			I255, I256, V259, M260, L264, L265, M267, L268, C269, V271, A272, M273, V284, Y308, Y322, F337, A338, A339,
			V340, V341, L342, V344, W349, F354, I355, L356, C358, A361, A367, V369, L371, V391, I392, V394, A399, L440,
			V444, F452, I464, F465, A492
290	Dystrophin	P11532	V25, F29, L40, L50, L51, L54, V77, A80, L81, L84, I99, I111, I114, L140, W143, V144, V156, A168, A171, L172, I173,
			L196, A199, F200, A203, I228, Y231, I232, L235, Y344, L348, L355, V375, H382, I399, V420, L427, L445, L3053,
			V3070, Y3073, M3088, L3098, A3109, L3112, L3115, L3119, L3121, A3129, M3145, I3150, C3153, L3154, Y3158,
			V3175, C3178, L3179, W3181, L3182, L3183, F3199, I3204, L3206, C3207, C3229, L3234, L3238, I3242, I3244, V3263,
			C3266, W3294, L3295, V3297, L3298
291	C-1-tetrahydrofolate	P11586	L20, V24, L38, A39, I40, L41, I53, A60, I63, V81, I85, V94, F97, L98, V114, V124, L135, C152, L155, I156, A168, V169,
	synthase, cytoplasmic		V170, M181, L185, C195, V206, I211, L212, V213, V214, V222, I227, A231, V233, I234, V256, A261, I268, M278,
			A281, L283, M284, A291, L393, V394, A396, L397, V405, F406, A407, V480, L497, I502, F518
292	Cholesteryl ester transfer	P11597	A26, V29, A36, A51, V72, I103, V106, V108, I188, I200, I207, F267, L313, V328, V329, A336, C350, F367, V376,
	protein		F380, L426
293	B-lymphocyte antigen CD20	P11836	F146, L147, L152, I162, I164, C167, Y182, C183
294	Amyloid beta A4 protein	P12023	Y476, A479, V490, Y497, L509, F512, A523, I537, L548, M580, L749, M752
295	Collagen alpha-3	P12111	C3112, C3158, C3162
296	Coagulation factor V	P12259	V36, A37, A38, V65, Y66, L85, L86, A92, I98, V100, F102, L110, I112, H113, A126, V142, Y150, W152, I154, C167,
			I171, Y172, L186, I187, L190, I192, C193, L213, L214, F215, A216, F218, V234, V238, I245, V247, I253, W255, H256,
			L257, L258, F267, I269, H270, F271, L276, L288, V289, A296, M298, W306, I308, H315, M320, I324, I354, A355, A356,
			Y363, Y391, V394, M395, L431, F435, Y443, Y483, I487, C500, A516, L519, L523, L524, I525, C526, A546, F548,
			M586, I589, V593, V608, W610, H611, F612, I621, I624, H629, F631, L643, V651, V653, M655, W661, L663, L675,
			F679, I1584, A1585, A1586, V1618, F1620, I1643, I1648, A1650, I1656, V1658, F1660, Y1668, L1670, H1671, A1672,
			L1675, Y1677, Y1708, W1710, A1712, A1729, Y1730, L1744, I1745, L1748, I1750, C1751, F1769, V1770, L1771, L1772,
			F1776, A1807, I1808, L1818, M1820, V1826, L1828, L1830, I1839, H1840, V1841, V1842, F1844, H1845, L1849,
			L1864, L1872, W1882, L1884, V1888, M1896, F1900, I1902, C1907, L1913, A1937, A1947, W1948, I1963, V1971,
			F1993, F2032, I2043, L2054, L2056, M2072, A2101, A2111, W2112, A2114, L2123, I2125, I2133, A2135, I2136,
			C2141, V2150, Y2153, I2155, F2178, I2196, I2201, V2203, I2212, A2213, L2214, L2216, L2218
297	Low affinity	P12318	A41, L53, V58, L60, C62, I73, W75, A94, Y102, C104, L117, L120, L124, V125, L126, L131, F133, I139, L141, C143,
	immunoglobulin gamma Fc		H144, V154, F156, F157, F172, A177, Y185, C187, I203, V205
	region receptor II-a
298	Bone morphogenetic protein	P12643	F305, C329, A343, M371, C393, C395
	2
299	Bone morphogenetic protein	P12644	F317, C341, A355, M383, C405, C407
	4
300	Angiotensin-converting	P12821	A46, F49, A57, A86, W97, A101, Y105, L117, I121, L132, M147, L172, L176, L185, L186, A188, W189, W192, H193,
	enzyme		A196, L200, Y204, F207, A214, Y231, L240, Y244, L247, Y251, L254, H255, A256, V258, L262, I271, I277, A279, H280,
			L282, A287, W290, I293, V297, L306, V308, M312, A319, M322, F323, A326, F329, F330, L333, F342, F366, F372,
			I374, V388, H389, M392, I395, Y397, Y401, L408, F416, A419, I420, V423, L424, L426, L434, L439, Y453, L454, L455,
			M457, A458, L459, A463, L465, F467, L470, V471, W474, W492, L495, I502, C503, F513, A515, A517, V521, F531,
			V532, V535, L536, F538, F540, H541, L544, C557, I559, A565, L569, L573, V584, L585, A596, L599, Y602, F603,
			V606, A649, F652, Y674, Y700, A704, I717, I720, I721, L732, M747, L770, M774, L783, L784, A786, W787, W790,
			A794, I798, Y802, Y805, L808, A812, A821, Y829, L838, F842, L845, L848, Y849, L852, H853, A854, V856, A859, L860,
			I869, I875, A877, H878, L879, L880, A885, W888, I891, V895, A901, M904, A909, M910, M920, F921, A924, F927,
			F928, L931, F940, L946, V956, F964, F970, I972, L983, A986, H987, M990, I993, Y995, Y999, V1004, A1005, L1006,
			A1010, F1014, A1017, I1018, V1021, L1022, A1023, L1024, V1026, L1032, L1037, F1051, L1052, M1053, M1055,
			A1056, L1057, I1060, A1061, I1063, F1065, Y1067, L1068, V1069, W1072, W1090, L1093, L1100, C1101, F1111, A1115,
			I1119, F1129, V1130, I1133, I1134, F1136, F1138, H1139, A1141, L1142, C1143, H1153, C1155, I1157, A1163,
			L1167, A1170, M1171, F1175, A1182, M1183, I1186, A1194, A1196, M1197, Y1200, F1201, L1204, L1208
301	Cadherin-1	P12830	C163, I178, V188, V204, F205, L214, V216, L220, Y228, L230, A234, M246, I248, I250, V252, F262, V271, V284, A301,
			M316, I326, V328, Y341, L343, V344, V345, A347, A348, A359, A361, I363, V365, L396, L436, L442, L452, V454,
			V456, A471, V473, V475, Y508, I542, L548, Y561, A563, I565, A567, L581, L583, I600, I612, I650, L652, I665, L667,
			L669, M670, L681, V683
302	Xaa-Pro dipeptidase	P12955	V18, L22, F23, L30, C31, L34, I45, V46, V47, F71, H72, W73, A74, F75, V77, C82, V85, I86, V88, L95, F96, V97, L136,
			L144, L145, L176, I180, V185, V194, L195, A205, H206, V209, M210, L222, F226, C243, C245, I267, M272, C273,
			F275, M277, Y281, F284, A285, I288, F292, V305, Y306, A308, V309, V316, W326, H330, A333, L338, L341, I346,
			M354, L359, F363, M364, L368, L372, L394, L397, L403, M407, V408, L409, V411, I415, Y416, L422, A425, F443, V449,
			I451, V455, I475
303	Hemagglutinin [Cleaved	P13103	I21, C22, V23, V34, V44, I51, Y59, C60, L70, F75, I79, V80, Y96, L97, L119, L122, F123, I126, F129, I135, C151, F167,
	into: Hemagglutinin HA1		I177, V189, L190, V191, L192, I195, Y208, V217, M243, I245, I250, I256, F258, F264, L265, A266, Y271, I273, F282,
	chain; Hemagglutinin HA2		C295, I302, L328, A348, Y365, A387, L461, L469, H485, C487, C491
	chain]/strain
	A/Gull/Maryland/704/1977
	H13N6
304	Platelet glycoprotein Ib beta	P13224	V37, C39, L60, L62, L67, A69, L70, W91, C93, L97, L100, L104, L116, C118, L128, L129, L137
	chain
305	C-C motif chemokine 2	P13500	C34, C35, C59, A63, V64, I65, F66, I74, A76, V83
306	Cystic fibrosis	P13569	V1240, L1242, L1253, F1257
	transmembrane conductance
	regulator
307	Integrin alpha-4	P13612	Y44, F52, H59, L67, V69, A71, A74, A87, C91, L106, V142, C144, L160, C165, A196, C198, A200, V212, M213, A215,
			L225, V227, V245, L251, F260, V268, V269, A272, H275, A281, Y282, I283, F284, L291, F306, V313, L315, L323, L324,
			V325, A327, V339, V341, A349, A366, F368, L375, I378, V386, A387, I388, A390, A399, I400, Y401, Y403, I418,
			F430, Y445, A449, V450, A452, A458, V459, L460, L461, V466, F502, M519, L521, F535, V550, A562, A579
308	Sodium/potassium-	P13637	H34, M36, V41, A58, L94, A98, C101, V125, V130, V161, I162, V175, V176, L180, V181, A191, L193, I195, C201, V203,
	transporting ATPase subunit		F234, C239, A244, V247, V248, A264, I278, A289, A310, I312, F313, I317, L326, V332, A338, C346, V354, C364,
	alpha-3		L371, M376, A379, M381, W408, A410, L411, I414, A415, L417, C418, A421, V432, A445, L446, V457, L480, I482,
			H483, Y493, L494, L495, V496, M497, I504, L512, Y532, L535, F545, C546, H547, L550, L573, C574, F575, V576,
			L578, M581, A587, V589, A592, V593, C596, A599, I601, I604, M605, A614, A616, A618, I623, I624, A635, A636, A650,
			A652, I678, V679, F680, A681, I691, V692, C695, V702, V709, A714, L715, A718, I720, V722, A723, M724, I739, L740,
			F745, V752, L757, I758, Y768, L770, F783, L792, I800, A809, L812, L834, V835, L839, A843, I847, Y859, I862, L863,
			F868, L873, W880, C908, A911, F912, F913, V914, I916, V917, V918, V919, L924, I926, C927, L944, L948, A955, L968,
			M970, A981, I988, L999, Y1013
309	Delta-aminolevulinic acid	P13716	L31, Y33, I35, F36, V37, L50, V53, Y56, L61, L65, V76, L77, I78, F79, V81, A94, A101, A104, I105, L108, L115, V117,
	dehydratase		C119, V121, C122, L123, H129, C132, L134, L150, A151, V153, A154, Y157, C162, V164, V165, A166, M170, M171,
			V175, I178, L182, V193, M194, Y196, A198, F200, A211, A212, A234, V238, L249, M250, V251, V261, V264, H268,
			L273, A274, V275, Y276, H277, V278, F282, V300, A303, M304, F307, A310, A312, I315, I316, Y318, Y319, L323,
			L324
310	Tissue factor (TF)	P13726	A41, F51, L55, Y66, V68, I70, C89, L91, I95, A105, V107, V155, V157, V159, L175, F179, L183, Y185, L187, Y188,
	(Coagulation factor III)		Y189, F207, I209, V211, F219, V221, A223, V224, I225
311	HLA class I	P13747	L26, Y28, H30, F43, V49, F54, V55, F57, M66, A70, W72, M73, Y80, A88, A92, F95, L99, L102, L116, W118, M119,
	histocompatibility antigen,		C122, L124, F137, Y139, Y144, L145, L147, L151, W154, A160, A161, A174, L181, C185, V186, L189, Y192, L193,
	alpha chain E		L200, V210, A220, L222, C224, A226, F229, Y230, L236, W238, H245, A266, A267, V268, V269, V270, Y278, C280,
			V282, H284
312	HLA class II	P13765	F33, V34, F43, V50, F52, V53, F56, L60, V64, F66, F73, W87, L94, A100, C105, V117, V125, L135, L140, L141, H142,
	histocompatibility antigen,		C143, V145, F148, W157, V168, L187, V196, Y197, C199, V201, W214
	DO beta chain
313	Electron transfer	P13804	L23, V24, I25, I41, A43, A44, V51, C53, L54, V55, C60, V63, A64, L67, C68, V70, V76, A79, L92, L95, I96, I108, C109,
	flavoprotein subunit alpha,		A110, L119, V123, A124, A125, I135, F144, V165, F166, V168, V218, V219, L225, F231, L234, L237, A238, A243,
	mitochondrial		A244, A247, A251, V263, V270, Y275, I276, A277, V278, M290, A298, A305, I307, V323
314	Glycogen [starch] synthase,	P13807	V28, L80, Y102, W160, F165, L166, L190, F202, A215, A247, F287, H291, F293, F307, A345, I456, V473, F477, L482,
	muscle (EC 2.4.1.11)		C500, V504, L592
315	Endothelin-3	P14138	C107, C169
316	Macrophage migration	P14174	P2, F4, V6, F19, L23, L27, C57, A58, L62, Y76, L79, L80, L83, L84, L88, I90
	inhibitory factor
317	Folate receptor beta	P14207	A34, C51, W54, A58, C59, C60, M86, C90, F94, C99, L100, C103, V126, L128, C129, C133, W136, C140, F176, L182,
			C183, L186, C203, I204, M206, V219, A220
318	Hepatocyte growth factor	P14210	I39, F42, L50, C70, A71, C74, L80, C84, A86, F87, V88, C96, W98, F99, F101, F112, L118, Y136, C149, W152, L172,
			C177, C189, F190, C206, Y219, C232, W235, C260, W270, C271, Y272, C283, I285, C288, Y313, W329, C354, W364,
			C365, F366, C377, I380, C383, V495, M508, V509, L511, C519, L523, V529, L530, A532, C535, Y544, A546, L548,
			I550, L579, V580, L581, M582, L584, V594, I597, C612, V614, L629, A632, L634, C642, I657, C658, A659, C669,
			L677, C679, V687, V690, I691, F706, V709, A713, I716
319	Perform-1	P14222	V61, L249, F442
320	D(2) dopamine receptor	P14416	V78, F189
	(Dopamine D2 receptor)
321	Solute carrier family 2,	P14672	L24, A27, A31, Y40, V44, I45, I52, Y56, W81, V85, A86, F88, I99, M112, A119, M126, A129, L138, I145, Y148, L155,
	facilitated glucose		V156, M158, Y159, V160, I163, A187, W202, L205, L206, V210, A213, V218, L220, L230, A240, L244, L247, L260,
	transporter member 4		L278, L288, I290, A291, L294, A305, V306, Y309, I313, F314, V344, H353, L357, M360, C363, A364, M367, A370,
			A387, I388, F391, V392, I402, I406, V407, A408, F411, A419, A423, V449, F450, L457, I479
322	Platelet glycoprotein IX	P14770	L93
323	Interleukin-1 receptor type 1	P14778	I39, W57, H75, L81, F83, A86, C96, V97, V98, C104, I107, A111, L140, C142, M145, F148, W160, L181, V183, Y194,
			C196, A198, I209, I213, F215, V238, L246, C248, V250, W260, L296, I298, I301, F305, F310, C312, F313, A314, L327
324	Matrix metalloproteinase-9	P14780	A45, L49, L74, L78, C99, I121, I137, A140, F141, A144, F145, W148, L154, A164, I166, I168, L187, A189, H190, A191,
			F192, A202, F204, W210, V218, P219, F222, A225, C230, F234, G238, C244, W255, C256, C271, A283, C288, F292,
			C302, W313, C314, A315, C329, C347, F351, F353, W372, C373, A374, F379, W385, C388, L395, F396, V398, A399,
			A400, F403, H405, A406, L407, L409, A417, L418, M419, Y420, F425, L431, I439, A515, A523, L531, L533, F534, I556,
			F580, F581, F582, V587, L604, V613, L626, F627, F635, F673, C674, Y679, L702
325	Interleukin-2 receptor	P14784	C36, Y38, A42, I44, C46, W48, V61, A63, L88, L98, V101, V104, L106, V108, F124, F127, L130, L132, C148, I150, F167,
	subunit beta		A169, F206, V208, V210
326	Gamma-aminobutyric acid	P14867	V416
	receptor subunit alpha-1
327	Protein C-ets-1	P14921	A323, A327, F340, L341, L342, L345, C350, I354, F363, L365, V371, A372, L389, L393, I401, I402, V411, F414, L418,
			L429, L433
328	Junction plakoglobin	P14923	A140, A162, A163, V166, A174, L179, L185, V186, A188, V189, V190, M193, L209, L212, L219, I222, I228, A230,
			L231, V232, V242, A246, I247, L250, L253, A260, V264, L270, M273, F284, L285, A286, C291, L292, L295, A296,
			I306, A308, L315, V316, I318, M319, L327, V334, L335, L338, C341, I348, V349, A351, M354, A356, L357, L361, L368,
			V369, C372, L373, L376, L379, V382, A383, L389, V392, L393, L396, V397, L400, L408, C410, A411, L415, L418,
			V429, V435, L438, I439, A441, A445, I451, A455, V456, A458, L459, L462, A472, V476, I485, V486, L488, L489, L497,
			V498, A500, I502, L504, I505, L508, A509, L510, A513, A516, L518, V523, I524, L527, L530, L531, A534, M556, I559,
			V560, C563, A566, L567, L570, A571, I580, I586, L588, F589, V590, L592, L593, I600, A604, A605, V607, L608, L611,
			A612, A618, A620, I621, A623, A626, L630, L633, L634, A642, A645, A646, V648, L649
329	Leukemia inhibitory factor	P15018	L44, I48, L52, L55, A59, L62, Y66, F74, L81, C82, L102, L105, Y106, I108, V109, V110, L112, L116, I119, A130, L133,
			L137, L144, L147, L148, V151, L152, C153, L155, C156, V164, C185, L187, L188, Y191, I195, L198
330	Phosphoglycerate mutase 2	P15259	L6, V7, M8, V9, H11, F22, A28, A38, A42, A44, I45, F52, I54, C55, Y56, L60, A63, L67, I70, L71, L87, H91, L95, V112,
	(EC 3.1.3.13)		M126, I136, Y142, L156, I160, A163, W167, I171, I175, A177, V181, L182, I183, A184, A185, H186, L190, I193,
			V194, L197, I205, L210, I214, I216, V217, Y218, L220, V239
331	Interferon gamma receptor 1	P15260	V46, W48, F59, V61, V63, C85, I87, L98, V100, V102, A104, A120, I141, I143, I145, Y172, V174, V176, I187, C200,
			C214, V215, A217, I238
332	Arylsulfatase A	P15289	I23, V24, L25, I26, F27, A28, L31, L36, L49, Y63, V64, A74, A75, L76, L77, L100, V107, A108, L111, Y116, M120, A121,
			W124, L126, I147, Y149, H151, C156, C161, V177, I179, L181, L182, A189, L194, L197, Y201, A205, L208, M209,
			A212, F219, F220, L221, Y222, Y223, A224, H226, H227, F238, F247, L251, L254, A257, V258, L261, I265, L275,
			V276, F278, A280, V310, A314, L315, A331, L337, L340, A341, A344, L358, F375, Y376, V386, F387, A388, V389, Y394,
			A396, H397, C414, H415, P426, L428, L459, C500
333	Beta-1,4-	P15291	V154, V178, A179, I180, I181, I182, F184, L191, W194, L195, L198, H199, V201, L202, L207, Y209, I211, Y212, V213,
	galactosyltransferase 1		I214, A225, L227, L228, V230, A235, Y241, F244, V245, F246, L251, I252, Y260, H268, I269, A272, V289, A291,
			L292, F297, I300, F303, W308, W310, I317, L321, M366, L367, Y376, L386, V392, I394
334	V-type proton ATPase	P15313	V47, V52, V53, L54, V57, V66, F68, V80, V83, A88, I89, V90, V92, C106, V117, M121, V125, F126, I147, M163, I164,
	subunit B, kidney isoform		I168, I171, V173, I177, A178, I183, I185, F186, A188, I196, A197, A198, I200, C201, A204, L206, V207, H217, A222,
			I223, V224, F225, A226, A227, M228, F238, F242, V251, C252, L253, F254, L255, I266, I267, L271, A272, L273, A276,
			F278, L279, A280, V287, L288, V289, I290, L291, M294, Y297, A298, A300, L301, V304, A306, A307, M321, L325, I328,
			Y329, A332, V335, I342, I345, I347, L348, I359, F365, I371, V373, L377, I386, V388, A399, H409, V412, L416,
			C419, Y420, V426, F448, L449, F452, F456, I457, V467, L471, W475, L478, F481
335	Folate receptor alpha	P15328	C37, L53, C57, W60, A64, C65, C66, W86, M92, C96, F100, C105, L106, C109, V132, L134, C135, C139, W142, C146,
			C152, W156, F178, F182, L188, C189, I192, Y197, I210, M212, V225, A226, M233
336	B-lymphocyte antigen CD19	P15391	L36, C38, W52, F83, V87, F94, L96, C97, V113, L188, L196, L198, C200, W214, L225, L228, W240, L246, L248, W281,
			W283, L284, W290
337	Granulocyte-macrophage	P15509	L47, C60, L62, C81, F94, V96, I128, M134, C136, Y150, L152, C178, F192, V194, C233, W237, F251, Y253, L255, V257,
	colony-stimulating factor		L270, V294, I296, A298, A299
	receptor subunit alpha
338	Membrane cofactor protein	P15529	C80, A93, M123, F125, L139, C141, A148, V160, V187, I208, C210, V226, V252, I268, C270, C283
339	Vascular endothelial growth	P15692	C52, I61, I72, F73, V78, L80, L92, I106, F122, C213, C225
	factor A
340	Immunoglobulin lambda-	P15814	W67, C82, V97, L104, V106, L107, V116, A128, A131, L133, C135, L136, M137, F140, Y141, L145, V147, W149, A151,
	like polypeptide 1		A174, A175, L179, L181, Y192, C194, V196, H198, V203
341	Arylsulfatase B	P15848	L47, V48, F49, L50, L51, A52, L55, V60, L72, V80, Y85, Y86, L98, I105, V122, L128, L132, L133, M142, V143, W146,
			L148, C155, Y168, L169, Y175, H178, I184, A193, F196, F215, A219, L232, F233, L234, L236, A237, L238, V241,
			Y255, Y266, A267, M269, V270, M273, V277, V280, L284, V294, F295, I296, F297, L321, V326, V329, F331, V332, I348,
			H349, I350, L354, L357, A361, V376, I380, I389, L391, L392, A431, A432, I433, L440, L441, C447, L474, F475, L498,
			L502, W529
342	Beta-galactoside alpha-2,6-	P15907	L109, L144, F160, W165, A178, C184, A185, V187, L193, I202, A207, V208, L209, A214, V223, I229, L231, M232,
	sialyltransferase 1		F243, L254, I255, V256, W269, F277, Y281, Y284, F293, I295, L296, M300, L304, L308, M325, L326, I328, I329, I330,
			M331, M332, C335, V338, I340, Y341, L344, Y369, L378, V379, L382, I390, L392, A396, L398
343	Desmoplakin	P15924	C191, M195, V214, I228, L235, A247, L251, Y255, L258, I275, F312, A343, I347, I364, C367, I368, H371, F381, A385,
			Y403, L414, L421, V446, L463, C467, V476, C482, W493, V495, V508, L510, I512, A519, I526, M544, L547, C553,
			I560, A562, L568, V623, V1975, A1977, L1980, C1983, V2004, I2018, A2019, A2021, L2031, A2034, L2048, A2051,
			A2053, A2054, I2058, V2069, A2072, I2086, A2089, A2092, A2110, M2122, L2124, L2125, A2127, V2134, V2141,
			F2142, L2143, A2148, F2172, Y2183, L2186, L2201, V2217, L2222, I2250, I2260, A2261, I2263, A2277, A2288,
			L2292, A2294, A2296, A2297, I2301, V2312, A2315, L2329, A2332, V2336, Y2339, A2353, L2367, L2368, A2370,
			I2377, H2384, L2386, A2391, F2415, L2424, Y2426, L2429, L2443, L2444, I2619, A2621, I2622, I2631, L2650,
			L2651, A2653, C2656, I2660, L2671, A2674, V2679, L2688, A2691, A2694, A2709, A2712, F2726, F2729, L2736,
			V2737, A2750, L2774, I2783, Y2785, A2788, A2805
344	Mucin-1	P15941	I1049, F1054, L1058, Y1065, Y1066, L1069, F1086, F1094, V1099, F1107, L1134, V1141
345	P-selectin	P16109	W42, W53, C60, L67, V68, A69, L79, Y90, W91, I92, I94, A114, A118, C131, V132, I134, I136, W145, A156, L157,
			C158, C168, C194, C226, C244, C288, F290, C306
346	Integrin beta-4	P16144	L1544, V1546, Y1560, V1562, I1577, V1587, F1598, V1600, A1602, I1618
347	Toxin A (EC 3.4.22.—)	P16154	L9, A13, Y23, I26, L27, L30, L36, Y45, L48, L51, I55, F58, M59, L71, L74, I78, V82, L97, H98, F99, V106, A110, Y113,
			W117, L128, W129, A134, F135, L136, V137, L140, A143, I144, A152, L156, F170, Y171, M175, I178, Y179, F185,
			I201, I204, I205, H208, L209, I231, I239, L244, F245, I253, Y254, L258, L259, A266, A267, I270, V271, L273, L274,
			A275, L276, V282, Y283, L284, M288, L289, I314, L316, A318, I319, F334, F345, I349, I358, F359, L362, V367, L370,
			I372, I374, A375, A385, L386, I387, L394, V398, V402, Y406, L409, L413, A416, F423, F430, L434, F445, L446, I449,
			L453, F457, A461, L467, A472, Y473, A476, Y477, F480, L483, L497, F500, A526, L561, V580, Y582, I583, I584, C597,
			F600, I608, I609, I610, Y636, I638, L642, V648, V650, F652, I653, F665, L673, I677, F680, I684, I688, V693, V695,
			L697, C700, M702, F703, Y713, L717, L718, I721, I725, L729, V732, I737, I739, A741, L756, I764, A769, I770, I780,
			A791, I806, L857, V867, L871, L885, I886, F888, V900, F902, I903, F920, Y923, I927, L961, F965, I967, V987, V989,
			L991, A993, L1000, I1003, L1009, A1016, L1050, V1068, A1078, I1084, V1122, Y1125, F1126, L1129, L1152, V1153,
			I1154, C1169, I1171, A1173, I1204, M1222, L1224, A1227, F1232, L1253, I1256, F1264, I1276, L1279, I1288, I1290,
			F1299, I1304, F1317, Y1324, L1326, L1328, I1333, I1337, L1339, W1345, I1346, F1347, V1353, L1383, I1390, L1405,
			I1413, L1415, I1416, I1417, I1419, L1430, L1441, I1448, L1451, I1458, A1473, I1474, I1482, L1493, F1503, F1516,
			M1517, I1524, I1538, F1540, I1542, V1550, V1552, L1555, L1557, V1561, Y1565, V1569, M1582, F1585, L1586, F1591,
			L1594, F1608, L1610, V1611, F1621, F1633, F1646, V1653, V1654, V1655, L1671, Y1675, L1678, V1688, L1689, I1690,
			Y1695, I1701, I1714, I1728, L1730, W1739, F1746, I1768, L1769, F1782, L1790, I1793, F1864, L1872, F1883,
			F1905, A1906, F1936, F1956, A1961, A1963, A1964, V1965, F1977, F1998, F2006, F2017, F2039, A2040, F2070,
			F2090, A2095, A2097, A2098, Y2109, Y2110, F2111, F2132, F2151, F2153, I2158, I2161, F2173, A2174, F2204,
			F2224, A2229, A2231, A2232, Y2244, F2245, F2263, F2265, F2287, A2288, F2318, F2338, A2343, A2345, A2346, I2352,
			Y2357, F2359, F2380, F2399, F2401, I2406, I2409, F2421, A2422, L2445, F2452, F2472, A2477, V2478, A2479, V2480,
			Y2492, F2493, F2512, F2514, F2534, A2535, F2565, F2585, A2590, A2593, I2599, F2604, Y2605, F2606, F2625,
			A2626, F2656, F2676, A2681, A2683, A2684, A2685, I2691, F2697, F2698
348	Beta-galactosidase (EC	P16278	F41, I51, I55, H56, Y57, W65, L69, M72, A75, A79, I80, V84, W86, H89, V104, F107, L108, A111, H112, L116, V118,
	3.2.1.23)		I119, L120, Y125, I126, A128, W130, M132, L135, A137, L139, L140, L146, L147, Y154, V158, W161, L162, L165,
			L166, M169, L172, L173, V180, I181, V183, Y189, Y199, L200, L203, F207, V215, F218, L228, L236, Y237, V240, A251,
			F269, V289, L293, I296, A301, V303, L305, M307, F308, I309, A320, L337, A340, Y347, L350, I353, I354, A387, A388,
			L392, F406, F415, V416, Y418, C426, L432, V439, A443, V447, L455, I465, A471, L473, L475, V477, V483, I489,
			L495, L499, L501, W509, I511, A519, L524, A550, F551, I558, I571, F573, V581, W582, I583, L588, Y591, L601, V603,
			I616, V618, A624, A635, V636, F638
349	Histone H1.5	P16401	I47, L65, I83, L87, L90, L96
350	Cytotoxic T-lymphocyte	P16410	V40, A48, A54, F56, C58, Y60, A66, V69, V71, V73, C85, A86, A87, L95, V112, L114, I116, Y127, C129, V131, I149,
	protein 4		V151
351	Epithelial cell adhesion	P16422	Y32, C48, C66, V68, A122, I144, H150, L162, L176, F180, L185, I191, L195, V207, I209, A213, Y215
	molecule
352	Histo-blood group ABO	P16442	A92, I94, I116, L118, V120, A122, I123, L130, F133, L134, A137, F141, M142, H145, V147, H148, Y149, Y150, V151,
	system transferase		F152, M189, M191, I192, F195, C196, F200, V204, Y206, L207, V208, C209, V210, V212, M214, F216, V220, V222,
			I224, L225, L228, F229, L232, A254, I256, Y264, Y265, L266, G268, F269, F270, V274, V277, L280, C284, M288, V290,
			A298, H305, L306, L310, V318, L319, Y323, L324, W325, L336, L339, F341
353	Thyrotropin receptor	P16473	C41, L57, L59, L64, I67, F72, I78, I81, V83, L89, L92, F97, V103, I106, I108, L114, A121, L122, L125, L128, L131, I133,
			L144, V147, F154, L156, I158, M164, I167, L175, L180, L182, L184, F189, V192, A196, F197, V205, L207, L213,
			A220, L231, V233, L252
354	Interleukin-7 receptor	P16871	L55, C57, I73, Y92, I107, V109, L123, V127, F146, V148, V160, V167, A168, I203, V205
	subunit alpha
355	Fumarylacetoacetase	P16930	L17, V21, F22, I32, V34, A35, I36, I40, L41, L43, I46, F50, L55, F62, L67, F70, M71, A77, A81, L85, L89, L96, L102,
			A106, L196, M198, L200, M202, A203, F204, F205, V206, A221, M228, V229, L230, M231, W234, A236, V259, V263,
			V264, A268, L269, L287, F295, I297, V301, L303, C315, W324, M326, L327, L330, L345, L346, A347, I351, M362,
			L375, V390, I392, C396, I403, F405, C408, V412
356	Alpha-N-	P17050	W30, A32, C49, I50, L54, F55, M58, A59, M62, W67, Y72, L75, I77, C80, W81, L91, I102, L105, A106, V109, L116, I118,
	acetylgalactosaminidase		Y119, A120, M122, V138, A142, F145, V150, L153, L155, Y169, M172, A184, F185, C187, L205, C209, L211, W212,
	(EC 3.2.1.49)		I218, V225, I228, L229, L239, V242, W248, M253, L254, L255, I256, A268, M270, A271, L272, W273, V275, L276,
			A277, A278, L280, M282, I296, L297, M302, I305, I324, V326, Y327, A337, L338, V339, F340, F341, L355, I365,
			A368, F386, I390, M397, L400
357	Aspartate aminotransferase,	P17174	V34, L36, L51, V53, V54, V57, F80, A84, A88, A95, V104, A112, L113, I115, A117, L120, A121, V134, V136, H144,
	cytoplasmic		F148, F174, L178, A181, I186, V187, V188, L189, A193, H194, I209, A210, M213, F221, F222, A238, A240, I241, F244,
			F251, C253, A254, F257, F261, V268, L271, M288, V292, A304, I306, V307, A308, W320, V324, M327, A328, L338,
			L342, I354, M360, F361, L374, I380, L382, I388, V390, L393, L398, V401, A402, A408
358	HLA class I	P17693	M29, Y31, A34, A35, F46, A48, V52, F57, V58, F60, M69, A73, W75, V76, Y83, A95, L102, L105, L119, W121, M122,
	histocompatibility antigen,		C125, L127, Y140, Y142, Y147, L148, L150, L154, W157, A163, A164, V176, A177, L184, C188, V189, L192, Y195,
	alpha chain G		L196, L203, V213, A223, L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283,
			V285, H287
359	Neuronal acetylcholine	P17787	V56, L60, L83, W87, L119, A135, V137, I143, W145, A149, F173, I183, L185
	receptor subunit beta-2
360	ATP-dependent 6-	P17858	I18, V20, L21, A27, M30, A32, A33, V34, A36, V37, A46, V48, I51, L58, V59, V73, I77, A101, A102, L105, L113, C114,
	phosphofructokinase, liver		V115, I116, L122, F128, L135, A159, L161, V162, I165, F169, I176, A181, I185, M186, I189, A196, F203, V204, L205,
	type		V207, C212, L215, A216, L217, F229, I230, M243, C244, L247, I260, I261, I262, A263, A266, V279, V283, V284, V293,
			L296, A307, L312, A320, V321, L324, L325, A333, V335, V336, L348, V358, A370, A389, A403, I404, L405, V407,
			A411, A412, M414, A416, A417, V418, V422, V432, Y433, V434, V435, F439, V455, I480, L493, V494, V495, A500,
			Y501, L505, A510, C518, M521, C522, V523, I524, A526, V532, L539, A544, M549, C552, A559, V566, F567, I568,
			V569, C576, L579, A580, I585, A586, V594, L604, V608, M611, M615, L623, V624, L625, L639, Y643, L678, A682,
			M683, L686, L690, A701, V709, I710, V722, L725, W741, L744
361	Ganglioside GM2 activator	P17900	L80, C106, C136, C183
362	Complement receptor type 1	P17927	C43, A52, L69, I84, C86, C99, I121, I127, Y129, A143, C145, V152, I164, C166, V191, Y193, I213, C215, C238, F256,
			V262, V278, C280, C493, I534, I571, I577, C595, V641, C665, C688, F706, V712, V728, C730, C943, I984, C986,
			C1004, I1021, I1027, A1043, C1045, A1052, I1064, C1066, V1091, Y1093, C1095, I1113, C1115, C1138, F1156, V1162,
			V1178, C1180, C1396, I1437, V1480, C1498, V1544, C1568, C1591, F1609, I1615, V1631, C1633
363	Vascular endothelial growth	P17948	F135, M148, L154, I156, C158, V160, V167, L169, F192, I194, A197, L205, C207, A209, Y220
	factor receptor 1
364	TFIIH basal transcription	P18074	L40, M42, L53, A54, M57, A58, L70, Y72, C73, I80, V83, I84, L87, L102, L107, A108, L109, L115, A139, L170, L177,
	factor complex helicase		C190, Y192, L194, A195, A202, Y209, V231, V232, A236, I239, C243, L251, L256, C259, L263, A298, V309, C375,
	XPD subunit (EC 3.6.4.12)		L382, A404, L406, C437, A443, I444, I455, I456, L461, L471, F473, M493, I494, Y520, A537, F539, I561, Y584, A594,
			L596, L597, V599, A617, I619, M620, F621, V623, A635, A656, A660, V664, A667, M677, V678, F684, W696, A704
365	Toxin B (EC 3.4.22.—)	P18177	L9, A13, Y24, I27, L28, L31, M37, Y46, L49, I52, Y59, L72, F75, L79, V83, L98, H99, F100, I107, Y114, W118, V129,
			F130, A135, F136, L137, I138, L141, V145, A149, F171, F172, M176, I179, F186, I202, I205, V206, L210, I232, V240,
			F246, L254, Y255, L259, V260, W263, A267, A268, I271, L272, I274, A276, L277, M283, Y284, L285, M289, L290, L317,
			A319, I320, F335, F346, L350, I359, F360, L363, A368, L371, V373, I375, A376, L387, I388, C395, I399, I403, Y407,
			L410, L414, A417, F431, I435, M447, L450, L454, F458, V462, L468, A473, Y474, A476, A477, Y478, L481, F484,
			L498, F501, A527, L562, I578, Y580, I581, V582, A594, C595, F598, A599, V606, L607, F608, A618, Y634, I640, I646,
			L648, F650, F663, L671, I675, A678, A682, I686, I691, I693, L695, M700, F701, Y711, L715, L716, V719, I723, M727,
			I730, I735, V737, A739, L754, I762, I778, V789, F1866, F1888, F1908, A1909, F1938, H1956, F1958, F1979, F1999,
			F2019, F2039, A2040, F2069, F2090, A2095, F2305, A2306, F2335, F2355, A2360
366	Vinculin	P18206	F4, H5, I9, L13, A17, I20, L70, M74, A77, V81, C85, A91, A92, L95, A104, I109, L116, L124, A129, V131, I134, C138,
			L145, A148, Y160, L164, M171, I175, L182, L191, V192, V198, L201, L205, A208, M209, V213, I223, A226, M237, I241,
			I244, V247, L248, A269, I273, A280, W283, A298, I299, I302, A306, I321, V335, A353, L360, L363, V367, I384, I388,
			A391, I408, A411, A415, A419, I431, I438, L445, V466, L470, L473, A480, A500, A518, C545, V548, L551, L576,
			L580, L609, A613, F626, F633, A644, A679, L683, F695, L734, A760, I763, V766, V783, A786, L790, V828, V831, A909,
			M956, I966, A970, L973, A977, I987, I988, A990, A991, M994, A995, M998, M1001, L1015, C1018, A1019, I1022,
			A1023, A1025, V1029, A1033, A1037, C1040, L1049, V1052, C1053, I1056, L1063, A1071, A1087, L1091, A1095,
			L1098, M1099, V1102, V1106, A1109, A1112
367	Interleukin-1 receptor	P18510	F38, I40, V56, A57, V73, A80, L81, F82, L83, C91, L92, C94, L103, F123, F125, F136, C147, A149, V156, L158, F171
	antagonist protein
368	Cytidine deaminase/strain	P19079	L6, A10, A13, A28, A29, L30, L31, A54, A58, L59, A62, L73, A74, V75, A76, A77, C89, I93, V101, V103, V104, V117
	168
369	Erythropoietin receptor	P19235	A39, L41, L42, L50, C52, F53, L60, C62, F63, W64, F79, Y81, L83, F105, C107, L120, L122, V124, I139, V142, V143,
			L144, L145, V152, V162, L164, W166, I178, Y180, V182, V184, L207, F218, A219, V220, A222, M224
370	Lymphocyte function-	P19256	F43, V54, W56, V63, A64, L90, I92, L95, Y103, F116, L118, L121, L129, C131, V140, M156, M163, C166
	associated antigen 3
371	Vascular cell adhesion	P19320	A37, V43, L45, C47, L80, M82, V85, Y93, C95, A97, I108, F115, I133, V135, C137, V139, V142, F145, I150, L152, L178,
	protein 1		L193, C195, A197, L199, A325, V331, L333, C335, L368, L370, V373, Y381, C383, V385, I396, F403, V421, V423,
			C425, V427, V430, L433, I438, L440, L466, L481, C483, A485, L487
372	Tumor necrosis factor	P19438	C59, C62, C72
	receptor superfamily
	member 1A
373	Hemagglutinin [Cleaved	P19694	I25, C26, M27, V38, V48, L54, V55, L63, C64, L70, C76, I78, I79, A82, L83, C88, L91, V98, F99, I100, V106, C109, Y110,
	into: Hemagglutinin HA1		F112, Y117, L120, L124, A125, F130, F137, A150, C151, F159, F160, L163, L166, Y191, W193, V195, H196, H197,
	chain; Hemagglutinin HA2		Y208, V215, V217, I243, F245, Y246, I249, V250, L255, I256, F258, L264, I265, A266, Y271, I288, C295, H296, V302,
	chain]/strain		V323, L330, A331, A348, W357, Y365, A387, A439, L461, L469, C480, F481, I483, H485, C487, C491, I492, I495,
	A/Budgerigar/Hokkaido/1/1977		A509
	H4N6
374	Nuclear factor NF-kappa-B	P19838	F57, L69, V84, A93, V95, I96, V97, L99, V100, H109, A110, H111, L113, I122, C123, A127, V133, V134, L139, L153,
	p105 subunit		M157, A160, C161, L170, L175, I196, A199, A200, V212, L214, F216, A218, A238, I239, A247, L250, V262, I268,
			L270, L271, I282, F284, I311, V312, F313, V329, V331, L333, F347, Y349, Y350, M808, L819, Y820, L823, L835, A836,
			F848, L858, M859, L872, A875, L876, A884, I888
375	C-X-C motif chemokine 3	P19876	C45, I52, C69, V74, A76, L78, C85, L86, V93, I96, L101
376	Complement receptor type 2	P20023	I47, I58, L63, C65, V96, Y108, V114, V130, C132
377	HLA class II	P20036	M54, F55, F63, V65, F83, A87, A92, I94, L136, I137, C138, I140, F143, W152, F179, L182, V185, Y192, C194, V196,
	histocompatibility antigen,		H198
	DP alpha 1 chain
378	Myeloid cell surface antigen	P20138	V82
	CD33
379	Kallikrein-2 (EC 3.4.21.35)	P20151	I25, C31, V40, A41, V53, L54, V55, V60, L61, A63, A64, C66, V73, L75, V90, V92, L121, L123, L124, L126, I132, V135,
			V136, C152, A154, F165, C173, V174, L176, C184, C198, A199, L217, C219, L223, I226, A241, V242, Y243, V246, I253
380	B-cell receptor CD22	P20273	W24, W35, C39, V40, I42, C44, L53, L76, F94, L95, C102, L117, L119, W128, M129, L134, V136, I145, C161, C167,
			Y170, I172, W176, V198, L204, F206, W210, C219, L229, L236, V238, V255, C265, W279, L294, L296, Y307, C309,
			L325, V327, Y329, V349, C353, A357, W366, Y394, C396, L413, V415, V422, I426, I432, V438, L440, C442, V451,
			W456, L470, I472, V475, W477, C484, A486, C491, L499, V501, Y503, A504, V508, V510, L527, C529, V539, W543,
			L556, I561, Y569, C571, I577, V589, Y591, L596, V598, V606, L614, C616, A620, Y627, W629, F630, L644, L646,
			Y657, C659, V677, Y678, Y679, I684
381	Integrin alpha-L	P20701	F45, I57, V58, L70, C73, L109, A110, C111, C119, C129, Y130, V155, L157, V158, F159, L160, F161, L167, I175, F178,
			M179, V182, M183, L186, Y191, F193, A194, A195, V196, F198, F206, F208, Y211, A236, I237, V240, V244, V258,
			L259, I260, I261, I262, I273, A276, I279, Y282, I283, I284, I286, F290, L299, F302, A303, F310, F317, L320, L323,
			F324, L327, V364, V365, A367, A370, A374, F377, L378, L404, L411, L420, A421, V433, L434, L435, V467, L477, L478,
			L479, I480, A482, V494, L510, F521, L528, I531, V539, A540, V541, A543, A550, Y552, I553, F554, L561, I569, I578,
			F581, A597, A600, A603, M607, I608
382	Integrin alpha-X	P20702	F30, F37, V49, V50, V51, A53, L66, C69, A87, M90, L92, L105, L106, A107, C108, C126, F127, I152, V153, F154, L155,
			I156, M170, F173, V174, V177, F188, L190, M191, F193, F201, F203, F206, L216, A229, A231, I232, V235, L239, I253,
			L254, I255, V256, I257, V272, I273, A276, I282, A285, I286, V288, A291, F292, L301, I304, A305, F314, V316, F319,
			L322, L329, I333, F334, A352, V366, L367, A369, A379, I391, M400, L405, A412, L420, V421, L422, A424, A433,
			V434, I435, F436, V465, V467, L475, V476, L477, I478, A480, V492, V494, C495, L510, F521, L528, V531, V539,
			V540, I541, A543, A552, V553, Y554, L555, F556, I572, A573, L581, F584, L602, A603, V604, A606, V610, L613, V618,
			L619, I632, V650, I658, L671, V675, L681, A690, F692, L700, F715, L717, L719, I730, L732, L734, L749, L765, L793,
			V795, L801, A803, V805, V807, I819, F821, H823, C863, A880, F882, A888, L894, L896, A898, V924, A951, H953,
			Y955, V957, L965, V967, I969, F971, V973, L977, V982, W983, I1014, L1020, A1025, C1027, C1032, F1037, V1039,
			L1043, F1045, L1047, L1051, W1055, I1059, V1064, V1066, A1070, I1072, L1097
383	B-cell lymphoma 3 protein	P20749	L139, V143, V151, F158, L176, H177, A179, V180, V188, L191, A208, H210, A212, C213, C220, L221, A223, L224,
			A245, L246, H247, A249, V250, V258, L260, L261, L280, I281, A283, V284, M291, V292, L294, L295, A312, L313,
			A316, V325, L328, V354
384	Calpain-3 (EC 3.4.22.54)	P20807	L138, L145, L189, F200, A210, L212, Y216, A218, F239, A335, V363, F404, F658, A662, I668, L673, L677, V681,
			C697, M700, M704, L712, F717, L720, I724, F731, I742, M747, A750, V751, A754, Y763, I777, F779, F782, I783,
			C785, F786, L815
385	Collagen alpha-1	P20849	L59, V65, A86, F113, L114, F117, M119, W128, I130, W131, I133, I144, I146, V153, F155, F169, I183, M184, I185,
			V187, A192, L194, A218, V219, V231, L235, M238, I240
386	Nebulin	P20929	A6617, F6631, I6637
387	N(4)-(beta-N-	P20933	I91, L105, I108, A111, I112, V114, A115, V118, A132, A136, A243, A253, A254, A256, L263, A272, V273, A285, C286,
	acetylglucosaminyl)-L-		I290, I293, F300, A303, V304, C306, C317
	asparaginase (EC 3.5.1.26)
388	Filamin-A	P21333	F49, C53, L57, I64, L67, L71, L77, I78, L80, L81, V107, V109, A110, L111, F113, L114, I129, I137, L138, L140, I141,
			L144, I145, I150, L172, I176, L180, I185, F188, W192, A197, L198, A200, L201, V202, A206, C210, A225, A228, M229,
			A232, L236, I238, V241, I242, I247, V257, M258, Y260, L261, F264, A284, A302, V306, A311, V318, V344, H354, V356,
			V358, F360, I365, V372, V495, A501, V505, A510, V519, F540, Y542, Y550, V552, I554, I561, V568, A595, F597,
			V598, V599, V633, Y635, Y643, A644, V647, I654, A661, V675, V697, H743, A745, V747, V761, V1070, F1088, I1090,
			A1095, V1124, Y1126, Y1134, I1136, I1138, I1145, A1152, V1154, V1163, C1165, F1181, V1183, A1188, I1197,
			I1219, Y1221, Y1229, V1231, I1233, Y1235, L1247, V1258, V1270, F1278, V1280, V1297, Y1317, V1319, Y1321,
			H1329, V1331, V1333, V1347, V1358, F1376, V1378, A1383, V1412, Y1414, Y1422, L1424, V1426, V1433, V1440,
			V1451, V1463, V1473, A1478, V1487, V1509, I1521, V1523, Y1525, V1530, V1537, V1539, V1548, V1560, A1562,
			F1568, I1570, A1572, A1575, I1584, V1606, Y1608, Y1616, I1618, I1620, Y1622, I1627, V1634, A1636, A1642, C1645,
			I1672, V1674, A1679, V1684, V1688, I1710, A1714, Y1720, I1722, V1724, V1731, V1738, A1740, F1791, I1795, I1799,
			V1808, V1828, V1830, H1840, M1842, I1844, I1851, L1856, F1858, V1860, V1868, A1870, L1875, F1886, V1888,
			I1902, V1922, Y1924, Y1932, I1934, V1936, V1943, F1948, A1950, V1952, V1987, I2009, F2011, H2019, V2021,
			V2023, I2039, A2047, V2050, L2057, F2068, I2070, A2075, L2080, L2082, I2084, V2104, Y2106, Y2114, I2116, I2118,
			F2120, V2125, V2132, V2134, A2176, V2178, Y2198, I2200, H2210, V2212, V2214, V2230, A2238, V2241, A2257,
			F2259, I2261, A2268, I2273, V2275, V2295, Y2297, V2299, Y2305, V2307, V2309, F2311, I2316, V2323, V2325,
			A2326, A2332, L2335, L2345, V2355, L2357, A2360, I2364, V2368, V2390, Y2400, I2402, V2404, F2406, I2418,
			V2432, L2439, F2450, V2452, A2457, V2485, Y2487, A2491, Y2495, I2497, I2499, Y2501, I2507, A2514, A2557,
			V2560, A2570, V2580, C2582, V2616, Y2618, L2620, L2628, V2630, W2632, I2637, V2644
389	Neurofibromin	P21359	I1592, I1605, F1606, Y1607, V1609, F1613, L1623, V1642, A1670, Y1680, L1715, I1719, A1743, I1755, A1761,
			V1762, V1772, A1785, I1788, F1799, L1801, I1803, F1812, C1817, I1820, I1824
390	Phosphatidylcholine	P21439	A64, M81, L109, M113, Y120, V127, A131, F137, A141, A142, I146, I149, F153, F154, A156, I157, L158, I162, L173,
	translocator ABCB4		L177, I181, I184, I188, A200, V208, L216, I220, A235, A252, A256, A259, A262, V266, A268, F269, Y279, L283, A286,
			A294, I303, A304, A310, A313, A315, F316, M334, V336, F337, I340, A350, A360, A364, I367, I371, I377, L394, V399,
			L412, L415, V419, V425, A426, L427, V428, C433, L441, I442, I453, I460, F463, V465, L468, I472, V475, L481, F482,
			I486, I490, I502, V506, A509, A511, I515, V526, I541, A542, I543, A544, A546, I553, L555, L556, A559, V571, A574,
			L575, A578, I585, I587, V594, I600, A601, F603, L617, Y624, V700, C717, A718, I735, I736, I753, I757, F758, L761,
			A779, L783, L787, A791, F792, M795, L796, L817, A821, V824, A827, A833, A840, L856, A896, A899, I900, I903,
			V906, F915, A934, C955, A960, L975, V976, F982, A1000, A1004, H1006, L1007, I1034, F1036, V1039, F1041, L1052,
			L1055, V1059, L1065, A1066, L1067, V1068, V1078, V1079, L1081, L1082, V1093, A1107, L1110, V1112, L1115,
			L1119, V1122, F1129, A1134, I1137, I1151, A1154, A1155, A1158, I1160, Y1171, V1175, A1191, I1192, A1193,
			L1196, L1204, L1205, V1220, A1223, C1233, I1234, I1236, I1243, I1249, V1250, V1251, L1266, Y1273
391	Tumor necrosis factor alpha-	P21580	L10, A18, I21, I37, H38, H39, F40, M43, H44, L48, F51, I64, A67, L68, L77, L83, A94, L104, M105, H106, A107, Y111,
	induced protein 3		M112, W113, V115, L122, A125, L126, F138, A175, H195, I196, F197, V198, L199, C200, I202, L203, I207, I208,
			V209, V229, I232, Y233, L234, I248, V249, L250, V258, L260, V261, A272, V273, V288, H289, F290, L291, L302, L307,
			V314, I325, A327, A328, L330, I339, L341, Y345, V349, C404, C624, C779
392	Kit ligand (Mast cell growth	P21583	V40, L43, L55, I70, M73, V74, L77, L81, I100, I101, L104, I107, V108, F140, F141, F144
	factor)
393	Ephrin type-A receptor 1	P21709	L81, A92, V95, H96, V97, L99, F101, V103, F122, L124, V148, L181, L183, A184, F185, A190, V192, L194, V197,
			V199
394	Fibroblast growth factor 7	P21781	L69, C71, L77, I79, V85, M98, I100, V108, I110, L119, A120, M121, C137, F139, Y151, V165, A166, L167, A186,
			F188
395	Fibroblast growth factor	P21802	M162, V169, V175, F177, C179, A181, F198, L216, M218, V221, Y229, C231, V233, Y244, L246, F276, C278, W290,
	receptor 2		I324, C342, A344, A355, L357
396	Ryanodine receptor 1	P21817	L13, V19, V20, L21, C23, A25, L34, C35, L36, A37, A38, I63, C64, F66, L68, L77, L100, Y102, A105, I106, L108, H110,
			L117, A131, V134, L136, C145, W147, M149, V162, I168, L170, L179, V190, A192, W199, M201, V213, L219, L221,
			H223, C229, L230, I232, V244, Y246, V251, A255, L258, W259, L261, L273, L279, V281, H283, V284, Y289, L290,
			A291, V299, V300, A306, F313, F315, I338, C345, V347, L356, A375, L387, L389, A399, A400, M402, I403, Y410,
			F413, L435, V440, L444, L447, I448, F451, L470, L476, F477, M482, V486, C489, I490, L493, F502, A506, I517, V518,
			L521, L524, L528, W685, A686, V706, C745, I754, V779, V780, A874, F909, V984, A988, H992, L1038, V1042, A1093,
			V1101, W1103, A1104, L1114, A1120, V1122, F1123, V1148, C1150, I1152, I1159, F1161, I1181, V1190, A1449,
			W1451, V1452, L1465, V1471, V1473, M1475, I1515, M1526, F1528, A1550, F2754, A2759, Y2761, H2763, A2767,
			L2813, A2815, M2816, L2862, M2874, L2878, A2879, A2923, L2926, L2927, L2930
397	Receptor tyrosine-protein	P21860	L52, Y53, C56, V58, V59, L63, I65, L77, I80, V83, V87, L88, V89, A90, F94, L97, L99, L102, V104, V105, A116, I117,
	kinase erbB-3 (EC 2.7.10.1)		F118, V119, L121, A130, L131, L134, L136, L139, I142, V147, I149, L155, M158, I161, I166, V167, C190, C194, W195,
			C231, A232, A245, C255, C259, V295, V296, C331, V343, I348, F351, C354, I357, L361, F363, I376, L384, F387, V390,
			I393, L397, I399, F409, V411, F412, L415, I418, F428, L430, I432, V438, L441, F443, L446, I449, I454, I456, L462,
			C463, H465, V473, L474, C493, C504, C509, W510, C529, C533, C552
398	Succinate dehydrogenase	P21912	F42, I44, V63, V72, A75, L76, I79, L87, C101, M103, L111, A112, I127, F146, L183, A190, C191, Y199, Y206, A210,
	[ubiquinone] iron-sulfur		V211, L212, A215, L234, L240, A262, I263, I266
	subunit, mitochondrial (EC
	1.3.5.1)
399	Tenascin-X	P22105	C435, C466, L3669, L3671, A3679, F3683, L3685, A3716, L3718, L3729, L3731, A3859, L3861, Y3873, V3875,
			V3877, L3898, A3909, V3911, A3947, L3949, Y3961, L3963, L3977, L3986, Y3995, A3997, L3999, A4001
400	Cadherin-3	P22223	V116, L131, I141, V157, F158, L167, L169, L173, L183, A187, I201, I203, V224, V237, A254, M269, I279, V281, Y294,
			L296, I298, A300, A312, A314, V316, I318, L349, L390, L396, L406, V408, V410, A425, I427, V429, Y462, V495, L501,
			Y514, V516, V518, A520, L534, L536, I553, L565, V602, L604, V617, L619, L621, I633, A635
401	Interleukin-10	P22301	L41, L44, A47, V51, F55, L66, L70, A82, L83, M86, Y90, V94, A98, V109, L112, L116, C126, L130, V139, A157, M158,
			F161, F164, I165, I168
402	C-C motif chemokine 1	P22362	I47, L62, F64, A74, V81
403	Ectonucleotide	P22413	C164, C166, C170, A392, I507, I632, F638, L826
	pyrophosphatase/phosphodi-
	esterase family member 1
404	Potassium voltage-gated	P22460	I124, I126, L138, L146, F165, F172, I175, Y179, V191, F196, I200, Y203, I260, V445, A451, V452, A455, A470, A474,
	channel subfamily A		C500
	member 5
405	Protein-glutamine gamma-	P22735	V709, I711, L721, V724, F726, L728, I744
	glutamyltransferase K (EC
	2.3.2.13)
406	Carbonic anhydrase 4 (EC	P22748	Y25, I54, I56, Y75, W81, V83, V90, M92, L94, I100, Y109, A111, L114, L116, W118, H128, M137, M139, H140, I141,
	4.2.1.1)		H143, A164, L166, A167, F168, L169, V170, F180, L187, I190, Y217, C229, V233, V237, F238, I242, L244, F252,
			L256, M266
407	Peptidyl-prolyl cis-trans	P23284	V42, V44, V46, Y47, F48, L50, I52, V60, I61, F62, L64, F65, V69, V73, F76, A78, L79, A80, F86, Y88, F93, V96, I97,
	isomerase B		M101, I102, I118, F123, L130, H132, W137, V138, M140, F152, F153, I154, V167, V168, F169, V172, V178, V179, V182,
			L194, V197, I198, I199, I205
408	Glycine receptor subunit	P23415	V65, V67, C69, I71, I73, Y86, V88, I90, L92, W96, L101, L111, L146, I148, V154, I160, L162, L164, C166, L170, F173,
	alpha-1		C180, M182, L184, L194, F196, C237, I238, A240, F242, L244
409	Receptor-type tyrosine-	P23468	A41, F43, C45, W57, F69, V81, L82, I84, L87, Y96, C98, A100, L113, V115, A143, M145, C147, A148, A149, W159,
	protein phosphatase delta		L192, I194, Y205, C207, A209, A221, L223, I255, C257, A259, V267, W269, V294, C302, A304, A315, I317, I339,
			L341, I356, V373, V380, F391, V393, V394, A395, I434, V436, V453, V463, I479, V490, V492, A494, I532, L534, Y547,
			L549, I564, L575, F583, L585, A586, A587, I626, V628, I647, A651, L674, I685, V687, A689, L937, L956, L981, V992,
			V994, A996
410	Tumor necrosis factor ligand	P23510	V64, F66, M86, V93, I95, C97, Y101, I103, L105, V113, I115, L117, V135, V149, L151, L170, L172
	superfamily member 4
411	Brain-derived neurotrophic	P23560	C141, A150, V164, V166, V170, C196, A217, I226, I231, I233
	factor
412	Follicle-stimulating hormone	P23945	F30, C32, V37, A48, L51, F53, L58, I61, F66, F69, L72, I75, I77, L83, I86, V90, F91, L94, L97, I100, I102, A105, L108,
	receptor		L109, A115, F116, L119, L122, L125, I127, I132, L135, V138, I141, V147, L149, I151, I157, I160, F165, L168, V173,
			L175, L177, I182, A189, F190, L195, L198, L200, L206, V213, L223, I225, I230, L238, L241, L244, A246, L261, A267
413	Sodium-dependent	P23975	L95, L109, A145, I156, L238, F272, L284, I291, A305, I309, L319, V325, Y367, V379, L386, V387, F388, I389, L390,
	noradrenaline transporter		Y391, A394, A405, I428, F459, I466, L469, L472, A477, L486, I490, F495, F540, I549, A554, W556, V569
414	Protein kinase C eta type	P24723	V360, M370, L371, A372, V383, V390, I406, L407, A410, F415, L416, L429, F430, F431, V432, L441, A456, Y459,
	(EC 2.7.11.13)		A460, A461, I463, I464, A466, L467, L470, I475, Y477, V485, L487, C493, L495, F498, W537, M540, L543, L544,
			M547, A581, I584, L585, F588, I608, F613, F614, V641, F644, F671, F674
415	Deoxyribonuclease-1 (EC	P24855	I25, A26, A27, F28, I30, F33, M38, V44, I47, V48, I50, L51, Y54, I56, A57, L58, V59, V62, A69, V70, L73, L77, Y102,
	3.1.21.1)		L103, F104, V105, V111, F131, I137, V138, F140, V147, F150, A151, I152, V153, L155, A157, A162, I166, L169, V172,
			V176, V185, M186, L187, M188, F191, A193, I206, L208, I218, C231, A232, I236, V237, V238, A239, L243, A246,
			F257, A268, I271, V277, V279, L281
416	C-X-C chemokine receptor	P25024	L37, C110, C187, V190
	type 1
417	C-X-C chemokine receptor	P25025	L155
	type 2
418	Adenomatous polyposis coli	P25054	L137, L204, I224, C344, L356, A383, A386, L387, I391, V406, L407, L410, I413, Y416, C417, C420, I446, V450, L453,
	protein		A465, M466, L469, L472, A474, I475, A476, L478, L479, V481, L497, A501, A504, L505, L508, L519, C520, C525,
			M526, L529, L540, I544, A545, V547, L548, L551, L563, V569, L572, M573, C575, A576, V588, L589, A591, L592,
			L595, I606, A612, L613, L616, I631, I638, L639, V642, I646, L656, C661, L665, I676, A680, C681, L684, L687,
			A703, L707, I718, A725, L729
419	Myelin protein P0	P25189	L48, C50, F64, W66, F80, F95, I112, I114, F125, C127, L144
420	Tumor necrosis factor	P25445	C63, C73, C85, C119
	receptor superfamily
	member 6
421	Integrin beta-7	P26010	C54, I55, C61, W63, C64, L86, L123, A124, V128, V130, L132, V142, F144, V152, L154, Y155, Y156, L157, M158,
			L160, M164, I191, F193, F196, V197, F204, V205, C216, F229, F242, V246, V251, A264, I265, L266, A268, A269,
			C271, I275, L283, L284, V285, F286, Y327, L337, A340, I345, A347, V348, Y356, A367, V378, A385, L395, Y408,
			C428, V431, V437, F439, V441, L443, A445, L455, L457, A459, L466, V468, L470
422	Hemagglutinin [Cleaved	P26136	I29, C30, L31, A35, V42, V52, L58, V59, L67, C68, L74, C80, L82, I83, A86, L87, C92, L95, V102, F103, I104, V110,
	into: Hemagglutinin HA1		C113, Y114, F116, Y121, L124, L128, A129, L134, F141, A154, C155, F163, F164, L167, L170, I181, Y195, W197,
	chain; Hemagglutinin HA2		V199, H200, H201, Y212, V219, V221, I247, I249, Y250, L253, V254, I260, F262, L268, I269, A270, Y275, I292,
	chain]/strain		C299, L300, I306, V327, L334, A335, A352, W361, Y369, A391, A443, L465, L473, C484, F485, I487, H489, C491,
	A/Mallard/Astrakhan/263/		C495, I496, I499, A513
	1982 H14N5 (Influenza A
	virus (strain
	A/Mallard/Gurjev/263/1982
	H14N5))
423	Hepatocyte growth factor-	P26927	C157, C169, Y199, W215, C240, W250, C251, Y252, C263, L265, C391, W394, H400, L414, C419, C431, C443, V484,
	like protein		W494, V496, L498, L511, I517, L518, A520, V536, L538, V555, L569, V570, L571, L572, V584, C602, I604, A605,
			L624, C632, M645, C646, L665, A666, C667, L675, I678, I679, V697, I704
424	Serum	P27169	L28, I48, A63, F64, I65, I85, M88, L129, L130, V131, V132, V141, L143, F144, L153, I159, L167, I170, F178, Y179,
	paraoxonase/arylesterase 1		G180, V205, F220, A223, I226, V235, I237, A238, I245, V247, L267, V268, L280, V282, C284, H285, V304, I307, A322,
			L328, V333, A334, L341, L342, I343, A350, L351, C353
425	Dipeptidyl peptidase 4 (EC	P27487	Y43, Y68, L69, A81, L90, I114, L116, A130, Y132, I134, L142, L164, A165, V167, I172, V174, I198, W201, V202, Y203,
	3.4.14.5)		V207, A213, L223, A224, Y225, A226, F228, I236, Y238, Y241, A259, A261, F268, V270, V271, I287, M293, Y299,
			L300, C301, V303, I311, L313, W315, V324, M325, I327, C328, C339, L340, I346, W353, V354, F371, H383, I384,
			C385, I389, V404, L415, Y416, Y417, I418, L431, I434, V442, L445, C447, C454, Y468, L470, C472, L482, L500, V507,
			L514, L519, M528, L530, L542, L543, L544, V546, A548, C551, A555, L567, A568, I573, I574, V575, A576, F578,
			M591, A593, I594, L598, V603, I607, A609, A610, F613, V619, I624, A625, I626, Y631, Y634, V635, M638, V639, L640,
			C649, I651, A652, V653, A654, V656, W659, Y661, Y662, V665, Y666, Y670, M671, Y683, V688, A692, F695, Y700,
			L701, L702, I703, H704, V711, I719, L723, V724, V726, F730, Y735, H740, I742, I751, M755, F758, I759, C762, F763
426	Genome polyprotein	P27909	L29, M48, M126, V128, C148, C167, C180, C182, V189, Y191, A251, A255, M281, C283, V301, V303, V304, L305,
	[Cleaved into: Capsid		C310, V311, M314, A315, L321, I323, L325, V330, L339, C340, I341, A360, C385, L394, C396, A397, F399, L405,
	protein C/strain Brazil/97-		V410, L415, Y417, V419, V421, I444, I453, L455, L461, L463, C465, L471, V477, L478, L479, M481, V488, F493, L517,
	11/1997 (DENV-1)		V518, L544, H562, L563, C565, L567, M569, L572, C582, F586, V592, V600, V602, V604, Y606, C613, I615, I632, V638,
			I647, I658, V660, W671, I963, I993, L1396, L1398, I1497, Y1498, I1500, V1513, V1515, F1516, V1520, F1521, H1522,
			M1524, L1533, M1534, V1547, L1551, I1552, Y1554, W1558, F1560, V1570, V1572, I1573, A1574, V1575, V1584,
			F1591, A1600, I1601, I1614, V1615, V1622, L1624, Y1625, V1630, Y1636, V1637, A1643, L1680, I1683, V1684,
			A1687, L1695, I1696, L1697, A1698, V1703, A1704, M1707, A1708, L1711, V1733, L1735, M1736, H1738, F1741,
			Y1754, M1756, I1757, I1758, M1759, A1762, I1770, A1771, A1772, I1776, A1785, A1786, A1787, I1788, F1789,
			M1790, I1827, V1835, W1836, F1837, V1838, I1847, A1848, C1850, L1851, I1859, L1861, F1866, W1878, Y1880, V1881,
			V1882, A1891, V1898, I1899, V1917, V1925, A1928, A1930, A1931, I1937, Y1948, V1949, L1955, A1962, A1967,
			L1970, L1971, I1974, L1984, F2009, V2010, L2012, L2018, W2021, L2022, V2026, A2027, W2038, C2039, V2048,
			I2057, L2067, A2074, F2086, F2089, A2090, W2506, Y2521, I2526, V2529, L2538, A2547, V2548, A2553, L2555,
			F2558, V2559, V2564, V2570, I2571, L2573, C2575, C2584, A2585, V2590, V2593, Y2596, V2625, C2633, L2636,
			L2637, C2638, I2649, L2655, V2657, L2658, V2661, W2664, L2665, C2671, I2672, I2674, L2675, Y2678, V2682, L2686,
			M2689, M2696, L2697, H2708, M2710, Y2711, W2712, V2713, I2720, V2724, M2730, L2731, I2769, I2776, V2817,
			L2820, W2824, I2865, M2866, A2870, L2873, V2904, A2914, A2917, F2923, C2939, C2942, V2943, Y2944, M2969,
			L2971, A2973, L2976, A2980, F2983, M2984, W2989, F2990, V2999, L3007, Y3009, L3011, I3014, I3017, M3022,
			I3034, A3057, I3060, Y3065, V3069, V3070, V3072, V3081, V3084, I3085, L3101, F3104, M3107, V3109, L3111,
			I3112, M3115, L3126, V3135, L3139, L3147, M3150, A3151, I3152, V3158, V3159, F3166, A3169, L3170, A3172,
			L3173, M3176, V3198, F3200, F3205, I3216, V3217, V3218, C3220, V3227, A3230, A3236, A3244, A3251, W3254, L3256,
			F3259, H3260, L3264, A3267, A3268, A3270, I3271, A3274, V3275, V3277, H3290, L3302, W3305, V3308, W3309,
			W3315, V3328, L3331, A3352, I3355, I3359, L3365, L3372, M3375, M3378
427	Interleukin-1 receptor type 2	P27930	V46, L48, W69, A92, L93, L95, A98, C108, I121, L150, W169, L192, V194, Y205, C207, I220, I224, C258, V260, L262,
			A276, I281, V328
428	Genome polyprotein	P27958	V194, V203, C207, C226, C229, V230, C238, W239, V240, L258, I262, L265, A269, C272, L275, C281, L286, F291,
	[Cleaved into: Core protein		W353, V355, A426, L427, W437, F442, C459, F465, C486, C494, A499, V502, C503, V506, C508, F509, F537, L539,
	p21/genotype 1a (isolate H)		W549, C552, W554, C564, A566, C569, C581, C585, F586, A592, Y594, C597, I603, C607, M608, V609, Y611, V629,
	(HCV)		M631, A642, A643, C644, C652, L665, V674, A684, I690, L692, V699, Y701, V720, L724, L725, L754, C922, V949,
			L964, A1004, I1061, L1070, A1071, C1073, I1074, V1077, C1078, W1079, V1081, A1085, V1097, L1108, V1109, L1120,
			L1130, L1132, I1140, V1142, I1158, L1161, L1169, C1171, A1176, V1177, L1179, F1180, A1190, A1192, V1193,
			F1195, I1196, V1198, L1201, L1228, V1251, L1252, V1253, L1254, M1268, I1291, Y1293, Y1296, A1301, I1312,
			I1314, C1315, C1318, I1326, I1329, V1332, A1336, L1343, V1344, V1345, L1346, A1347, I1362, I1373, F1375, I1380,
			V1384, I1385, L1391, I1392, F1393, C1394, C1400, L1403, L1407, I1412, V1432, V1433, V1434, V1435, L1440, F1444,
			F1448, V1451, I1452, F1470, A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528, L1539, Y1542, L1555,
			F1557, W1558, V1561, L1565, I1568, F1572, L1586, V1587, A1588, A1591, C1594, A1599, L1611, H1619, L1624,
			L1625, L1628, I1641, I1645, V2128, L2441, L2450, L2451, V2457, Y2458, A2465, Y2484, V2487, V2491, A2493, A2494,
			A2495, V2498, A2500, A2508, C2509, Y2523, A2525, V2528, A2532, A2535, I2539, L2546, L2547, I2558, C2566,
			A2577, L2579, V2581, L2585, V2587, V2589, C2590, A2594, L2595, V2598, V2599, L2602, A2605, V2606, Y2611,
			V2621, L2624, A2627, M2635, L2637, Y2639, V2648, I2653, I2659, Y2660, C2662, C2663, A2669, A2672, I2673,
			L2676, L2680, Y2681, L2686, C2694, C2699, A2701, V2704, L2705, C2709, L2713, A2719, A2721, A2722, C2723,
			A2726, L2728, M2733, L2734, V2735, L2740, V2741, V2742, I2743, C2744, A2754, L2756, F2759, A2762, M2763,
			Y2766, A2768, I2783, V2790, A2793, Y2802, L2804, L2812, A2813, A2815, A2816, L2829, I2832, I2833, A2836,
			L2839, W2840, A2841, I2844, L2845, M2846, H2848, F2849, F2850, L2859, A2862, C2865, I2867, A2870, C2871,
			Y2872, I2874, L2877, L2879, I2882, I2883, L2886, A2891, F2892, V2905, A2906, C2908, L2909, L2912, V2914,
			A2919, W2920, A2924, V2927, L2931, L2932, A2938, A2939, C2941, L2945, F2946, A2949, A2961, A2962, F2971,
			A2973, Y2975, I2980
429	Proteasome subunit beta	P28062	L76, A77, F78, F80, V84, I85, A86, A87, V88, A92, A94, V106, I107, L113, L114, M117, C124, L131, C135, L137, I146,
	type-8 (EC 3.4.25.1)		V148, A150, A151, L155, M159, M169, M172, I173, C174, L183, V186, A207, M211, A224, L227, A231, I232, A233,
			A235, V245, V246, M248, Y249, H250, M251
430	HLA class II	P28068	L51, M61, A73, L90, C97, V117, V119, M132, L133, A134, C135, V137, F140, W149, C192, V194
	histocompatibility antigen,
	DM beta chain
431	Gamma-aminobutyric acid	P28472	V63, M65, I67, I69, Y82, L84, M86, W92, L97, I141, V149, A159, L165, C175, L177, I179, I189, A199, L233, L235,
	receptor subunit beta-3		F237
432	Mitogen-activated protein	P28482	A9, V14, F19, V21, Y25, I31, A35, Y36, M38, C40, A42, V49, V51, A52, I53, I56, C65, L69, I72, I74, L75, I83, I84, I86,
	kinase 1		I89, I95, M98, V101, Y102, I103, V104, L112, L115, L116, L121, H125, I126, C127, F129, L130, I133, L134, L137,
			I140, H141, A143, V145, L146, H147, L150, L155, L156, L157, L163, I165, F168, L170, A171, L184, A189, W192, Y193,
			A195, I198, M199, L200, Y205, I209, I211, W212, V214, C216, I217, L218, A219, M221, L222, I227, F228, L234, L237,
			I240, L241, L244, L252, I255, A260, L264, L267, F279, A286, L287, L289, L290, M293, L294, A307, L308, L313, F329,
			M333, L335, L338, L343, I347
433	Granulins (Proepithelin)	P28799	C133, C157, C215, C239, C290, C314, C372, C396
	(PEPI) [Cleaved into:
	Acrogranin (Glycoprotein of
	88 Kda) (GP88)
	(Glycoprotein 88)
	(Progranulin); Paragranulin;
	Granulin-1 (Granulin G);
	Granulin-2 (Granulin F);
	Granulin-3 (Granulin B);
	Granulin-4 (Granulin A);
	Granulin-5 (Granulin C);
	Granulin-6 (Granulin D);
	Granulin-7 (Granulin E)]
434	ADP-ribosyl cyclase/cyclic	P28907	F59, V63, C67, Y70, M77, V85, F89, A92, F93, I101, Y106, L109, M110, C119, I122, L123, L124, A132, F135, L145,
	ADP-ribose hydrolase 1 (EC		L149, L150, L153, A154, W159, C160, V187, F188, V192, A197, A199, A200, V204, V206, M207, L208, I215, F216,
	3.2.2.6)		F222, V225, V227, L230, V235, L238, A240, V242, L253, I259, L262, I266
435	Tumor necrosis factor	P28908	C44, C45, C48, C58, C65, C69, Y74, C81, A83, C84, V85, C87, L92, V93, C98, V105, C106, C108, F113, C114, C122,
	receptor superfamily		A123, C125, C131, I136, V137, C233, C240, C244, Y249, L250, C256, C259, V260, C262, L267, V268, C273, W275,
	member 8		C281, C283, C289, C297, A298, C300, C306, V311
436	Gap junction beta-2 protein	P29033	W44, F51, C60, C64, H73, C169, A171, C180
437	Neuroendocrine convertase	P29120	C319, A393, V411, A511, L525
	1
438	Amyloid beta A4 protein	P29216	C49, C53
439	Ephrin type-A receptor 3	P29320	L33, Y68, V70, L82, V87, A92, I95, Y96, V97, L99, F101, L103, V112, F120, L122, I146, M155, V171, F179, Y180, L181,
	(EC 2.7.10.1)		A182, F183, A188, V190, A191, L192, V195, V197, A436
440	Ephrin type-B receptor 2	P29323	W43, V61, W72, L73, I78, A83, I86, V88, M90, F92, V94, V103, F111, L113, I141, V150, I159, F166, V169, F174, Y175,
	(EC 2.7.10.1)		L176, A177, F178, L187, V190, V192, A435
441	Collagen alpha-5	P29400	I1464, L1490, Y1491, L1503, Y1537, W1538, L1539, I1561, C1564, A1565, V1566, C1567, A1569, F1599, H1602,
			C1620, F1629, I1630, C1632, C1638, C1678, V1680, C1681, M1682
442	Interleukin-12 subunit alpha	P29459	V48, M51, A55, I105, C123, L131, M141, M159, I163, C196, L199, I209
443	Interleukin-12 subunit beta	P29460	V30, V32, V33, V46, I58, W60, V79, A85, C90, L102, L104, I116, A133, F140, C142, W144, V191, C193, I208, V210,
			V212, A214, Y220, Y223, I229, I233, V252, V254, L271, F273, C274, V275, V277, A304, I306, V308, A310
444	Protein PML	P29590	C57, C66, L73, H74, L76, C129, C140, C148
445	Non-receptor tyrosine-	P29597	L28, V30, A53, V56, I60, A61, V64, L73, L76, A81, L91, L101, F103, F109, Y151, L152, F153, F160, A165, L184, M186,
	protein kinase TYK2 (EC		A187, L191, H193, C214, I215, F219, Y259, L260, L263, A267, V277, L280, L283, V316, V318, I324, C378, F380,
	2.7.10.2)		V393, I395, C402, L403, L405, L407, A413, F416, V417, L419, V420, Y423, L426, V438, H452, Y471, L472, L483, L485,
			V487, I507, V526, L529, I563, V639, L641, L644, F655, A659, V676, C677, I684, M685, V686, L695, L699, V714,
			A715, L718, A719, A721, L722, L725, V735, I740, L742, I755, L757, V762, V773, I776, A780, W798, F800, A802, L804,
			L805, I807, C838, L841, L844, C848, F859, I862, L866, L913, V927, V929, A934, W944, I948, L951, H958, I959, I960,
			C966, L974, L976, V977, L986, L990, L1000, L1001, F1003, A1004, I1007, C1008, M1011, L1014, I1020, H1021, L1024,
			A1025, A1026, V1029, L1031, V1037, I1039, F1042, L1044, A1045, A1069, C1072, F1078, V1084, F1087, V1089, L1091,
			Y1092, L1094, L1124, L1127, L1128, L1134, C1140, V1144, M1148, C1151, W1152, L1165, L1169
446	CD40 ligand	P29965	A124, V126, L138, V153, L161, V163, Y169, I171, A173, V175, F177, F189, A191, L193, L231, A235, V237, V239,
			V241, F256, L258
447	Peroxiredoxin-5,	P30044	V67, V76, L78, F82, V88, L89, F90, V92, F96, C100, H104, L105, F108, A112, L115, A117, V123, A124, C125, L126,
	mitochondrial (EC		V128, A131, W137, A140, A143, L150, A151, F157, L178, F181, M183, V184, V185, V190, A207, I210
	1.11.1.15)
448	T-cell differentiation antigen	P30203	V58, V60, A78, A79, A81, V82, C83, A126, A151, V153, A171, V174, M176, V185, C186, A195, V197, V198, C199,
	CD6		A255, A257, V278, V280, F282, V289, C290, A299, V301, L302, C303, C308, M326, Y328, L337, A355, V358, C360
449	Lens fiber major intrinsic	P30301	A12, A15, A19, Y23, V24, L28, L32, V44, A45, F48, A51, V67, A70, V71, A74, A86, Y89, A97, A101, V112, L116, V127,
	protein		A130, V142, I145, F146, A161, V164, L168, H172, A181, M183, A186, A190, A192, V203, Y204, I209
450	HLA class I	P30460	M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, I76, Y83, F91, L102, L105, L119, M122, C125, V127, Y140, Y142,
	histocompatibility antigen,		Y147, I148, L150, L154, W157, A163, A164, V176, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
	B-8 alpha chain		L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, V285, H287
451	Tyrosine-protein kinase	P30530	L54, C56, L58, V98, L102, C117, V119, V133, C160, W173, F203, C205, A207, A219, I221
	receptor UFO (EC 2.7.10.1)
452	Type-1 angiotensin II	P30556	I27, C101
	receptor
453	Fibroblast growth factor 9	P31371	L66, C68, L74, I76, I94, L95, V105, I107, L116, M118, C134, F136, Y148, V164, A165, L166, F184, F187, V197, L200
454	Cytokine receptor common	P31785	C62, V64, M70, C72, W74, L85, L87, C102, L106, C115, L117, L124, F128, V129, V130, L132, L146, L148, V152,
	subunit gamma		L162, L165, L170, L172, W174, L183, H185, V187, F221, V223, F227, A234
455	Low affinity	P31994	A50, L62, V67, L69, W84, A103, Y111, C113, L126, L129, L133, V134, L135, L140, F142, I148, L150, C152, L160,
	immunoglobulin gamma Fc		V163, F165, F166, F181, A186, Y194, C196, I212, V214
	region receptor II-b
456	Low affinity	P31995	A50, L62, V67, L69, W84, A103, Y111, C113, L126, L129, L133, V134, L135, L140, F142, I148, L150, C152, L160,
	immunoglobulin gamma Fc		V163, F165, F166, F181, A186, Y194, C196, I212, V214
	region receptor II-c
457	Carcinoembryonic antigen-	P31997	L36, A45, V51, L52, L53, V55, Y65, W67, I79, I80, A105, L107, M109, V112, Y120, L122, V124, F138
	related cell adhesion
	molecule 8
458	Neuronal acetylcholine	P32297	A139, L140, A153, I187, L189
	receptor subunit alpha-3
459	4-hydroxyphenylpyruvate	P32754	V22, F24, A29, A33, M40, F42, V61, I62, I67, V68, F69, L71, I96, F98, C103, V107, A110, V131, A134, L136, H144,
	dioxygenase (EC 1.13.11.27)		L146, V147, C176, I184, V185, Y200, V217, L224, V228, V229, A230, I236, M238, I240, I252, I267, A268, L269,
			I274, A277, I278, L281, Y296, L317, I322, Y331, L332, L333, I335, L346, F347, L348, V350, I351, F368
460	T-lymphocyte activation	P33681	A46, L48, C50, I64, W66, V73, L74, L99, I101, I103, Y114, C116, V118, I160, C162, W175, V200, L204, F214, C216,
	antigen CD80		I218
461	Surface antigen S/isolate	P33795	F36, A66, L83, I210, V238
	Human/India/Ind3/1967
	(VARV) (Smallpox virus)
462	N-acetylgalactosamine-6-	P34059	I33, L34, L35, L36, L37, M38, M41, L46, M62, F69, F72, Y73, A75, A84, A85, L86, L87, L91, F97, A104, I113, I117,
	sulfatase (EC 3.1.6.4)		L123, L124, L128, I137, V138, W141, L143, H154, W159, H166, V180, Y190, A203, Y209, A213, F216, I217, F226,
			F227, L228, Y229, W230, A231, V232, A234, Y240, A241, Y254, A257, V258, I261, I265, I268, L272, V283, F284,
			F285, A291, I294, C308, F314, M318, A322, L323, A324, W325, I342, F346, L350, L368, Y384, M391, A392, A393,
			A400, H401, V427, I441, F442, A464, I468, L486
463	Neurotrophin-4	P34130	V118, V120, A179, I193
464	Catenin alpha-1	P35221	A128, L141, L150, V157, I161, L164, L173, L187, A191, L198, M207, A208, L221, L229, L243, I244, L248, V252,
			I255, A258, A259, F285, L305, I312, A316, M319, I333, A339, V340, L344, L347, L348, M371, L378, L382, A385, V386,
			H389, V390, L395, L401, L404, A407, A408, V416, F423, A427, L430, V433, A434, A437, C438, V450, M452, L457,
			A459, L460, V464, A468, L471, A480, W491, V497, L498, A501, V502, F511, L512, V514, I519, C526, A529, L530,
			L538, A542, I545, A549, V552, V556, V572, L573, L579, V583, F587, A594, F611, A614, V618, I622, I625, F691, L698,
			I712, A716, M719, M723, M726, V742, A745, A746, I749, A752, M756, L759, I763, L776, L780, I783, L790, C793,
			A815, L818, I819, A821, A822, L825, M826, A828, V829, V833, A839, A896, A902
465	Catenin beta-1	P35222	A149, I153, L160, V168, A171, A172, V175, I188, M194, V195, A197, I198, V199, M202, C213, A215, L218, L221,
			L228, I231, I237, A239, L240, V241, V251, L252, A255, I256, L259, L262, L263, A269, V273, L279, M282, L285, F293,
			L294, A295, C300, L301, L304, A305, I315, A317, L324, V325, I327, M328, L336, L337, V343, L344, L347, C350, I357,
			V358, A360, M363, A365, L366, L368, L370, L377, V378, C381, L382, L385, L388, A391, A392, M398, L401, L402,
			L405, V406, L408, L409, V417, C419, A420, A421, I423, L424, L427, V438, I444, L447, V448, V451, A454, I460, A464,
			I465, A467, L468, L471, A481, A484, V485, L491, V494, V495, L497, L498, L506, I507, A509, V511, L513, I514, L517,
			A518, L519, A522, A525, L527, A532, I533, L536, L539, L540, A543, V564, M566, I569, V570, C573, A576, L577,
			L580, A581, V584, I590, I596, L598, F599, V600, L602, L603, I610, V613, A614, A615, V617, L618, L621, A622,
			A627, A628, A630, I631, A633, A636, L640, L643, L644, V651, A652, A655, A656, V658, L659, L781
466	Interleukin-13	P35225	L43, L46, I47, L50, C62, V67, M76, Y77, A79, A80, L81, L84, I93, L100, C104, V125, F128, V129, L132, L136
467	Thrombospondin-2	P35442	I600, C619, A639, C707, C715, C720, C756, C779, C815, C838, C876, A882, C912, C932, C948, F959, V965, L967,
			L988, I998, A999, V1000, F1005, F1010, V1016, Y1024, A1025, F1027, V1028, F1029, Y1031, F1037, Y1038, V1039,
			M1041, A1057, L1065, V1067, V1068, L1078, A1081, L1082, W1083, V1092, L1114, H1116, I1123, V1125, Y1145,
			L1150, L1152, F1153, V1154, F1155, V1160, F1162, L1165, Y1167, C1169
468	D(3) dopamine receptor	P35462	C103
	(Dopamine D3 receptor)
469	Alpha-L-iduronidase (EC	P35475	V32, V34, W47, F52, A61, V65, L72, L74, A75, Y76, V77, A79, V88, W92, L93, L94, L96, V97, L114, Y117, L120, L121,
	3.2.1.76)		F130, L132, M133, A136, F140, F143, V149, W152, L155, V156, L159, A160, Y163, V172, W175, F177, W180, F198,
			Y201, Y202, A204, C205, L209, L216, L218, F225, L237, L238, Y258, I259, L261, I272, V279, I283, A300, A314,
			V316, Y318, A319, A320, M321, V322, V323, V325, I326, A327, H329, L333, A340, L346, A351, L353, F360, L365, A367,
			V371, L381, L382, V386, L387, A389, L393, A394, L396, L401, V418, L421, A422, A436, A437, V438, L439, I440,
			Y441, A442, A448, V456, L460, V472, L476, C481, F501, M504, A507, L530, L535, L537, V538, H539, V540, C541,
			V551, L564, V565, L566, V573, C577, L578, Y581, I583, L604, V614, Y618, V620, A622
470	Fibrillin-1 [Cleaved into:	P35555	C67, C80, C100, C134, C145, C853, C875, A882, I911, C1526, C1534, C1562, C1564, A1569, I1607, L1613, L1616,
	Asprosin]		C2061, C2083, C2084, C2085, I2110, C2111, C2137, C2164, C2190, C2363, C2364, C2365, W2371, C2378
471	Myosin-9	P35579	V34, A44, A54, V56, L58, M86, L89, A95, V97, L98, L101, Y105, L109, I110, Y111, Y113, F117, C118, V119, V120,
			I121, I129, I134, V135, Y138, M146, H149, I150, Y151, I153, A157, M161, I170, L171, C172, A178, V187, I188, Y190,
			L191, A192, V194, A195, A214, I217, L218, A220, F221, A224, F235, F238, I239, I241, F243, V250, A252, Y257, L258,
			A264, F274, I276, F277, Y278, Y279, L280, L288, L292, L293, F302, L303, I310, F319, A325, M326, M329, L339, L340,
			V342, I343, V346, L347, L349, I352, F354, A363, A370, A371, V374, L377, L378, F385, I389, L390, A410, F412, A413,
			I414, A416, L417, A418, A420, Y422, M425, F426, L429, V430, I433, L437, I448, I450, L451, F456, F464, L467, C468,
			Y471, L479, F480, Y492, I497, F504, L508, C511, I512, L514, I515, I524, L525, L527, L528, F542, V546, F556, F568,
			C569, I570, I571, H572, V577, Y579, A581, W584, M589, I596, A597, L600, F607, V608, W612, V646, Y650, L654,
			L657, M658, L661, F668, V669, C671, I672, I673, V688, L689, L692, V697, I701, I703, F708, F714, F717, Y721,
			I729, A739, C740, M743, I744, V761, F762, F763, V767, L771, I783, F786, M809, M871
472	Alpha-actinin-2	P35609	F44, C48, L70, L75, L76, V100, L114, A119, I122, V123, I134, I138, A142, I143, I146, L157, C161, I173, W180, L184,
			L186, C187, A188, L189, I190, L203, I209, I212, A215, M216, A219, A231, V235, A244, I245, M246, Y248, V249,
			F252, Y253, A262, L289, A290, I297, L304, A315, M316, L348, L378, A381, L389, A403, F406, A410, H413, A417,
			L424, V437, H444, I461, A465, L468, V479, I486, L493, L504, M507, H518, F521, A525, M532, A535, I551, L565, I575,
			V582, I593, L607, V614, L625, A646, I649, I667, L678, H683, L695, V707, M717, I720, L727, I731, M798, A839, Y844,
			I845, L850, A859, I863, A878
473	Metalloproteinase inhibitor 3	P35625	I40, I42, A44, V46, L60, I64, V79, I82, L104, M113
474	Copper-transporting ATPase	P35670	V145, L147, V149, I161, V165, A183, I185, Y187, L197, V201, F206, C271, I279, V285, A297, V299, L311, I315, I363,
	2 (EC 3.6.3.54)		I365, I377, I381, V401, L413, I417, C490, L492, I494, V503, I506, L510, V516, V519, L520, A528, I530, Y532, I542,
			A543, I546, A553, I566, L568, I570, I582, L586, A595, A604, V606, F608, I618, I619, I622, A629, V820, C1079, V1106
475	Myosin-11	P35749	V38, A48, V58, V60, L62, M90, L93, A99, V101, L102, L105, Y109, L113, I114, Y115, Y117, F121, C122, V123, V124,
			V125, I133, I138, V139, Y142, M150, H153, I154, Y155, I157, A158, A161, M165, I174, L175, C176, A182, V191, I192,
			Y194, L195, A196, V198, A199, A221, I224, L225, A227, F228, A231, F242, F245, I246, I248, F250, V257, A259,
			Y264, L265, A271, F281, I283, F284, Y285, Y286, M287, M295, L299, L300, F309, L310, I317, F326, A332, M333,
			M336, I346, L347, V349, V350, V353, L354, L356, I359, F361, A370, A377, A378, V381, C382, L384, M385, F392, I396,
			L397, A417, F419, A420, V421, A423, L424, A425, A427, Y429, L432, F433, I436, L437, V440, L444, L455, I457, L458,
			F463, F471, L474, C475, Y478, L486, F487, Y499, I504, F511, L515, C518, I519, L521, I522, V531, L532, L534, L535,
			F549, L553, F563, F575, I577, I578, H579, V584, Y586, A588, W591, M596, V603, L607, F614, V615, W619, V653,
			Y657, L661, L664, M665, L668, F675, V676, C678, I679, I680, A692, V695, L696, L699, V704, I708, I710, F715,
			F721, F724, Y728, I736, A746, C747, M750, I751, I768, F769, F770, V774, L778, F806, W832, L885
476	Glutaredoxin-1	P35754	V6, I10, V15, V16, V17, F18, I19, C26, A29, I32, L33, I48, I57, L61, V73, F74, I75, L86, L95, L99, A104
477	Vascular endothelial growth	P35968	V136, I148, C150, L161, C162, A163, F185, I187, I192, A195, V198, C200, A202, I223, L244, C246, A248, V254, L292,
	factor receptor 2		I294, V297, Y305, C307, A309, V322
478	Tyrosine-protein kinase	P35991	V219, A221, L233, L235, Y241, A254, I264, A291, V427, I429, I432, F442, M449, L457, V458, Y461, V463, C464,
	BTK (EC 2.7.10.2)		I470, I472, I473, L482, L486, L498, C502, V505, C506, A508, M509, L512, H519, L522, A523, A524, C527, V529,
			V535, V537, F540, V568, I580, W581, F583, V585, L586, M587, W588, I590, I610, A622, I629, M630, C633, W634,
			F644, L647, I651
479	Chitinase-3-like protein 1	P36222	L24, V25, C26, Y27, Y28, C41, L46, L50, C51, I54, I55, Y56, F58, A59, L76, Y77, L80, L90, L93, L94, V96, F101, F106,
			I109, A110, F119, I120, V123, L127, F132, L135, L137, A138, W139, F150, L153, I154, M157, F161, L172, L173, L174,
			A176, A177, L178, A180, I185, I191, I194, L198, F200, I201, I203, H218, H219, L222, A240, V241, M244, L254, V255,
			M256, I258, F265, V274, A276, A295, Y297, I299, V316, Y318, A319, W325, V326, Y328, V334, V338, L341, A349,
			M350, V351, A353, L354, F359, F370, L372, A375, I376
480	Phosphoglucomutase-1	P36871	L22, V26, Y35, A36, F39, I40, I43, I44, A55, L57, V58, V59, A70, I71, I74, A75, I77, A78, A79, I83, L86, I88, L94, A98,
			V99, I103, I106, I112, I113, L114, A116, F127, I129, I147, C160, L163, V165, F184, V186, V192, Y195, L199, L208,
			L212, L218, I220, I222, A224, V228, Y232, V233, I236, L237, L241, F257, A269, L272, M276, F283, A285, A286, F287,
			M295, I296, L297, V304, V310, A311, V312, I313, I320, F323, F331, A332, M335, L341, A345, F362, L371, L373, C374,
			I386, L392, W393, A394, V395, L396, A397, W398, L399, I401, V409, I412, L413, F424, V433, A438, M441, L445,
			M449, F454, V468, L490, L492, F494, I500, V501, F502, I514, L516, Y517, I518, I528, L536, L539, A543, L549
481	Receptor-type tyrosine-	P36888	L143, L182, C231, A233, L268, I270, C272, A274, C330, F369, F418, A420, A443
	protein kinase FLT3 (EC
	2.7.10.1)
482	Bone morphogenetic protein	P36894	A428, I437, V450, V473, V496, L499, W504, A509, L515, L521, M524, V530
	receptor type-1A
483	Activin receptor type-1B	P36896	A401, Y410, H423, V446, M469, M472, W477, A482, L488, L494, L497, V503
	(EC 2.7.11.30)
484	TGF-beta receptor type-1	P36897	A399, F408, H421, V444, M467, I470, W475, A480, L486, L492, L495, I501
485	Guanine nucleotide-binding	P36915	I363, C365, V366, F368, L376, I377, L380
	protein-like 1
486	Tumor necrosis factor	P36941	C80
	receptor superfamily
	member 3
487	Pigment epithelium-derived	P36955	L54, A55, A57, F61, L65, Y66, V78, L80, V85, A86, A88, L89, L92, A96, I104, L108, Y122, L125, V129, V143, F144,
	factor		F154, L158, V184, M188, I205, L207, L208, V210, A211, F213, F231, M244, C261, A264, I274, I275, L293, I298, A310,
			V314, L317, V325, L329, L337, I346, L353, H358, A360, F362, Y388, L390, F394, I395, F396, V397, L398, L407,
			F408, I409, I412
488	Serine/threonine-protein	P37023	L405, V418, V441, L464, M467, W472, L483, L489, I492
	kinase receptor R3
489	TGF-beta receptor type-2	P37173	C51, C61, C84, V85, A86, V87, V100, C121, F133, C136, C138, I147
490	Electron transfer	P38117	V6, L7, V8, V13, A45, V46, A49, V61, I62, A63, V64, I75, A78, L79, A83, I87, H88, V89, V91, A105, V107, L108, L111,
	flavoprotein subunit beta		A112, L119, V120, A139, A150, L160, V162, A179, V180, V181, A183, A201
491	40S ribosomal protein S19	P39019	V6, F14, L18, A19, F53, A57, A58, A61, L64, V99, A100, V103, L104, V113, L131, A135
492	60S ribosomal protein L3	P39023	A45, F46, L47, I56, V76, I78, V79, M84, V87, I89, V105, C114, M153, I160, V162, A164, H165, M168, A178, V185,
			L194, A197, V207, I217, V219, I220, V222, V231, I284, I314, F320, F330, V331, M332, L333, L345, L347, I368, M382
493	Collagen alpha-1	P39060	M1454, V1461, I1467, V1469, L1581, L1583, V1584, A1585, L1586, A1600, C1604, A1608, A1619, F1620, L1621,
			L1628, I1631, V1632, I1642, W1654, L1657, V1679, W1685, V1690, W1691, H1692, C1706, W1709, A1720, L1723,
			L1728, L1729, C1736, I1741, V1742, L1743, C1744, I1745
494	Glial cell line-derived	P39905	V127, F190, A205
	neurotrophic factor
495	Thrombopoietin	P40225	L33, L56, V60, L62, A81, I84, L85, V88, L91, V95, A98, L111, L114, V118, I148, F149, F152, L156
496	Thrombopoietin receptor	P40238	L30, L31, C40, F41, F45, L48, C50, F51, W52, L65, Y67, C77, C93, F95, V101, L103, F104, L107, L109, V111, V127,
			V130, L132, A134, I139, A141, L150, I152, W154, F164, L165, Y167, L234, L246, Y252, W269, W272, L396, I401,
			L406, L408, W410, A418, Y423, Y427, W435, V437, L438, A444, L449, L451, Y457, A463, Y470, W474, W477
497	B-cell antigen receptor	P40259	V61, M63, C65, W76, A105, L107, I109, Y120, C122
	complex-associated protein
	beta chain
498	Alcohol dehydrogenase class	P40394	A24, A25, V26, L27, F34, I39, V41, V49, I51, I53, A55, I58, H64, V65, V76, I77, V78, H80, A82, V96, V102, I103, L105,
	4 mu/sigma chain (EC		L107, C116, C124, L135, A136, F142, C144, V149, H151, F152, F158, V163, V164, V169, A170, I172, A176, V181,
	1.1.1.1)		C182, L183, I184, F188, Y192, A194, A195, C207, V208, V209, F210, L212, L217, V219, I220, C223, I231, I232, I234,
			A244, I253, V265, L266, V274, F278, A290, L291, C294, V302, V303, F331, V340, L343, V344, L354, L357, F364, I367,
			F371, V383, L384
499	Leptin	P41159	I35, I38, L72, M75, L79, Y82, I85, I97, L101, L104, L108, A112, A146, L150, L154, M157
500	Extracellular calcium-	P41180	A46, V115, I135, F320, A321
	sensing receptor
501	Aquaporin-2	P41181	I112, L116, A127, C181, M183, A186, A190, A192
502	Glycine--tRNA ligase (EC	P41250	M124, L128, F133, A137, L157, I161, W165, F169, L189, V203, A214, L218, L222, M239, L254, L280, A301, I304, F305,
	3.6.1.17)		F308, A323, A324, A349, I351, F354, V368, A369, L373, A380, A387, L392, A395, I401, V405, L406, F409, I410, I413,
			Y416, L417, V420, L427, F429, W445, A447, I458, V459, C461, C466, L469, L480, A482, A503, I504, V515, I521,
			I542, L551, V574, I575, F579, L581, I584, M585, Y586, V588, F589, F593, F605, F607, V611, A612, C616, V618, L619,
			F627, L634, L638, V643, Y658, V666, A667, F668, V670, I672, A684, L686, I695, A697, L702, I705, V706, V719
503	T-lymphocyte activation	P42081	A36, L38, C40, L53, V54, V55, L95, L97, L100, C110, I111, I112
	antigen CD86
504	Glutamate receptor 1	P42261	I25, I27, L30, F31, A41, F42, L46, L55, M70, F74, V82, A84, I85, F86, V94, L97, C101, V106, F108, I109, F113, F121,
			V122, L123, L125, L129, A132, L133, I136, I137, F145, V146, Y147, V161, A165, I177, L192, V200, V201, V202, C204,
			L209, L213, I216, I217, Y228, I229, L230, A231, L233, F235, F243, A248, V250, F253, V256, I266, W270, V281, A291,
			L292, V297, V299, M300, A303, F304, L307, A320, I337, A340, L341, L349, V353, L366, V368, Y409, I410, V411,
			Y419, V420, L422, F429, Y435, Y438, C439, V440, L442, A443, A444, I446, A447, L456, A466, M477, V478, L481,
			A486, V488, A489, V490, A491, L493, I495, I503, F509, L512, I514, I516, M517, I518, I647, L653, A654, Y661, F672,
			F673, M684, Y687, M688, V695, V697, M704, V707, Y714, A715, Y716, L717, L718, Y725, Y746, I748, A749, V760,
			A763, V764, L765, L767, L772, L773, L776, W780, W781
505	Glutamate receptor 3	P42263	I34, I36, L39, F40, A50, F51, V55, F69, L71, V86, F90, V98, A100, I101, F102, M110, L113, C117, F124, V125, F129,
			F137, V138, I139, M141, L145, A148, I149, L152, L153, F161, V162, Y163, I177, A181, V193, M209, Y217, L218, I219,
			C221, I226, L230, V233, V234, Y245, M246, L247, A248, L250, F252, V260, A265, I267, F270, V273, V280, F283,
			W287, A298, A301, L303, A308, L309, A313, I314, V316, I317, A320, F321, L324, A337, I354, A357, L358, M366, I370,
			I383, V385, I425, V426, V427, Y435, V436, Y438, L445, Y451, Y454, C455, V456, L458, A459, Y460, I462, A463, L472,
			A482, M493, V494, L497, A502, I504, A505, V506, A507, L509, I511, I519, F525, L528, I530, I532, M533, I534, I665,
			L671, Y679, F690, F691, M702, Y705, M706, V713, V722, V725, F732, A733, F734, L735, L736, Y743, Y764, V766,
			A767, V778, A781, V782, L783, L785, L790, L791, L794, W798, W799
506	Phosphatidylinositol 4,5-	P42336	M16, L21, V22, C24, L25, L26, M30, I31, V32, C36, L42, I45, L49, A53, L61, I69, F70, V71, V73, F82, F83, L89, L92, L94,
	bisphosphate 3-kinase		F95, L99, V101, I117, A120, I121, V125, F128, V136, F139, I143, L144, C147, A150, A163, Y165, I181, I190, V192,
	catalytic subunit alpha		V193, I194, L209, I211, V220, I221, A222, A224, L239, L244, L252, V254, C255, C257, Y260, F261, L262, L267, Y270,
	isoform		Y272, I273, C276, L285, L293, L327, I330, L334, I336, I338, A341, I354, Y355, V356, I360, Y361, V376, L387, Y389,
			I393, L396, A399, A400, L402, C403, L404, I406, C407, V409, C420, L422, A423, L429, F430, L443, L445, L452, L456,
			V461, L473, L475, V484, I492, A496, L531, I534, L540, L551, C558, V559, I564, L565, L568, L569, L570, V580,
			A581, M583, V587, I593, A598, M599, L601, L602, V611, F614, A615, V616, C618, L619, L628, Y631, L632, L635,
			V636, V638, L639, L648, L649, V650, L653, L654, A657, L658, I663, H665, F667, F668, W669, L671, V680, F684, L686,
			L687, L688, Y691, C692, A694, C695, Y698, L699, L702, V706, A708, M709, L712, L715, I718, L719, L735, M739,
			F744, A747, L748, F751, L755, L761, L764, C769, I771, L779, L781, W783, I788, M789, L792, L793, I799, F801, L807,
			L812, L814, I816, I817, M820, W824, L831, M833, L834, L839, L847, I857, I860, L877, H878, L881, A893, L896, F897,
			C901, A902, Y904, C905, V906, A907, F909, I910, L911, I913, I921, M922, V923, L929, F930, H931, F934, F937, L938,
			F954, F960, L961, I962, V963, I964, C971, F977, F980, C984, A987, Y988, A990, I991, A995, F998, I999, L1001,
			F1002, M1004, M1005, M1010, L1013, F1016, I1019, Y1021, I1022, L1026, A1035, F1039, M1043, W1051
507	Protein AF-9	P42568	V7, L11, L13, H15, A17, V34, V36, F47, V48, V51, V52, F53, Y71, I82, L83, I85, V87, F89, Y102, L104, F131, L135,
			I522, I526, I530, V555, L558
508	Dipeptidyl aminopeptidase-	P42658	V131, V133, F156, V165, A201, L202, V220, L242, A245, I255, F256, I257, I262, W291, L292, Y293, A303, A314, I318,
	like protein 6		L328, L356, H357, V358, L361, L368, M370, Y382, I383, V394, A395, V396, W398, I407, C411, A413, W429, F447,
			H462, I463, V487, I500, F502, L514, A517, V520, L528, C536, F550, C554, V564, H565, L606, M608, I610, L624,
			L625, M649, V650, A655, V656, V657, L672, V676, M689, V692, M695, V706, A707, V708, Y716, L717, I721, F733,
			C735, A738, I742, F745, A749, A751, L757, Y767, V772, V776, L785, I786, I787, H788, I795, F797, H799, L807,
			I839, F843
509	Leukemia inhibitory factor	P42702	V81, I112, L134, L153, V170, V176, L211, H216, V218, I220, V254, F269, C270, C271, V277, A280, I299, V314, F316,
	receptor		I327, A329, I349, C351, W353, L371, F397, Y406, F408, L410, A412, I427, V431, L451, F459, C466, I468, V494, I509
510	Wiskott-Aldrich syndrome	P42768	F258, L267, L270, F271, L281, I290, F293, I294, V303, L326, I438, L470
	protein
511	Growth/differentiation factor	P43026	C400, F409, C433, A447, I476, C498, C500
	5
512	Platelet-activating factor	P43034	V111, M123, V124, A126, I132, L146, V153, L165, A166, C168, I174, L176, W177, M188, V195, V198, I207, V208,
	acetylhydrolase IB subunit		A210, I216, W219, V237, V240, I249, A250, C252, V258, V260, L272, V279, C281, L311, L312, I320, L334, V341,
	alpha		I353, L354, C356, A357, L362, W365, Y367, V383, V396, V404, V406
513	Cathepsin K (EC 3.4.22.38)	P43235	I44, L48, Y126, V130, C136, C139, W140, A141, A147, L148, L159, L162, L167, V168, V171, A185, F186, V189, I195,
			Y201, M211, A219, C221, I227, L235, A238, V239, V242, V245, V247, A248, I249, A251, F256, F258, Y264, Y265,
			L274, H276, A277, V278, L279, A280, V281, Y283, W292, I294, W302, I308, M310, A311, A317, C318, I320, A321,
			L323, A324
514	Hemagglutinin [Cleaved	P43258	A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94,
	into: Hemagglutinin HA1		C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
	chain; Hemagglutinin HA2		V182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
	chain]/strain A/Duck/Hong		C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
	Kong/64/1976 H3		I478, I481, A495
515	Hemagglutinin [Cleaved	P43259	A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, Y94,
	into: Hemagglutinin HA1		C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
	chain; Hemagglutinin HA2		I182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
	chain]/strain A/Duck/Hong		C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
	Kong/231/1977 H3		I478, I481, A495
516	Hemagglutinin [Cleaved	P43260	A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94,
	into: Hemagglutinin HA1		C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
	chain; Hemagglutinin HA2		V182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
	chain]/strain A/Goose/Hong		C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
	Kong/10/1976 H3		I478, I481, A495
517	Neuronal acetylcholine	P43681	A141, H142, A155, V165, I189, L191
	receptor subunit alpha-4
518	2-C-methyl-D-erythritol 2,4-	P44815	H11, L19, I20, I21, V26, F32, I33, A34, V40, A41, L42, H43, A44, L45, A48, I49, L50, A52, A53, I58, L77, L78, A81, V85,
	cyclodiphosphate synthase/		I92, V95, I97, I99, M106, I110, M113, A115, I117, A118, L121, I125, V128, A132, I147, A148, C149, A151, A153, L154,
	strain ATCC 51907/DSM		L155, I156
	11121/KW20/Rd
519	Aspartoacylase (EC	P45381	I11, V14, A15, I16, F17, V31, I41, A57, L69, F73, A93, I96, F100, I111, I112, F113, M122, C124, L126, L128, L136, I137,
	3.5.1.15)		M139, F140, I143, V154, L156, I170, V175, I177, V179, M195, M198, A202, L203, F205, I206, F209, I220, V222, I225,
			A241, L247, V281, V283, A294, F295, A296, I308
520	Short/branched chain	P45954	A72, I76, M83, V93, L97, M103, I105, V107, V122, L123, V124, I125, L128, A129, A133, V135, A136, C139, I146, L149,
	specific acyl-CoA		I150, L163, L166, C175, A181, A192, L201, I208, A211, A214, L216, F217, L218, V219, M220, A221, I232, F235,
	dehydrogenase,		L236, V237, L244, C261, L263, V268, V270, L276, A286, I295, I297, A298, A299, M301, L302, L304, A305, C308, I316,
	mitochondrial		L332, L343, A346, A353, A354, A367, A370, A374, A378, C385, V400, A407
521	Chemokine XC receptor 1	P46094	A26, W27, V28, F29, A30, L32, A33, V36, L37, C39, L40, F42, L46, V47
522	Large proline-rich protein	P46379	V19, V21, A35, V39, F42, I46, V50, L59, L72, V77, I82, L84
	BAG6
523	Vesicle-fusing ATPase (EC	P46459	V23, I74, F121, V514, A551, A554, L623, L627, L677
	3.6.4.6)
524	Neurogenic locus notch	P46531	C423, C438, C449, C456, C461, C487, C525, C942, C1056, C1180, C1454, C1467, C1496, C1509, L1515, C1536, L1574,
	homolog protein 1		V1575, V1576, V1577, V1578, L1585, F1592, L1596, L1600, I1616, V1676, L1678, I1680, C1685, A1696, V1699,
			A1700, L1703, A1705
525	40S ribosomal protein S10	P46783	L15, F16, M21, A23, V45, A48, M49, L79
526	E3 ubiquitin-protein ligase	P46934	G451, Y463, L499, L529, L563, Y785, F858, F948, M964, I979, L988, A990, L992, F996, A1008, W1011, F1012, I1015,
	NEDD4 (EC 6.3.2.—)		M1019, F1027, F1054, F1056, I1057, V1060, A1061, M1063, A1064, V1065, L1071, F1075, Y1080, M1083, L1084,
			M1093, L1104, F1119, I1121, V1143, Y1151, V1155, M1168, F1171, F1175, L1178, I1179, I1184, F1187, L1192,
			M1196, C1197, W1207, V1223, I1224, F1227, W1228, A1230, V1231, L1242, L1243, V1246, F1257, L1260, F1269,
			V1271, L1290, L1292, L1301, L1305, I1309
527	3-hydroxyanthranilate 3,4-	P46952	L32, I48, L64, V66, L85, V89, V100, V104, L116, Y119, L194, V211, A213, L230, L248, L255, A272
	dioxygenase (EC 1.13.11.6)
528	F-actin-capping protein	P47756	A9, L25, L39, L60, V119, Y120, A129, V131, L133, I134, H152, V154, V156, A165, Y167, L169, V173, M174, V217,
	subunit beta		M220, I224
529	Tumor necrosis factor ligand	P48023	A147, L149, L160, L181, I183, Y189, V191, V195, F197, L207, H209, V211, L257, V259, F276, L278
	superfamily member 6
530	Stromal cell-derived factor 1	P48061	I59, A61, I72, I79
531	Glycine receptor subunit	P48167	V80, V82, V84, I86, Y101, V103, I105, W111, L116, L128, L163, I165, V171, I179, L181, C183, L187, F190, C197,
	beta		M199, L201, L211, F213, C255, V256, V258, F260, L262, V273, I280, V281, F288, L309, A328, L329, L333, C336,
			V350, M353, A370, A470
532	Transcription factor SOX-9	P48436	V114, A116, L123, L135, L139, F154
533	G protein-activated inward	P48544	W108, A139, L168, A206, V207, I208, L217, V221, I234, A236, L238, L252, I257, L274, M289, V301, V303, L305,
	rectifier potassium channel 4		A318, Y322, F351, A368
534	T-complex protein 1 subunit	P48643	A33, A41, M48, A75, I77, I87, M91, V109, V110, A113, L116, L123, I133, A140, A144, A169, L173, A186, A189, A192,
	epsilon		V204, I229, M239, A246, I248, A249, I250, L251, F255, I289, I292, A297, L299, A300, I301, C302, A310, L314, L319,
			A321, I330, I333, A356, V359, V373, I374, I385, F386, I387, L402, A405, V408, I409, L412, V419, A424, A425, I427,
			A430, V433, A437, F451, A452, A454, A461, V477, L510, A520, I527
535	Protein ERGIC-53	P49257	V64, I80, V82, A83, V93, W94, A99, V106, V108, F110, V112, A120, L123, A124, W126, Y127, A128, V137, F138, V147,
			F150, F151, I165, I167, I168, I174, F194, V201, A203, I205, L212, V214, I216, A231, F244, I246, A248, H257,
			V259, F262, F265
536	Alpha-aminoadipic	P49419	L33, L42, Y55, C70, I77, A78, V80, V92, A95, A98, W102, V114, I117, L121, I125, L128, L131, V132, L134, M136,
	semialdehyde		V147, Y150, V151, I153, C154, A157, I179, L187, V188, I190, I191, V198, A199, V200, Y201, A206, I207, A208, M209,
	dehydrogenase		I210, C211, V214, C215, L216, W217, L225, I226, V228, A229, V230, I234, L238, A246, I247, L250, C252, I257, A260,
			M261, A262, V267, L269, L270, V286, L294, A302, I303, I304, A305, V314, A318, A321, A326, A333, L336, F337,
			I338, V346, L350, Y369, L372, F381, A384, V385, A388, Y408, V409, I413, V414, A424, A430, I432, L433, V435, F436,
			F438, V444, L455, I459, F460, W470, Y516
537	Alanine--tRNA ligase,	P49588	I10, F14, F17, F18, A42, A44, M46, F49, A69, A70, C75, I76, F97, L101, W104, C115, M117, A118, L121, L122, Y134,
	cytoplasmic (EC 6.1.1.7)		V135, F138, C152, W156, C184, C187, I190, H191, A200, L212, W215, L217, F219, I220, I238, M242, L244, L247,
			V248, Y258, F263, Y266, I270, A288, A294, Y295, V297, L298, A299, H301, A302, I305, V307, A308, L309, L324,
			I327, L328, A331, V332, A335, L339, F346, A347, L349, V350, V353, L357, F361, I375
538	Prolactin-releasing peptide	P49683	A44
	receptor
539	Cartilage oligomeric matrix	P49747	C287, C292, C328, C351, C387, C410, C448, C484, C504, F531, L539, L570, A571, V572, F577, F582, H587, V588,
	protein		Y596, A597, I600, F601, F609, Y610, V611, M613, A629, A631, I635, L637, A639, V640, L650, A653, L654, W655,
			V664, W684, L686, H688, Y694, I695, V697, M717, L722, V724, F725, C726, I732, W734, A735, L737, C741
540	Presenilin-1	P49768	V89, C92, M93, V96, A136, I213, L226, A231, A234, L235, A246, V261, A285, V379, L381, F386, Y389, V391, L392,
			V393, A396, C410, I414, I439, M457
541	Bis(5′-adenosyl)-	P49789	F23, A24, V36, L37, V38, C39, L58, V65, V69, H94, V99, A139, L142
	triphosphatase (EC 3.6.1.29)
542	Presenilin-2	P49810	V95, C98, M99, V102, I219, L232, A237, A240, L241, A252, V267, A291, L362, F367, Y370, L373, V374, A377, C391,
			I395, I420
543	Glycine amidinotransferase,	P50440	V66, W72, V78, I79, V80, A83, A86, C87, V88, V95, A97, Y107, F115, A123, I127, M130, C131, L134, L163, Y164,
	mitochondrial (EC 2.1.4.1)		A166, M167, I171, L172, I173, V174, I179, I180, A182, M184, A185, W186, A195, Y196, I200, Y203, M218, L222, I229,
			V245, C252, F253, A255, A256, I259, A261, I265, F266, A267, V272, M281, I294, I304, F308, I310, I311, V316, L317,
			F330, M353, M360, V362, L363, M364, L365, V370, M371, V372, I379, F383, V393, I395, A398, L401, F405, H406,
			W408, C410, V412
544	Serpin H1	P50454	L102, V107, A109, A203, V226, M271, L324
545	Dynamin-2 (EC 3.6.5.5)	P50570	V13, L16, F20, L29, I34, A35, V36, V37, A42, V47, L48, F51, V52, F56, L57, L69, L71, L73, I74, A81, F83, F91, V97, I120,
			L122, V124, V129, L132, L134, I135, L137, I140, I152, I156, I160, I164, I171, L172, A173, V174, A177, A186, A190,
			V193, I201, V203, I204, L207, A216, I232, V234, F259, Y265, A269, L277, L281, L285, I289, L293, L300, L304, L305,
			F336, F340, F370, L374, L384, I388, I392, A408, F409, V413, V417, C424, C427, V428, V431, L435, V439, C442, L452,
			I459, V460, I475, I479, L526, I528, Y541, F543, L545, L550, W552, I572, F586, A587, I588, F589, I603, L605, C607,
			V613, W616, F620, V625, V664, M675, I679, M683, I691, L695, L699, L729, A732
546	Palmitoyl-protein	P50897	V36, V88, V95, L99, L105, F120, A123, V124, H143, F147, C160, I163, V181, A183, Y195, F201, L202, A203, I205,
	thioesterase 1		Y215, L222, V228, F230, L258, L263, L269, L283
547	Sodium/potassium-	P50993	H42, L44, L49, A66, L102, A106, C109, V133, V138, V169, I170, V183, V184, L188, V189, A199, L201, I203, C209,
	transporting ATPase subunit		V211, C241, F242, C247, A252, I255, V256, A272, I286, A297, A318, I320, F321, I325, L334, V340, A346, C354, V362,
	alpha-2		C372, L379, M384, A387, M389, W416, A418, L419, I422, A423, L425, C426, A429, V440, A453, L454, V465, L488,
			I490, H491, H500, V501, L502, V503, M504, I511, L519, Y539, L542, F552, C553, L557, L580, C581, F582, V583,
			L585, M588, A594, V596, A599, V600, C603, A606, I608, I611, M612, A621, A623, A625, I630, I631, A642, A643, A657,
			A659, I685, V686, F687, A688, I698, V699, C702, V709, V716, A721, L722, A725, I727, I729, A730, M731, I746,
			L747, F752, V759, L764, I765, Y775, L777, F790, L799, I807, A816, L819, L841, V842, L846, A850, I854, Y866, I869,
			L870, F875, L880, W887, C915, A918, F919, F920, A921, I923, V924, V925, V926, L931, I933, C934, L951, L955, A962,
			L975, M977, A988, I995, L1006, Y1020
548	Ras-related protein Rab-7a	P51149	L9, V11, I12, I13, L14, V19, L24, M25, Y28, V52, V57, M59, I61, A65, Y78, C83, C84, V85, L86, V87, F88, V90, L99,
			F106, F120, V121, V122, L123, V134, A139, C143, A156, V162, A165, F166, I169, A170, A173
549	Ras-related protein Rab-27A	P51159	L13, Y27, L96
550	Transcription activator	P51532	M1462, I1465, V1466, V1469, I1501, F1507, I1510, I1514, L1525, V1529, C1533, A1536, L1553, F1557, V1560
	BRG1 (EC 3.6.4.—)
551	Galactokinase (EC 2.7.1.6)	P51570	A16, V32, A34, L53, V64, V73, A107, V110, V113, A120, A127, V128, V130, V133, L139, A143, V147, A148, F152,
			L153, A167, C170, A173, V211, I222, C243, V246, L255, L263, A266, A278, H280, V281, A291, A292, A294, Y318,
			C322, L328, V329, A332, C351, L356
552	Methyl-CpG-binding protein	P51608	L124, F132, L138, F142
	2
553	Fatty aldehyde	P51648	V8, L27, A29, L30, M33, V34, I41, I45, L49, V56, V61, V64, I68, M71, L75, V104, V105, L106, I107, F115, L117, I119,
	dehydrogenase (EC 1.2.1.3)		L122, I123, A125, I126, A127, A128, A131, V132, I133, I134, L150, L151, L159, Y160, L173, F182, V193, A196, A197,
			C214, I216, V225, C226, I229, Y234, C237, I247, L248, C249, I257, I261, I282, F288, I291, L294, I313, A314, V317,
			L318, V327, M328, I332, I336, L337, I339, A348, L359, A360, L361, Y362, V363, F364, M374, V388, Y410, F419
554	C-C chemokine receptor	P51681	Y187
	type 5
555	N-sulphoglucosamine	P51688	A25, L26, L27, L28, L29, A30, L58, F60, A63, F64, V67, A75, L77, L81, M88, L107, L111, I120, I121, V126, V131, Y132,
	sulphohydrolase (EC		I152, I155, V159, F162, F171, F172, L173, Y174, V175, A176, F177, F193, C194, I207, A232, L236, Y240, V250,
	3.10.1.1)		V253, L257, L267, I276, F278, L285, V296, A311, V313, L318, I322, L323, L348, A351, M376, V379, L386, F408, L411,
			L438, L464
556	Arylsulfatase E	P51690	M61, L163, L292
557	Amyloid-like protein 1	P51693	F395, A398, V409, L413, L467, L477
558	Potassium voltage-gated	P51787	W379, W392, I394, I396
	channel subfamily KQT
	member 1
559	Chloride channel protein	P51800	V547, L558, A559, V567, Y579, V582, V594, L599, L618, L635, L641, A644, F648, V658, V668, M673, A676
	ClC-Ka
560	Ribosomal protein S6 kinase	P51812	V85, A93, A98, I121, F129, V131, I146, L155, F165, V170, Y173, L174, A175, L177, A178, A180, L181, L184, L187,
	alpha-3		I189, I190, Y191, L194, I199, L201, H206, I207, L209, F212, A225, A236, H245, A249, W251, W252, F254, V256,
			L257, M258, M261, F268, I280, L281, L285, F290, A295, L298, L299, L302, A308, V318, I321, F327, L335, A347, C439,
			V450, I453, I464, I466, L467, Y470, I476, V491, V492, L501, L502, I505, L506, A516, L520, I523, V527, L530, V535,
			V536, H537, L540, I545, I557, I559, F562, M576, I601, L604, V606, L607, L608, Y609, M611, L612, F618, A619, I629,
			W645, A652, L655, V656, M659, L660, A670, V673, W678, V699, A702
561	Cytoplasmic tyrosine-protein	P51813	V442, V444, A461, L467, L472, V478, C479, V488, L497, L513, M516, C517, V520, C521, M524, L527, L537, A538,
	kinase BMX (EC 2.7.10.2)		A539, C542, V544, V550, V552, V561, A580, V595, W596, F598, I600, L601, M602, V605, F606, V621, A637, M645,
			C648, F659, I666
562	Spermine synthase	P52788	L9, F11, L13, L26, F30, A36, L48, A49, Y51, A59, L61, I63, V69, L71, L73, I89, V93, Y134, I150, I152, I161, I163, I181,
			V194, L195, I196, L197, I204, L205, I208, V216, M218, V219, C229, V259, L260, Y263, V273, I274, I298, L299,
			M303, V305, L306, F313, V348, Y358, V360
563	Ephrin-A5	P52803	V34, W36, I50, V52, L58, V60, Y77, L79, C102, F118, F130, Y138, I139, L154, V156, V158
564	Biliverdin reductase A	P53004	V11, V12, V13, V14, V16, F42, A62, V70, A71, Y72, I73, H80, I84, F87, L88, V94, L95, V96, M100, A107, L110, H122,
			L136, L150, A166, F167, I170, L173, W175, L176, M201, V203, L205, L213, W215, F231, F258, I278, C281, L282,
			A285, I288
565	Collagen alpha-4	P53420	L1468, L1494, Y1495, L1507, Y1541, W1542, L1543, V1563, C1566, A1567, V1568, C1569, A1571, F1601, H1604,
			C1622, F1631, L1632, C1634, C1641, C1683, V1685, C1686, V1687
566	Dipeptidyl peptidase 1 (EC	P53634	C30, L35, W39, F41, V66, L68, A74, F84, I86, I87, F92, I94, F102, A103, F105, H127, W134, C136, F137, Y259, A262,
	3.4.14.1)		M264, M266, A269, I271, L283, V288, Y294, Y304, L305, I306, A307, A311, L316, V317, Y347, Y352, M360, L364,
			M370, A371, V372, F374, F380, V407, L408, L409, V410, W423, V425, F439, I441, I450, A454, A456, A457
567	DNA polymerase subunit	P54098	F139, A143, A153, L157, W175, Y178, A194, L195, V196, F197, C202, A212, V213, A214, I215, A219, W220, C224,
	gamma-1 (EC 2.7.7.7)		A242, L244, A253, L265, V266, V267, A276, I278, Y282, M289, M297, H298, A300, I301, L304, V359, M393, A397,
			V400, V406, F407, V422, A425, M427, L428, V432, Y434, L435, V437, W441, A448, L463, A467, F610, I798, W801,
			A804, I808, A839, L841, A847, V870, L874, A876, V878, A880, V887, A889, V891, I898, A899, A900, L902, A908,
			A915, A936, A982, A1045, L1061, C1077, I1079, A1082, W1099, V1100, V1101, A1105, V1106, Y1108, H1110, L1111,
			L1113, V1114, A1115, M1116, L1119, C1130, Y1139, L1140, V1141, A1149, A1150, A1152, L1153, C1162, M1163,
			A1165, L1168, A1178, A1182, V1183, C1197, A1217, L1218
568	Tyrosine--tRNA ligase,	P54577	I14, L27, L36, I38, Y39, F53, M56, I59, F62, C67, V69, I71, F73, H77, A78, A85, V94, Y96, Y97, V100, I101, M104, L105,
	cytoplasmic (EC 6.1.1.1)		Y129, L136, A171, L172, A181, F183, I191, F192, A195, L199, V208, H209, L210, M211, I232, L234, V241, L245,
			V260, L261, I264, V267, I277, Y289, L295, F299, V304, L309, V313, L317, L321, I324, L336, A339, A340, I370, V372,
			I375, I392, V394, V402, V403, L406, L415, V420, V421, V422, L423, L440, L441, C442, A443, L455, V469, L491,
			F495, I497, A503, F510, I517, C519, I527
569	Ephrin type-A receptor 4	P54764	I67, V72, L84, I89, A94, V97, Y98, I99, I101, F103, L105, V114, F122, L124, I148, V157, V173, F181, Y182, L183,
	(EC 2.7.10.1)		A184, F185, A190, I192, A193, L194, V195, V197, V199, C204, A212, F214, M245, C247, C273, C276, C325, V344, L346,
			V398, I400, Y409, F411, I413, A415, V419, V434, A440, V447, V457, L459, V476, I500, Y509, F511, V513, A515, A519
570	Alpha-N-	P54802	V32, L35, V36, L67, V75, V77, V83, A84, A85, A86, L89, Y92, C99, Y132, I154, M157, A158, I162, L164, A165, A167,
	acetylglucosaminidase (EC		I174, V178, A181, I189, A197, F198, A200, L230, M233, F236, V241, L242, F245, V253, F271, L281, I291, F295, L296,
	3.2.1.50)		Y309, L327, V334, M338, A345, F354, A368, L378, L379, V380, V390, F397, F402, I403, W404, C405, M406, L407,
			L420, A430, A444, V453, V454, L457, V475, F478, A479, A490, A493, V501, L517, V518, V536, F537, A539, W540,
			L550, F556, L560, L561, L563, A567, V568, L571, V572, Y575, L584, L591, V597, L598, A599, L602, L603, L606, V609,
			L610, F616, L618, L622, A625, A635, Y638, L646, L648, W649, A659, L666, V667, Y670, Y671, W675, F678, L679,
			L682, V701, V709, V724, A727, Y734
571	Galactocerebrosidase	P54803	L83, L95, L98, F437, V576, V607
572	Adenylate kinase 2,	P54819	I16, A18, V19, L20, L21, A26, A32, L35, F39, V41, L64, V80, L82, I83, F96, L97, L98, F101, A108, L111, M115, L122,
	mitochondrial		V125, I126, F128, L134, L135, I139, L143, H145, A182, L183, L187, L197, Y200, Y201, I210, A212, I223, F227
573	Allograft inflammatory	P55008	L24, L47, F50, Y54, F57, L59, I65, L70, M73, L74, L86, I90, F101, Y103, F106, L107, A116, L118
	factor 1
574	Transitional endoplasmic	P55072	L26, V28, V38, V39, L41, M46, V57, L59, A67, V68, C69, V71, I82, M84, V88, L92, V94, I100, I102, C105, I114, V116,
	reticulum ATPase		I119, Y134, L135, F139, L153, V154, V161, F163, V165, V166, C174, V176, A177, V181, C184, A214, I216, V220, I241,
			L242, L243, Y244, I254, A255, A257, V258, A259, I269, I274, L286, A289, F290, A293, A299, I300, I301, F302,
			I303, L306, I309, A310, I324, V325, L328, L329, M332, L335, V341, I342, V343, M344, A345, A346, I353, L357, F363,
			V367, I369, L381, V399, A400, H406, V407, L411, L414, C415, A418, A419, A422, A439, V447, F452, A455, L489,
			V493, V514, L515, F516, L527, A528, A530, I531, A532, F539, I540, I542, L547, L548, V559, F563, A566, C572, V573,
			L574, F575, F576, I582, V600, I601, M608, I619, I620, A622, L639, I645, L657, A676, L687, I690, A694, I731, H735,
			A739, V747, I752, L762
575	Fibroblast growth factor 8	P55075	L74, V83, V85, A93, A95, A102, I126, C127, M128, I135, C145, F147, A158, M169, A170, F171, V190, F192
576	Laminin subunit beta-2	P55268	C519
577	Cadherin-8	P55286	V70, F109, I118, A120, L124, L134, A138, I154, I155, V157, V176, V189, A223, I224, I225, V242, I244, A246, L262,
			V264, A300, F324, L353, V355, A357, V378, I380
578	Cadherin-15	P55291	L138
579	FAD-linked sulfhydryl	P55789	A114, A115, A146, L153, F166, L170, C171
	oxidase ALR (EC 1.8.3.2)
580	Eukaryotic translation	P56537	F7, I13, A17, Y23, C24, L25, V26, A27, F34, F38, V49, I53, I59, V64, L70, L71, V72, I84, V97, L104, V107, A115, L116,
	initiation factor 6		V117, L129, L133, V142, V148, V153, L160, V161, L173, L177, V179, V186, I193, A194, M197, V198, C203, A204,
			F205, C206, V218, F222
581	Ubiquitin-associated and	P57075	L28, A38, A41, L42, A53, L57
	SH3 domain-containing
	protein A
582	Ras-related protein Rab-25	P57735	V15, V16, L17, I18, V23, L28, L29, V47, A60, V61, A63, I65, A69, Y74, A76, Y81, Y82, A85, A88, L89, L90, V91, F92,
			L94, V103, L110, V120, M121, L122, V123, V135, A140, A144, A156, L157, V162, A165, F166, V169, L170, I173
583	Anthrax toxin receptor 2	P58335	F43, L45, Y46, F47, V48, L49, V55, I62, V66, L69, A70, L80, F82, I83, V84, F85, I91, I102, L109, I120, L124, A127, I131,
			I142, I143, I144, A145, L146, A159, A163, V173, Y174, C175, V176, V178, L186, I189, L206, I209, I213
584	Spike glycoprotein/SARS-	P59594	V328, V337, I345, A350, L374, V382, A384, F387, V388, V389, I397, A398, I405, A406, Y410, L412, C419, V420,
	CoV (Severe acute		L421, A422, F483, V496, V497, V498, L499, V510
	respiratory syndrome
	coronavirus)
585	CD81 antigen	P60033	Y127, L131, A134, V147, H151, C156, V169, L174, C190, I194
586	Phosphatidylinositol 3,4,5-	P60484	L25, I33, A34, M35, A39, I50, V53, F56, L57, I67, Y68, L70, I101, F104, C105, L108, A120, A121, I122, H123, A126,
	trisphosphate 3-phosphatase		V133, M134, I135, C136, A137, L139, A148, A151, Y155, Y174, V175, Y180, L193, F195, M198, F200, F206, V217,
	and dual-specificity protein		F241, V249, V255, F257, H259, M270, F271, F273, V275, F279, V317, L325, A328, F341, V343
	phosphatase PTEN (EC
	3.1.3.16)
587	Interleukin-2	P60568	L34, L37, L38, L41, I44, L45, I48, M59, F62, F64, M66, L73, H75, L76, C78, L79, L83, L86, V89, L90, F98, L105, I106,
			I109, I112, V113, F123, I134, V135, F137, L138, W141, F144, C145, I148
588	Proteasome subunit alpha	P60900	A31, V40, A41, V42, C47, A48, V49, I50, V51, C78, V79, V91, A94, Y96, A99, L114, C115, I118, A119, C136, M138,
	type-6 (EC 3.4.25.1)		I139, L140, I141, V151, C154, A165, A167, A168, V195, A198, I199, C201, L202, V217, V219, V220
589	Cell division control protein	P60953	I4, C6, V7, V8, V9, A13, V14, C18, L19, L20, F28, V36, F37, V42, V44, I46, Y51, L53, L55, A59, L70, Y72, V77, F78, L79,
	42 homolog		V80, C81, F82, V84, V85, F90, V93, W97, V98, I101, C105, F110, L111, L112, V113, I117, L129, I137, A142, L145,
			A146, L149, V155, C157, A159, L165, V168, F169, A172, I173, A175, A176
590	Pterin-4-alpha-	P61457	L17, W25, A33, I34, F40, A46, F49, V53, A57, V73, I75, L77, L85, L92, A93, I96, V99
	carbinolamine dehydratase
591	Lysozyme C (EC 3.2.1.17)	P61626	C24, L26, A27, L30, M35, L43, A44, W46, M47, C48, L49, A50, I74, F75, I77, C83, C95, C99, L102, I107, A108, A110,
			V111, C113, A114, V117, V118, I124, W127, C134, V139, C146
592	Beta-2-microglobulin	P61769	V29, Y30, L43, C45, V47, F50, H51, L59, L60, F82, L84, Y86, F90, Y98, A99, C100, V102, H104, W115
	[Cleaved into: Beta-2-
	microglobulin form pI 5.3]
593	Transforming growth factor	P61812	C317, C318, L319, F326, C350, L388, I390, C413
	beta-2
594	Epididymal secretory protein	P61916	V37, C42, C47, Y55, V59, F61, I101, Y109, L124, W128, L130, L138, F139, C140, W141
	E1
595	Ras-related protein R-Ras2	P62070	Y15, L17, V18, V19, V20, V25, L30, F34, V40, C55, I57, A62, L64, I66, L67, A70, M78, M83, F89, L90, L91, V92, F93,
			V95, F101, I104, F107, I111, V114, F120, M122, I123, L124, I125, L131, V137, L145, A146, A156, A158, V164, A167,
			F168, L171, V172
596	40S ribosomal protein S7	P62081	L27, L30, L36, L40, L43, I51, A59, I61, V64, F72, L79, V93, I95, L130, L133, V134, V156, F173, V176, Y177, V185
597	Actin, aortic smooth muscle	P62736	A9, L10, V11, C12, C19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
			M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
			V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221,
			A222, I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301, Y308, I311,
			M315, I319, W342, I347, F354, W358, I359, I371, V372, C376
598	40S ribosomal protein S26	P62854	A78
599	60S ribosomal protein L11	P62913	L22, A36, L40, V70, V74, I82, L87, F105
600	Guanine nucleotide-binding	P63092	L43, L44, L45, L46, I56, M60, I95, L99, A102, I103, I106, L113, I131, F146, A150, L153, V159, C162, C174, A175, F178,
	protein G		I182, I185, F219, M221, V224, A243, I244, F246, V247, V248, Y253, F273, L282, V287, I288, L289, L291, L296, L297,
			V301, A337, I341, F345, A351, I372, C379, I383, H387
601	Inward rectifier potassium	P63252	V161, L245, I250, I267, L298, A362, F374
	channel 2
602	Casein kinase II subunit beta	P67870	F21, C23, V25, I30, L36, L39, A49, I53, A75, A76, L79, Y80, I83, H84, Y87, I88, I94, M97, F106, C114, M119, L120,
			V133, C137, F159, F163, L167
603	Actin, alpha cardiac muscle	P68032	A9, L10, V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
	1		M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
			V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221,
			A222, I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301, Y308, I311,
			M315, I319, W342, I347, F354, W358, I359, I371, V372, C376
604	Ubiquitin-conjugating	P68036	A3, L7, I14, F22, W35, I39, Y46, A50, F51, I53, I55, F70, H76, I79, V104, I105, L108, L111, V112, L125, F136, A140
	enzyme E2 L3 (EC 2.3.2.23)
605	Actin, alpha skeletal muscle	P68133	A9, L10, V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
			M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
			V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221, A222,
			I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, M301, Y308, I311, M315,
			I319, W342, I347, F354, W358, I359, I371, V372, C376
606	Hemoglobin subunit beta	P68871	L4, V12, L15, V24, A28, L29, L32, L33, L49, V55, V61, L69, F72, L79, L82, F86, C94, L111, V114, L115, F119, V127,
			A130, Y131, V134, V135, A139, A141, A143
607	Hemoglobin subunit alpha	P69905	V11, A13, A14, W15, V18, A22, Y25, A27, A29, L30, M33, F34, V56, A64, A66, A70, V71, V74, M77, L81, A89, C105,
			L106, V108, L110, L114, A124, L126, F129, L130, V136
608	Tyrosine-protein	P78324	A51, L53, C55, I66, W68, I106, I111, C121, V122, F168, C170, F175, W184, A213, V215, L217, V226, C228, V230,
	phosphatase non-receptor		L246, I250, V271, C273, V275, F278, L285, W287, C331, V333
	type substrate 1
609	Retinal-specific ATP-	P78363	F1968, L1970, L1971, F1982
	binding cassette transporter
610	Oxidized low-density	P78380	C155, C172, L179, L180, I182, I191, I195, F202, W203, M204, L206, C243, A244, I246, V251, A260, I263
	lipoprotein receptor 1
611	Protein jagged-1	P78504	F35, L37, C71, F75, L79, Y132, L134, V136, A138, I161, A177, F179, I183, V185, C196, C200, C229, C262, C265,
			C293, C324, C333, C522, C560, C664
612	Reelin (EC 3.4.21.—)	P78509	C674, C700, C1772, C1794, C2485, C2507
613	ETS-related transcription	P78545	V72, W75, I76, C95, L102, L110, F114, L121, I279, F303, F305, V311, A312, L329, M333, L342, F354
	factor Elf-3
614	C-C motif chemokine 7	P80098	C34, C35, C59, A63, V64, I65, F66, I74, A76, V83, F86
615	Protein crumbs homolog 1	P82279	C107, C221, C336, C1332
616	Mothers against	P84022	V12, L15, A34, V35, L38, V39, L42, A54, I55, I65, I67, V77, Y88, C89, C109, A112, V120, C121, V122, H126, Y127,
	decapentaplegic homolog 3		V130, C233, I235, Y237, V244, A250, M255, V257, L271, V283, I290, V294, L296, V303, A305, C307, I313, V315,
			C320, I334, I342, F343, F348, V363, C370, I372, M374, F376, W380, C394, I396, L398, L400, L407
617	Disabled homolog 2	P98082	I124, A155, V168
618	Basement membrane-	P98160	A4204, F4206, F4214, F4219, I4230, L4232, V4234, L4242, L4243, L4244, F4259, I4260, L4262, L4264, L4269,
	specific heparan sulfate		V4270, Y4273, L4275, A4280, V4296, A4298, I4307, V4332, I4334, C4355, V4356, L4359, L4376
	proteoglycan core protein
619	Polycystin-1	P98161	A290, I294, W305, F307, H323, Y325, V333, A335, L337, V352
620	Nuclear factor NF-kappa-B	Q00653	L65, V80, A89, I91, V93, V96, H105, A106, H107, I119, C120, A131, L136, M150, L174, A178, V190, L192, F194, A196,
	p100 subunit		I217, L228, V246, L248, L249, V260, F262, I287, V288, F289, V305, L307, L309, F323, Y325, Y326, H493, I496, I504,
			I511, V520, L531, H532, A534, V543, L546, A551, A563, M564, H565, A567, L578, H605, A607, V608, L619, A637,
			H639, A641, V650, L653, A675, L687, V742, L778, L782, L794, A795, L817, L818, L831, A834, L835
621	Beta-1,4 N-	Q00973	I281, I299, V308, V309, I310, A311, V325, M330, L342, A343, V347, Y351, F361, V382, F426, C429, V449
	acetylgalactosaminyltransferase
	1 (EC 2.4.1.92)
622	Ankyrin-2	Q01484	F35, A39, V47, L65, A67, H69, L70, A71, A72, V80, L83, A100, L101, H102, A104, V112, V113, L116, L134, Y135,
			A137, A138, V145, V146, L149, A168, V169, A170, A178, L182, H197, A199, A200, A208, L212, V226, L237, H238,
			A240, A241, V248, A249, L252, L270, H271, V272, A273, M281, V282, L285, L303, H304, C305, A306, A307, V314,
			V315, L318, L336, H337, M338, A339, A340, C347, V348, L351, V371, A372, V380, L384, L468, H469, A471, A472, V480,
			L501, H502, I503, A504, V513, L516, L534, H535, I536, A538, V545, A546, L549, L567, H568, V569, A570, A571,
			A579, L582, V602, A603, V611, L615, M839, V970, V974, I991, I993, V1004, C1006, V1009, A1027, I1031, V1033,
			V1077, V1079, I1081, A1085, F1147, F1151, A1152, V1153, V1154, I1164, V1179, A1181, A1187, V1194, L1196,
			V1220, L1222, I1233, M1235, I1237, L1260, L1261, V1289, A1297, W1300, L1301, I1302, C1304, A1314, V1317,
			A1328, F1330, V1332, A1334, A1342, L1344, C1346, F1347, C1348, L1389, F1403, L1413, V1415, L1428, F1430,
			L1503, L3573, I3576, A3577, L3587, A3588, I3601, L3616, L3617, W3620, A3628, L3633, L3637, I3645, M3649
623	Collagen alpha-3	Q01955	F1448, L1474, F1475, L1487, Y1521, W1522, L1523, I1545, C1548, V1550, C1551, F1583, F1586, C1604, F1613,
			L1614, C1616, C1622, C1662, V1664, C1665, M1666
624	Inositol polyphosphate 5-	Q01968	C28, L30, L32, A33, L41, I42, I43, I56, I58, F62, C64, C82, I84, V86, F96, I98, C104, F107, L108, V111, A114, F242,
	phosphatase OCRL-1 (EC		F243, V244, W247, V249, L258, W261, L262, I271, Y272, C273, I274, F276, L279, A285, W297, V301, M322, M323,
	3.1.3.36)		L324, L325, I326, F327, A328, V358, A359, V360, F362, F364, F369, C370, I371, V372, L376, I393, F399, I411, V417,
			W419, L420, L423, Y425, V435, L447, L453, Y479, A496, W497, C498, I501, L502, L519, V527, A529, F531, I533, V535,
			F572, F574, V577, I589, F599, W614, A617, L624, I632, L634, V636, V638, V643, L657, L659, L661, L669, C679, F680,
			L684, L687, C688, I738, L741, V742, L745, A749, L755, L765, I768, L772, V787, A788, A790, L791, F794, L795,
			V802, I803, C811, L812, V824, I825, L828, V835, F836, L839, F842, L843, L846, V855, I860, A861, F864, L868, F890,
			L891
625	Tumor necrosis factor	Q02223	C24, C37, C41
	receptor superfamily
	member 17
626	Pro-neuregulin-1,	Q02297	C196, C221
	membrane-bound isoform
627	Collagen alpha-1	Q02388	C2876, C2925
628	Desmoglein-1	Q02413	C58, I70, A71, I73, V83, Y85, F100, I109, I111, V115, F123, I125, C127, A129, L143, V145, V147, L179, I218, L225,
			L235, V237, C255, I257, I259, I290, A305, L331, V333, L337, L347, I349, V351, I372, V374, V376, V394, A409, Y423,
			L433, L442, Y460, I464, I479, I481
629	Desmocollin-2	Q02487	L185, L195, V201, F209, I211, I231, I233, I252, I304, L311, Y319, L321, I323, V325, C341, I343, V376, F404, L417,
			V419, L433, I435, V437, V458, V460, A495, I506, W517, L533, Y545, I547, A551, L563, I565, I584, C585, A633, L635,
			V648, I650, V652, L664, V666
630	Aminoacylase-1	Q03154	Y19, L20, A34, F38, A42, V52, V60, V62, L63, H80, V83, A98, M114, L122, M141, F158
631	Trefoil factor 2	Q03403	C31, C52, C58, C69, F70, L73, C81, C101, C118, F119
632	Mevalonate kinase	Q03426	V8, A10, V14, H20, A21, V27, L29, V31, L33, L39, L41, V49, L51, L91, V109, A111, F112, L113, L115, Y116, L117, I119,
			C120, L129, L143, A147, A148, V151, C152, L153, A154, A155, A156, L157, L158, I185, A189, A206, V207, A213,
			L214, L233, L234, V250, I268, C275, M282, L305, V310, L315, L318, L331, C339, V353, L360, A374, V377, I379
633	Complement factor H-	Q03591	Y53, I70, C87, V110, I127, C129, I249, C251, C266, A296, C317
	related protein 1
634	1,4-alpha-glucan-branching	Q04446	L31, L38, F45, I59, F69, C88, A92, A95, V98, L100, V136, L142, V144, V145, I146, I157, A161, V164, L197, I199, Y200,
	enzyme (EC 2.4.1.18)		H203, V204, I206, Y216, F219, V223, L224, I227, L230, Y232, C234, I235, L237, M238, I240, M241, H243, F249,
			I253, F256, F257, A258, A259, L269, L272, V273, A276, I281, V283, L284, L285, V287, V288, H289, A292, L300, F303,
			Y310, F311, H319, I334, L335, F337, L338, L339, I342, W345, L346, Y349, F351, F354, F356, V359, M362, L363, Y364,
			A389, L390, Y392, L393, M394, L395, A396, L399, V400, I410, A411, M417, A419, L420, I439, W443, L446, W455,
			M457, I460, L464, I474, A475, Y476, A477, H480, L490, A491, M503, I513, I517, L519, H520, M522, I523, L525, I526,
			H528, L530, Y535, L536, F538, M539, F543, L549, F551, A563, L580, F583, M587, L590, W596, L597, I613, I614,
			A615, F616, L621, L622, F623, I624, F625, V638, F646, L650, A654, L683, V685, I687, V691, A692, L693, I694,
			L695, V698
635	Glutamate carboxypeptidase	Q04609	F61, I70, L74, F77, L83, A84, A93, V108, L110, Y113, V115, L117, I128, I130, V158, F161, A163, F164, L174, V175,
	2 (EC 3.4.17.21)		Y176, V177, A180, L188, C196, I200, V201, I202, A203, V214, A217, V225, I226, L227, Y228, Y234, A236, V253, I258,
			L259, A264, L268, A274, V287, V294, I297, A302, L305, L306, M309, A313, W319, V329, V342, M344, I346, I355, V358,
			L362, V372, I373, L374, H377, V382, F383, I386, A393, V394, H396, I398, V399, F402, L405, I416, L417, F418,
			A419, W421, A423, F426, L428, L429, A435, L442, V447, A448, Y449, I450, A452, I456, Y460, L462, V464, C466,
			L469, M470, V474, L477, W93, W497, L515, F521, V523, F524, F525, I530, A531, A535, Y537, Y549, L551, H553,
			V555, L561, V562, F565, F570, H573, V576, A577, V579, M583, V584, L587, A588, C597, Y600, A601, V603, L604,
			Y607, A608, I611, V627, L632, V636, F639, A643, F646, L661, M664, L668, M669, L671, F675, L679, F686, Y687,
			H689, I691, Y692, A693, F705, I708, L712, V728, I732, Y733, A735, A736, V739, A742, A743, L746
636	Copper-transporting ATPase	Q04656	V10, I12, V14, M17, C22, V23, I26, I30, A48, I50, Y52, L62, I66, L173, M175, V177, I189, I193, A211, I213, Y215, V222,
	1 (EC 3.6.3.54)		M225, I229, F234, F281, I283, V292, I295, L299, A317, V319, L331, I335, I381, I383, M386, C391, V392, I395, I399,
			V419, Y421, L431, I435, C490, I492, V503, I506, L510, I516, L520, A528, V530, Y532, I542, I546, L566, L568, V570,
			I582, L586, C595, A604, I606, Y608, I618, I619, I622, A629, V837
637	Neurogenic locus notch	Q04721	C315, C491, C642, C1184, C1443, C1455, C1484, L1490, C1509, C1522, W1529, L1547, I1549, V1551, L1558, F1565,
	homolog protein 2		L1573, V1623, L1625, I1627, C1632, F1640, A1646, A1647, L1649, L1650, A1651
638	Activin receptor type-1 (EC	Q04771	V402, L411, V424, V447, L470, L473, W478, L489, L495, I498
	2.7.11.30)
639	Acetylcholine receptor	Q04844	V49, I51, L53, V55, I61, V74, I76, I78, W80, V105, W106, V111, L112, A123, V128, V130, V136, W138, A142, C148,
	subunit epsilon		V150, W159, F166, V176, F178, V230
640	Focal adhesion kinase 1	Q05397	V39, H58, V64, I67, I68, V72, C82, L87, L124, Y128, F137, F146, F147, Y148, A160, A168, L171, C173, L174, L188,
			Y194, L203, F207, A217, F228, L241, F243, F244, L247, F258, L272, A273, I274, I280, A294, I302, L316, L318, A323,
			V329, A331, A337, M340, A341, L343, I344, C348, A369, I373, V436, V451, A452, I453, C459, F468, A472, M475, I483,
			V489, I490, V495, I497, I498, M499, C502, L507, L511, I524, Y526, A527, L530, A533, L534, L537, I547, A548, A549,
			V552, L553, V554, V560, L562, F565, L567, A579, M589, A590, V605, M607, F608, C611, M612, I615, V631, I635,
			L651, L654, M655, C658, W659, F669, L672, L676, V928, L931, V932, M938, I942, Y950, V957, L961, L964, V968,
			I983, L990, L997, A1004, M1020, A1024, L1027, A1028, A1031, L1034, I1038, A1041
641	External core antigen/	Q05495	Y35, F38, L44, L45, F53, A63, H81, L84, A87, A98, V118, L129, L130, F132, H133, V144, L148
	genotype F2 (isolate
	Brazil/w4B) (HBV-F)
642	Glutamate receptor	Q05586	A71, V107, Y109, A111, Y158, I163, A236, L269, A279, A284, I301, V309, I314, I400, V401, F408, V409, C436, C454,
	ionotropic, NMDA 1		C455, F458, C459, I460, L462, L463, L466, V479, M501, M502, L505, A510, M512, I513, V514, A515, L517, L538, I540,
			L541, V542, L672, Y681, A682, V689, F693, M702, Y703, M706, A717, V721, L726, A728, F729, I730, W731, V735,
			L736, F738, L746, F758, I760, M762, V772, I776
643	Tyrosine-protein	Q06124	W6, F7, H8, A16, L19, L20, F29, L30, A31, L43, V45, I54, I56, Y63, L65, F71, A72, L74, A75, L77, V78, Y81, L88, I96,
	phosphatase non-receptor		L98, L102, A122, L125, L126, F135, L136, V137, F147, V148, L149, V151, I172, L190, L193, V194, V209, L210, L212,
	type 11 (EC 3.1.3.48)		L216, I221, A223, I226, V230, L233, F247, L254, I282, L283, F285, V290, Y304, A307, I309, I310, Y327, I328, A329,
			C333, V338, F341, W342, M344, V345, V352, I353, V354, M355, C367, Y370, W371, Y380, M383, V385, L401, L403,
			V419, Y422, H423, F424, W427, V439, F442, L443, V446, I453, V459, V460, V461, H462, C463, A465, I467, G468,
			F473, I474, V475, I476, I478, L479, I480, I482, I483, V488, I492, V494, I498, V501, M508, V509, Y515, F517,
			I518, Y519, A521, V522, I526
644	Tyrosine-protein kinase	Q06187	L31, V427, I429, I432, F442, A446, M449, M450, L452, L457, V458, V463, C464, I470, I472, I473, L482, L486, L498,
	BTK (EC 2.7.10.2)		M501, C502, V505, C506, A508, M509, L512, H519, L522, A523, A524, C527, V529, V535, V537, F540, L542, V568,
			I580, W581, F583, V585, L586, M587, W588, I590, Y591, Y598, I610, L616, A622, V626, M630, C633, W634, F644,
			L647, I651
645	Acetylcholine receptor	Q07001	V52, V54, L56, L58, I79, W83, V108, W109, L115, V131, V133, V139, W141, A145, C151, I153, W162, F169, I179,
	subunit delta		L181, I253, V330
646	Early activation antigen	Q07108	Y97, A109, C113, L120, A121, I123, L132, W142, V143, L145, C173, V174, L176, I193, C194
	CD69
647	Neuraminidase (EC	Q07599	M83, A92, F95, I104, I112, V114, I115, F119, V120, F130, F131, L132, L156, V159, A174, A176, W177, A179, A181,
	3.2.1.18)/strain		C182, M189, V191, V193, A200, V201, A202, I204, V214, L222, C231, I232, C236, Y237, W238, V239, M240, A249,
	A/Duck/Ukraine/1/1963		Y251, I253, A256, I261, H273, I274, C277, C279, Y280, V286, C288, V289, C290, L302, I304, L315, C316, A317, I319,
	H3N8		V346, F349, F351, V357, W358, M359, I363, F371, I373, L374, I376, V393, V394, L397, F406, L418, C421, F422,
			W423, V424, M426, W437, I443, V444, M445
648	Prolow-density lipoprotein	Q07954	F859, C861, C879, C895, F900, C902, I908, C914, C920, C936, C943, C955, C961, F982, C984, C1002, F1020, C1022,
	receptor-related protein 1		C1040, F1067, C1069, C1088, F1110, C1112, C1131, C1152, V1158, L1160, C1172, C2679, C2696, C2715, F2739,
			C2741, C2759, C2781, V2786, V2788, L2793, C2794, C2800, A2804, C2812, C2818, C2837, F2863, C2865, C2884,
			C2912, C2930, F3379, C3381, C3399, C3453, F3458, C3460, I3467, C3473, C3479, C3494, F3499, C3501, I3508,
			C3514, C3520, C3536, C3543, V3549, C3555, C3561, C3575, F3580, C3582, I3588, C3594, C3600, C3613, C3620,
			C3632, F3659, C3661, C3679, C3703, C3749, C3767
649	Hemagglutinin [Cleaved	Q07FI5	V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, V74, A75, W77, I78, L79, C84, L87,
	into: Hemagglutinin HA1		W93, Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A150, C152, H154, L164, L165, W166, L167, L173, L177,
	chain; Hemagglutinin HA2		V189, L190, V191, L192, W193, V195, H196, H197, Y208, Y214, V215, V217, V218, I243, Y245, Y246, L249, L250, I256,
	chain]/strain		F258, A260, L264, I265, A266, Y269, A270, F271, A272, L273, F277, I281, I282, C291, C295, A301, I302, H312, I316,
	A/China: Nanchang/11/1996		V323, L328, M330, V331, A348, M360, Y365, A387, I388, A439, L451, V458, L461, V465, L469, C480, H485, C487,
	H1N1		C491, M492
650	Hepatocyte growth factor	Q08048	F43, C71, A72, C75, C85, A87, F88, V89, C97, W99, L119, W153, C178, C190, F191, C207, C233, W236, C261, C272, C284
651	Interleukin-10 receptor	Q08334	L38, A54, L57, C74, F76, L87, V89, A91, V108, L127, M145, V156, V189, V191, L195, V208
	subunit beta
652	Epithelial discoidin domain-	Q08345	M37, A72, W73, L87, V89, V97, V100, I141, M159, A161, V164, F166, L178, V180, L182, L191, Y194, A196, V208,
	containing receptor 1		L210, L231, F241, Y255, V256, W258, V268, M270, F274, F280, M283, V285, C287, A295, V301, C303, F305, V336,
			L338, A343, L346, C348, F350, L357, L358, F359
653	Tyrosine-protein kinase	Q08881	I358, V388, I390, I393, A397, F403, A407, L418, V419, V424, C432, V434, L443, L447, L459, M462, C463, V466,
	ITK/TSK (EC 2.7.10.2)		C467, M470, L473, H480, L483, A484, A485, C488, V490, I496, V498, F501, V522, V541, W542, F544, V546, L547,
			M548, W549, V551, V567, I571, A583, I590, M591, C594, W595, F605, L608, L612
654	ATP-binding cassette sub-	Q09428	I701, I703, L708, M710, I711, V712, C717, L722, L723
	family C member 8
655	Potassium voltage-gated	Q09470	A347
	channel subfamily A
	member 1
656	Neuraminidase (EC	Q0A2R1	L86, V93, A104, I105, I113, V115, Y120, V121, C123, M130, Y131, A132, L133, L157, I158, C175, V176, C183, M190,
	3.2.1.18)/strain		I192, C193, V194, A201, A203, V205, Y207, A219, L223, C230, V231, C232, A238, V239, V240, M241, V254, M255,
	A/Chicken/Victoria/1/1985		Y256, F257, I275, C278, C280, Y281, I287, C289, V290, C291, A298, I302, I303, I305, Y316, V317, C318, V321, L322,
	H7N7		V349, F352, F354, W361, L362, F374, M376, L377, I379, A382, I396, V397, F409, I410, Y420, F424, Y425, V426,
			L428, V439, L446, I447, A448, L449, A465, I467
657	Hemagglutinin [Cleaved	Q0A448	A26, V50, L58, C59, M60, Y65, L68, C71, V74, M76, I78, C83, W91, L94, I95, I101, C104, L115, I119, I125, M128,
	into: Hemagglutinin HA1		I138, C147, Y156, L159, L162, Y178, H186, L187, I188, I189, W190, I192, H193, Y205, I212, V214, I240, F242, V247,
	chain; Hemagglutinin HA2		I253, F255, H257, L261, I262, A263, V267, L270, I277, C287, C291, F292, A345, Y362, A384, L458, L466, H482, C484,
	chain]/strain		C488, A506
	A/Duck/Germany/1949
	H10N7
658	Endogenous retrovirus group	Q0ED31	A54, H65, A69, M94, M99, V100, M103, L110, W111, L115, V119, V154, I165, Y193, C220, V226, I227, L228, C230,
	K member 13-1 Env		C241, V244, I253, L261, I272, I286, I287, V288, H289, L290, V294, I296, C298, I327, A330, C332, I334, W339, L343,
	polyprotein		V346, L350, I359, I360, F361, H374, C378, F382, F383, Y384, C385, L390, F391, L410, C412, I414, I417, I418, A427,
			M428, I437, I443, I446, L447, L448, F462, W473, L477, Y480, V483, I485, V499, I542, L549, A552, I553, A555, L559,
			L560, V564, I567, L570, V574
659	Carcinoembryonic antigen-	Q0Z7S6	L36, A45, V51, L52, L53, V55, Y65, W67, I79, I80, A105, L107, M109, V112, Y120, L122, V124, F138
	related cell adhesion
	molecule 8
660	Spike glycoprotein/isolate	Q0ZME7	F67, F103, V106, V125, I137, V138, A150, C151, C156, V162, L198, H201, F209, A211, Y212, A214, F222, Y236,
	N5 (HCoV-HKU1)		V237, M238, C242, Y256, Y266, L267, L268, A279, C282, L333, C352, F383, V388, F391, A392, L409, C423, Y427,
			Y458, A477, I588, F589, L624, F633, A680, C719, C743, V765, I943, A1025, A1070, A1084, L1085, L1098, A1103,
			A1106, F1143, I1144
661	NS3 protease	Q0ZNA6	C16, V33, V35, V36, L44, A45, C47, V48, V51, C52, W53, V55, A59, L64, I71, L82, V83, W85, L94, L104, L106, V107,
			V113, I114, V116, V132, L135, L143, L144, C145, A150, V151, I153, F154, A164, A166, V167, F169, V170, V172,
			M175
662	Calcium-activated potassium	Q12791	F815, L907, M922, C923, C943, A946, F955, L1026, A1037, I1060, A1104
	channel subunit alpha-1
663	Potassium voltage-gated	Q12809	I30, A32, C44, F48, C49, L51, C52, A57, V59, C64, C66, A78, I82, A83, I96, A97, F98, C105, V110, V112, L127, A763,
	channel subfamily H		A778, I782, I787, I804, F805, V822, A824, L830, V841
	member 2
664	Glutamate receptor	Q12879	M112, I116, A136, M162, F170, F177, V187, V191, V203, V217, L248, L260, V292, L307, I408, V409, F416, V417,
	ionotropic, NMDA 2A		V419, C436, V440, C455, C456, F459, C460, I461, I463, L464, L467, L479, W493, M496, I497, V500, A505, V506,
			M507, A508, V509, L512, V522, V529, V535, M536, V537, V662, L665, F670, F682, I694, M701, M705, A716, A727,
			F728, I729, A732, A733, V734, L735, Y761, I763, A764, L765, I775, A778, L779, F782, M788, L791, V807
665	Unconventional myosin-Ie	Q12965	A1058, F1072, I1078, F1100
666	Glutamate receptor	Q13002	L36, F38, I41, A56, F57, A60, V61, I64, L71, I83, A91, A95, L99, V103, A104, A105, I106, F107, A115, V118, C122, V127,
	ionotropic, kainate 2		H129, I130, V147, L149, F153, L156, A159, I160, L163, V164, V172, V174, V175, L185, L188, A191, L197, L204,
			A211, L215, M218, V226, I227, F228, A235, A236, I238, L239, A242, M247, Y254, I255, F256, L259, L261, L264,
			M276, F279, L282, W296, M316, A320, A321, L322, M323, A326, V327, V329, V330, A333, M340, L345, W353, F359,
			I363, A366, I375, F387, L389, V391, I392, W405, L433, I434, V435, Y443, V444, F446, L453, F459, Y462, C463, I464,
			L466, L467, L470, I480, A490, M501, V502, L505, A510, L512, A513, V514, A515, L517, A518, I527, F533, L536, I538,
			I540, L541, Y542, L674, A675, I680, Y682, A684, M691, F694, M705, M709, V716, V718, V728, Y733, A734, F735,
			L736, M737, I742, L752, Y764, V766, I778, A781, I782, L785, L791, M794, W799
667	T-lymphoma invasion and	Q13009	M40, A441, L446, V454, V467, L469, L474, F476, V497, I501, V502, V514, F515, C516, L517, A524, F527, L535, W538,
	metastasis-inducing protein		I542, H543, A545, C546, A547, A551, L563, M616, C623, Y624, L639, M651, F662, A664, V666, A667, A668, I848,
	1		Y858, L873, A884, I895, I898, A903, L906, L920, V924
668	Secretory phospholipase A2	Q13018	F182, C204, C219
	receptor
669	Platelet-activating factor	Q13093	I56, C67, M71, F80, L81, Y84, Y85, W97, I98, Y103, L111, L116, M117, L124, F125, A132, Y144, L146, V147, V148,
	acetylhydrolase		H151, F156, I165, A168, F172, I173, A175, H179, A184, A186, Y189, V222, A226, C229, A232, L233, I239, I267,
			A268, V269, I270, A277, V279, I280, L283, F289, C291, I293, A294, A297, M299, V306, I310, L314, F315, F316, I317,
			I328, M331, C334, I344, F354, F357, A380, A387, L389, A390, F391, L392, F402, I422
670	S-methyl-5′-thioadenosine	Q13126	I12, I14, I15, L26, L45, C55, V56, L57, L58, A76, I78, A80, L81, H88, V89, I90, V91, C95, L98, I107, V108, I109, I110,
	phosphorylase (EC 2.4.2.28)		A132, L152, A156, M169, V170, F186, A191, V193, V199, V202, L204, A205, I210, C211, Y212, A213, I215, A216,
			M217, A218, L250, I255, I258
671	Glutamate receptor	Q13224	I35, I37, A38, V39, I40, V65, I81, I85, V97, V98, F99, A100, I108, A109, I111, L112, I115, A117, I123, L124, I126, A135,
	ionotropic, NMDA 2B		F146, A154, V156, M157, I160, M161, F169, I171, V172, F176, F182, I186, I190, V202, L205, I216, L220, L223, I228,
			L229, L230, Y231, C232, A237, I240, F241, A244, L249, W256, I257, V258, L261, V262, A263, L277, I278, V280,
			V293, I299, I300, A303, A304, M307, L308, I329, L335, L339, V342, V363, I364, I365, L367, V376, I408, V409, F416,
			V417, V419, C436, I440, C456, C457, F460, C461, I462, I464, L465, I468, L480, W494, M497, I498, V501, A506, Y507,
			M508, A509, V510, L513, V523, I530, V536, M537, V538, V663, L666, F671, F683, I695, M702, M706, A717, A728,
			F729, I730, A733, A734, V735, L736, Y762, I764, A765, I766, V776, A779, I780, L783, M789, L792, V808
672	Chitotriosidase-1 (EC	Q13231	L24, V25, C26, Y27, F28, A32, A39, F41, L46, L50, C51, L54, I55, Y56, A57, F58, A59, M61, Y77, F80, L90, L93, L94, A95,
	3.2.1.14)		I96, F101, F106, M109, V110, F119, V120, A123, L127, F132, L135, L137, W139, F155, L158, V159, L162, F166, L178,
			L179, L180, A182, A183, V184, A186, V191, V197, I200, A201, L204, F206, V207, L209, A211, H224, L228, V243,
			A246, V247, W250, L260, I261, L262, M264, F271, V281, A283, A302, Y304, V306, V322, Y324, I325, W331, V332,
			F334, F340, V344, L347, A355, M356, V357, A359, L360, F365, Y375, L377, I378, L381, C420
673	Noggin	Q13253	L66, V173, C184, V202, L203
674	Butyrophilin subfamily 1	Q13410	A40, A46, L48, C50, A58, L63, W65, A73, V74, Y91, L109, I111, V114, Y122, C124, F126, L136, V137, L139, I208,
	member A1		V364, V379, F452, F460
675	Mesothelin	Q13421	I311, L315, I316, L323, C326, V327, L332
676	Alpha-1-syntrophin	Q13424	L13, V31, L33, L40, V42, V88, V90, I112, I114, A122, A123, L129, A134, I135, V138, L143, A151, V162, V163, L164,
			V166, M215, L236, I238, A241, L247, L249, A251, A257, I264
677	Interleukin-18 receptor 1	Q13478	I28, V31, L38, H40, W56, V82, L83, F85, V88, Y96, F98, W107, L109, F136, C140, L154, A175, C185, H187, L189,
			C237, A239, L241, A278, L282, I284, C298, V300, L313
678	Myotubularin	Q13496	I185, L321, Y329, I350, L385, L388, L393, F438, A455, F475, L479, I539
679	Sequestosome-1	Q13501	A8, L10, L47, V51, F55, A65, F77, A86, I97, I99, L394, M401, L413, L417, A427, I431
680	Polycystin-2	Q13563	L736, L745, L770
681	Myotubularin-related protein	Q13614	A88, V91, L105, V107, L112, F114, A127, L129, V131, I132, L151, I158, L161, F163, A164, I175, L179, F184, A194,
	2		W225, I227, C237, Y240, L244, V245, V246, I250, L255, V258, I267, V269, L270, A279, I281, C284, Y302, L303,
			A305, I306, I316, I318, F319, A321, A327, I353, L363, L366, Y371, W388, I392, I395, L396, A399, I402, A403, V406,
			V413, V414, V415, H416, A425, L427, L430, A431, M432, L433, M434, L435, Y439, I442, F445, V447, L448, V449,
			W453, F456, H458, F460, H466, A472, F480, L481, F483, I484, C486, V487, M490, A497, F498, F504, L505, I508, L509,
			F517, F520, L521, L533, L540, W541, I544, F551, L564, W576, Y579, Y580, I581
682	Cullin-4B	Q13620	L220, A223, V224, A226, L240, A243, V244, L256, L260, C264, L286, I289, M300, I303, I306, F307, L310, V315, I324,
			M327, F332, I336, I337, V342, I347, I350, L351, I354, L368, L371, L372, M374, L375, L378, Y381, F385, F389, Y397,
			V410, Y413, L414, V417, L421, L428, L440, V444, L448, L449, I456, L457, L461, L464, L465, L473, L476, L479,
			F480, L490, W494, I498, I505, V506, M515, V516, L519, L520, V526, I529, I532, C533, F534, F540, A543, M544, A547,
			F548, F551, I552, A560, L562, I563, A564, V567, L571, L587, I590, I593, F594, I597, V602, F603, F606, Y607, L611,
			A612, M629, L633, L645, M648, F708, F711, A734, L743, V745, F748, V752, I767, L778, L782, L785, A786, F808, I823,
			I850, A853, I854, M858, L869, V873, L886, I890, L893, M899, Y909
683	Interleukin-10 receptor	Q13651	A36, F39, H41, L43, V59, A60, L83, A98, V100, A102, F118, V123, L125, V130, Y157, F161, Y167, I169, V203, V205,
	subunit alpha		V209
684	Voltage-dependent L-type	Q13698	A603, V610, V1010, A1023, A1312, L1329
	calcium channel subunit
	alpha-1S
685	Laminin subunit gamma-2	Q13753	C550, C570
686	Ectonucleotide	Q13822	C59, C76, C80, F90, C94, C118, C120, C124, C130, C131, W144, L166, I167, F169, V171, F174, Y178, M186, I189, L192,
	pyrophosphatase/phosphodi-		M202, Y206, Y222, H226, I228, V229, M233, F242, W254, L260, A264, I280, I286, I289, L295, V303, Y304, F306,
	esterase family member 2		M325, L329, V336, L339, M340, L343, C351, V352, I355, F356, V357, H360, M362, V365, C367, F372, L373, L390,
			I393, I409, L412, Y424, I444, H445, L446, L447, V454, F477, M484, F488, V489, F495, V501, F504, I507, L509, Y510,
			M513, C514, L517, L534, M544, A603, V604, Y610, L613, F618, Y622, M628, W631, Y634, C652, V653, V659, A669,
			L681, F682, A692, A696, F697, V699, M702, V703, M705, A708, V712, W713, F716, V719, L720, V721, A725, V731,
			V733, I738, F739, V757, I762, V764, Y768, Y769, I771, I772, I795, L796, V816, M820, H823, A825, V827, I830, L833,
			L836, F838, I849, L850, L852
687	Plakophilin-1	Q13835	A250, L254, A266, I269, C273, A279, V283, L292, V293, V303, A306, A307, A308, A310, L311, L314, V315, L338,
			I346, L350, L354, L367, A371, L372, L375, A376, V379, I380, V402, F403, A406, C409, L410, L434, M444, L450, I451,
			L454, M455, V458, V472, C475, M476, V478, L479, L482, L486, L543, A548, I549, Y552, L555, A567, C568, A569,
			A571, L572, L575, M582, M586, I590, L597, I600, V611, A616, L618, L619, M622, L628, M632, V636, F637, I657,
			A661, V665, L668, A670, A700, A704
688	Bone morphogenetic protein	Q13873	L492
	receptor type-2
689	Voltage-dependent L-type	Q13936	I702, V1131, A1453, M1470
	calcium channel subunit
	alpha-1C
690	Coactosin-like protein	Q14019	C10, A12, A13, Y14, V17, W26, V27, F29, I36, F48, C52, L58, F59, A60, F61, V62, F64, A77, L78, I79, W81, I82, V101,
			V104, V105, I114, L120, I125, L129
691	Heterogeneous nuclear	Q14103	M99, I101, L104, L113, F117, L130, V143, V154, H160, I167, I184, V186, I198, F202, C226, I228, F230, V236, I239,
	ribonucleoprotein D0		H245, V247, I254
692	Lysosome membrane protein	Q14108	V42, L43, F64, F66, F67, V69, I75, Y89, F102, I109, A111, I133, L136, I138, V140, V143, I156, L160, L167, V173, L177,
	2		I184, I188, L201, Y213, I228, C245, F256, F269, F273, C274, V287, A292, F293, Y295, A299, I301, L302, V323, V326,
			M337, F342, F349, V350, I353, I369, I376, L377, A379, I387, V389, F395, V396, F406, V408, M409, V415, A422
693	Low-density lipoprotein	Q14114	F52, C54, C72, C93, H97, I99, C111, C134, V142, C154, A158, F172, C174, L180, C192, F211, C213, A220, C234, C285,
	receptor-related protein 8		C340, I350, C351, C362, C374, L424, F426, I435, L437, I446, A454, A503, Y512, L570, V601, I634, A635, I651, C700
694	Dihydropyrimidinase	Q14117	L7, L8, I9, V14, V15, A23, V25, V27, V32, L35, A54, V59, L60, I64, H67, H69, M70, M75, I80, F83, A89, A90, L91,
			M97, I98, I99, F101, A102, L110, I111, A113, W117, A121, V125, C126, C127, Y129, L131, H132, V133, A134, V135,
			V142, M146, L149, V150, V155, F158, M160, M162, A163, Y168, V170, L175, A178, F179, C182, I185, A187, I188,
			A189, V191, H192, A193, H217, A229, A233, I234, I236, A237, L244, Y245, I246, V247, H248, V249, M250, A254, A255,
			I258, A261, V268, I273, A274, A275, L277, Y284, A292, A293, H295, V296, M297, L301, L311, M312, L314, L315, L320,
			C328, F330, F342, I345, V349, V352, M356, V358, I359, W360, V364, F374, V375, V377, A382, A383, I385, F386, I395,
			A401, I403, V404, I405, W406, I414, V423, F428, C433, V439, I441, V447, F462, I463, A469, I472, Y473, I476
695	Desmoglein-2	Q14126	L58, L64, I85, Y87, I101, F102, L111, V113, L117, F125, L127, A131, L145, I147, I181, V210, I220, L227, L237, V239,
			A241, A256, V258, I260, I293, V295, A308, V334, L336, V340, V352, I375, V377, F413, A415, Y428, W437, I438, I447,
			Y465, V467, I469, A471, V485, I487, V515, W544, V554, L556, I568, F570, I572, L586, L588
696	Cytoplasmic dynein 1 heavy	Q14204	L2837, V2838, M2953, L2956, I2993, L3115, V3352, V3472, L3645, I3669, V3780, V3790, I3811, L3856, L3947, V4031,
	chain 1		L4158, L4331, F4482, L4514
697	Filamin-C	Q14315	F42, C46, L50, L57, L60, L64, L70, I71, L73, L74, V100, V102, A103, L104, F106, L107, I122, I130, L131, L133, I134,
			L137, I138, I143, L165, I169, V173, F181, W185, A190, L191, A193, L194, V195, A199, C203, A218, A221, M222,
			A225, L229, V231, V234, I235, I240, V250, M251, Y253, L254, A278, A296, V300, A305, V312, V338, H348, V350, V352,
			F354, I359, V366, A590, F592, V593, V594, C626, V628, Y630, Y638, V640, V642, A656, C665, A688, I692, A697,
			C728, I740, I741, I742, V756, V758, V1065, F1083, I1085, A1090, V1119, Y1121, Y1129, I1131, I1133, I1140, A1147,
			I1149, V1158, A1160, V1178, A1183, I1192, I1214, Y1216, Y1224, I1226, I1228, Y1230, V1242, V1253, V1265,
			F1273, V1275, V1292, Y1312, V1314, Y1316, H1324, V1326, V1328, V1342, V1353, F1371, V1373, A1378, V1407, Y1409,
			Y1417, V1419, I1421, I1428, V1435, V1437, V1446, V1457, V1467, A1472, V1481, V1503, V1515, V1517, Y1519,
			V1524, I1531, V1533, V1542, I1554, A1556, F1562, I1564, A1566, A1569, I1578, V1600, Y1602, Y1610, I1612,
			I1614, Y1616, I1621, I1628, A1630, A1636, C1639, I1666, V1668, A1673, V1678, V1682, I1704, A1708, Y1714, I1716,
			I1718, I1725, V1732, A1734, V1793, V1802, I1822, V1824, H1834, M1836, I1838, I1845, V1862, F1880, I1882, V1916,
			Y1918, Y1926, I1928, V1930, F1932, I1937, A1944, I1946, I2003, F2005, H2013, V2015, V2017, V2033, A2041,
			V2044, V2064, V2098, Y2100, Y2108, I2110, I2112, F2114, V2126, V2128, V2254, Y2274, V2276, H2286, V2288,
			V2290, V2306, V2317, F2335, I2337, V2371, Y2373, V2375, Y2381, V2383, I2385, I2392, V2399, V2401, A2402,
			A2408, L2411, L2421, V2431, L2433, A2436, I2440, V2444, I2466, H2476, I2478, V2480, F2482, I2494, V2508,
			L2515, F2526, V2528, A2533, V2561, Y2563, A2567, Y2571, I2573, I2575, Y2577, I2583, A2590, A2635, V2638,
			A2648, V2658, C2660, A2663, V2694, Y2696, V2698, L2706, V2708, W2710, V2715, V2722
698	UDP-glucose 4-epimerase	Q14376	V5, L6, V7, H17, V19, L20, L22, V30, V31, I32, L49, V52, V60, A72, L73, L76, F82, A84, V85, I86, H87, Y104, L115,
	(EC 5.1.3.2)		I118, M119, V124, L127, V128, F129, A133, V135, Y136, L144, H148, I164, I168, W178, A180, V181, L182, L183,
			A191, I197, M209, V212, V225, I242, H243, V244, L247, A248, H251, A253, A254, L255, L258, Y267, L269, M280, V281,
			A283, M284, A309, L313, A314, L318, W320, M329, C330
699	Semaphorin-3A	Q14563	I110, L308, V373, I451, V475, L476, L494, L529
700	Inositol 1,4,5-trisphosphate	Q14571	L9, I11, V15, A19, I27, C37, V38, V39, Y66, V115, L123, H125, L132, A146, F161, I176, L193, V209, W218, L242, H244,
	receptor type 2		C253, L264, A280, W282, I284, H307, A315, A316, L354, F367, H391, V398, I417, F429, A448, L452, L476, V483,
			I514, V518, C556, H562
701	Inositol 1,4,5-trisphosphate	Q14573	L8, I10, V14, A18, I26, C36, V37, V38, Y65, V116, L124, H126, L133, A147, L162, V177, L194, V210, W219, L243,
	receptor type 3		H245, C254, L265, A281, W283, V285, H308, A316, A317, L354, F367, H391, I398, L417, F429, A448, L452, L476,
			V483, I514, V518, C556, H562
702	ATP-sensitive inward	Q14654	L149, L233, L255, L287
	rectifier potassium channel
	11
703	Metabotropic glutamate	Q14833	L83, L86, A328, V341, L353, A363
	receptor 4
704	Transmembrane	Q14956	L274, I279, W283, F285, V293, V299, Y303, F309, A317
	glycoprotein NMB
705	Importin subunit beta-1	Q14974	I6, L7, A21, L25, L40, L44, A53, A56, A57, L59, I61, L65, W80, V91, V95, A109, C112, V113, A114, I116, A117, L129,
			L133, V137, L151, A153, I157, I161, L166, I173, A176, I177, I178, V190, A194, A197, L198, L202, F209, I218, M219,
			V221, V222, V233, A236, A237, L241, I244, M245, M252, L260, A267, M268, V275, A276, I280, F282, W283, V286,
			C287, A300, A301, A315, A318, L319, L322, V323, L326, L330, C345, A347, A348, C351, L352, L355, A356, I363,
			V367, A385, A386, V387, A389, C392, I393, L394, L402, V406, L413, V424, A428, A429, V432, I435, C436, L439,
			A442, A443, L452, C455, L456, L460, A467, V470, C471, A473, F474, L477, A478, A481, L499, F503, I506, V507, L510,
			L524, A528, Y529, L532, M533, I535, V536, A540, C543, A546, V547, I554, L558, V561, L562, L584, C585, L588,
			V591, L592, V595, A600, I603, V607, M608, L611, M614, F615, V624, A628, L629, A631, V632, L635, V636, L639, F643,
			M647, F650, L658, V666, C667, A670, V671, L673, V674, L677, C678, L681, M693, L696, V709, I713, L714, V716,
			F717, I720, A721, F728, V735, L736, L739, A742, L758, C765, L766, A768, Y769, I772, V773, L776, V787, V790,
			V794, I797, L798, F800, I801, I804, V814, V815, A816, A818, A819, L821, I822, L825, A828, V833, V837, I843, L846,
			L847, A858, L861, A862, A865
706	Arf-GAP with coiled-coil,	Q15027	V411, C421, C423, A431, V437, L439, C443, H447, L472, M473, I481, I484, I510, L575, M588, A591, A593, A614,
	ANK repeat and PH domain-		A622, C623, L626, A647, L655, A656, F659, A680, I688, L691, L713
	containing protein 1
707	Lysine--tRNA ligase (EC	Q15046	I84, L105, F108, V128, I132, Y145, L147, L154, V156, A158, L176, I182, V184, I198, I199, L232, V240, I250, I254,
	6.1.1.6)		L258, F263, I266, I274, I298, H304, V308, V315, Y316, I318, C338, F340, L350, M357, V358, M361, V362, V385, F387,
			F391, I394, M396, V397, L400, F414, L423, C427, L443, L444, L447, V448, L452, C456, F461, I462, H465, L472, A473,
			F486, L488, F489, V490, M491, C496, A498, L502, L511, F533, C534, A545, W547, M549, I551, V554, A555, M556, F557, V567
708	Advanced glycosylation end	Q15109	L36, W51, L53, W72, A76, L84, L86, V89, F97, C99, A101, V115, V117, L133, V141, C144, W157, L192, C208, F210,
	product-specific receptor		L214, V238, L257, W271, C301
709	Programmed cell death	Q15116	A50, F52, C54, F56, L65, W67, A80, A81, F106, M108, V110, A113, Y121, C123, A125, A140, L142, V144
	protein 1
710	Plectin	Q15149	F185, W188, V189, L193, A196, L203, L207, L213, I214, L216, L217, V240, A243, L244, L247, L254, I262, A263, L271,
			L273, I274, I277, I278, I283, I286, L301, W304, V309, C317, F320, W324, L329, F330, A332, I333, I334, L341, V347,
			L353, L356, A359, F360, A363, V369, L372, L373, V378, I388, I389, Y391, V392, L395, Y396, Y421, V425, L428, M432,
			I451, L483, V503, L510, L521, C545, L549, A552, L556, V575, L579, A582, L589, V593, L596, V611, L618, L662,
			L665, W668, V669, V688, I702, F705, A712, Y727, L731, L734, L741, L752, L755, F758, V759, A762, L769, L798,
			A826, V830, L837, M844, L847, C850, I851, H854, F864, A871, L875, L918, L921, A925, L931, L946, C950, V988,
			V991, C992, F993, V995, A1002, V1006, L1009, A4418, I4420, I4431, A4434, L4448, L4449, A4453, C4454, I4458,
			I4459, V4469, A4472, I4486, A4489, A4492, A4507, A4508, A4510, A4520, F4524, L4525, A4548, L4562, A4567,
			L4572, A4586, L4600, A4603
711	Nectin-1	Q15223	L49, C51, V65, W67, V78, A79, Y93, I109, L111, Y122, C124, F126, L138, V142, L168, A170, C172, L213, A219, L224,
			C226, I227, V228, L239, V243, L267, C269, L300, F302, Y314, C316, A318
712	Receptor-type tyrosine-	Q15262	Y77, M78, V80, A91, L93, L95, H104, F108, L123, I125, V127, I138, A152, L154, A155, V156, Y164, V166, F168, A170,
	protein phosphatase kappa		I180, A181, I182, F214, C216, L230, A253, F255, Y268, C270, V271, V280, A284, L308, I310, L312, V328, I361,
			L365, I406, V408, C420, I427, V454, V463, L465, M467, L469, I507, L509, Y524, I526, F558, Y567, F569, I571, A573
713	Receptor tyrosine-protein	Q15303	Y53, C56, V58, V59, L63, I65, I68, L77, V80, V83, V87, L88, V89, A90, F94, L97, L99, L102, I104, I105, A116, A118,
	kinase erbB-4 (EC 2.7.10.1)		I119, L131, L134, L136, L139, I142, V147, V149, A158, I166, V167, C197, C234, A235, A248, C258, V298, C334, I337,
			V348, I353, F356, C359, I362, L366, F368, L389, F392, V395, I398, L402, I404, F414, V416, F417, L420, I423, L434,
			I436, I442, L445, F447, L450, I453, I458, I460, L466, C467, L477, C496, C507, C512, W513, C532, V748, I750, A769,
			A773, M775, L780, V786, C787, V795, L804, V808, L820, L821, W823, C824, I827, A828, M831, L834, H841, L844, A845,
			A846, V849, V851, V857, I859, L864, A888, C891, V903, W904, Y906, V908, I910, L913, M914, I929, L933, L939,
			V949, M953, C956, W957, F967, L970, F974, M977, L985
714	Sonic hedgehog protein	Q15465	A58, A94, M98, C102, L106, L109, A110, V113, L122, V124, W128, L139, H140, A145, V146, I148, M160, L161, A162,
			A165, V173, I181, C183, V185, A187, A193
715	Transforming growth factor-	Q15582	V505, M506, L509, F515, L518, A521, I522, L531, V539, F540, A541, A546, L565, H572, I573, L589, L597, V599, V606,
	beta-induced protein ig-h3		V608, V624, V625, H626, V627, I628, L632
716	Myosin light chain kinase,	Q15746	M1536, I1688, L1714
	smooth muscle
717	Neuronal acetylcholine	Q15822	A163, H164, A177, I211, L213, V286, I314, V349
	receptor subunit alpha-2
718	Serine/threonine-protein	Q15831	V77, L80, M127, V128, M139, L140, A153, F157, I161, L164, L167, I172, V173, H174, I177, L182, L190, I192, C210,
	kinase STK11 (EC 2.7.11.1)		V236, W239, A241, V243, L245, F255, I267, L285, L286, M289, I303
719	Syntaxin-binding protein 2	Q15833	L6, V10, I14, V18, I19, V22, V30, L31, I32, M33, I40, L41, I50, I57, I61, A73, I74, Y75, L77, V84, L87, F91, Y99, A102,
			I104, F105, F106, L114, L118, L123, L135, A136, F137, V144, F145, L147, A149, L169, L172, A173, I176, A177, L179,
			C180, A188, I189, L201, A202, V205, L209, L230, L231, I232, M233, A236, A237, V240, L243, L247, F249, M252, A253,
			L291, V299, V303, L326, H346, H348, L349, A350, C353, V361, L364, C365, L371, L388, I389, V392, L393, L394,
			I404, V406, L407, L408, L409, Y410, I411, L412, L422, L425, I426, A429, L437, I438, L441, L444, V448, M466, I479,
			V482, M483, A486, L534, I535, V536, Y537, V538, M539, V542, M544, M547, A549, A550, V553, V563, L564, I565,
			H569, L571, F576, L577, L580, L583
720	Adiponectin	Q15848	A6, L13, P25, V27, L29, G34, G38, I74, P76, I97, A114, F115, V117, F132, F150, L157, Y158, F160, A161, Y162, V166,
			V171, V173, L175, L183, V201, L202, L203, L205, V211, L213, F234, F237, L238
721	NT-3 growth factor receptor	Q16288	I71, L134, L157, L182, A298, V301
	(EC 2.7.10.1)
722	Solute carrier family 15	Q16348	I653, V660
	member 2
723	Acid-sensing ion channel 2	Q16515	F99, L117, Y190, L217, I219, L221, I248, I257, I402, L428, I432
724	Interleukin-17A	Q16552	C94, C99, V121
725	Calcium/calmodulin-	Q16566	C63, L74, V117, L126, F127, Y136, A141, A142, A144, V145, L149, A151, L165, L170, L181, I183, A209, V222, W225,
	dependent protein kinase		V227, I229, I233, L234, C236, F241, I254, W266, L271, A273, L276, V277, L280, A294, W299, L317, F320
	type IV
726	Laminin subunit alpha-3	Q16787	L272
121	Receptor-type tyrosine-	Q16827	L920, F923, M930, F938, F942, L945, A957, Y974, V979, Y992, A995, I998, Y1007, I1008, A1009, F1021, W1022,
	protein phosphatase O		M1024, V1025, I1032, I1033, V1034, M1035, L1036, C1047, Y1050, V1065, F1081, I1083, V1092, H1094, Y1097,
			W1100, I1114, F1117, V1118, V1121, M1132, I1133, I1134, H1135, C1136, V1140, F1146, I1147, A1148, L1149,
			L1152, V1162, I1164, L1165, V1168, M1171, M1178, V1179, Y1185, F1187, I1188, C1191, V1192
728	Toxin B (EC 2.4.1.—)/strain	Q189K3	L562, I578, Y580, I581, V582, A594, F598, A599, V606, L607, F608, A618, L648, F650, F663, L671, I675, I686, I693,
	630 (Clostridium difficile)		L695, M700, F701, Y711, L715, L716, V719, I723, M727, I735, V737, A739, I762, I778
729	Toxin A (EC 2.4.1.—)/strain	Q189K5	L9, A13, Y23, I26, L30, L48, L51, I55, F58, L71, L74, I78, V82, L97, H98, F99, V106, Y113, W117, L128, W129, A134,
	630 (Clostridium difficile)		F135, L136, A152, F170, Y171, M175, I178, I204, I205, L209, I231, I239, L244, Y254, L258, A266, A267, V271, A275,
			L276, V282, L284, M288, L289, I314, L316, A318, I319, F334, F345, I349, I358, F359, V367, L370, I372, I374, A375,
			A385, L386, I387, L394, V398, Y406, L409, L413, A416, F430, L434, L446, I449, F457, A461, L467, A472, Y473, A476,
			Y477, F480, L483, L497, A526
730	Protein Dok-7	Q18PE1	V7
731	Spike glycoprotein	Q1HLC5	Y60, M70, L78, F83, F91, F96, A97, V99, F114, A116, I117, I119, F123, V130, V131, L147, I149, V151, C152, M156,
			C157, H161, I163, L200, H203, F204, F211, A213, F224, Y238, V239, L240, L242, C244, Y252, Y262, L264, C278, A520
732	Lipoprotein, Lp	Q1HP67	W1640, C1665, C1676
733	Endogenous retrovirus group	Q1PHM6	A54, F92, M94, M99, M103, I107, V119, V126, M145, L156, A220, I221, C235, V266, I281, L284, V288, I321, C326, I328,
	K member 113 Env		L337, V340, V341, I353, Y378, C379, F385, C417, I422, I423, V429, A432, M433, L452, L453, I469, F470, W481, L485,
	polyprotein		V491, I493, V507, I550, V551, L557, L558, A560, I561, A563, M567, L568, V572, I575, L578, V582, I637, I644
734	CTLA-4 protein	Q28090	A52, V67, V71, C101, V110, C127, V129, I147
735	Hemagglutinin [Cleaved	Q289M7	V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, V74, A75, W77, I78, L79, C84, L87,
	into: Hemagglutinin HA1		W93, Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A150, C152, H154, L164, L165, L167, L173, L177, V189,
	chain; Hemagglutinin HA2		L190, V191, L192, W193, V195, H196, H197, Y208, Y214, V215, V217, V218, I243, Y245, Y246, L249, L250, I256,
	chain]/strain A/New		F258, A260, L264, I265, A266, Y269, A270, F271, A272, L273, F277, I281, I282, C291, C295, A301, I302, H312,
	Zealand: South		M330, V331, A348, Y365, A387, I388, L461, L469, H485, C487, C491
	Canterbury/35/2000 H1N1
736	HLA class II	Q29974	F36, L37, F46, F47, V53, F55, L56, Y59, V67, F69, Y76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145,
	histocompatibility antigen,		C146, V148, F151, W160, M171, L190, V199, Y200, C202, V204
	DRB1-16 beta chain
737	MHC class I polypeptide-	Q29980	L28, L32, V34, F45, L51, F56, L57, Y59, A66, A73, L96, L100, L113, C119, F133, F140, L141, L145, A158, A162, V165,
	related sequence B		L191, Y194, V223, C225, A227, F230, W239, V268, I272, C282
738	MHC class I polypeptide-	Q29983	L28, V34, V49, L51, F56, C59, C64, A73, L96, L100, L113, C119, F133, F140, L141, A162, V165, L191, I221, V223,
	related sequence A		C225, A227, F230, W239, V268, I272, C282
739	Kinesin-like protein KIF7	Q2M1P5	V18, A19, L20, V47, L49, V70, Y71, V75, A88, V90, F91, A92, M104, I119, V120, A123, V143, Y145, L146, V148, F153,
			L156, V192, V220, F221, V223, L225, F248, F250, V251, A281, L282, V285, I286, A288, I306, I309, L310, L314,
			A318, M322, I323, A324, C325, V326, L340, A343
740	Endogenous retrovirus group	Q2N0S5	A54, A69, M94, M99, V100, M103, L121, L124, L128, L145, C148, M152, F167, L192, A203, C217, A218, A223, I224,
	K member 24 Env		L225, C238, V241, L258, V269, F287, V291, I293, F314, A316, I324, C329, V331, L340, V343, V344, L347, I357,
	polyprotein		F381, C383, F389, L413, C415, I420, I421, I427, A430, M431, Y432, A433, I446, L449, I450, L451, F465, W476,
			L480, V486, I488, V502, I545, V546, L552, L553, A555, I556, A558, L562, L563, V567, I570, L573, V577, I632, I639
741	Endogenous retrovirus group	Q2N0S6	W44, F52, C53, A54, W68, A69, F92, M94, W95, M99, V100, M103, L110, C118, V119, L121, L124, C125, L128, C130,
	K member 8 Env		L145, C148, F150, M152, Y164, F167, L192, C195, I200, A203, C204, C217, A218, A223, I224, L225, C227, C238, V241,
	polyprotein		I250, L258, V269, V285, F287, V291, I293, C295, F314, A316, I324, C329, V331, W336, L340, V343, V344, L347,
			I357, F359, H372, C376, F381, Y382, C383, L388, F389, L413, C415, I417, I420, I421, I427, A430, M431, Y432, A433,
			C442, I446, L449, L451, F465, W476, L480, Y483, V486, I488, A494, V502, I545, V546, L552, L553, A555, I556, A558,
			L562, L563, V567, I570, L573, V577, I632, I639
742	HLA class II	Q30154	F36, L37, F46, F47, V53, F55, L56, L67, F69, Y76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145, C146,
	histocompatibility antigen,		V148, F151, W160, V171, L190, V199, Y200, C202, V204
	DR beta 5 chain
743	Hereditary hemochromatosis	Q30201	L30, Y32, A49, V53, F58, V59, Y61, L87, L91, I105, L118, L122, C124, H145, L146, A162, A176, L183, C187, L191,
	protein		L223, C225, A227, Y230, W239, I268, V272, C282, V284
744	Genome polyprotein	Q32ZE1	I291, C293, V311, V313, V314, L315, C320, V321, V323, M324, A325, V331, I333, L335, V340, Y349, C350, Y351,
	[Cleaved into: Protein		A370, V381, C395, L403, V404, C406, A407, F409, M415, I420, L425, Y427, I429, M430, L431, V433, V455, A464,
	C/strain Mr 766 (ZIKV)		L466, L472, L474, C476, L482, Y488, Y489, L490, M492, H496, W497, V499, F504, H512, L528, V529, V541, L555,
			H574, L575, C577, L579, M581, L584, C594, F598, V612, V614, V616, Y618, C625, I627, M631, A632, L644, I645,
			I651, M660, L662, L664, I673, V674, I675, I811, V978, I1008, V1536, M1539, H1545, M1547, V1570, L1574, V1575,
			Y1577, W1581, V1593, L1595, A1597, V1598, I1613, A1623, V1624, I1637, I1645, L1647, Y1648, V1653, V1660,
			L1703, I1706, V1707, A1710, V1718, I1719, L1720, A1721, V1726, A1727, M1730, L1734, V1756, L1758, M1759,
			H1761, F1764, Y1777, L1779, I1781, M1782, A1785, I1793, A1794, A1795, I1799, A1808, A1809, A1810, I1811,
			F1812, M1813, V1850, V1858, W1859, F1860, V1861, I1870, A1871, C1873, L1874, A1877, I1882, L1884, F1889,
			W1901, F1903, V1904, I1905, A1914, V1921, I1922, V1938, V1946, A1949, A1951, A1952, I1958, Y1969, M1970, A1976,
			A1983, A1988, L1991, L1992, I1995, L1997, A2003, L2005, F2030, V2031, L2033, L2039, W2042, L2043, A2044, V2047,
			A2048, W2059, C2060, I2069, V2078, L2088, A2095, F2107, F2110, A2111, W2528, Y2543, I2548, V2551, A2556,
			A2559, L2560, A2570, V2571, A2576, I2578, L2581, L2587, V2593, V2594, L2596, C2598, A2607, A2608, V2613,
			V2616, Y2619, V2648, C2656, L2659, L2660, C2661, V2672, L2678, V2680, L2681, V2684, W2687, L2688, F2695,
			C2696, I2697, V2699, L2700, C2701, Y2703, M2707, M2711, L2714, L2722, V2725, H2733, M2735, Y2736, W2737,
			V2738, I2745, V2749, L2755, L2756, I2794, I2801, V2842, L2845, W2849, V2880, V2890, M2891, L2898, I2929, A2939,
			A2942, F2948, C2964, C2967, V2968, Y2969, M2994, L2996, A2998, L3001, A3005, F3008, L3009, W3014, M3015,
			V3024, L3032, Y3034, L3036, M3039, A3042, M3047, I3059, A3082, V3085, Y3090, V3094, V3095, V3097, V3107,
			I3110, I3111, V3123, A3126, L3127, F3130, L3133, V3134, V3135, L3137, I3138, M3141, M3149, L3152, V3161,
			L3165, L3173, M3176, A3177, V3178, V3184, V3185, F3192, A3195, L3196, F3198, L3199, M3202, V3224, F3226,
			F3231, I3242, V3243, V3244, C3246, I3253, A3256, A3262, A3270, A3273, A3277, W3280, L3282, F3285, H3286,
			L3290, M3293, A3294, A3296, I3297, A3300, V3301, V3303, H3316, L3328, W3331, V3334, W3335, H3341, I3354,
			L3357, A3378, I3381, V3385, I3391, M3399, L3402
745	N-acetylglucosamine-1-	Q3T906	L139, L154, F161, V191, A228, L230, L243, L251, A267, L269, L271, A300
	phosphotransferase subunits
	alpha/beta (EC 2.7.8.17)
746	Integrin beta-2-like protein	Q3UV74	V127, L129, Y130, F131, L132, M133, V146, L149, L153, L154, L157, I166, F168, I171, F176, F189, L193, L209, A211,
			V212, V213, V215, A216, I222, L231, V232, L233, Y265, L279, I291, F292, V293, V294, Y302, I309, V324, I328
747	Tyrosine-protein kinase (EC	Q3ZC95	F10, L11, F30, L31, L32, L37, I61, C63, V64, V67, F98, F102, V104, Y112, V113, F114, W124, L128, A384, V427, I429,
	2.7.10.2)		I432, F442, A446, M450, L457, V463, C464, I470, I473, L482, L486, L498, L499, C502, V505, C506, A508, M509,
			L512, H519, L522, A523, A524, C527, V529, V535, V537, Y545, V561, V568, I580, W581, F583, V585, L586, M587,
			I590, Y591, I610, L616, A622, V626, I629, M630, C633, W634, F644, L647, I651, V654
748	Envelope glycoprotein	Q3ZLH8	A54, H65, A69, V94, V100, M103, V119, I150, L189, C214, A220, I221, C224, C235, V238, I247, L255, I266, I280,
	gp160		I281, V282, L284, V288, I290, A293, I321, C326, V328, W333, L337, V340, A341, I342, L344, I352, I353, F354, H367,
			C371, F376, C378, L383, F384, L407, C409, I411, I414, I415, V421, A424, M425, I440, L444, L445, F462, W473, L477,
			V483, I485, V499, I542, V543, L549, L550, A552, I553, A555, L559, L560, V564, I567, L570, V574, I629, I636
749	Cytotoxin L	Q46342	L9, V13, Y24, I27, L31, Y46, L49, I52, Y59, L72, F75, L79, V83, L98, H99, F100, Y114, W118, V129, A135, L137, I138,
			L141, I145, A149, F171, M176, I179, F186, I206, L210, L254, L259, V260, A267, A268, I274, L277, V283, Y284, L285,
			I289, L290, L317, A319, I320, F335, F346, I359, F360, L363, V368, L371, V373, I375, A376, A386, L387, I388, C395,
			V399, I403, Y407, L410, F431, I450, L454, F458, L468, V473, Y474, A477, Y478, L481, F501, A527
750	Envelope glycoprotein	Q49DS8	I13, V15, L17, V21, I23, I53, C58, I60, L69, V72, A74, L76, I84, V85, H99, F108, C110, L115, F116, I127, L129, C131,
			I136, I137, V143, A146, M147, I162, L165, L166, L167, F181, W192, L196, V202, I204
751	Cell adhesion molecule-	Q4KMG0	V737, V739, W741, F754, V756, V782, Y791, F793, V795, A797, V815, I832, I843, L845, F862, I864, I891, Y900, I902,
	related/down-regulated by		M904, C906
	oncogenes
752	Cordon-bleu protein-like 1	Q53SF7	V187, I189, L207, L210, I214, C215, L227, L228, L251, A253
753	Receptor protein-tyrosine	Q59FL8	I611, V613, I615, A634, M637, V640, V645, C646, I651, L659, I660, L669, V673, L685, L686, W688, C689, I692, A693,
	kinase (EC 2.7.10.1)		L699, V705, H706, L709, A710, A711, V714, V716, V722, I724, F727, A753, V768, Y771, V773, V775, L778, I794,
			L798, L804, V814, M818, C821, W822, F832, L835, F839, M842, L850
754	Integrin beta	Q59H50	C81, C88, C91, C107, L113
755	Filaggrin-2	Q5D862	L33
756	Guanine nucleotide-binding	Q5JWF2	L686, L687, L688, L689, I699, M703, I738, L742, A745, I746, I749, L756, I774, F789, A793, L796, V802, C805, C817,
	protein G		A818, F821, I825, I828, F862, M864, V867, A886, I887, F889, V890, V891, Y896, F916, L925, V930, I931, L932, L934,
			L939, L940, V944, A980, I984, F988, A994, I1015, C1022, I1026, H1030
757	MAGUK p55 subfamily	Q5T2T1	A73, L96, L108, V164, A173, L185, V188, I201, I212, F214
	member 7
758	Dyslexia-associated protein	Q5VV43	L354, A356, W372, L393, L395, Y403, F405, V407, V409, V422, V424, A629, L644, W660, A679, V681, L684, F691,
	KIAA0319		L693, V695, V709
759	Disabled homolog 2-	Q5VWQ8	L653
	interacting protein
760	Renalase (EC 1.6.3.5)	Q5VYX0	L5, I6, A9, L15, C16, A17, A31, V32, W33, A56, L58, L80, V106, A107, I111, I114, I115, I135, W142, V144, F154, I157,
			V158, L159, V163, I166, I173, L185, Y194, A195, L198, F199, I221, V224, V243, V262, V266, F311, L312, A313,
			C314, F319, I328, A331, V334
761	Hemagglutinin [Cleaved	Q67333	I7, I18, C19, I20, Y22, A24, V31, I34, V41, I47, L48, L56, C57, L59, L65, L67, C70, I72, A73, W75, L76, L77, C82, L85,
	into: Hemagglutinin HA1		W91, Y93, I94, M95, Y106, L116, L119, L120, V123, F126, L132, A148, C149, V151, M161, V162, W163, L164, A174,
	chain; Hemagglutinin HA2		M186, L187, I188, I189, W190, V192, H193, H194, Y205, Y211, V212, V214, L219, L236, M240, F242, L246, L247,
	chain]/strain		I253, F255, L261, I262, A263, Y266, F268, I270, I278, M279, C288, C292, A298, I299, H306, H309, I313, V320, L325,
	A/Singapore/1/1957 H2N2		L327, A328, L331, A345, M357, Y362, A384, F385, A436, L448, H451, V455, L458, V462, L466, C477, H482, C484,
			C488, M489
762	Envelope glycoprotein	Q69994	A52, H63, A67, M92, M97, V98, M101, W109, V117, V124, I172, Y239, C240, A246, I247, C250, C261, V264, I273,
	gp160		L281, L282, V292, I306, I307, I308, L310, V314, I316, C318, I346, C351, I353, W358, L362, I365, V366, A367, L369,
			I378, V379, F380, H393, F395, F402, C404, L409, F410, L430, C432, I434, I437, I438, V444, A447, M448, I463, L466,
			L467, L468, I483, F484, W495, L499, V505, I507, V521, I565, V566, L572, L573, A575, I576, A578, L582, L583, V587,
			I590, L593, V597, I652, I659
763	Hemagglutinin/A/Viet	Q6DQ33	F8, I19, C20, I21, A25, V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71, V73, A74, W76, L77, L78, C83, F86, W92,
	Nam/1203/2004(H5N1)		Y94, I95, V96, A99, C106, Y107, L117, L120, L121, I124, F127, I133, A150, C151, Y153, V163, V164, W165, L166,
			I167, I176, L188, L189, V190, L191, W192, I194, H195, H196, A201, Y207, Y213, I214, V216, L221, M242, F244, F245,
			I248, L249, I255, F257, F263, I264, A265, Y268, A269, Y270, I272, I280, M281, C290, C294, A300, I301, H308, H311,
			I315, V322, L327, L329, A330, A351, M363, Y368, A390, I391, A442, L454, V461, L464, V468, L472, C483, H488,
			C490, C494, M495, A512
764	Tau-tubulin kinase 2 (EC	Q6IQ55	V17, V23, Y36, A38, V47, L49, V51, V67, L68, L71, C78, V92, V93, L101, L119, L121, I125, L126, I129, I132, H139,
	2.7.11.1)		F147, C159, M161, L209, L212, F213, Y214, M215, L216, F219, W226, V235, F255, F258, I262, L276, V279, F280,
			I284
765	Growth/differentiation factor	Q6KF10	F363, C387, A401, I430, C452, C454
	6
766	Iodotyrosine deiodinase 1	Q6PHW0	I116, A123, I149, I181, A188, I190, L191, I192, L193, I194, F195
767	Spike glycoprotein/HCoV-	Q6Q1S2	I485, F487, A489, A491, L509, W541, C577, F579, L581, A583, L596, V598
	NL63
768	Nucleoprotein/strain	Q6TXC0	V33, I36, F39, M43, L56, I57, I63, M66, V67, L68, A70, I96, I116, I119, W120, M136, M137, W139, A153, L154, M163,
	A/Equine/Santiago/1/1985H3N8		M189, V190, L193, I194, I197, I201, Y219, C223, L226, F230, A234, M238, M239, V242, L256, L259, A263, I265,
			L266, C275, L276, A278, Y281, F291, Y296, L307, I312, L315, L328, V329, W330, M331, A332, C333, H334, A336,
			A337, L341, I347, V352, V363, M371, L381, A387, A427, A428, I444, Y487
769	Hemagglutinin/	Q6VMK1	V58, I66, C67, L76, C79, L81, L82, I85, C91, A99, L101, I102, I103, C112, L123, L127, I133, I145, C154, Y162, M165,
	A/Netherlands/219/2003		L168, Y184, A192, L193, I194, I195, W196, I198, H199, Y211, I218, V220, I246, F248, L253, V259, F261, F263, A266,
	(H7N7)		F267, I268, A269, P270, A273, F275, L276, I283, C293, C297, Y298, A353, Y370, A392, L466, L474, H490, C492, C496,
			A514
770	Neuraminidase (EC	Q6XV28	L87, V94, A105, I106, I114, V116, Y121, L122, C124, M131, F132, A133, L134, A145, L158, I159, W161, C176, I177,
	3.2.1.18)/strain		C184, M191, I193, C194, M195, A202, A204, V205, V206, Y208, A220, L224, C231, V232, C233, V240, V241, M242,
	A/Budgerigar/Hokkaido/1/1977		I255, I256, Y257, F258, I276, C279, C281, Y282, V285, I288, C290, I291, C292, A299, V303, I304, I306, Y317, L318,
	H4N6		C319, V322, L323, V350, F353, A354, F355, W362, L363, Y375, M377, L378, V380, A383, I397, I398, A409, F410, I411,
			F420, F424, Y425, V426, L428, V438, I445, V446, A447, L448, A464, I466
771	Tubulin alpha-1A chain	Q71U36	C4, I5, I7, H8, V9, V14, I16, C20, W21, L23, Y24, C25, H28, I30, F52, F53, V62, A65, V66, F67, V68, L70, V74, I75, V78,
			L86, I93, A99, A100, Y103, A104, I115, V118, L119, I122, L125, F135, L136, V137, F138, H139, L153, M154, L157,
			L167, F169, Y172, A174, Y185, I188, L189, L195, C200, A201, F202, M203, V204, A208, I209, I212, C213, L227, L230,
			I231, I234, V235, I238, A240, L242, V250, L252, F255, L259, V260, I265, H266, F267, L269, A270, A273, V288, I291,
			C295, M302, V303, C305, Y312, M313, C315, C316, L317, L318, Y319, V323, V328, A331, I335, V344, I355, V363,
			A369, A374, V375, C376, M377, L378, A383, I384, A387, W388, L391, F395, Y399, Y408, F418, A421, M425, L428,
			Y432
772	Endogenous retrovirus group	Q75760	A54, A69, M94, M99, V100, M103, I107, V119, L121, V126, I151, C154, A171, L190, A221, I222, C225, C236, L256,
	K member 9 Env		L257, V267, I281, I282, V283, L285, V289, I291, C293, F312, I322, A325, C327, I329, W334, L338, I341, V342, I343,
	polyprotein		L345, I354, V355, F356, H369, F371, C373, F378, C380, L385, F386, L407, C409, I411, I414, I415, V421, A424, M425,
			I440, L443, L444, L445, I458, F459, W470, L474, Y477, V480, I482, V496, I539, V540, L546, L547, A549, I550, A552,
			M556, L557, V561, I564, L567, V571, I626, I633
773	Rho-related GTP-binding	Q7L0Q8	V50, C52, V53, L54, V55, V60, L65, V66, Y74, A82, V90, V92, V97, L99, L101, A105, Y118, I123, F124, L125, L126,
	protein RhoU		C127, F128, V130, F136, V139, W143, V144, I147, C151, I156, I157, L158, V159, L175, V183, A188, L190, C191,
			A192, I195, C203, L211, V214, F215, A217, A218, I219
774	Ribonucleoside-diphosphate	Q7LG56	L34, I52, A66, W78, F88, I89, I92, L93, A94, F95, F96, F111, V115, V117, A120, F123, Y124, H134, M137, L141, I142,
	reductase subunit M2 B (EC		Y145, I146, A158, I159, Y164, A169, W171, V187, V188, A189, A191, A192, V196, F197, F198, A203, A204, I205,
	1.17.4.1)		L208, L213, M214, L217, I224, F234, A235, C236, M238, F239, V251, I254, I255, A258, V259, F265, L266, A269, L270,
			V272, L274, I275, M282, I286, A290, L294, F303
775	Ankyrin repeat and sterile	Q7Z6G8	V815, W818, L819, L831, F836, M842, M847, L852, I857, I866, A869, I870, V889, L893, F905, I933, I939, A1064,
	alpha motif domain-		F1065, A1084, C1085, I1105, L1107, V1109, V1114, I1130, I1133, F1146, A1147, Y1148, I1149, C1160, V1162,
	containing protein 1B		F1163, A1171, I1174, L1178, A1181
776	E3 ubiquitin-protein ligase	Q7Z6Z7	A1335, A1338, A1348, L1352, F4001, V4019, V4021, V4026, F4027, L4034, M4042, W4065, Y4066, I4069, M4073,
	HUWE1 (EC 6.3.2.—)		L4080, I4093, F4107, F4109, V4110, I4113, V4114, A4115, A4117, L4124, C4126, F4128, F4132, Y4133, I4136,
			M4146, F4174, V4207, V4210, C4211, M4215, F4226, F4230, I4234, L4238, I4239, I4241, L4247, I4251, I4278, F4281,
			A4284, L4285, A4294, V4300, F4311, F4323, I4325, C4341, L4345, L4347, Y4350, L4356, L4360, A4363, I4364
777	Hemagglutinin [Cleaved	Q82559	A26, L28, C29, L30, A34, V41, V51, L57, V58, I66, C67, V73, C79, L81, I82, M85, L86, C91, F94, L101, F102, I103, F109,
	into: Hemagglutinin HA1		C112, Y113, Y115, Y120, A121, L123, V127, A128, L133, F140, A153, C154, F162, F163, L166, L169, L179, Y193,
	chain; Hemagglutinin HA2		W195, I197, H198, H199, Y210, V217, V219, I245, I247, Y248, I251, V252, I257, L258, I260, L266, V267, A268, F273,
	chain]/strain		I289, C296, I297, I303, I324, L331, A332, A349, W358, Y366, A388, A440, L462, L470, C481, F482, I484, H486, C488,
	A/Equine/Kentucky/1/1981		C492, I493, I496, A510
778	Fusion glycoprotein F0	Q84850	I233, F237, V247, M251, L257, I261, M274, V281, F342, V349, C382, A412, V414, C416, C422, A424, V450
779	Regulating synaptic	Q86UR5	V600, L602, A614, L616, L618, A633, I635, A644, L650, V656, W659, L664, V672, I676, V685, I687, V689, L746,
	membrane exocytosis		V748, L750, L759, V761, V763, A766, V782, M784, V818, F823, L828, I830, V832, L846, I849, L853
	protein 1
780	Fermitin family homolog 3	Q86UX7	L73, L74, I358, V378, F380, L404, I422, V426, L437, C439, A446, W448, M449, A450, C452, L454, A455
781	Transmembrane protease	Q8IU80	I504
	serine 6 (EC 3.4.21.—)
782	Sodium channel subunit	Q8IWT1	L51, C53, L64, W68, L79, I80, V84, I101, I114, I116, L118, L121, C131, V133, L149
	beta-4
783	Interferon lambda-3	Q8IZI9	L27, L45, A59, L65, L75, L82, L85, A93, L94, A96, L98, L102, L126, C136, A161, C169, V174, L181
784	Interferon lambda-2	Q8IZJ0	L31, L49, A63, L69, L89, A100, L106, C140
785	Abl interactor 1	Q8IZP0	V451, A453, L465, I473, V475, I476, C488, F495
786	Kin of IRRE-like protein 3	Q8IZU9	I438, C440, I442, A452, W453, L483, I485, I488, Y497, C499, A501, L514
787	Envelope glycoprotein	Q8J581	C50, A51, H62, A66, M91, M96, V97, M100, I104, L107, V116, L143, I210, Y212, C213, A219, I220, C223, C234, V237,
	gp160		I246, L254, I265, I267, I279, I280, V281, L283, V287, I289, C291, I320, A323, C325, V327, W332, L336, V339, A340,
			L343, I351, I352, H366, F375, C377, F383, L408, C410, I412, I415, I416, A422, A425, M426, I441, L444, L445, L446,
			F460, W471, L475, Y478, V481, I483, V497, I540, V541, L547, L548, A550, I551, A553, L557, L558, V562, I565, L568,
			V572, I627, I634
788	Endogenous retrovirus group	Q8JDI3	A54, H65, A69, F92, M94, M99, V100, M103, I107, L110, V126, I145, M152, V173, I175, L189, F206, I211, Y213, C214,
	K member 21 Env		A220, I221, C235, V238, I247, L255, V266, I280, I281, V282, L284, V288, I290, I321, C326, V328, L337, V340, V341,
	polyprotein		L344, I352, F354, H367, F369, C371, F376, C378, F384, L405, C407, I409, I412, I413, V419, A422, M423, I438, L441,
			I442, L443, F457, M464, W468, L472, Y475, V478, I480, V494, I537, V538, L544, L545, A547, I548, A550, L554, L555,
			V559, I562, L565, V569, I624, I631
789	Neuroligin-4, X-linked	Q8N0W4	I55, V70, Y73, V76, Y78, F88, V109, C110, L132, C146, L147, L149, I151, V153, V168, M169, V170, I172, H173, L190,
			A191, V196, I197, V198, I199, I201, Y203, I207, F210, L211, A218, L224, I228, A230, L231, W233, I234, V238, V248,
			I250, F251, A257, C259, V260, L262, L263, A276, I277, I278, A288, I299, L300, A301, V304, C306, V315, L318, L326,
			I338, I349, Y365, I367, M368, L369, V380, V390, V399, F402, V403, L416, I420, L440, L443, V450, A457, H460,
			Y470, A471, F472, A488, V493, Y495, V496, F497, F508, L519, V523, M524, Y526, W527, F530, A531, A558, L570,
			I572, A584, F589, I603
790	Jouberin	Q8N157	V1057, A1058, I1072, I1078, V1080, F1101
791	Gamma-aminobutyric acid	Q8N1C3	I436
	receptor subunit gamma-1
792	TGF-beta-activated kinase 1	Q8N5C8	L13, L16, V27, V28, M32, C42
	and MAP3K7-binding
	protein 3
793	Inactive dipeptidyl peptidase	Q8N608	L69, V94, V95, L117, V139, A142, A155, V158, L180, A183, L192, I193, Y194, I195, I200, L230, Y231, L235, A241,
	10		L251, A252, L254, I256, I266, Y280, L294, Y295, V296, V297, L299, L306, Y320, I321, V324, V333, V334, W336,
			L337, I345, C349, F385, V388, H400, V401, A402, V425, I438, F440, L452, C475, F489, L490, C493, L503, L545, L547,
			L549, A562, L563, L564, L565, V576, L588, V594, I595, V596, A597, L609, I615, V622, V631, I647, Y655, A657, F668,
			C670, A675, L680, A684, A686, F687, L692, V711, I721, H723, V730, F732, H734, L742, I773, F777, L781
794	Proprotein convertase	Q8NBP7	V80, L82, A95, L98, A102, F122, V124, L130, A134, V140, I143, F150, I161, V180, V182, Y183, L184, L185, H193, I196,
	subtilisin/kexin type 9 (EC		H229, L230, A231, V233, V234, A242, A245, M247, L250, V252, I271, L283, V284, V285, L286, L287, C301, L304,
	3.4.21.—)		V309, V310, L311, V312, A314, A315, A322, A328, A330, V333, I334, V336, A338, V346, V359, L361, F362, A363,
			I368, A371, A388, A389, A390, H391, V392, A393, I395, A396, A397, M399, L400, A409, L411, L415, I424, F429,
			V441, A442, A473, A475, L484, C486, F489, C509, A511, V520, A522, I523, A524, C526, C527, A542, C588, A594,
			I596, H597, A598, C600, C601, A603, L606, V622, A625, L632, C654, V656, V672, A674, A676, C678, C679
795	Cytoplasmic dynein 2 heavy	Q8NCM8	L1352, F1356, F1368, C1411, L1419, L1438, M1476, V1484, V1496, L1511, L1515, W1626, C1640, M1644, Y1655,
	chain 1		C1671, L1675, A1678, V1699, A1736, V1750, L1751, A1753, V1754, A1764, F1788, V1815, A1826, V1872, A1901,
			L1943, A1962, V1975, V1976, I1977, V1978, W1989, L1992, A1995, M2008, I2053, V2069, F2094, A2105, I2113,
			C2182, L2200, F2208, F2254, F2275, W2278, L2279, L2301, A2304, L2354, V2355, L2374, A2376, V2395, V2403,
			L2427, V2474, V2476, V2480, L2524, I2526, A2531, F2548, F2572, L2634, I2640, F2646, L2651, L2653, A2654,
			V2668, A2701, V2708, L2712, F2722, L2751, H2777, L2780, C2803, V2805, M2808, I2819, C2862, Y2872, F2875,
			A3208, A3209, A3317, V3318, L3324, V3332, V3353, I3360, A3383, V3390, L3403, A3496, L3509, A3522, F3571, A3572,
			F3575, W3648, Y3651, C3657, A3694, L3724, L3740, A3754, M3755, A3771, W3776, L3777, A3811, L3822, A3861,
			A3868, F3870, H3871, A3872, C3874, Y3927, I3931, L3944, L4021, L4040, V4090, Y4140, L4141, L4144, I4151,
			A4202, I4217, C4225, C4248, A4301
796	Semaphorin-6D	Q8NFY4	L150, A179, Y199, I211, Y252, A256, V269, F292, L297, A407, V417, L465, C521
797	Protein CASC5	Q8NG31	F2149, Y2151, I2154, L2156, I2158, L2197, I2202, V2233, C2236, L2239, I2243, L2265, L2267, F2269, F2278,
			I2280, L2282, I2309, Y2322, V2326, V2327, I2330
798	Envelope glycoprotein	Q8Q7Z9	M23, I24, I30, L69, A100, I101, C115, V118, V131, L135, L136, V146, I160, I161, V162, L164, V168, I170, C172,
			A192, F193, I196, M202, H206
799	CTLA4	Q8TDA6	A54, C58, Y60, V69, V71, V73, C85, L95, V112, I116, C129, V131, I149
800	2-amino-3-	Q8TDX5	I5, H6, H8, I9, L10, L17, A37, L39, C53, M63, A72, L73, M79, F80, Y82, L92, C93, L96, L100, F111, L114, L117, M119,
	carboxymuconate-6-		A125, M129, C132, V141, I143, V147, L152, L157, V160, Y161, A163, A164, C169, L171, F172, V173, A202, I203,
	semialdehyde decarboxylase		M206, I207, V211, V220, C221, F222, A223, F229, F262, L274, L277, V286, I287, I305, M308, L319, A321, A324, F327
	(EC 4.1.1.45)
801	Partitioning defective 3	Q8TEW8	I12, L434, I499, L509, I527, I533, L550, V553, L558, A566, I584
	homolog B
802	Protein Shroom3	Q8TF72	A30, L32, A63, L70, V76, I79, A91, L102, L104, V106
803	Intelectin-1	Q8WWA0	C41, C48, L58, C70, L81, V82, A83, V85, C94, W100, A129, Y139, L147, I149, H151, V152, W161, L167, L176, L183,
			I186, Y187, W200, V236, F238, V240, F241, A246, A247, A249, L250, C251, M254, H264, C265, F272, C280, F283,
			F286, I303, A306, A307, L309, L310, F311, Y312
804	Palladin	Q8WX93	F1020, C1022, V1024, I1032, W1034, C1058, L1060, Y1073, I1075, A1077, L1090, C1152, M1154, C1156, V1158,
			L1193, I1195, V1198, Y1206, C1208, A1210, L1253, C1255, W1267, I1291, L1293, I1295, A1298, Y1306, V1308,
			A1310
805	Relaxin receptor 2	Q8WXD0	C52, L59
806	Nesprin-2	Q8WXH0	A191, V203, W210, A215, F216, A218, I219, I220, L242, A245, F246, A249, V264, I274, M275, Y277, V278, A279,
			F281, L282
807	Mucin-16	Q8WXI7	L14325, F14327, I14329, L14332, I14353, L14357, L14360, V14389, C14393, A14399, I14407, F14411, L14421,
			V14431
808	Hemagglutinin [Cleaved	Q91MA7	A27, L29, C30, L31, A35, V42, V52, L58, V59, I67, C68, I74, C80, L82, I83, A85, L86, L87, C92, F95, L102, F103, V104,
	into: Hemagglutinin HA1		F110, C113, Y114, Y116, Y121, A122, L124, V128, A129, L134, F141, A154, C155, F163, F164, L167, L170, Y177, L180,
	chain; Hemagglutinin HA2		L193, Y194, I195, W196, V198, H199, H200, Y211, V218, V220, I246, I248, Y249, I252, V253, V258, L259, I261,
	chain]/strain A/Hong		L267, I268, A269, F274, I290, C297, I298, I304, V325, L332, A333, A350, W359, Y367, A389, A441, L463, L471,
	Kong/1/1968 H3N2		C482, F483, I485, H487, C489, C493, I494, I497, A511
809	Alpha-N-acetylneuraminide	Q92185	W68, F78, C85, C86, F92, M105, Y107, I117, C138, A139, V140, V141, I146, L147, C152, I156, F161, V162, C165,
	alpha-2,8-sialyltransferase		L167, V178, L184, V185, I191, I192, L199, F206, Y213, A222, F223, L233, V235, Y236, L239, A244, F262, W263,
	(EC 2.4.99.8)		A270, L273, A282, A283, L284, L286, C287, V290, Y293, W296, F298, I307, Y311, Y312, L316, F321, A323, M324,
			L334, L340, C347
810	Nicastrin	Q92542	C50, L53, L54, C62, I73, V85, M95, V96, L98, F103, M108, L111, L121, A122, V123, W164, L171, F176, F178, I180,
			F181, L182, L183, V191, I192, L212, C213, A214, M215, L217, C230, C248, L251, V256, W257, M259, V275, V276,
			V277, A278, A279, L282, F288, A292, A295, A298, V299, A300, F302, V303, L306, A307, A308, A309, A311, L312,
			A315, V325, M326, F327, V328, F329, F330, F335, Y337, I338, M347, V354, F362, L365, V368, L376, M378, V394,
			L397, L401, F430, V439, L441, A442, L471, A484, L487, A488, V490, A491, V493, L494, L498, Y499, L501, A502,
			V511, A513, V518, L521, L522, F525, A529, F534, L538, H553, I555, V566, V567, A570, L571, V605, C620, A628,
			A630, A634, A658, I660
811	Protein NDRG1	Q92597	Y73, C92, A119, I145, W183, H214, L284
812	Nectin-2	Q92692	L52, C54, V68, W70, A83, F85, L103, L127, Y138, F142, L156, V180, A181, C183, V236, C238, V240, L255, V257,
			V263, W272, L314, C329, V331
813	Ryanodine receptor 2	Q92736	L14, V20, V21, L22, C24, A26, L35, C36, L37, A38, A39, I64, C65, F67, L69, L78, L113, Y115, A118, I119, L121, H123,
			L130, C131, A144, V147, L149, C158, W160, I162, V175, L181, L183, L192, V203, A205, A206, W212, V214, L228,
			L234, L236, H238, C244, L245, V247, V260, Y262, V267, A271, L274, W275, L277, I289, F295, L297, H299, V300,
			Y305, L306, L315, L316, A322, F329, F331, I354, C361, I363, L372, A391, I403, L405, A416, V418, I419, F426, F429,
			L447, V452, L456, L459, I460, F463, L482, L488, F489, M494, V498, C501, I502, L505, F514, A518, I529, L530, L533,
			L536, A539, L540, W697, A698, V718, C757, I766, V791, V792, A886, F921, V996, A1000, H1004, L1050, V1054, V1115,
			W1117, L1128, A1134, A1136, F1137, V1162, C1164, V1166, M1173, F1175, F1195, V1204, V1443, W1445, I1446,
			L1459, V1465, V1467, L1469, I1507, L1518, F1520, A1542, F2720, A2725, H2727, H2729, L2779, M2782, M2828,
			M2840, M2844, A2845, A2889, I2892, L2893, L2896
814	Serine protease HTRA1 (EC	Q92743	C53, C76, L132, L150, V175, I179, A182, V183, V184, H185, I186, L188, F207, I208, I215, V216, A219, V221, V222,
	3.4.21.—)		V228, V230, A240, A249, I251, A252, I254, I256, V279, V280, A281, I282, V297, I317, A321, I323, L332, V333, V339,
			I340, I342, F353, A354, I355, I360, F363, I383, A395, L398, A412, I414, A423, L428, V433, I434, I437, V448, I452,
			L458, M460, V462, I471, V473
815	Secreted frizzled-related	Q92765	A63
	protein 3
816	Ras-responsive element-	Q92766	C701, C792, C805, C1514
	binding protein 1
817	Disks large homolog 3	Q92796	I132, L134, L141, A146, V154, I160, I162, A170, A171, V179, V183, L184, V186, V191, A199, A202, L203, A206,
			V210, L212, V214, V227, L229, L236, I240, I255, I257, A265, A266, L278, V281, L286, A294, L298, V305, L307,
			V309, A310, I387, L389, I409, F410, V411, A420, L426, I432, V435, A448, A451, V459, I461, A463
818	X-linked retinitis	Q92834	A13, V14, H46, A48, V49, V50, L56, M58, F59, L67, V81, V89, A92, H98, L100, V101, V108, A110, L119, I133, A153,
	pigmentosa GTPase		A154, L155, L161, M163, W164, I172, H201, A203, F204, V205, L211, V213, F214, L222, L228, H254, V256, V257,
	regulator		V263, F266, L274, L280, I289, H306, A308, L309, L315, M316, F319, C343, H360, M361, V362, V363, A365
819	Ectodysplasin-A	Q92838	L90, V251, L253, V262, L271, L293, V295, Y301, I303, V307, V309, Y311, I312, F314, A318, Y320, V322, I336, C346,
	(Ectodermal dysplasia		I360, V362, I369, I371, M373, F380, A382
	protein)
820	Canalicular multispecific	Q92887	A668, V669, L680, A683, M684, I1330, V1332, V1333, L1343, L1347, F1348
	organic anion transporter 1
821	Tumor necrosis factor	Q92956	C53, C54, C57
	receptor superfamily
	member 14
822	Lipoma-preferred partner	Q93052	C444, L451, C476, I483, A494, F500, C524
823	Homogentisate 1,2-	Q93099	L61, Y62, W97, F112, V113, L119, C120, L131, A132, I133, I135, F136, L137, C138, C146, F147, F154, L155, I156,
	dioxygenase (EC 1.13.11.5)		V157, L163, I165, F169, M172, V174, I179, C180, V181, I182, M186, F188, I190, Y199, I200, L201, V203, F208, L221,
			F227, V239, V245, I246, L253, A256, F263, V265, A267, W268, Y277, V300, L301, A303, A313, F315, I317, F342,
			L345, A397, F398, F400, Y423
824	Interleukin-22 receptor	Q969J5	F41, L45, F61, V62, C118, L120, Y131, V135, F152, V176, L178, L183, V205, A241, I243
	subunit alpha-2
825	SH3 domain-containing	Q96B97	A4, V6, L18, I20, I26, W37, F48, V53, C103, V105, L117, L119, I125, V127, L140, F147, I152, C272, V274, L286, I288,
	kinase-binding protein 1		V294, W307, F318, V323
826	Interleukin-17 receptor A	Q96F46	L48, V93, A94, I96, W98, A112, L114, F129, L135, F144, F149, V150, V151, Y157, V159, V161, H163, V182, M190,
			C196, L217, V219, F221, Y230, I232, L234, V281, I283, F287
827	Leucine-rich repeat and	Q96FE5	V55, C57, L76, L78, I83, L86, F91, L97, L100, L102, V107, A114, F115, L118, L121, L124, L131, V138, L142, L145,
	immunoglobulin-like		L148, I150, L158, F163, L166, L169, L172, V174, L179, A186, F187, L190, L193, L196, L198, C201, A210, L211, L214,
	domain-containing nogo		L217, L220, L222, I230, L241, L244, I246, W249, L252, C259, L260, L265, L268, I270, A282, L286, L289, I299, L310,
	receptor-interacting protein		L313, L318, L323, A330, F331, L334, L340, V342, L347, L350, V354, L361, L364, L366, L371, L377, V380, F381,
	1		L387, F389, C396, V402, F407, A424, F444, C446, W458, L482, V484, A487, Y495, C497, A499, A510, L512
828	PDZ and LIM domain	Q96HC4	L8, W14, L28, I30, A39, V49, V50, I53, A58, M61, A66, I70, L77, M79, L81, C420, I427, L432, C446, M453, F458,
	protein 5		V459, C467
829	E3 ubiquitin-protein ligase	Q96J02	L20, I22, V24, V43, V45, V47, V71, V73, L79, F81, V83, L95, I102, L106, L113, L122, L135, I137, L139, L328, L440,
	Itchy homolog		F456, F496, F535, C539, I550, V552, F558, I565, L573, V579, I580, V592, W596, F597, L600, L611, F638, F640, I641,
			F644, I645, A646, M647, A648, Y664, I667, L677, F705, A742, F757, F761, I764, L765, L770, F773, L778, L782, W793,
			I809, F812, F815, V816, M825, L827, L828, V831, F842, F854, C855, I856, C871, L875, L877, L886, L890, A893, I894
830	Serine/threonine-protein	Q96J92	L210
	kinase WNK4 (EC 2.7.11.1)
831	Roundabout homolog 3	Q96MS0	C143, I572, L574, I591, V616, F627, V629, A631
832	NACHT, LRR and PYD	Q96P20	L10, L14, F25, L29, L54, A55, M58, A67, W68, A69, M70, A71, I74, F75, A87
	domains-containing protein
	3
833	Interleukin-17F	Q96PD4	C102, C107, V129
834	SLIT and NTRK-like protein	Q96PX8	Y61, L63, L65, L70, L73, F78, L87, M89, L94, A101, F102, L105, V108, L111, I113, I118, F121, L129, L132, L135,
	1		A137, L142, A149, F150, L153, L156, L159, L161, I166, V173, F174, L182, L184, L189, V197, L198, I201, I207, L208,
			L209, W214, C216, L220, L223, A234, V239, C241, L247, L252, I387, I390, F395, L401, L404, L406, I411, F419, L422,
			L425, L428, M430, L435, L438, F443, L446, L449, L452, V454, I459, I462, F467, M470, L473, L476, L478, L483, V490,
			F491, L496, L499, L501, F506, V514, L515, I524, L526, W531, I537, F540, L556, F569
835	Membrane-associated	Q96QZ7	F318, Y377, L475, L496, I498, A507, M513, V518, I519, V520, V522, V527, L528, V535, V548, L550, L552, C553,
	guanylate kinase, WW and		I646, I686, V689, V694, V702, V715, L717, V719, I842, L844, I865, I867, A876, L888, I889, V891, V896, V904, A911,
	PDZ domain-containing		V917, L919, V921, V999, I1001, I1038, A1047, L1053, V1062, I1075, V1086, L1088, V1153, L1166, L1176, A1187,
	protein 1		M1193, I1199, I1202, A1215, L1218, V1226, L1228, L1230
836	Envelope glycoprotein	Q993A8	A13, M38, V44, M47, I51, V63, V70, I97, L136, A167, I168, C182, V185, I194, L202, L203, V213, I227, I228, V229,
	gp160		L231, V235, I237, C239, M269, C274, I276, W281, L285, I288, A289, L292, I302, I303, F304, H317, F319, C321, F326,
			C328, L333, F334, L359, C361, I366, I367, V373, A376, M377, I392, L395, L396, L397, I410, F411, M418, W422, L426,
			V432, I434, V448, I491, V492, L498, L499, A501, I502, A504, L508, L509, V513, I516, L519, I523, I578, I585
837	Neurogenic locus notch	Q99466	C472, C510, C548, C586, C965, L1638, H1639, A1641, A1642, A1650, L1671, H1672, A1674, V1675, A1679, V1682,
	homolog protein 4		C1683, L1686, L1705, M1706, L1707, A1708, A1709, L1716, L1720, A1737, L1738, H1739, A1741, A1742, A1749,
			A1750, L1753, L1771, F1772, L1773, A1774, A1775, V1782, A1783, L1786, V1806, A1807, L1815
838	Protein deglycase DJ-1	Q99497	A6, L7, V8, I9, L10, A11, A14, V25, M26, V33, A36, L58, A61, Y67, V69, V70, V71, L72, A79, L82, V88, L92, I102,
			A103, A104, I105, A111, L112, L113, H115, I117, V123, M133, M134, I152, L153, F164, A165, I168, V169
839	Histone H2B type 1-N	Q99877	V42, V45, L46, A59, M63, V67, I70, F71, I74, A75, A78, A82, I90, I95, A98, V99, L103, A108, A111, A118
840	Myocilin (Myocilin 55 kDa	Q99972	V269, W270, W286, I288, V298, Y301, F307, H316, L318, A327, V329, L334, F336, V344, I345, Y347, L349, I360,
	subunit) (Trabecular		A363, L381, V383, L388, V390, I391, I401, L403, L406, L411, V426, A429, F430, I431, I432, L436, V449, M476,
	meshwork-induced		L486, W489, M494
	glucocorticoid response
	protein) [Cleaved into:
	Myocilin, N-terminal
	fragment (Myocilin 20 kDa
	N-terminal fragment);
	Myocilin, C-terminal
	fragment (Myocilin 35 kDa
	N-terminal fragment)]
841	Semaphorin-3C	Q99985	L305, L449, L472, I473, I491, L526
842	Sclerostin	Q9BQB4	C80, L146, C165
843	Programmed cell death	Q9BUL8	L22, A41, A46, A51, L81, F100, L103, A107, L110, L114, I117, F127, I134, L141, V145, V148, L160, F167, F174,
	protein 10		V190, F191, A194, L197, I198, I204, L205, F208
844	Brother of CDO	Q9BWV1	V622, V624, W626, F639, V641, I668, Y677, F679, V681, A683, V701, I718, I729, L731, F748, I750, I777, Y786, I788,
			M790, C792
845	Complement C1q tumor	Q9BXJ0	A108, L123, F125, F143, C145, Y151, F153, V155, V159, L164, L168, L199, V205, V207, F227
	necrosis factor-related
	protein 5
846	Periaxin	Q9BXM0	V44, A53
847	Complement factor H-	Q9BXR6	Y53, I70, C87, V110, I127, C129
	related protein 5
848	Disintegrin and	Q9BZ11	L212, L214, Y215, I216, V217, A218, L237, V240, V244, L247, L248, I253, W263, L279, F282, L283, A298, L300,
	metalloproteinase domain-		L301, V328, A339, A340, M343, A344, I347, L351, M373, L405, C433, C444, C457, C462, C488, C495
	containing protein 33
849	NACHT, LRR and PYD	Q9C000	L13, L21, F24, L28, V53, A54, L57, A66, A70, W74, L82, V136, F365, F801, A824, V825, L828, L842, L844, C847, L849,
	domains-containing protein		C854, L870, L872, L877, A882, C886, L899, C904, C910, C911, L918, L927, L929, V939, L942, C943, L946, L953,
	1		L956, L958, M967, L971, L974, I983, L1379, V1382, L1389, I1390, V1393, V1396, V1399, L1400, L1403, L1408,
			V1416, M1426, L1429, L1444, A1447, L1448, L1459
850	MCG4778	Q9D1H1	L75, F77, I79, L82, I88, I103, L107, L110, V140, C144, A150, I158, F162, L172, V182
851	Amyloid beta A4 precursor	Q9DBR4	V594, L611, A614, V630, M632, V639, V641, C654, V656, L659, F661, M662, V664, F671, A672, F673, I674, C684,
	protein-binding family B		V686, F687, C689, A693, V696, V700, A703, N738
	member 2
852	Sperm-egg fusion protein	Q9EQF4	M28, C47, W50, C55, C86, A93, C95, F96, C99, L103, V120, V123, L125, C126, C130, W133, C137, F169, F173, L179,
	Juno		C180, I183, F188, C200, L201, V216
853	Fibroblast growth factor 23	Q9GZV9	H41, L42, L53, I55, A72, L73, I85, L94, C95, M96, C113, F115, V126, L135, V136, F157
854	ADP-ribosylation factor-like	Q9H0F7	V20, L21, C22, L23, I33, I34, F58, M70, A89, I90, F92, V93, I94, V104, L109, L112, I118, I125, L126, F127, F128,
	protein 6		A129, V143, L149, C160
855	Magnesium transporter	Q9H0U3	L44, I54, M56, L64, V65, Y72, V74, I75, V76, M77, F78, C90, A93, F97, L100, A101, I114, F116, V119, V127, F128,
	protein 1		F139, A163, I166, I170
856	ATP-binding cassette sub-	Q9H221	L195, L234, L264, A422, A546, A548, A549
	family G member 8
857	ATP-binding cassette sub-	Q9H222	V72, I81, M82, C83, I84, L85, L95, L96, L139, L142, V144, L148, Y150, A155, V168, M172, I185, A204, M214, L215,
	family G member 5		F216, L235, A239, I244, V245, I249, I263, A264, F273, M280, F284, F298, Y301, Y329, L371, V375, A415, L423,
			F426, V427, M435, A438, F442, V448, Y458, M463, M464, A466, Y467, V471, A478, F482, C486, Y487, L490, L492,
			A505, L506, A508, H510, L511, L518, L521, V530, V534, C571, I574, L575, V576, F580, C613, A616, L627, F642
858	Cadherin-23	Q9H251	I42, L55, F78, V87, L89, V103, F105, V107, V118, I120, V122, V154, V187, V189, V205, A207, L222, I224
859	DnaJ homolog subfamily C	Q9H3Z4	L16, Y17, L20, I31, A53, I60, A63, L67, I75, V95
	member 5
860	SPARC-related modular	Q9H4F8	I416
	calcium-binding protein 1
861	Anthrax toxin receptor 1	Q9H6X2	L45, Y46, F47, I48, L49, V55, I62, Y63, F65, V66, L69, L78, M80, F82, I83, V84, F85, L109, L113, M120, F124, A127,
			I131, I145, I146, A147, L148, F159, A165, V175, C177, V178, V180, L188, I191, A192, L208
862	Pleckstrin homology	Q9HB21	L14, F30, L32, F39, F81, V82, M83, L92, W103, V106, L107, C198, L215, I220, I235, C246, L257, F258, I260, V269,
	domain-containing family A		V284
	member 1
863	Transient receptor potential	Q9HBA0	L487
	cation channel subfamily V
	member 4
864	Interleukin-21	Q9HBE4	L35, V39, L42, A56, C64, A68, F69, C71, F72, L77, I89, L96, F129, L130, F133, L136, L137, I141
865	E3 ubiquitin-protein ligase	Q9HCE7	I15, L17, V19, A22, L25, L33, A38, I40, V42, L68, I76, I78, V80, I86, F94, I133, V135, F324
	SMURF1
866	Roundabout homolog 2	Q9HCK4	C110, A435, L437, W451, L473, L478, Y486, C488, A490, A501, L503, V538, L540, I557, V582, F593, V595, A597,
			V637, V652, V654, I665, Y668, V670, L699, I710, V712
867	Golgi-associated PDZ and	Q9HD26	L291, I313, I315, A324, L330, A335, I336, A338, V339, L344, A352, L356, I363, F365, V367
	coiled-coil motif-containing
	protein
868	Neurexin-3-beta	Q9HDB5	I96, L113, V115, F117, I125, L126, V127, I129, L139, L141, I143, I148, V150, F152, I159, I161, V168, V176, A185,
			L187, V189, V194, L204, F207, I213, I215, F224, L228, L231, Y233, V238, L239, V255, V261
869	Neuraminidase (EC	Q9IGQ6	L85, I106, V114, V116, F121, I122, F132, F133, L134, L158, C161, A178, W179, A181, A183, C184, L191, I193, I195,
	3.2.1.18)/strain A/Brevig		A202, V203, A204, L206, L224, A232, C233, V234, F239, I241, M242, A251, Y253, I255, I258, V263, H275, Y276, C279,
	Mission/1/1918 H1N1		C281, Y282, V288, C290, V291, C292, V304, F306, L310, C318, V321, F322, F349, F351, Y353, V357, W358, I359,
	(Influenza A virus (strain		F371, M373, I374, F387, I393, V394, F406, V407, M418, C421, F422, W423, V424, L426, W437, I443, F445
	A/South Carolina/1/1918
	H1N1))
870	Spike glycoprotein	Q9J3E7	L79, V87, F92, F100, I104, A106, V108, F123, I126, V127, I128, F132, V139, V140, I141, I148, V152, C153, C158,
			C165, A201, F202, F206, F213, A215, F226, I232, V241, L242, F244, C246, Y258, V260, A482, Y891, V900, V906,
			A994, A1053, L1067, I1113
871	Interleukin-23 subunit alpha	Q9NPF7	C33, L40, A44, L82, C89, L90, I93, H94, L97, Y100, F109, L124, L128, L131, L150, L169, V173, A176, V179, F180
872	SLAM family member 7	Q9NQ25	F39, I51, W53, L90, L95, L122, V124, Y125, L128, W164, L180, C195
873	Serine protease inhibitor	Q9NQ38	C30, F33, C44, C63, C66, C161, L173, C194, C197, C225, L237, C258, C261, C297, L309, C330, C333, C367, L379,
	Kazal-type 5		C400, C403, C437, L449, C470, C473, C496, L508, C529, C532, C567, L579, C600, M602, C603, C632, L644, V653,
			C665, M667, C668, C707, L719, C740, C743, C774, L786, C807, C810, C849, L861, C882, C885, C916, L928, C949,
			C952, C1014, Y1021, L1027, C1028, I1040
874	Ubiquitin carboxyl-terminal	Q9NQC7	V131, V133, V146, V165, L167, C193, V195, F196, V236, L238, V249, L255, V265, V267, C286, I295, A476, I488,
	hydrolase CYLD (EC		A502, L504, A531, I594, L603, L607, F608, C609, L610, F611, A612, Y633, L640, V645, V654, I659, L662, L666, F685,
	3.4.19.12)		L689, I693, L700, I717, I730, F745, L752, I754, M756, L775, I777, L780, C788, C802, F816, A863, V864, L865, C866,
			A874, F875, V876, L886, F888, V906, C909, V912, A935, C945, Y947
875	Potassium voltage-gated	Q9NS40	I30, A32, C44, F48, C49, M51, V59, C64, C66, I82, A83, V96, Y98, I112, I127, A766, A781, L785, I790, I807, F808,
	channel subfamily H		V825, A827, L833, V844
	member 7
876	Septin-11	Q9NVA2	F42, I44, L45, C46, V47, L57, M58, V92, L94, L96, V99, Y114, I117, I121, F125, L129, A149, C150, L151, I154, M169,
			L172, V176, I178, I179, I181, I182, A183, F196, I200, M228, F234, V237, A252, V262, F270, L273, M276, L285,
			H293, Y294
877	Alpha-parvin	Q9NVD7	L268, V272, H275, L276, V283, L286, F290, L296, V297, L299, M300, V308, V327, A330, M334, L339, I349, L358,
			V360, L361, L364
878	Sodium channel subunit	Q9NY72	L43, C45, V60, W62, V103, I105, V107, Y118, C120, V122
	beta-3
879	Endoplasmic reticulum	Q9NZ08	F47, Y57, Y63, L65, I67, L71, F76, V82, I84, A86, I93, I94, L95, A105, L107, L115, L123, I131, A132, L133, L139, L140,
	aminopeptidase 1 (EC		V141, Y145, V147, V148, I149, Y151, Y163, L177, A178, F182, A186, A187, A190, F191, C193, F194, A201, F203, I205,
	3.4.11.—)		I207, F236, M242, Y245, L246, V247, A248, F249, I250, I251, V267, V269, A271, A279, Y281, A282, L283, A285,
			A286, L289, L290, Y293, F297, L308, A309, A310, I311, F314, A318, M319, W322, L324, Y327, A331, L332, L333,
			I347, V351, A352, L355, A356, H357, W359, F360, L363, M366, W369, L372, W373, L374, F378, A379, F381, M382,
			V387, L394, V396, F405, A407, M408, A412, V419, V423, M432, V436, A442, C443, I444, L445, L448, F457, I461,
			L465, L478, W479, M482, V517, M520, M521, W524, F530, L532, I533, I535, V542, M544, Y549, W563, V565, L567,
			L582, F600, M604, Y607, Y608, I609, V610, L620, L624, V631, A637, L639, I640, A643, L646, I654, A657, L658,
			L660, Y663, L664, V673, L680, M687, V695, F699, F702, L703, L731, L732, A735, C743, A747, V767, A770, V771,
			A776, W782, L785, I801, A804, L805, C806, L814, L817, L818, I827, F832, I835, L836, I839, A849, W850, L853,
			L860, F864, I871, M874, V875, F882, V891, F895, L898, L905, I915, I929, L933
880	Interleukin-1 receptor	Q9NZN1	L66, V347
	accessory protein-like 1
881	Programmed cell death 1	Q9NZQ7	V21, M36, I38, C40, L53, V55, W57, M59, I64, I65, F67, Y81, L92, A97, A98, L99, I101, V104, Y112, C114, I116, I126,
	ligand 1		V128, A132, Y134, L153, C155, A157, A163, W167, V193, L197, F207, C209, F211, L214, L224, I226
882	Potassium voltage-gated	Q9NZV8	L66, F84
	channel subfamily D
	member 2
883	Signal-regulatory protein	Q9P1W8	A49, L51, C53, V64, W66, I104, I109, C119, V120, F166, C168, F173, W182, A211, V213, L215, V224, C226, V228,
	gamma		L244, A247, I248, V269, C271, V273, F276, L283, W285, C329, V331
884	Spastin (EC 3.6.4.3)	Q9UBP0	V116, A123, A130, A145
885	Glyoxylate	Q9UBQ7	V9, V11, L23, A24, A26, V49, A50, A52, L55, L56, C57, V63, L68, V77, I78, I93, A112, A115, L118, L119, C123, V156,
	reductase/hydroxypyruvate		I158, A167, I168, A169, L172, L181, A192, L205, A206, F211, I212, V213, V214, C226, F230, F231, A238, V239,
	reductase (EC 1.1.1.79)		F240, I241, V248, L254, A257, A264, A266, L268, V270, L282, A309, A310, L313
886	Beta-1,4-	Q9UBV7	L95, A96, V97, L98, V99, F111, V112, M115, L119, I128, V130, L131, A142, L144, I145, V147, I159, A160, H162,
	galactosyltransferase 7		L166, L167, L173, Y175, H184, V185, A186, L190, V200, I203, L204, L205, L206, Y211, M217, F231, I235, L242,
			L258, A262, A305, L310, I312, C324
887	Fibulin-5	Q9UBX5	C166, C286
888	5′-AMP-activated protein	Q9UGJ0	M265, C270, I273, V289, A292, L296, A304, L306, L318, I320, F323, I324, I326, L327, L341, I346, A368, L370, A373,
	kinase subunit gamma-2		V374, L377, L385, V387, L399, H401, I404, L405, L408, F420, L425, I430, I445, A448, L449, I457, L460, V462, Y473,
			V478, A482, L490, V494, L498, C511, L517, I520, V529, L532, V533, V534, V535, I545, L547, I550, L551, A553, L554
889	Deleted in malignant brain	Q9UGM3	A1896, V1899, I1901, V1910, C1911, A1920, V1922, V1923, C1924, A1981, V1983
	tumors 1 protein
890	Interleukin-20 receptor	Q9UHF4	M50, L54, L82, C95, L97, A110, V112, I151, V153, M172, L179, Y181, V183, V185, V216, V218
	subunit alpha
891	Doublecortin domain-	Q9UHG0	I141, L143, I144, I158, V169, V173, L187, V195, Y207, V208, A209, V210, Y220
	containing protein 2
892	DNA polymerase subunit	Q9UHN1	L69, C73, F78, L79, L106, L110, W114, V118, V125, A130, L185, A189, L190, Y193, L197, Y206, L208, A209, C214,
	gamma-2, mitochondrial		A237, L239, V240, W241, F242, W255, W262, W263, F266, F273, L289, F293, W295, I303, L303, L311, L322, V335,
	(EC 2.7.7.7)		L336, V338, L342, M346, L347, A348, Y349, V371, L372, L374, L378, A379, V383, A384, L385, V387, L395, C399,
			L402, L406, L407, L418, I437, L438, V441, V443, I453, L471
893	C-type lectin domain family	Q9UHP7	C86, F87, C103, A108, L110, A111, V113, L122, H131, W132, I133, L135, F155, C163, A164, L166, I183, C184
	2 member D
894	Apolipoprotein	Q9UIR5	W35, C60, C71
895	Gap junction delta-2 protein	Q9UKL4	C62
896	Endoplasmic reticulum	Q9UKM7	V253, F257, A260, Y264, A268, L274, L287, L289, L291, I292, A294, L295, M298, A310, V314, L318, F320, V326,
	mannosyl-oligosaccharide		L328, I335, L336, L339, L340, A342, F351, A355, F358, L362, A365, I372, V377, I379, V395, I401, L403, F405, L408,
	1,2-alpha-mannosidase (EC		F417, V421, V424, I428, L438, V439, I443, L458, A462, Y466, Y468, L470, I474, Y487, A490, I491, V494, L498, F509,
	3.2.1.113)		V510, L513, M522, C527, L529, L533, A534, H545, L548, A549, L552, M553, C556, M559, L567, V572, V585, L596,
			V601, L604, F605, L607, Y616, I623, L624, I641, V644, M656, F660, L661, L665, Y667, L668, L670, L671, V685, F686,
			A690, H691, L693
897	Disintegrin and	Q9UKQ2	C423, C434, C452, C453, C485
	metalloproteinase domain-
	containing protein 28
898	Frizzled-4	Q9ULV1	I50, C53, A75, L79, L94, F97, L98, C99, V101, Y102, V103, C117, C121, V124, C128, L132, F135, L143
899	Heat shock factor protein 4	Q9ULV5	L21, L24, L27, V28, I37, F46, V48, F54, V58, L59, F71, L75, F101, F106, L114, V117
900	Neurogenic locus notch	Q9UM47	C194, C428, C466, C504, C617, C884, C921, C1405, C1417, F1437, C1446, C1451, F1456, C1475, A1476, L1513,
	homolog protein 3		V1514, L1515, V1517, L1524, F1531, L1535, L1539, V1582, L1584, I1586, A1604, A1607, A1608, L1611, A1613
901	Unconventional myosin-VI	Q9UM54	A9, I31, A43, C63, L65, A71, L73, L74, I77, I86, V90, I93, L94, I95, A96, I103, I112, V127, F128, A129, I130, A131,
			A134, M138, V140, I147, I148, V149, A155, V164, Y167, L168, A185, L188, L189, A191, F192, A195, F206, F209, I212,
			F214, V220, I235, Y245, H246, I247, F248, Y249, L251, C252, L265, F271, Y273, L274, Y281, F282, I318, M320,
			M324, I327, L337, V340, V341, A342, V344, L345, L347, I350, L372, C375, A376, L378, L379, L381, L386, L390, A416,
			A419, A422, L423, A424, V427, Y428, L431, F432, V435, V436, V439, I452, V454, L455, F471, Y475, C476, L480, F483,
			F484, I488, L489, Y496, C514, I515, L517, I518, I525, I528, L529, F543, V547, F577, I578, I579, V586, Y588, F593,
			L605, I609, I617, L651, L654, L655, L658, F665, I666, C668, I669, I685, L689, M694, V697, L698, M701, Y705, A709,
			L714, Y718, Y721, L729, F734, C735, A737, L738, F739, L753, V756, F757, F758, F763, A764, I769, L777, L780, V784,
			I1171, F1180, A1204, H1205, F1206, A1212, M1215, L1226, V1227, M1235, L1245, F1258, W1262, L1271, A1274,
			I1275, A1280, A1285, L1289
902	Rho GTPase-activating	Q9UNA1	A761, A763, L775, F783, V786, L795, I806
	protein 26
903	Tumor necrosis factor ligand	Q9UNG2	A82, F84, C100, V101, L109, I111, Y117, I119, V123, A124, V137, L139, Y140, I155, V158, L164, I170, L172, V180,
	superfamily member 18		W187, I189
904	Protein unc-13 homolog A	Q9UPW8	L1494, L1500
905	Neuraminidase (EC	Q9W7Y7	I87, V95, V97, F102, I103, F113, F114, L115, L139, C142, A159, W160, A162, A164, C165, L172, I174, I176, A183,
	3.2.1.18)/strain A/Hong		V184, A185, L187, L205, A213, C214, V215, F220, V222, M223, A232, Y234, I236, I239, V244, H256, Y257, C260,
	Kong/156/1997 H5N1		C262, Y263, A266, I269, C271, V272, C273, V285, F287, C299, V302, F303, F330, F332, Y334, V338, W339, I340, F352,
	genotype Gs/Gd		M354, I355, F368, I374, I375, F387, I388, M399, C402, F403, W404, V405, L407, W418, I424, F426
906	Hemagglutinin [Cleaved	Q9WFX3	V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, I74, A75, W77, L78, L79, C84, L87,
	into: Hemagglutinin HA1		W93, Y95, I96, V97, C107, Y108, L118, L122, V125, F128, F134, A151, A152, C153, Y155, A158, L165, L166, W167,
	chain; Hemagglutinin HA2		L168, Y175, L178, V190, L191, V192, L193, W194, V196, H197, H198, Y209, Y215, V216, V218, Y223, A233, M244,
	chain]/strain A/Brevig		Y246, Y247, L250, L251, I257, F259, A261, L265, I266, A267, Y270, A271, F272, A273, L274, I282, I283, C292,
	Mission/1/1918 H1N1		C296, A302, I303, H313, I317, V324, L329, M331, A332, A349, M361, Y366, A388, I389, A440, L452, V459, L462,
	(Influenza A virus (strain		V466, L470, C481, H486, C488, C492, M493
	A/South Carolina/1/1918
	H1N1))
907	Genome polyprotein	Q9WMX2	L754, V1061, L1070, A1071, C1073, V1074, V1077, C1078, W1079, V1081, A1085, I1097, L1108, V1109, L1120,
	[Cleaved into: Core protein		L1130, L1132, I1140, V1142, V1158, L1161, L1169, C1171, A1176, V1177, I1179, F1180, A1190, A1192, V1193,
	p21/genotype 1b (isolate		F1195, V1196, V1198, M1201, Y1244, V1251, V1253, L1254, A1259, A1260, M1268, I1291, Y1293, Y1296, A1301, I1312,
	Con1) (HCV)		I1314, C1315, C1318, I1326, L1327, I1329, V1332, A1336, A1341, L1343, V1344, V1345, L1346, A1347, I1373, F1375,
			I1380, I1385, L1391, I1392, F1393, C1394, C1400, L1403, L1407, V1432, V1434, V1435, A1436, L1440, F1444,
			F1448, V1451, I1452, F1470, A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528, L1539, Y1542, L1555,
			W1558, V1561, I1568, F1572, L1586, V1587, A1588, A1591, C1594, W1608, L1611, H1619, L1624, L1625, L1628,
			I1641, I1645, M2025, C2029, I2035, C2052, F2060, I2062, C2070, Y2090, V2091, V2093, V2102, M2105, F2122,
			V2128, F2147, L2160, L2440, L2449, L2450, V2456, Y2457, A2458, A2464, Y2483, V2486, M2490, A2492, A2494,
			V2497, A2499, A2507, C2508, Y2522, A2524, V2527, A2534, I2538, L2545, L2546, I2557, C2565, A2576, L2578,
			V2580, L2584, V2586, V2588, C2589, A2593, L2594, V2597, V2598, L2601, A2604, V2605, Y2610, V2620, L2623,
			A2626, M2634, F2636, Y2638, V2647, I2652, I2658, Y2659, C2661, C2662, A2665, A2668, A2671, I2672, L2675,
			L2679, Y2680, L2685, C2693, C2698, A2700, V2703, L2704, C2708, L2712, C2714, A2718, A2719, A2720, A2721,
			C2722, A2725, L2727, M2732, L2733, V2734, L2739, V2740, V2741, I2742, C2743, A2753, L2755, F2758, A2761,
			M2762, Y2765, A2767, I2782, V2789, A2792, Y2801, L2803, L2811, A2812, A2814, A2815, L2828, I2831, I2832,
			A2835, L2838, W2839, A2840, I2843, L2844, M2845, H2847, F2848, F2849, L2858, A2861, C2864, I2866, A2869,
			C2870, Y2871, I2873, L2876, L2878, I2881, I2882, L2885, A2890, F2891, V2904, A2905, C2907, L2908, L2911,
			V2913, V2918, W2919, A2923, V2926, L2930, L2931, A2937, A2938, C2940, L2944, F2945, A2948, A2960, A2961,
			F2970, A2972, Y2974, I2979
908	Tumor necrosis factor ligand	Q9Y275	L112, C146, L147, L149, V166, A177, L178, I185, V187, F193, F194, I195, Y196, V199, Y201, M208, H210, I212,
	superfamily member 13B		L224, L226, M236, C245, A248, L253, L259, L261, A262, I263, A268, V276, F278, F279, A281, L282
909	Cofilin-2	Q9Y281	V11, V14, M18, A35, V36, L37, F38, I47, I48, I55, V57, Y68, F71, V72, L75, C80, Y82, A83, L84, Y85, A87, V100,
			F101, W104, A109, Y117, I124, F128, V137, L149, L161
910	Ragulator complex protein	Q9Y2Q5	L11, L23, L24, L25, A42, A46, V81, A82, I83, L89, L90, L91, C92, M93, L104, A108
	LAMTOR2
911	Kinesin-like protein KIF3A	Q9Y496	V15, V17, V18, V19, I46, V48, V76, I85, V88, I96, A98, M110, I122, F127, I130, Y149, L150, I152, V157, L160, M195,
			H216, F224, I226, I235, L246, L248, V249, A252, L267, V283, I284, L302, L310, M318, C319, A320, I322, A325, L336,
			A339, A342, I345
912	Neurexin-3	Q9Y4C0	F337, L576, L582, L585, F711, I824, F875, F896, L909, L949, L988, Y993, V1022, I1101, L1118, V1120, F1122,
			I1130, L1131, V1132, I1134, L1144, L1146, I1148, I1153, V1155, F1157, I1164, I1166, V1173, V1181, A1190,
			L1192, V1194, V1199, L1209, F1212, I1218, I1220, F1229, L1233, L1236, Y1238, V1243, L1244, V1260, V1266
913	Dystrobrevin alpha	Q9Y4J8	C258, L266, C270
914	Kallikrein-4 (EC 3.4.21.—)	Q9Y5K2	I31, A46, A47, L48, V59, L60, V66, L67, A69, C72, I79, L81, L83, A99, A114, L117, M118, L119, I132, I135, C148,
			V150, W153, V168, C178, C192, A193, L211, C213, L217, L220, V236, Y237, L240
915	CD2-associated protein	Q9Y5K6	Y4, V6, L18, I20, I26, L38, F49, V54, C113, V115, L127, L129, I135, F157, V162, C274, L288, F290, I296, F320, A325
916	Brefeldin A-inhibited	Q9Y6D5	F654, A679, Y711, F722, A739, A769, I776, I822
	guanine nucleotide-exchange
	protein 2
917	Cadherin-10	Q9Y6N8	L63, F102, I111, A113, I117, L127, A131, V147, I148, I150, V169, V182, I217, I218, V235, I237, A239, V255, I257,
			A293, F317, L346, V348, A350, V371, I373
918	Tumor necrosis factor	Q9Y6Q6	C47, C50, A113, C114, C133
	receptor superfamily
	member 11A

Example 4: Assays Measuring Alterations in Conformational Dynamics

Alterations in conformational dynamics can be measured by standard methods known in the art. In preferred embodiments, alterations in conformational dynamics can be shown by measuring changes in melting temperatures, in urea-induced equilibrium unfolding studies, and/or Gibbs free energy as compared to the starting protein.

Changes in melting temperature can be shown by the following protocol. For example, a peptidogenic protein (0.20 mg/ml) and a starting protein (as a control) is heated from 10° C. to 72° C. in a 0.1 cm quartz cuvette with a heating rate of 1 degree×min−1 controlled by a Jasco programmable Peltier element. The dichroic activity at 209 nm and the photomultiplier tube voltage (PMTV) are continuously monitored in parallel every 0.5° C. All the thermal scans are corrected for the solvent contribution at the different temperatures. Melting temperature (Tm) values are calculated by taking the first derivative of the ellipticity at 209 nm with respect to temperature. All denaturation experiments are performed in triplicate (see Lori et al., PLoS One, 5; 8(6):e64824 (2013)).

A change in urea-induced equilibrium unfolding can be shown by the following protocol. A peptidogenic protein (final concentration 40 ug/ml) and a starting protein (as a control) is incubated at 10° C. in increasing concentrations of urea (0-8 M) in 25 mM Tris/HCl, pH 7.5, in the presence of 0.2 M NaCl and 2 mM DTT (for non-disulfide containing proteins). After 10 min, equilibrium is reached and the intrinsic fluorescence emission, absorbance at 287 nm, and/or far-UV CD spectra (0.5-cm cuvette) are recorded in parallel at 10° C. To test the reversibility of the unfolding, a peptidogenic protein is unfolded at 10° C. in 7.0 M urea at 0.4 mg/ml protein concentration in 25 mM Tris/HCl, pH 7.5, in the presence of 2 mM DTT and 0.2 M NaCl. After 10 mM, refolding is started by 10-fold dilution of the unfolding mixture at 10° C. into solutions of the same buffer used for unfolding containing decreasing urea concentrations. The final protein concentration is 40 ug/ml. After an incubation period of 15 min to 24 h, the intrinsic fluorescence emission, absorbance at 287 nm, and/or the CD spectra are recorded as a function of urea concentration at 10° C. (see Lori et al., PLoS One, 5; 8(6):e64824 (2013)).

Alterations in Gibbs free energy can be shown by the following protocol. In order to measure Gibbs free energy, differential scanning calorimetry (DSC) experiments are performed on a VP-DSC (Microcal Inc., Northampton, Mass.) instrument at a scan rate of 1.5 deg/minute. Where possible, temperature-induced unfolding of a peptidogenic protein is checked for reversibility by comparing first and second DSC scans. It is understood that reversibility of folding and unfolding is not a requirement for the peptidogenic proteins described herein. The partial molar heat capacity of the protein, Cp,pr(T), is obtained from the experimentally measured apparent heat capacity difference between the sample (containing protein solution) and reference (containing corresponding buffer solution) cells, ΔC_p̂app (T). Protein concentration is measured spectrophotometrically using a known molar extinction coefficient. Analysis of the heat capacity profiles according to a two-state model is done using non-linear regression routine NLREG and in-house written scripts. The standard thermodynamic functions under reference conditions are calculated as:

$\Delta H_{\mathrm{ca}l}\left(T\right)=\Delta H\left(T_m\right)+\Delta C_p\left(T-T_m\right)$ $\begin{array}{c}\Delta S\left(T\right)=\Delta S\left(T_m\right)+\Delta C_p\ln \left(T/T_m\right)\\ =\frac{\Delta \mathrm{Hcal}\left(\mathrm{Tm}\right)}{\mathrm{Tm}}+\Delta \mathrm{Cp}\ln \left(T/\mathrm{Tm}\right)\end{array}$ $\Delta G\left(T\right)=\left(T_m-T\right)\left(\Delta H_{\mathrm{ca}l}\left(T_m\right)/T_m-\Delta C_p\right)-T\Delta C_p\ln \left(T/T_m\right)$

Where ΔH(T), ΔS(T), and ΔG(T) are the enthalpy, entropy and Gibbs energy functions of a peptidogenic protein, respectively, ΔHcal is the enthalpy of unfolding at the transition temperature Tm, and ΔCp is the heat capacity of unfolding (see Loladze et al., J. Mol. Biol. 320, 343-357 (2002)).

Example 5: Assays Measuring Peptidogenicity

One of the intracellular conditions that may participate in processing of the peptidogenic proteins as described herein is proteolysis. The influence of the differential stability of the peptidogenic proteins on proteolysis can be determined using one of several in vitro or ex vivo assays.

(a) Cathepsin L Proteolysis

In one embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of cathepsin L, one of the enzymes known to be critical in protein antigen processing (Hsieh, C. S., deRoos, P., Honey, K., Beers, C., and Rudensky, A. Y. (2002) J. Immunol. 168, 2618-2625). Susceptibility of the peptidogenic proteins to proteolysis is assessed using lysosomal cathepsin L. The peptidogenic proteins (0.5 ug/ul) are incubated with various amounts (e.g., 1.5 munits) of enzyme in 50 mM sodium acetate buffer, pH 4.5, for various lengths of time at 37° C. Digestion is stopped using 0.1% TEA, and proteolysis is monitored by reversed-phase HPLC on C18 reverse phase columns (Vydac, Hesperia, CA). Elution of the proteolytic products is carried out with a linear gradient of acetonitrile/water containing 0.1% TEA.

(b) Proteolysis Using Alpha-Chymotrypsin and Carboxypeptidase Y

In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of alpha-chymotrypsin and carboxypeptidase Y. Alpha-chymotrypsin is an endopeptidase which cleaves at the carboxyl terminus of aromatic amino acids; carboxypeptidase Y is an exopeptidase which removes amino acids sequentially from the carboxyl terminus. Proteolytic digestion with these enzymes is specific for unstable conformations, hence, the conformational stability of the peptidogenic proteins determines their resistance/susceptibility to proteolytic digestion. The peptidogenic proteins at 1 mg/ml in 0.5 ml of 20 mM HEPES-buffered saline, pH 7.5, are incubated at 37° C. with 100 ug of alpha-chymotrypsin from bovine pancreas and carboxypeptidase Y from yeast. Each incubation is terminated at various time-points and the digested samples are stored at −20° C. until analyzed. Samples are analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), through a 15% acrylamide gel and under reducing conditions, then stained with Coomassie Brilliant Blue for visualization.

(c) Proteolysis Using Lysosomal Extracts

In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of lysosomal extracts of bone marrow-derived dendritic cells. The peptidogenic proteins are incubated at various concentrations in the presence of equal amounts of proteins from crude lysosomal extracts from bone marrow-derived dendritic cells. The mixtures are incubated in 0.1 M sodium citrate buffer, 0.5% Triton X-100, and 2 mM dithiothreitol at pH 4.5. Each incubation is terminated at various time-points and the digested samples are stored at −20° C. until analyzed. Samples are analyzed by SDS-PAGE. The experiments are repeated with and without prior adsorption of peptidogenic proteins onto an adjuvant such as aluminum hydroxide. Bone marrow-derived dendritic cells are purified with use of anti-CD11c microbeads from bone marrow cultured in granulocyte macrophage-colony stimulating factor. See, for example, Delamarre et al., FIG. 4.

(d) Proteolysis after Internalization by Bone Marrow-Derived Dendritic Cells

In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by labeling them with FITC per the manufacturer's protocol, incubating bone marrow-derived dendritic cells with the FITC-proteins, and measuring the percentage of FITC+, CD11c+ cells over time. Bone marrow-derived dendritic cells are loaded with 0.5 mg/ml of the FITC-labeled peptidogenic proteins for 1 hour, are washed, and then are cultured at 37° C. for various amounts of time. FACS is then used to determine the percentage of FITC+, CD11c+ cells at each time point subtracted to the percentage of FITC+, CD11c+ cells at time 0 h. This represents the percentage of proteolysis of the peptidogenic proteins. The experiments are repeated with and without prior adsorption of FITC-labeled peptidogenic proteins onto an adjuvant such as aluminum hydroxide.

Example 6: Antibody Production and Sequencing

Ig-seq of antibody repertoires may follow previously described protocols (10, 29) with minor modifications. B cells can be isolated from the serum, spleen, or other tissues of hyperimmunized rabbits. In order to reduce the complexity of the sequencing library, this population can be sorted to enrich for CD19⁺CD3⁻CD27⁺CD38^int memory B cells or B cells that recognize the target antigen (5, 30, 31). These cells are then lysed and mRNA is isolated using standard methods, and reverse transcribed to cDNA using 5′ RACE with 3′ primers specific for the IgH or IgL constant region (9, 32). The cDNA library is then amplified with primers containing the required paired-end adapter sequences and optional barcodes to enable quantification of template and error correction by averaging multiple reads (8, 9).

Complete determination of antibody sequences requires identifying native VH-VL pairs. As each VH and VL sequence is encoded by a separate mRNA, clonal sequencing may be performed by isolating single B cells in subnanoliter volume wells (5) or microemulsion (9) prior to mRNA isolation, reverse transcription, and overlap extension or linkage PCR. As an alternative, endogenous VH-VL pairs can be identified through partial cross-linking of purified Fabs prior to LC-MS/MS. Under the appropriate conditions, this will result in a fraction of the Fab heavy and light chains forming interchain crosslinks, and the resulting peptide masses will be used to determine native pairing.

In order to identify the antibodies raised in response to a mixture of peptidogenic proteins, sequence information can be combined with data from high-resolution mass spectrometry. Protein A-purified IgGs can be digested with papain to release the two Fabs from the Fc domain. These can then be immunoaffinity purified on a custom column prepared using the peptidogenic protein immobilized on a solid support, the eluted Fabs proteolytically digested, and the peptide products subjected to mass spectrometry. The resulting peptide masses can be compared with the complete antibody sequencing data to identify the CDR sequences that recognize the antigen. Pairing of IgG VH and VL sequences can be accomplished through chemical cross-linking of the immunoaffinity purified Fabs prior to the proteolytic digest; Young et al have demonstrated the feasibility of this approach (33).

Example 7: Immunization Using a Mixture of Peptidogenic Proteins

Methods of raising antibodies in mammals are well known in the art. In one example, polyclonal antiserum against peptidogenic proteins is raised by immunization of pathogen free rabbits with a total of 500 μg of a mixture of peptidogenic proteins over a period of two months. For example, the peptidogenic proteins can be dissolved in PBS and emulsified with an equal volume of Freund's adjuvant. After the final booster, the serum of the rabbits can be separated to determine the titer of the polyclonal antiserum. To obtain monoclonal antibodies, 4-6 week old Balb/c mice can be immunized with a peptidogenic protein (for example 4 times with 2 week intervals with 10-100 μg/injection dissolved in Freunds complete adjuvant for the first injection, and Freund's incomplete adjuvant for subsequent immunizations). Splenocytes are isolated and fused with a fusion cell line such as Sp2/0 myeloma cells, followed by limiting dilution. Growing clones are screened using for example an enzyme-linked immunosorbant assay (ELISA). 96 cells plates are coated with peptidogenic proteins or with a control protein. The culture supernatant is added, followed by washing and addition of a labeled anti-mouse antibody for detection. After limited dilution cloning of the peptidogenic protein-specific antibody producing hybridomas stable hybridomas are obtained. From each cell, supernatant is collected and by affinity chromatography using protein A sepharose columns monoclonal antibodies can be purified.

Example 8: Another Example of Immunization Using a Mixture of Peptidogenic Proteins

In an additional animal model, groups of 5 mice (C57BL/6J; Jackson Labs) can be subcutaneously immunized with 5 μg of endotoxin-free peptidogenic proteins emulsified in alum, which is the adjuvant most commonly used in human vaccines. Three weeks later, mice are bled and the presence of peptidogenic protein-specific antibodies can be determined by titering the seras by ELISA (direct binding of antibodies in sera to wild type BPTI or APP-KI coated, directly or indirectly (via a biotinylated tag and streptavidin), on the wells). To confirm that the peptidogenic proteins have a similar conformation as the starting protein, competitive inhibition assays are performed in which titrated amounts of starting protein and peptidogenic proteins are pre-incubated with the seras prior to adding to the starting protein coated plates. This provides additional evidence, with an immunological probe, that the 3D structure of the peptidogenic proteins has not been compromised by the engineered mutations.

To determine whether the peptidogenic proteins result in better secondary antibody responses, groups of mice can be immunized as described above, and 6 weeks after the primary immunization they can be immunized a second time. One week post-secondary immunization, mice are bled and antigen-specific antibody responses are determined by ELISA as described above. Mouse dendritic cells are pulsed in vitro with the peptidogenic proteins that can generate a strong antibody response, and 24 hrs later the peptidogenic protein-derived peptides presented by MHCII are isolated and their masses analysed by liquid chromatography and mass spectrometry (LC/MS). These studies require large numbers (>10⁷) of dendritic cells which are purified from mice previously injected with a mouse tumor line expressing FLT-3L, a cytokine that drives dendritic cell development in vivo (the spleens of these mice fill up with dendritic cells; Segura et al, 2009). To allow for peak identification and the quantiifcation of MHCII-peptides by mass spectrometry, the peptidogenic protein can be biosynthetically labeled with stable isotopes such as 13C and 15N (during production of the recombinant protein—see above) prior to feeding to the DCs (Hoedt et al 2014).

Example 9: Immunization Using Sequences Encoding a Mixture of Peptidogenic Proteins

Methods of directly injecting polynucleotides into animals are well described in the art. See, for example, U.S. Pat. Nos. 5,676,954; 6,875,748; 5,661,133. Briefly, using the known degeneracy of the genetic code, polynucleotides encoding a mixture of peptidogenic proteins described herein can be synthesized using standard DNA synthesis techniques. The polynucleotide(s) can then be directly injected into the animal, such as, for example, mice. Specifically, a mixture of polynucleotides encoding the mixture of peptidogenic proteins can be injected into the quadriceps muscles of restrained awake mice (female 6-12 week old BALB/c or Nude, nu/nu, from Harlan Sprague Dawley, Indianapolis, Ind.). In one embodiment, 50 μg of a polynucleotide in 50 μl solution using a disposable sterile, plastic insulin syringe and 28G ½ needle (Becton-Dickinson, Franklin Lakes, N.J., Cat. No. 329430) fitted with a plastic collar cut from a micropipette tip can be used to inject the mice, as described in Hartikka, J., et al., Hum. Gene Ther. 7:1205-1217 (1996)).

Alternatively, 6-week old Sprague Dawley female mice (body weight 20-25 grams) can be given 5000 ppm ZnOSO4 in their drinking water beginning 24 hours prior to injection. This amount of zinc has been shown to be able to activate the metallothionein promoter. Each mouse is then injected intravenously through a tail vein puncture with a 25 gauge needle with 30 μg of polynucleotides encoding the mixture of peptidogenic proteins complexed with 150 μg liposome (Lipofection TM) in a total volume of 30 μl. In one embodiment, the polynucleotides mixture injected into the mice encodes for different peptidogenic proteins relating to the same starting protein. Alternatively, a library of peptidogenic proteins can be encoded by the mixture of polynucleotides, wherein the library relates to different starting proteins. Animal care should be maintained throughout the study and should be performed in compliance with the “Guide for the Use and Care of Laboratory Animals”, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Academy Press.

After the injected polynucleotide encoding the peptidogenic proteins are delivered into the cells in the animal, the peptidogenic proteins are then expressed in vivo. The peptidogenic proteins can then stimulate the production of antibodies specific to the peptidogenic proteins. These antibodies can be isolated and used as a polyclonal mixture or further isolated into single species or monoclonals. The process of the immune response and production of antibodies against foreign antigens in vivo are well known in the art. Unlike the traditional protocols of antibody generation, the platform invention described herein allows the simultaneously raising of a group of antibodies against multiple peptidogenic proteins (whether or not they rely on the same starting protein). This simultaneous production of antibodies to multiple proteins using a mixture of polynucleotides has the potential to change how antibody production is currently being performed.

Example 10: Immunization Using mRNA Encoding Peptidogenic Proteins

The methods of directly injecting in vitro transcribed (IVT) mRNA into animals are also well known in the art. See, Sahin et al., Nat Rev Drug Discov. 2014 October; 13(10):759-80; Kariko et al., Mol Ther, 2008 November; 16(11):1833-40; Kariko et al., Nucleic Acid Res, 2011, November; 39(21):e142; U.S. Pat. No. 6,511,832. For example, linearized DNA plasmid templates which encode a mixture of peptidogenic proteins can be used. All mRNAs can be designed to contain 5′ and 3′ untranslated regions, the open reading frames, and long poly(A) tails, which can help determine the translational activity and stability of the mRNA molecule after its transfer into cells.

For example, mRNAs (including a poly(A) tail) encoding peptidogenic proteins can be synthesized using triphosphate-derivatives of pseudouridine and 5-methylcytidine (m5C) (TriLink) to generate a modified nucleoside containing RNA. A 5′-cap can be added to the mRNAs by supplementing the transcription reactions with 6 mmol/l 3′-O-Me-m7GpppG, a nonreversible cap analog (New England Biolabs, Beverly, Mass.) and lowering the concentration of guanosine triphosphate (3.75 mmol/1). Purification of the transcripts can be performed by Turbo DNase (Ambion, Austin, Tex.) digestion followed by LiCl precipitation and 75% ethanol wash. The concentrations of RNA reconstituted in water can be determined by measuring the optical density at 260 nm. Efficient incorporation of modified nucleotides to the transcripts can be determined by HPLC analyses. All RNA samples can be analyzed by denaturing agarose gel electrophoresis for quality assurance. Lipofectin (Invitrogen, Carlsbad, Calif.) and mRNA are then complexed in phosphate buffer in order to enhance transfection. To assemble a 50 μl complex of RNA-lipofectin, first 0.4 μl potassium phosphate buffer (0.4 mol/1, pH 6.2) containing 10 μg/bovine serum albumin (Sigma, St. Louis, Mo.) is added to 6.7 μl DMEM, then 0.8 μl lipofectin is mixed in and the sample is incubated for 10 minutes. In a separate tube, 0.25-3 μg of RNA is added to DMEM to a final volume of 3.3 μl. Diluted RNA is added to the lipofectin mix and incubated for 10 minutes. Finally, the RNA-lipofectin complex is further diluted by adding 38.8 μl DMEM.

The RNA encoding the peptidogenic proteins can then be injected into the mouse models described herein. In general, a composition comprising 60 μl final volume with 1 μl lipofectin and different amounts of polynucleotides encoding the peptidogenic proteins are injected into the lateral vein using a 1-ml syringe with a 27G1/2 needle (Becton Dickinson, San Diego, Calif.). Alternatively, the polynucleotides can be injected via intramuscular, intradermal, intranasal, subcutaneous, intravenous, intratracheal, and intrathecal deliveries. After the polynucleotides are delivered into the cells, the peptidogenic proteins are synthesized in vivo. The immune responses triggered by the peptidogenic proteins and the subsequent production of antibodies in the animals are described herein.

Example 11: Affinity Maturing Antibodies to Peptidogenic Protein Using Phage Display

Once antibodies have been raised to the peptidogenic proteins by presenting and allowing the peptidogenic protein to undergo processing by an antigen presenting cell such as described in the Examples herein, the resulting antibodies can be matured using a display approach. For example, a library of phage displaying scFvs or Fabs derived from B cell mRNA encoding the target-specific antibodies can be screened in an assay to identify those phage displaying scFvs or Fabs that immunospecifically bind to a peptidogenic protein or to a starting protein. Phage displaying scFvs or Fabs that bound to immobilized peptidogenic protein or starting protein can be identified after panning on immobilized peptidogenic protein or starting protein and assessing by ELISA for binding to immobilized peptidogenic protein or starting protein. The peptidogenic protein or starting protein that is immobilized on plates for these assays can be purified from supernatants of Sf9 cells infected with a baculovirus expression construct as described in Moore et al., Science 285:260-263 or from supernatants from HEK293 cells. Each of the identified scFvs or Fabs can then be sequenced.

To determine the specificity of each of the unique scFvs or Fabs, a phage ELISA can be performed for each scFvs or Fabs against the peptidogenic protein or starting protein and control wells. Individual E. coli colonies containing a phagemid representing one of the unique scFvs or Fabs can be inoculated into 96-well plates containing 100 μl 2TYAG medium per well. Plates are incubated at 37° C. for 4 hours, shaking. M13K07 helper phage is then added to each well to a MOI of 10 and the plates are incubated for a further 1 hour at 37° C. The plates are centrifuged in a benchtop centrifuge at 2000 rpm for 10 minutes. The supernatant is removed and cell pellets are resuspended in 100 μl 2TYAK and incubated at 30° C. overnight, shaking.

The next day, plates are centrifuged at 2000 rpm for 10 min and the 100 μl phage-containing supernatant from each well are carefully transferred into a fresh 96-well plate. Twenty μl of 6×MPBS is added to each well, and incubated at room temperature for 1 hour to pre-block the phage prior to ELISA.

Flexible 96-well plates (Falcon) are coated overnight at 4° C. with a peptidogenic protein (directly or indirectly, at 1 mg/ml) in PBS, BSA (1 g/ml) in PBS, or PBS. After coating, the solutions are removed from the wells, and the plates are blocked for 1 hour at room temperature in MPBS. The plates are washed 3 times with PBS and then 50 μl of pre-blocked phage is added to each well. The plates are incubated at room temperature for 1 hour and then washed with 3 changes of PBST followed by 3 changes of PBS. To each well, 50 μl of an anti-gene VIII-HRP conjugate (Pharmacia) at a 1 to 5000 dilution in MPBS is added and the plates are incubated at room temperature for 1 hour. Each plate is washed three times with PBST followed by three times with PBS. Then 50 μl of an HRP-labelled anti-mouse antibody (DAKO EnVision) diluted 1/50 in 3% MPBS is added and incubated for 1 hour at room temperature. Each plate is then washed three times with PBST followed by three times with PBS. Fifty μl of TMB substrate is then added to each well, and incubated at room temperature for 30 minutes or until color development. The reaction is stopped by the addition of 25 μl of 0.5 M H2SO4. The signal generated is measured by reading the absorbance at 450 nm (A450) using a microtiter plate reader (Bio-Rad 3550).

Conversion of scFvs or Fabs to IgG1 format can be performed as follows. The VH domain and the VL domains of scFvs or Fabs that we wish to convert into IgG molecules can be cloned into vectors containing the nucleotide sequences of the appropriate heavy (human IgG1, IgG2, etc.) or light chain (human kappa or human lambda) constant regions such that a complete heavy or light chain molecule could be expressed from these vectors when transfected into an appropriate host cell. Further, when cloned heavy and light chains are both expressed in one cell line (from either one or two vectors), they can assemble into a complete functional antibody molecule that is secreted into the cell culture medium. Methods for converting scFvs or Fabs into conventional antibody molecules are well known within the art.

The purification of the IgG from the fermentation broth is performed using a combination of conventional techniques commonly used for antibody production. Typically the culture harvest is clarified to remove cells and cellular debris prior to starting the purification scheme. This would normally be achieved by using either centrifugation or filtration of the harvest. Following clarification, the antibody would typically be captured and significantly purified using affinity chromatography on Protein A Sepharose. The antibody is bound to Protein A Sepharose at basic pH and, following washing of the matrix, is eluted by a reduction of the pH. Further purification of the antibody is then achieved by gel filtration. As well as removing components with different molecular weights from the antibody this step can also be used to buffer exchange into the desired final formulation buffer.

Example 12: Assays Used to Characterize Antibodies and Measure Cross-Reactivity

Antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) (including scFvs or Fabs and other molecules comprising, or alternatively consisting of, antibody fragments or variants thereof) may be screened in a variety of assays, some of which are described below to identify those antibodies that bind to the peptidogenic protein and/or starting protein.

In one particular assay, antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) that bind to a biotinylated protein (whether the peptidogenic protein and/or starting protein) can be captured on streptavidin coated magnetic beads. This assay may be applied to identify antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) that neutralize and/or bind to the peptidogenic protein and/or starting protein. Additionally, antibodies may be assayed in neutralization assays described herein or otherwise known in the art. For example, where the target protein is BlyS, antibodies may be tested for their ability to inhibit the peptidogenic protein and/or starting protein from binding to IM9 cells. In this assay, labeled peptidogenic protein and/or starting protein (e.g., biotinylated) is incubated with antibodies to allow for the formation of protein-antibody complexes. Following incubation, an aliquot of the protein-antibody sample is added to IM9 cells. Binding may be determined using techniques known in the art. For example, the binding of biotinylated protein (whether the peptidogenic protein and/or starting protein) to IM9 cells may be detected using a fluorimeter following the addition of streptavidin-delfia. Biotinylated protein, if it is not bound by antibodies that neutralize the protein, will bind to the cells and can be detected. Thus, an antibody that decreases the amount of biotinylated-protein that binds to IM9 cells (relative to a control sample in which the protein had been preincubated with an irrelevant antibody or no antibody at all) is identified as one that binds to and neutralizes the protein.

Other immunoassays which can be used to analyze cross-reactivity and/or characterize the antibodies raised against the peptidogenic protein include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York.

Exemplary immunoassays are described briefly below (but are not intended by way of limitation) Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the cross-reacting antibody of interest to the cell lysate, incubating for a period of time (e.g., 1 to 4 hours) at 4° C., adding protein A and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a peptidogenic protein and/or a starting protein can be assessed by, e.g., western blot analysis or mass spectrometry. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to a peptidogenic protein and/or a starting protein and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.16.1.

Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 1211) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.8.1.

In a further example, ELISAs comprise preparing peptidogenic protein and/or a starting protein, coating the well of a 96-well microtiter plate (directly or indirectly) with the peptidogenic protein and/or a starting protein, washing away the peptidogenic protein and/or a starting protein that did not bind the wells, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound antibodies or non-specifically bound antibodies, and detecting the presence of the antibodies specifically bound to the peptidogenic protein and/or a starting protein coating the well. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well.

Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, the detectable molecule could be the peptidogenic protein and/or a starting protein conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase). One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1. The binding affinity of an antibody to a peptidogenic protein and/or a starting protein and the off-rate of an antibody-protein interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled peptidogenic protein and/or a starting protein (e.g., 3H or 1251) with the antibody of interest in the presence of increasing amounts of unlabeled peptidogenic protein and/or a starting protein, and the detection of the antibody bound to the labeled peptidogenic protein and/or a starting protein. The affinity of the antibody of the present invention for a peptidogenic protein and/or the starting protein and the binding off-rates can be determined from the data by Scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, a peptidogenic protein and/or starting protein is incubated with an antibody of interest conjugated to a labeled compound (e.g., 3H or 1251) in the presence of increasing amounts of an unlabeled second anti-peptidogenic protein antibody.

In a preferred embodiment, BIAcore kinetic analysis can be used to determine the binding on and off rates of antibodies to peptidogenic protein and/or starting protein. BIAcore kinetic analysis comprises analyzing the binding and dissociation of peptidogenic protein and/or starting protein from chips with immobilized antibodies on their surface.

Example 13: Vaccination

Further, a mixture of peptidogenic proteins as described herein can be used as a vaccine. For example a concentration of 320 ug/mL in phosphate-buffered saline (PBS, 155 mM NaCl, 1 mM KH2PO4, 3 mM Na2HPO3) of the peptidogenic proteins are aseptically emulsified with an equal volume of Montanide ISA 51 to give a final vaccine concentration of 160 ug/mL. The emulsion is achieved by homogenizing the mixture in a volume of 200 mL in a 400-mL vessel at room temperature for 6 min at 6000 rpm using an Omni Mixer-ES homogenizer (Omni International, Warren-ton, VA). Each vaccine undergoes comprehensive quality control analyses to ensure general safety, purity, identity, integrity, and uniform water-in-oil droplet size. Stability of vaccines stored at 2-8° C. is evaluated regularly using mouse immunogenicity tests and physical and biochemical assays to verify the vaccine safety, potency, uniformity, purity, and integrity until 4-10 months after the termination of the human immunizations. The 160 ug/mL peptidogenic protein vaccines are diluted with the PBS/ISA 51 (the adjuvant control vaccine) to the final dose forms of 10 ug/mL or 40 ug/mL prior to immunizations. As a result of different degrees of dilution, these vaccines contained two different ratios of vaccine-containing vs. vaccine-free water droplets, namely ratios of 1:15 and 1:3 for the 10 ug/mL and 40 ug/mL formulations, respectively. The test and control vaccines may be highly viscous and require vortexing prior to and after manipulation to ensure homogeneity. The vaccine can be administered intramuscularly by needle and syringe. Vaccine-induced T-cell responses are further evaluated by means of a qualified intracellular cytokine staining assay. Peripheral-blood mononuclear cells are quantified to determine the proportion of total and memory CD4 and CD8 T cells producing interleukin-2, interferon-γ, or tumor necrosis factor (TNF).

Polynucleotides encoding a mixture of peptidogenic proteins can also be used as a vaccine by administering to a patient the polynucleotide described herein.

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Claims

1. A method of generating an immune response in an animal wherein said method comprises: a. designing a mixture of peptidogenic proteins derived from a starting protein, wherein the peptidogenic proteins have altered conformational dynamics as compared to the starting protein and wherein the peptidogenic proteins are similar in conformation to the starting protein;b. introducing the mixture of peptidogenic proteins to an animal; andc. generating an immune response in the animal.

2. The method of claim 1, wherein the conformational dynamics are altered by: a. examining the 3-D structure of the starting protein, identifying non-surface amino acid residues of the starting protein and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic proteins; orb. examining a model of the 3-D structure of the starting protein, identifying non-surface amino acid residues of the starting protein and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic proteins; orc. comparing the pattern of conserved amino acid homology across proteins orthologous to the starting protein from different species to identify non-surface amino acid residues of the starting protein and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic proteins; ord. replacing at least one non-surface amino acid residue of the starting protein to generate the peptidogenic proteins; ore. replacing at least one non-surface amino acid residue with a smaller amino acid residue; orf. replacing at least one non-surface amino acid residue with an alanine or glycine; org. eliminating at least one disulfide bond in the starting protein.

3. The method of claim 1, wherein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids are replaced in the starting protein.

4. The method of claim 1, wherein the conformational dynamics of the starting protein are altered by replacing: a. at least one threonine with a valine, alanine, glycine or serine; orb. at least one cysteine with alanine, valine, glycine, serine or threonine; orc. at least one valine with alanine, glycine, leucine or isoleucine; ord. at least one leucine with alanine, valine, glycine, or isoleucine; ore. at least one isoleucine with alanine, valine, leucine, or glycine; orf. at least one proline with methionine, alanine, valine, leucine, isoleucine, or glycine; org. at least one methionine with alanine, valine, leucine, isoleucine, or glycine; orh. at least one phenylalanine with tyrosine, methionine, histidine, alanine, valine, leucine, isoleucine, or glycine; ori. at least one tyrosine with phenylalanine, methionine, histidine, alanine, valine, leucine, isoleucine, or glycine; orj. at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, alanine, valine, leucine, isoleucine, or glycine; ork. at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; orl. at least one asparagine with glycine, serine, threonine, alanine, valine, leucine, isoleucine, glutamine, glutamic acid, or aspartic acid; orm. at least one glutamic acid with aspartic acid, asparagine, glutamine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; orn. at least one glutamine with glutamic acid, aspartic acid, asparagine, glutamine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; oro. at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; orp. at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; orq. at least one histidine with phenylalanine, tyrosine, lysine, arginine, glycine, serine, threonine, alanine, valine, glutamine, asparagine, leucine, methionine or isoleucine; orr. at least one alanine with a glycine or proline; ors. at least one glycine with an alanine or proline; ort. at least one serine with an alanine or glycine; oru. at least one residue with a non-natural amino acid; orv. any of the above combinations.

5. The method of claim 1, wherein the change in conformational dynamics of the peptidogenic proteins is measured by: a. a change in melting temperature as compared to the starting protein; orb. a change in Gibbs free energy of stabilization or proteolytic sensitivity assay; orc. a change in Gibbs free energy, wherein the change in Gibbs free energy of stabilization is measured by denaturant modulated equilibrium unfolding, such as an urea or guanidinium hydrochloride unfolding.

6. The method of claim 1, wherein the similar conformation is measured by: a. a cross-reacting antibody that binds to both the peptidogenic proteins and the starting protein; orb. the cross-reacting antibody of (a), wherein cross-reactivity is measured by an immunoprecipitation assay, surface plasmon resonance, isothermal titration calorimetry, oblique-incidence reflective difference (OI-RD), western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and/or protein A immunoassays; orc. the cross-reacting antibody of (a), wherein cross-reactivity is measured by a binding assay; ord. The cross-reacting antibody of (a), wherein the cross-reacting antibody has a dissociation constant (KD) of less than or equal to 10−9M; ore. The cross-reacting antibody of (a), wherein the cross-reacting antibody has a dissociation constant (KD) of less than or equal to 10−9M, less than or equal to 10−7M, or less than or equal to 10−6M.

7. The method of claim 1, wherein the starting protein is selected from: a. an envelope glycoprotein of the human immunodeficiency virus (HIV), HIV gp120, HIV gp41, HIV gp160, an ebola antigen, a viral antigen, a bacterial antigen, a parasite antigen, an allergen, a venom, a toxin, a tumor-associated antigen, a transmembrane domain protein, a G-protein coupled receptor, an ion channel, a hepatitis C virus antigen, a hepatitis B virus antigen, a MERS-CoV antigen, a Zika virus antigen, an influenza virus antigen, a malaria antigen; and/orb. any one of the malaria antigens listed in Table 2; and/orc. any one of the Targets listed in Table 5; and/ord. a tumor associated antigen selected from MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, GAGE-I, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I, RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I, SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocyte differentiation antigens, p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase, Melan-A, MART-1, gp100, gp75, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAAO205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml-RAR alpha fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, NA-88, SP17, and TRP2-Int2, (MART-I), E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, alpha-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS, tyrosinase related proteins, TRP-1, TRP-2, or cytomegalovirus phosphoprotein 65 (pp65).

8. The method of claim 1, wherein the mixture of peptidogenic proteins are introduced into the animal by: a. administering the mixture of peptidogenic proteins to the animal;b. administering a mixture of polynucleotides encoding a mixture of peptidogenic proteins to the animal; and/orc. administering antigen presenting cells transfected with the mixture of polynucleotides and/or placed in contact with a mixture of peptidogenic proteins.

9. The method of claim 1, wherein the peptidogenic proteins are derived: a. from the same starting protein; orb. from multiple starting proteins; orc. from multiple related starting proteins.

10. (canceled)

11. The method of claim 8, wherein the polynucleotides are: a. synthesized in vitro; orb. DNA; orc. in vitro transcribed (IVT) mRNA; ord. IVT mRNA comprising a poly(A) tail; ore. IVT mRNA comprising a 5′ Cap,and preferably wherein the polynucleotides are: 1) not associated with any targeting components; or2) are associated with a targeting component capable of targeting the polynucleotides to a cell or an organ; or3) are associated with a targeting component capable of targeting the polynucleotides to a cell or an organ, wherein the targeting component is a vector.

12. (canceled)

13. A non-human animal used in the method of claim 1.

14. The method of claim 1 wherein the animal is a mammal, a human, mouse, rabbit, llama, or a cow.

15. The method of claim 8, wherein the animal is injected with the polynucleotides, and preferably wherein the polynucleotide is a. injected directly into the muscle of the animal; and/orb. injected into the animal on multiple occasions.

16. (canceled)

17. The method of claim 1, wherein the immune response generates antibodies.

18. The method of claim 17, wherein the method further comprises isolating the antibodies.

19. The method of claim 18, wherein the antibodies are fully human antibodies, chimeric antibodies, humanized antibodies, monoclonal antibodies, and/or polyclonal antibodies, preferably wherein the polyclonal antibodies are further fractionated to obtain a single, isolated antibody species.

20. The antibodies produced by the method of claim 17.

21. (canceled)

22. (canceled)

23. The method of claim 17, wherein the antibody is affinity matured, preferably wherein the affinity maturation occurs by: a. phage display, yeast display or ribosome display; orb. a panning technique.

24. (canceled)

25. (canceled)

26. A polynucleotide encoding the antibody of claim 20.

27. The polynucleotide of claim 26 further comprising a heterologous promoter and/or vector sequence.

28. (canceled)

29. A host cell comprising the polynucleotide of claim 26.

30. A mixture of polynucleotides encoding a mixture of peptidogenic proteins.

31. The mixture of polynucleotides of claim 30, wherein the polynucleotides: a. encode a mixture of peptidogenic proteins derived from the same starting protein; orb. encode a mixture of peptidogenic proteins derived from multiple starting proteins; orc. encode a mixture of peptidogenic proteins derived from multiple related starting proteins; ord. are synthesized in vitro; ore. are DNA; orf. are in vitro transcribed (IVT) mRNA; org. are IVT mRNA comprising a poly(A) tail; orh. are IVT mRNA comprising a 5′ Cap.

32. The method of claim 1, wherein the mixture of peptidogenic proteins further comprises the starting protein.