Novel nucleic acids and polypeptides

Abstract

The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof.

Description

2. BACKGROUND OF THE INVENTION

[0002] 2.1 Technical Field

[0003] The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.

[0004] 2.2 Background

[0005] Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lmphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides “directly” in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent “indirect” cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by maling available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.

[0006] Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.

3. SUMMARY OF THE INVENTION

[0007] The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.

[0008] The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides, and cells genetically engineered to express such polynucleotides.

[0009] The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases. The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins. These nucleic acid sequences are designated as SEQ ID NO: 1-124, or 249-330 and are provided in the Sequence Listing. In the nucleic acids provided in the Sequence Listing, A is adenine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases or unlcnown. In the amino acids provided in the Sequence Listing,* corresponds to the stop codon.

[0010] The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-124, or 249-330 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ ID NO: 1-124, or 249-330. A polynucleotide comprising a nucleotide sequence having at least 90% identity to an identifying sequence of SEQ ID NO: 1-124, or 249-330 or a degenerate variant or fragment thereof. The identifying sequence can be 100 base pairs in length.

[0011] The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-124, or 249-330. The sequence information can be a segment of any one of SEQ ID NO: 1-124, or 249-330 that uniquely identifies or represents the sequence information of SEQ ID NO: 1 -124, or 249-330.

[0012] A collection as used in this application can be a collection of only one polynucleotide. The collection of sequence infonnation or identifiing information of each sequence can be provided on a nucleic acid array. In one embodiment, segments of sequence information are provided on a nucleic acid array to detect the polynucleotide that contains the segment. The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment. The collection can also be provided in a computer-readable format.

[0013] This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences; and host cells or organisms transformed with these expression vectors. Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA or RNA, their chemical analogs and the like.

[0014] In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-124, or 249-330 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art. In a particularly preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-124, or 249-330 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the airt and exemplified byVollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.

[0015] The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set foith in SEQ ID NO: 1-124, or 249-330; a polynucleotide comprising any of the full length protein coding sequences of SEQ ID NO: 1-124, or 249-330; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-124, or 249-330. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-124, or 249-330; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in SEQ ID NO: 1-124, or 249-330; (c) a polynucleotide which is an allelic variant of any polynucleotides recited above; (d) a polynucleotide which encodes a species homolog (e.g. ortlhologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in SEQ ID NO: 125-248, or 331-412, or Tables 3, 5, 6, or 8.

[0016] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing; or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ ID NO: 1-124, or 249-330; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions. Biologically active variants of any of the polypeptide sequences in the Sequence Listing, and “substantial equivalents” thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated. The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g. host cells) of the invention.

[0017] The invention also provides compositions comprising a polypeptide of the invention. Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.

[0018] The invention also provides host cells transformed or transfected with a polynucleotide of the invention.

[0019] The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells. Preferred embodiments include those in which the protein produced by such processes is a mature form of the protein.

[0020] Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology. These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chiromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like. For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue MRNA in a sample using, e.g., in situ hybridization.

[0021] In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.

[0022] The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins. For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide. Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue. The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.

[0023] Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable carrier.

[0024] In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.

[0025] The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample. Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions. The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected. The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.

[0026] The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention. Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.

[0027] The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention. Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein. Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention. The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.

[0028] The methods of the invention also provide methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies. In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products. Compounds and other substances can affect such modulation either on the level of target gene/protein expression or target protein activity.

[0029] The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in Table 2); for which they have a signature region (as set forth in Table 3); or for which they have homology to a gene family (as set forth in Table 4). If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.

4. DETAILED DESCRIPTION OF THE INVENTION

[0030] 4.1 Definitions

[0031] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[0032] The term “active” refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide. According to the invention, the terms “biologically active” or “biological activity” refer to a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule. Likewise “immunologically active” or “immunological activity” refers to the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.

[0033] The term “activated cells” as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.

[0034] The terms “complementary” or “complemenatarity” refer to the natural binding of polynucleotides by base pairing. For example, the sequence 5′-AGT-3′ binds to the complementary sequence 3′-TCA-5′. Complementarity between two single-stranded molecules may be “partial” such that only certain portion(s) of the nucleic acids bind or it may be “complete” such that total complementarity exists between the single stranded molecules. The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.

[0035] The term “embryonic stem cells (ES)” refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells The termi “germ line stem cells (GSCs)” refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes. The term “primordial germ cells (PGCs)” refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells. PGCs are the source from which GSCs and ES cells are derived. The PGCs, the GSCs and the ES cells are capable of self-renewal. Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.

[0036] The term “expression modulating fragment,” EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.

[0037] As used herein, a sequence is said to “modulate the expression of an operably linked sequence” when the expression of the sequence is altered by the presence of the EMF. EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements). One class of EMFs are nucleic acid fragments which induce the expression of an operably linked ORF in response to a specific regulatory factor or physiological event.

[0038] The terms “nucleotide sequence” or “nucleic acid” or “polynucleotide” or “oligonucleotide” are used interchangeably and refer to a heteropolymer of nucleotides or the sequence of these nucleotides. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material. In the sequences herein A is adenine, C is cytosine, T is thyrnine, G is guanine and N is A, C, G, or T (U) or unknown. It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U (uracil). Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.

[0039] The terms “oligonucleotide fragment” or a “polynucleotide fragment”, “portion,” or “segment” or “probe” or “primer” are used interchangeably and refer to a sequence of nucleotide residues which are at least about 5 nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 1 1 nucleotides and most preferably at least about 17 nucleotides. The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides. Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 15 to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides. Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridization procedures, or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules. A fragment or segment may uniquely identify each polynucleotide sequence of the present invention. Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID NO: 1-124, or 249-330.

[0040] Probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al. (Walsh, P. S. et al., 1992, PCR Methods Appl 1:241-250). They may be labeled by nick translation, Kleniow fill-in reaction, PCR, or other methods well known in the art. Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York; or Ausubel, F. M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York N.Y., both of which are incorporated herein by reference in their entirety.

[0041] The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-124, or 249-330. The sequence information can be a segment of any one of SEQ ID NO: 1-124, or 249-330 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO: 1-124, or 249-330, or those segments identified in Tables 3, 5, 6, and 8. One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty- mer is fully matched in the human genome is 1 in 300. In the human genome, there are three billion base pairs in one set of chromosomes. Because 420 possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes. Using the same analysis, the probability for a seventeen-mer to be fully matched in the human genome is approximately 1 in 5. When these segments are used in arrays for expression studies, fifteen-mer segments can be used. The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately 5% of the entire genome sequence.

[0042] Similarly, when using sequence information for detecting a single mismatch, a segment can be a twenty-five mer. The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1.425) times the increased probability for mismatch at each nucleotide position (3×25). The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five. The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.

[0043] The term “open reading frame,” ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.

[0044] The terms “operably linked” or “operably associated” refer to functionally related nucleic acid sequences. For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence. While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g. repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.

[0045] The term “pluripotent” refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism. A pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.

[0046] The terms “polypeptide” or “peptide” or “amino acid sequence” refer to an oligopeptide, peptide, polyp eptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules. A polypeptide “fragment,” “portion,” or “segment” is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids. The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most } preferably less than 100 amino acids. Preferably the peptide is from about 5 to about 200 amino acids. To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.

[0047] The term “naturally occurring polypeptide” refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.

[0048] The term “translated protein coding portion” means a sequence which encodes for the full-length protein which may include any leader sequence or any processing sequence.

[0049] The term “mature protein coding sequence” means a sequence which encodes a peptide or protein without a signal or leader sequence. The “mature protein portion” means that portion of the protein which does not include a signal or leader sequence. The peptide may have been produced by processing in the cell which removes any leader/signal sequence. The mature protein portion may or may not include the initial methionine residue. The methionine residue may be removed from the protein during processing in the cell. The peptide may be produced synthetically or the protein may have been produced usilng a polynucleotide only encoding for the mature protein coding sequence.

[0050] The term “derivative” refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.

[0051] The term “variant” (or “analog”) refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, e g., recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.

[0052] Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the “redundancy” in the genetic code. Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system. Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.

[0053] Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. “Conservative” amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, All phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. “Insertions” or “deletions” are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids. The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.

[0054] Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides. Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention. For, example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate. Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression. For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.

[0055] The terms “purified” or “substantially purified” as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polylnucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).

[0056] The term “isolated” as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source. In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.

[0057] The term “recombinant,” when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived fiom recombinant (e.g., microbial, insect, or mammalian) expression systems. “Microbial” refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems. As a product, “recombinant microbial” defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation. Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.

[0058] The term “recombinant expression vehicle or vector” refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence. An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences. Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino termninal metlionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.

[0059] The term “recombinant expression system” means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally. Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linlked to the DNA segment or synthetic gene to be expressed. This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers. Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed. The cells can be prokaryotic or eukaryotic.

[0060] The term “secreted” includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell. “Secreted” proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. “Secreted” proteins also include without limitation proteins that are transported across the membrane of the endoplasmic reticulum. “Secreted” proteins are also intended to include proteins containing non-typical signal sequences (e.g. Interleukin-1 Beta, see Krasney, P. A. and Young, P. R. (1992) Cytokine 4(2): 134 -143) and factors released from damaged cells (e.g. Interleukin-1 Receptor Antagonist, see Arend, W. P. et. al. (1998) Annu. Rev. lnnunol. 16:27-55)

[0061] Where desired, an expression vector may be designed to contain a “signal or leader sequence” which will direct the polypeptide through the membrane of a cell. Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.

[0062] The term “stringent” is used to refer to conditions that are commonly understood in the art as stringent. Stringent conditions can include highly stringent conditions (i.e., hybridization to filter-bound DNA in 0.5 M NaHPO4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C.), and moderately stringent conditions (i.e., washing in 0.2×SSC/0.1% SDS at 42° C.). Other exemplary hybridization conditions are described herein in the examples.

[0063] In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligonucleotides), 48° C. (for 17-base oligonucleotides), 55° C. (for 20-base oligonucleotides), and 60° C. (for 23-base oligonucleotides).

[0064] As used herein, “substantially equivalent” or “substantially similar” can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences. Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35 % (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less). Such a sequence is said to have 65% sequence identity to the listed sequence. In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25% (75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10% (90% sequence identity) and in a further variation of this embodiment, by no more that 5% (95% sequence identity). Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least 95% sequence identity, more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity. Substantially equivalent nucleotide sequence of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code. Preferably, the nucleotide sequence has at least about 65% identity, more preferably at least about 75% identity, more preferably at least about 80% sequence identity, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least about 95% sequence identity, more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent. For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a new stop codon) should be disregarded. Sequence identity may be determined, e.g., using the Jotun Hein method (Hein, J. (1990) Methods Enzymol. 183:626-645). Identity between sequences can also be determined by other methods known in the art, e.g. by varying hybridization conditions.

[0065] The term “totipotent” refers to the capability of a cell to differentiate into all of the cell types of an adult organism.

[0066] The term “transformation” means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration. The term “transfection” refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed. The term “infection” refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.

[0067] As used herein, an “uptake modulating fragment,” UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell. UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below. The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence. The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined. As described above, a UMF will increase the frequency of uptake of a linked marker sequence.

[0068] Each of the above terms is meant to encompass all that is described for each, unless the context dictates otherwise.

[0069] 4.2 Nucleic Acids of the Invention

[0070] Nucleotide sequences of the invention are set forth in the Sequence Listing.

[0071] The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1-124, or 249-330; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO: 1-124, or 249-330; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the polynucleotides of any one of SEQ ID NO: 1-124, or 249-330. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent conditions to (a) the complement of any of the nucleotides sequences of SEQ ID NO: 1-124, or 249-330; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing, or Table 8; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homolog of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ED NO: 125-248, or 331-412 (for example, as set forth in Tables 3, 5, 6, or 8). Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof, domains in inmunoglobulin-like proteins include the variable inmmunoglobulin-like domains; domains in enzyme-like polypeptides include catalytic and substrate binding domains; and domains in ligand polypeptides include receptor-binding domains.

[0072] The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA. The polynucleotides may include entire coding region of the cDNA or may represent a portion of the coding region of the cDNA.

[0073] The present invention also provides genes corresponding to the cDNA sequences disclosed herein. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials. Further 5′ and 3′ sequence can be obtained using methods known in the art. For example, fall length eDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ID NO: 1-124, or 249-330 can be obtained by screening appropriate cDNA or genomic DNA libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ID NO: 1-124, or 249-330 or a portion thereof as a probe. Alternatively, the polynucleotides of SEQ ID NO: 1-124, or 249-330 may be used as the basis for suitable primer(s) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.

[0074] The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one or more public databases, such as dbEST, gbpri, and UniGene. The EST sequences can provide identifying sequence information, representative fragment or segment information, or novel segment information for the full-length gene.

[0075] The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above. Polynucleotides according to the invention can have, e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, 81%, 82%, 83%, 84%, more typically at least about 85%, 86%, 87%, 88%, 89%, more typically at least about 90%, 91%, 92%, 93%, 94%, and even more typically at least about 95%, 96%, 97%, 98%, 99% sequence identity to a polynucleotide recited above.

[0076] Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1-124, or 249-330, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides. Fragments of, e.g. 15, 17, or 20 nucleotides or more that are selective for (i.e. specifically hybridize to) any one of the polynucleotides of the invention are contemplated. Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.

[0077] The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof. Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1-124, or 249-330, a representative fragment thereof, or a nucleotide sequence at least 90% identical, preferably 95% identical, to SEQ ID NO: 1-124, or 249-330 with a sequence from another isolate of the same species. Furthermore, to accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein. In other words, in the coding region of an ORF, substitution of one codon for another codon that encodes the same amino acid is expressly contemplated.

[0078] The nearest neighbor or homology results for the nucleic acids of the present invention, including SEQ ID NO: 1-124, or 249-330 can be obtained by searching a database using an algorithm or a program. Preferably, a BLAST (Basic Local Alignment Search Tool) program is used to search for local sequence alignments (Altshul, S. F. J Mol. Evol. 36 290-300 (1993) and Altschul S. F. et al. J. Mol. Biol. 21:403-410 (1990)). Alternatively a FASTA version 3 search against Genpept, using FASTXY algorithm may be performed.

[0079] Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by maling suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.

[0080] The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.

[0081] The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids. These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide. There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation. Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature. These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions). Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site. Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous. Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues. Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.

[0082] In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed mutagenesis. This method uses oligonucleotide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucleotides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed. In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., DNA 2:183 (1983). A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res. 10:6487-6500 (1982). PCR may also be used to create amino acid sequence variants of the novel nucleic acids. When small amounts of template DNA are used as starting material, primer(s) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant. PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer. The product DNA fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.

[0083] A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Current Protocols in Molecular Biology, Ausubel et al. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids. Such DNA sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.

[0084] Polynucleotides encoding preferred polypeptide truncations of the invention could be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.

[0085] The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides of the desired sequence identities.

[0086] In accordance with the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ ID NO: 1-124, or 249-330, or functional equivalents thereof, may be used to generate recombinant DNA molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells. Also included are the cDNA inserts of any of the clones identified herein.

[0087] A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). Useful nucleotide sequences for joining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art. Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide. In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell. Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.

[0088] The present invention further provides recombinant constructs comprising a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-124, or 249-330 or a fragment thereof or any other polynucleotides of the invention. In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-124, or 249-330 or a fragment thereof is inserted, in a forward or reverse orientation. In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention. The following vectors are provided by way of example: Bacterial: pBs, phagescript, PsiXl74, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene), pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia); Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).

[0089] The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res. 19, 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art. General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990). As defined herein “operably linked” means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.

[0090] Promoter regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKK232-8 and pCM7. Particular named bacterial promoters include lacd, lacZ, T3, T7, gpt, lambda PR, and trc. Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. cerevisiae TRP 1 gene, and a promoter derived from a highly expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product. Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a funictional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, SIreptomyces, and Staphylococcus, although others may also be employed as a matter of choice.

[0091] As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, Wis., USA). These pBR322 “backbone” sections are combined with an appropriate promoter and the structural sequence to be expressed. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.

[0092] Polynucleotides of the invention can also be used to induce immune responses. For example, as described in Fan et al., Nat. Biotech 17, 870-872 (1999), incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeptide following topical administration of naked plasmid DNA or following injection, and preferably intramuscular injection of the DNA. The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.

[0093] 4.3 Antisense

[0094] Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1-124, or 249-330, or fragments, analogs or derivatives thereof. An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a protein of any of SEQ ID NO: 1-124, or 249-330 or antisense nucleic acids complementary to a nucleic acid sequence of SEQ ID NO: 1-124, or 249-330 are additionally provided.

[0095] In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence of the invention. The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence of the invention. The term “noncoding region” refers to 5′ and 3′ sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).

[0096] Given the coding strand sequences encoding a nucleic acid disclosed herein (e.g., SEQ ID NO: 1-124, or 249-330, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of an mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of an mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of an mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occuning nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, eg., phosphorothioate derivatives and acridine substituted nucleotides can be used.

[0097] Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-metlioxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subdloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0098] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a protein according to the invention to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0099] In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An (x-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual α-units, the strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids Res 15: 6625-6641). The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (lnoue et al. (1987) Nucleic Acids Res 15: 6131-6148) or a chimeric RNA -DNA analogue (Inoue et al. (1987) FEBS Lett 215: 327-330).

[0100] 4.4 Ribozymes and PNA Moieties

[0101] In still another embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of an mRNA. A ribozyme having specificity for a nucleic acid of the invention can be designed based upon the nucleotide sequence of a DNA disclosed herein (i.e., SEQ ID NO: 1-1 24, or 249-330). For example, a derivative of Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA. See, e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742. Alternatively, mRNA of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.

[0102] Alternatively, gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of the gene in target cells. See generally, Helene. (1991) Anticancer Drug Des. 6: 569-84; Helene. et al (1992) Ann. N.Y. Acad. Sci. 660:27-36; and Malier (1992) Bioassays 14: 807-15.

[0103] In various embodiments, the nucleic acids of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorg Med Chem 4: 5-23). As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyiibose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996) above; Perry-O'Keefe et a. (1996) PNAS 93: 14670-675.

[0104] PNAs of the invention can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup B. (1996) above); or as probes or primers for DNA sequence and hybridization (Hyrup et al. (1996), above; Perry-O'Keefe (1996), above).

[0105] In another embodiment, PNAs of the invention can be modified e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996) above). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996) above and Finn et al. (1996) Nucl Acids Res24: 3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA (Mag et al. (1989) Nucl Acid Res 17: 5973-88). PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment (Finn et al. (1996) above). Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment. See, Petersen et al. (1975) Bioorg Med Chem Lett 5:1119-11124.

[0106] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No. W089/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (See, e.g., Krol et al., 1988, BioTechniques 6:958-976) or intercalating agents. (See, e.g., Zon, 1988, Phann. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, etc.

[0107] 4.5 Hosts

[0108] The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention. For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods. The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.

[0109] Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cellsi express the polypeptide at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences. See, for example, PCT International Publication No. WO94/12650, PCT International Publication No. WO92/20808, and PCT International Publication No. WO9 1/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.

[0110] The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE, dextran mediated transfection, or electroporation (Davis, L. et al., Basic Methods in Molecular Biology (1986)). The host cells containing one of the polynucleotides of the invention, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.

[0111] Any host/vector system can be used to express one or more of the ORFs of the present invention. These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf9 cells, as well as prokaryotic host such as E. coli and B. subtilis. The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level. Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989), the disclosure of which is hereby incorporated by reference.

[0112] Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981). Other cell lines capable of expressing a compatible vector are, for example, the C127, moikey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Colo205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells. Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.

[0113] Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria. Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharoniyces pombe, Kluyveronlyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.

[0114] In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, and regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting. These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.

[0115] The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.

[0116] The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat. No. 5,272,071 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/US92/09627 (WO93/09222) by Selden et al.; and International Application No. PCT/US90/06436 (WO91106667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.

[0117] 4.6 Polypeptides of the Invention

[0118] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ ID NO: 125-248, or 331-412 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NO: 1-124, or 249-330 or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NO: 1-124, or 249-330 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO: 125-248, or 331-412 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions. The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID NO: 125-248, or 331-412 or the corresponding full length or mature protein; and “substantial equivalents” thereof (e.g., with at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, 86%, 87%, 88%, 89%, at least about 90%, 91%, 92%, 93%, 94%, typically at least about 95%, 96%, 97%, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity. Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID NO: 125-248, or 331-412.

[0119] Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S. McDowell, et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites. Fragments are also identified in Tables 3, 5, 6, and 8.

[0120] The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins. The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences. The predicted signal sequence is set forth in Table 6. The mature form of such protein may be obtained and confirmed by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell and sequencing of the cleaved product. One of skill in the art will recognize that the actual cleavage site may be different than that predicted in Table 6. The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form. Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided. In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed.

[0121] Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.

[0122] The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention. By “degenerate variant” is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode an identical polypeptide sequence. Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.

[0123] A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention. At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. This technique is particularly useful in producing small peptides and fragments of larger polypeptides. Fragments are useful, for example, in generating antibodies against the native polypeptide. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.

[0124] The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein. As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level. One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.

[0125] The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown. For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide. The polypeptide can be recovered from the culture, conveniently firom the culture medium, or from a lysate prepared from the host cells and firther purified. Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.

[0126] In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein. One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography. See, e.g., Scopes, Protein Purification: Principles and Practice, Springer-Verlag (1994); Sambrook, et al., in Molecular Cloning: A Laboratory Manual; Ausubel et al., Current Protocols in Molecular Biology. Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.

[0127] The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides. These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.

[0128] In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 125-248, or 331- 412.

[0129] The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.

[0130] The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications, in the peptide or DNA sequence, can be made by those skilled in the art using known techniques. Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat. No. 4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein. Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alailne, followed by testing the resulting alanine-containing variant for biological activity. This type of analysis determines the importance of the substituted amino acid(s) in biological activity. Regions of the protein that are important for protein function may be determined by the eMATRIX program.

[0131] Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are encompassed by the present invention.

[0132] The protein may also be produced by operably linking the isolated polynucleotide Aof the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBat™ kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agnicultural Experiment Station Bulletin No. 1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is “transformed.”

[0133] The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e., from culture mediuni or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl™ or Cibacrom blue 3GA Sepharose™; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or inuunoaffility chromatography.

[0134] Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as a His tag. Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.), Pharnacia (Piscataway, N.J.) and Invitrogen, respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope. One such epitope (“FLAG®”) is commercially available from Kodak (New Haven, Conn.).

[0135] Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an “isolated protein.”

[0136] The polypeptides of the invention include analogs (variants). This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted. Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent. Such analogs may exhibit improved properties such as activity and/or stability. Examples of moieties which may be fused to the polypeptide or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells. Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SK506, azathioprine, CD3 antibodies and steroids. Also, polypeptides may be fused to immune modulators, and other cytokines such as alpha or beta interferon.

[0137] 4.6.1 Determining Polypeptide and Polynucleotide Identity and Similarity

[0138] Preferred identity and/or similarity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, BLASTX, FASTA (Altschul, S.F. et al., J. Molec. Biol. 215:403-410 (1990), PSI-BLAST (Altschul S. F. et al., Nucleic Acids Res. vol. 25, pp. 3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp. Biol., Vol. 6, pp. 219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol. 4, pp. 202-209, herein incorporated by reference), Pfam software (Sonnhammer et al., Nucleic Acids Res., Vol. 26(1), pp. 320-322 (1998), herein incorporated by reference) and the Kyte-Doolittle hydrophobocity prediction algorithm (J. Mol Biol, 157, pp. 105-31 (1982), incorporated herein by reference). polypeptide sequences were examined by a proprietary algorithm, SeqLoc that separates the proteins into three sets of locales: intracellular, membrane, or secreted. This prediction is based upon three characteristics of each polypeptide, including percentage of cysteine residues, Kyte-Doolittle scores for the first 20 amino acids of each protein, and Kyte-Doolittle scores to calculate the longest hydrophobic stretch of the said protein. Values of predicted proteins are compared against the values from a set of 592 proteins of known cellular localization from the Swissprot database (http://www.exnasy.ch/sprot). Predictions are based upon the maximum likelihood estimation.

[0139] The BLAST programs are publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul, S., et al. NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990).

[0140] 4.7 Chimeric and Fusion Proteins

[0141] The invention also provides chimeric or fusion proteins. As used herein, a “chimeric protein” or “fusion protein” comprises a polypeptide of the invention operatively linked to another polypeptide. Within a fusion protein the polypeptide according to the invention can correspond to all or a portion of a protein according to the invention. In one embodiment, a fusion protein comprises at least one biologically active portion of a protein according to the invention. In another embodiment, a fusion protein comprises at least two biologically active portions of a protein according to the invention. Within the fusion protein, the term “operatively linked” is intended to indicate that the polypeptide according to the invention and the other polypeptide are fused in-frame to each other. The polypeptide can be fused to the N-terminus or C-terminus, or to the middle.

[0142] For example, in one embodiment a fusion protein comprises a polypeptide according to the invention operably linked to the extracellular domain of a second protein.

[0143] In another embodiment, the fusion protein is a GST-fusion protein in which the polypeptide sequences of the invention are fused to the C-terminus of the GST (i.e., glutathione S-transferase) sequences.

[0144] In another embodiment, the fusion protein is an immunoglobulin fusion protein in which the polypeptide sequences according to the invention comprise one or more domains fused to sequences derived from a member of the immunoglobulin protein farnily. The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand and a protein of the invention on the surface of a cell, to thereby suppress signal transduction in vivo. The immunoglobulin fusion proteins can be used to affect the bioavailability of a cognate ligand. Inhibition of the ligand/protein interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, e.g., cancer as well as modulating (e.g., promoting or inhibiting) cell survival. Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies in a subject, to purify ligands, and in screening assays to identify molecules that inhibit the interaction of a polypeptide of the invention with a ligand.

[0145] A chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Ausubel et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protein of the invention.

[0146] 4.8 Gene Therapy

[0147] Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein. The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention. Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments). See, for example, Anderson, Nature, supplement to vol. 392, no. 6679, pp.25-20 (1998). For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992). Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression). Qells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes. Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states. It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.

[0148] Other methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods known in the art. Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.

[0149] The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell. These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.

[0150] Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences. See, for example, PCT International Publication No. WO 94/12650, PCT International Publication No. WO 92/20808, and PCT International Publication No. WO 91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.

[0151] In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced maybe replaced, removed, added, or otherwise modified by targeting. These sequences include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.

[0152] The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.

[0153] Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.

[0154] The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat. No. 5,272,071 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/US92/09627 (WO93/09222) by Selden et al.; and International Application No. PCT/US90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.

[0155] 4.9 Transgenic Animals

[0156] In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals. Knockout animals, preferably non-human marnmals, can be prepared as described in U.S. Pat. No. 5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Patent No 5,489,743 and PCT Publication No. WO94/28122, incorporated herein by reference.

[0157] Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.

[0158] The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide. Such animals are useful as models for studying the in vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.

[0159] In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat. No. 5,557,032, incorporated herein by reference. Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human marnnals, are produced using methods as described in U.S. Pat. No. 5,489,743 and PCT Publication No. WO94/28 122, incorporated herein by reference.

[0160] Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.

[0161] 4.10 Uses and Biological Activity

[0162] The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA). The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment. Thus, “therapeutic compositions of the invention” include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the im overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity. Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein); antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.

[0163] The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.

[0164] 4.10.1 Research Uses and Utilities

[0165] The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to “subtract-out” known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.

[0166] The polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding polypeptide is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

[0167] Any or all of these research utilities are capable of being developed into reagent grade or kdt format for commercialization as research products.

[0168] Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation “Molecular Cloning; A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology: Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.

[0169] 4.10.2 Nutritional Uses

[0170] Polynucleotides and polypeptides of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the polypeptide or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.

[0171] 4.10.3 Cytokine and Cell Proliferation/Differentiation Activity

[0172] A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMK, HUVEC, and Caco. Therapeutic compositions of the invention can be used in the following:

[0173] Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., I. Immunol. 149:3778-3783, 1992; Bowman et al., I. hmnunol. 152:1756-1761, 1994.

[0174] Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human interleukin-y, Schreiber, R. D. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.

[0175] Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Boffomly, K., Davis, L. S. and Lipsky, P. E. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6—Nordan, R. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Aced. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11 —Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9—Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.

[0176] Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M.,Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. nnmunol. 140:508-512, 1988.

[0177] 4.10.4 Stem Cell Growth Factor Activity

[0178] A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoictic stem cells and/or germ line stem cells. Administration of the polypeptide of the invention to stem cells in vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors. The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson's, Alzheimer's and other neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.

[0179] It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein 1-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPO), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).

[0180] Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells. Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations. This can be accomplished by direct administration of the polypeptide of the invention to the culture medium. Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo. Stromal support cells for feeder layers may include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Pat. No. 5,690,926).

[0181] Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention. This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types. These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments. These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.

[0182] Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions. For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders. The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders which involve degeneration, death or trauma to neural cells or nerve tissue. In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.

[0183] Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types. A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker. The selectable marker allows only cells of the desired type to survive. For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48: 173-182, (1991); Klug et al., J. Clin. Invest., 98(1): 216-224, (1998)) or skeletal muscle cells (Browder, L. W. In: Principles of Tissue Engineering eds. Lanza et al., Academic Press (1997)). Alternatively, directed differentiation of stem cells can be accomplished by culturing the stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.

[0184] In vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity. Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al. Proc. Natl. Acad. Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines. The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-solid support e.g. as described by Bernstein et al., Blood, 77: 2316-2321 (1991).

[0185] 4.10.5 Hematopoiesis Regulating Activity

[0186] A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell disorders. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thuombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.

[0187] Therapeutic compositions of the invention can be used in the following:

[0188] Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.

[0189] Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.

[0190] Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells. R. I. Freslmey, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic,Cells. R. I. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J. In Culture of Hematopoietic Cells. R. L. Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, N.Y. 1994.

[0191] 4 .10.6 Tissue Growth Activity

[0192] A polypeptide of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.

[0193] A polypeptide of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals. Compositions of a polypeptide, antibody, binding partner, or other modulator of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.

[0194] A polypeptide of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells. Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes may also be possible using the composition of the invention.

[0195] Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation. Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.

[0196] The compositions of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.

[0197] Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.

[0198] Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular, (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarring may allow normal tissue to regenerate. A polypeptide of the present invention may also exhibit angiogenic activity.

[0199] A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.

[0200] A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.

[0201] Therapeutic compositions of the invention can be used in the following:

[0202] Assays for tissue generation activity include, without limitation, those described in: Intemational Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium).

[0203] Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, H. I. and Rovee, D. T., eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).

[0204] 4.10.7 Immune Stimulating or Suppressing Activity

[0205] A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A polynucleotide of the invention can encode a polypeptide exhibiting such activities. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, proteins of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.

[0206] Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a protein (or antagonists thereof, including antibodies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.g. anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dermatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, organ transplantation), may also be treatable using a protein (or antagonists thereof) of the present invention. The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125: 59-66, 1998), skin prick test (Hoffmann et al., Allergy 54: 446-54, 1999), guinea pig skin sensitization test (Vohr et al., Arch. Toxocol. 73: 501-9), and murine local lymph node assay (Kimber et al., J. Toxicol. Environ. Health 53: 563-79).

[0207] Using the proteins of the invention it may also be possible to modulate immune responses, in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both. Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.

[0208] Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, a lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.

[0209] The efficacy of particular therapeutic compositions in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of therapeutic compositions of the invention on the development of that disease.

[0210] Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self-tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms. Administration of reagents which block stimulation of T cells can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoiinmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).

[0211] Upregulation of an antigen function (e.g., a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy. Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response may be useful in cases of viral infection, including systemic viral diseases such as influenza, the common cold, and encephalitis.

[0212] Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.

[0213] A polypeptide of the present invention may provide the necessary stimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient mounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and β2 microglobulin protein or an MHC class II alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I or MHC class II proteins on the cell surface. Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.

[0214] The activity of a protein of the invention may, among other means, be measured by the following methods:

[0215] Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kluisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrrann et al., Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Hernann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai et al., I. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Bowman et al., J. Virology 61:1992-1998; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994.

[0216] Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Th1/Th2 profiles) include, without limitation, those described in: Maliszewski, J. lnmunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.

[0217] Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Thl and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Inuunol. 137:3494-3500, 1986; Takai et al., J. Inuunol. 140:508-512, 1988; Bertagnolli et al., J. Immunol. 149:3778-3783, 1992.

[0218] Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.

[0219] Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1 991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.

[0220] Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.

[0221] 4.10.8 Activin/Inhibin Activity

[0222] A polypeptide of the present invention may also exhibit activin- or inhibin-related activities. A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, U.S. Pat. No. 4,798,885. A polypeptide of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as, but not limited to, cows, sheep and pigs.

[0223] The activity of a polypeptide of the invention may, among other means, be measured by the following methods.

[0224] Assays for activin/inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc. Natl. Acad. Sci. USA 83:3091-3095, 1986.

[0225] 4.10.9 Chemotactic/Chemokinetic Activity

[0226] A polypeptide of the present invention maybe involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic compositions (e.g. proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.

[0227] A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.

[0228] Therapeutic compositions of the invention can be used in the following:

[0229] Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Marguiles, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-lnterscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995; Lind et al. APMIS 103:140-146, 1995; Muller et al Eur. J. Immunol. 25:1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994; Johnston et al. J. of hmmunol. 153:1762-1768, 1994.

[0230] 4.10.10 Hemostatic and Thrombolytic Activity

[0231] A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A composition of the invention may also be usefull for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).

[0232] Therapeutic compositions of the invention can be used in the following:

[0233] Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.

[0234] 4.10.11 Cancer Diagnosis and Therapy

[0235] Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis. Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer. For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy. Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition. Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.

[0236] Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness. Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi's sarcoma.

[0237] Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer. Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g. reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.

[0238] The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail. An anti-cancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery. The use of anti-cancer cocktails as a cancer treatment is routine. Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCl (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCl, Doxorubicin HCl, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyirea hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.

[0239] In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer. There are hereditary conditions and/or environmental situations (e.g. exposure to carcinogens) known in the art that predispose an individual to developing cancers. Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.

[0240] In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment. These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, N.Y. Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J. Natl. Can. Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev. Biol., 40: 1189-97 (1999) and Li et al., Clin. Exp. Metastasis, 17:423-9 (1999), respectively. Suitable tumor cells lines are available, e.g. from American Type Tissue Culture Collection catalogs.

[0241] 4.10.12 Receptor/Ligand Activity

[0242] A polypeptide of the present invention may also demoiistrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions. A polynucleotide of the invention can encode a polypeptide exhibiting such characteristics. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selecting, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral iimune responses. Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.

[0243] The activity of a polypeptide of the invention may, among other means, be measured by the following methods:

[0244] Suitable assays for receptor-ligand activity include without limitation those , described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1- 7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.

[0245] By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s). Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.

[0246] Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands. The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, calorimetric molecules or a toxin molecules by conventional methods. (“Guide to Protein Purification” Murray P. Deutscher (ed) Methods in Enzymology Vol. 182 (1990) Academic Press, Inc. San Diego). Examples of radioisotopes include, but are not limited to, tritium and carbon-14. Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other calorimetric molecules. Examples of toxins include, but are not limited, to ricin.

[0247] 4.10.13 Drug Screening

[0248] This invention is particularly useful for screening chemical compounds by using the novel polypeptides or binding fragments thereof in any of a variety of drug screening techniques. The polypeptides or fragments employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the polypeptide or a fragment thereof. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between polypeptides of the invention or fragments and the agent being tested or examine the diminution in complex formation between the novel polypeptides and an appropriate cell line, which are well known in the art.

[0249] Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.

[0250] Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening.

[0251] The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves. Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof. For a review, see Science 282:63-68 (1998).

[0252] Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries. Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers, Curr. Opin. Biotechnol. 8:701-707 (1997). For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al., Mol. Biotechnol, 9(3):205-23 (1998); Hruby et al., Curr Opin Chem Biol, 1(1):114-19 (1997); Dorner et al., Bioorg Med Chem, 4(5):709-15 (1996) (alkylated dipeptides).

[0253] Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to bind a polypeptide of the invention. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.

[0254] The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention. Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.

[0255] 4.10.14 Assay for Receptor Activity

[0256] The invention also provides methods to detect specific binding of a polypeptide e.g. a ligand or a receptor. The art provides numerous assays particularly useful for identifying previously unknown binding partners for receptor polypeptides of the invention. For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners. As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention. There are a number of different libraries used for the identification of compounds, and in particular small molecules, that modulate (i.e., increase or decrease) biological activity of a polypeptide of the invention. Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does not. The responses of the two cell populations to the addition of ligands(s) are then compared. Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s). As still another example, BIAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.

[0257] The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be determined. For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell. The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor. Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e. phosphorylation. Other methods known to those in the art can also be used to identify signaling molecules involved in receptor activity.

[0258] 4.10.15 Anti-Inflammatory Activity

[0259] Compositions of the present invention may also exhibit anti-inflammatory activity. The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material. Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflamation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.

[0260] 4.10.16 Leukemias

[0261] Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention. Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia).

[0262] 4.10.17 Nervous System Disorders

[0263] Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems:

[0264] (i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries;

[0265] (ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia;

[0266] (iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis;

[0267] (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis;

[0268] (v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wemicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration;

[0269] (vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;

[0270] (vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and

[0271] (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.

[0272] Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention:

[0273] (i) increased survival time of neurons in culture;

[0274] (ii) increased sprouting of neurons in culture or in vivo;

[0275] (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or

[0276] (iv) decreased symptoms of neuron dysfunction in vivo.

[0277] Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al. (1990, J. Neurosci. 10:3507-3515); increased sprouting of neurons may be detected by methods set forth in Pestronk et al. (1980, Exp. Neurol. 70:65-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.

[0278] In specific embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).

[0279] 4.10.18 Other Activities

[0280] A polypeptide of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.

[0281] 4.10.19 Identification of Polymorphisms

[0282] The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment. Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately. For exarnple, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.

[0283] Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA. For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced. Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides). In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed. Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms. The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention. In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.

[0284] Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.

[0285] 4.10.20 Arthritis and Inflammation

[0286] The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis is determined in an experimental animal model system. The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int. Arch. Allergy Appl. Immunol., 23:129. Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA). The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture. The polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg. The control consists of administering PBS only.

[0287] The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24. At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above. An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.

[0288] 4.11 Therapeutic Methods

[0289] The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods. Examples of therapeutic applications include, but are not limited to, those exemplified herein.

[0290] 4.11.1 Example

[0291] One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention. While the mode of administration is not particularly important, parenteral administration is preferred. An exemplary mode of administration is to deliver an intravenous bolus. The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician. It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient. Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 μg/kg to 10 mg/kg of patient body weight. For parenteral administration, polypeptides of the invention will be formulated in an injectable form combined with a pharmaceutically acceptable parenteral vehicle. Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin. The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient. The preparation of such solutions is within the skill of the art.

[0292] 4.12 Pharmaceutical Formulations and Routes of Administration

[0293] A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders. Such a composition may optionally contain (in addition to protein or other active ingredient and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), insulin-like growth factor (IGF), as well as cytokines described herein.

[0294] The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects. Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent (such as IL-IRa, IL-1 Hy1, IL-1 Hy2, anti-TNF, corticosteroids, immunosuppressive agents). A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.

[0295] As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition. A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0296] In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated. Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.

[0297] 4.12.1 Routes of Administration

[0298] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, initraperitoneal, parenteral or intravenous injection. Intravenous administration to the patient is preferred.

[0299] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation. In order to prevent the scarring process frequently occurring as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposorne coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue. The liposomes will be targeted to and taken up selectively by the afflicted tissue.

[0300] The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action. The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art. Preferably for wound treatment, one administers the therapeutic compound directly to the site. Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models. Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.

[0301] 4.12.2 Compositions/Formulations

[0302] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% protein or other active ingredient of the present invention, and preferably from about 25 to 90% protein or other active ingredient of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol., When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein or other active ingredient of the present invention, and preferably from about 1 to 50% protein or other active ingredient of the present invention.

[0303] When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic velicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0304] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well lknown in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0305] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0306] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0307] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder fonn for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0308] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0309] A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various types of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.

[0310] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions. Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.

[0311] The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) or other active ingredient(s) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.

[0312] The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.

[0313] The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient's response. Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein or other active ingredient of the present invention per kg body weight. For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body. Such matrices may be formed of materials presently in use for other implanted medical applications.

[0314] The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation. Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above-mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns. In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.

[0315] A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells. In further compositions, proteins or other active ingredients of the invention maybe combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β), and insulin-like growth factor (IGF).

[0316] The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention. The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be detennined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling.

[0317] Polynucleotides of the present invention can also be used for gene therapy. Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes.

[0318] 4.12.3 Effective Dosage

[0319] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal inhibition of the protein's biological activity). Such information can be used to more accurately determine useful doses in humans.

[0320] A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, BPLC assays or bioassays can be used to determine plasma concentrations.

[0321] Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0322] An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 μg/kg to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 μg/kg to 25 mg/kg of patient body weight daily, varying in adults and children. Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.

[0323] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0324] 4.12.4 Packaging

[0325] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0326] 4.13 Antibodies

[0327] Also included in the invention are antibodies to proteins, or fragments of proteins of the invention. The term “antibody” as used herein refers to imnmunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab′ and F(ab′)2 fragments, and an Fab expression library. In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG1, IgG2, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

[0328] An isolated related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polygonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as imnmunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in SEQ ID NO:, 125-248, or 331-412, or Tables 3, 5, 6, or 8, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the fall length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

[0329] In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a surface region of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human related protein sequence will indicate which regions of a related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydroplilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each of which is incorporated herein by reference in its entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0330] A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that inmmunospecifically bind these protein components.

[0331] The term “specific for” indicates that the variable regions of the antibodies of the invention recognize and bind polypeptides of the invention exclusively (i.e., able to distinguish the polypeptide of the invention from other similar polypeptides despite sequence identity, homology, or similarity found in the family of polypeptides), but may also interact with other proteins (for example, S. aureus protein A or other antibodies in ELISA techniques) thlrough interactions with sequences outside the variable region of the antibodies, and in particular, in the constant region of the molecule. Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al. (Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, N.Y. (1988), Chapter 6. Antibodies that recognize and bind fragments of the polypeptides of the invention are also contemplated, provided that the antibodies are first and foremost specific for, as defined above, full-length polypeptides of the invention. As with antibodies that are specific for fall length polypeptides of the invention, antibodies of the invention that recognize fragments are those which can distinguish polypeptides from the same family of polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins.

[0332] Antibodies of the invention are useful for, for example, therapeutic purposes (by modulating activity of a polypeptide of the invention), diagnostic purposes to detect or quantitate a polypeptide of the invention, as well as purification of a polypeptide of the invention. Kits comprising an antibody of the invention for any of the purposes described herein are also comprehended. In general, a kit of the invention also includes a control antigen for which the antibody is immunospecific. The invention further provides a hybridoma that produces an antibody according to the invention. Antibodies of the invention are useful for detection and/or purification of the polypeptides of the invention.

[0333] Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein.

[0334] The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify cells or tissues in which a fragment of the polypeptide of interest is expressed. The antibodies may also be used directly in therapies or other diagnostics. The present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and Sepharose®, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir, D. M. et al., “Handbook of Experimental Immunology” 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986); Jacoby, W. D. et al., Meth. Enzym. 34 Academic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immuno-affinity purification of the proteins of the present invention.

[0335] Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., incorporated herein by reference). Some of these antibodies are discussed below.

[0336] 4.13.1 Polyclonal Antibodies

[0337] For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface-active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants that can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

[0338] The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).

[0339] 4.13.2 Monoclonal Antibodies

[0340] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen-binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

[0341] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256, 495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

[0342] The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

[0343] Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63).

[0344] The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107, 220 (1980). Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.

[0345] After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.

[0346] The monoclonal antibodies secreted by the subdlones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0347] The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

[0348] 4.13.3 Humanized Antibodies

[0349] The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321, 522-525 (1986); Riechmann et al., Nature, 332, 323-327 (1988); Verhoeyen et al., Science, 239, 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Pat. No. 5,225,539). In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2, 593-596 (1992)).

[0350] 4.13.4 Human Antibodies

[0351] Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies”, or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80, 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).

[0352] In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227, 381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (BiolTechnology 10, 779-783 (1992)); Lonberg et al. (Nature 368, 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13, 65-93 (1995)).

[0353] Human antibodies may additionally be produced using transgenic nonhuman animals that are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells that secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be firther modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

[0354] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

[0355] A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat. No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

[0356] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

[0357] 4 .13.5 FAB Fragments and Single Chain Antibodies

[0358] According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246, 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by teclniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.

[0359] 4.13.6 Bispecific Antibodies

[0360] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

[0361] Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305, 537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., 1991 EMBO J., 10, 3655-3659.

[0362] Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121, 210 (1986).

[0363] According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers that are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted enid-products such as homodimers.

[0364] Bispecific antibodies can be prepared as full-length antibodies or antibody fragments (e.g. F(ab′)2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Bremnan et al., Science 229, 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0365] Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175, 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule. Each Fab′ fragmnent was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

[0366] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5), 1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90, 6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) coimected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152, 5368 (1994).

[0367] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147, 60 (1991).

[0368] Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as Fc-γRI (CD64), Fc′γRII (CD32) and FcγRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

[0369] 4.13.7 Heteroconjugate Antibodies

[0370] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

[0371] 4.13.8 Effector Function Engineering

[0372] It can be desirable to modify the antibody of the invention with respect to effector finction, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176, 1191-1195 (1992) and Shopes, J. Immunol., 148, 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53, 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3, 219-230 (1989).

[0373] 4.13.9 Immunoconjugates

[0374] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

[0375] Chemotherapeutic agents useful in the generation of such imnlunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

[0376] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

[0377] In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

[0378] 4.14 Computer Readable Sequences

[0379] In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, “computer readable media” refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. As used herein, “recorded” refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.

[0380] A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data processor structuring fonnats (e.g. text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.

[0381] By providing any of the nucleotide sequences SEQ ID NO: 1-124, or 249-330 or a representative fragment thereof; or a nucleotide sequence at least 95% identical to any of the nucleotide sequences of SEQ ID NO: 1-124, or 249-330 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes. Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium. The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence. Such ORFs may be protein-encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.

[0382] As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means. As used herein, “data storage means” refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.

[0383] As used herein, “search means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to, Smith-Waterman, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA). A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems. As used herein, a “target sequence” can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues. However, it is well recognized that searches for commnercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.

[0384] As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequences) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).

[0385] 4.15 Triple Helix Formation

[0386] In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polyn-ucleotide sequence to DNA or RNA. Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix-see Lee et al., Nucl. Acids Res. 6, 3073 (1979); Cooney et al., Science 15241, 456 (1988); and Dervan et al., Science 251, 1360 (1991)) or to the mRNA itself (anitisense-Olnmo, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisenise Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix-formnation optimally results in a shut-off of RNA transcription from DNA, while antis ense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.

[0387] 4.16 Diagnostic Assays and Kits

[0388] The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.

[0389] In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample. Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is amplified, a polynucleotide of the invention is detected in the sample.

[0390] In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.

[0391] In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.

[0392] Conditions for incubating a nucleic acid probe or antibody with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention. Examples of such assays can be found in Chard, T., An Introduction to Radioirnmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985). The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.

[0393] In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention. Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.

[0394] In detail, a compartment kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound antibody or probe. Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.

[0395] 4.17 Medical Imaging

[0396] The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection). See, e.g., Kunkel et al., U.S. Pat. No. 5,413,778. Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in vivo at the target site.

[0397] 4.18 Screening Assays

[0398] Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NO: 1-124, or 249-330, or bind to a specific domain of the polypeptide encoded by the nucleic acid. In detail, said method comprises the steps of:

[0399] (a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and

[0400] (b) determining whether the agent binds to said protein or said nucleic acid.

[0401] In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.

[0402] Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.

[0403] Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polyp/eptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.

[0404] Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound). Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound). Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.

[0405] The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents. The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.

[0406] For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention. Alternatively, agents may be rationally selected or designed. As used herein, an agent is said to be “rationally selected or designed” when the agent is chosen based on the configuration of the particular protein. For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides,” In Synthetic Peptides, A User's Guide, W. H. Freeman, New York (1992), pp. 289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.

[0407] In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or rationally designed/selected. Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control. One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA. Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.

[0408] Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6, 3073 (1979); Cooney et al., Science 241, 456 (1988); and Dervan et al., Science 251, 1360 (1991)) or to the mRNA itself (antisense-Okano, J. Neurochem. 56, 560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.

[0409] Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent. Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.

[0410] 4.19 Use of Nucleic Acids as Probes

[0411] Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurring nucleotide sequences. The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NO: 1-124, or 249-330. Because the corresponding gene is only expressed in a limited number of tissues, a hybridization probe derived from any of the nucleotide sequences SEQ ID NO: 1-124, or 249-330 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.

[0412] Any suitable hybridization technique can be employed, such as, for example, in situ hybridization. PCR as described in U.S. Pat. Nos. 4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences. Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both. The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.

[0413] Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA probes. Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerase as T7 or SP6 RNA polymerase and the appropriate radioactively labeled nucleotides. The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences. The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well-known genetic and/or chromosomal mapping techniques. These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like. The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York N.Y.

[0414] Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data. Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:198 1f). Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease. The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.

[0415] 4.20 Preparation of Support Bound Oligonucleotides

[0416] Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.

[0417] Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon. One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers. Immobilization can be achieved using passive adsorption (Inouye & Hondo, (1990) J. Clin. Microbiol. 28(6), 1469-72); using UV light (Nagata et al., 1985; Dahlen et al., 1987; Morrissey & Collins, (1989) Mol. Cell Probes 3(2) 189-207) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.

[0418] Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linlker. For example, Broude et al. (1994) Proc. Natl. Acad. Sci. USA 91(8), 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads. Streptavidin-coated beads may be purchased from Dynal, Oslo. Of course, this same linking chemistry is applicable to coating any surface with streptavidin. Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, Calif.).

[0419] Nunc Laboratories (Naperville, Ill.) is also selling suitable material that could be used. Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface tenned Covalink NH. CovaLiik NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridgeheads for fiter covalent coupling. CovaLiik Modules may be purchased from Nunc Laboratories. DNA molecules may be bound to CovaLink exclusively at the 5′-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal. Biochem. 198(1) 138-42).

[0420] The use of CovaLink NH strips for covalent binding of DNA molecules at the 5′-end has been described (Rasmussen et al., (1991). In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res. 11(8) 6513-29). This is beneficial as immobilization using only a single covalent bond is preferred. The phosphoramidate bond joins the DNA to the CovaLink NH secondary ainino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer armn. To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5′-end phosphate group. It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.

[0421] More specifically, the linkage method includes dissolving DNA in water (7.5 ng/μl) and denaturing for 10 min. at 95° C. and cooling on ice for 10 min. Ice-cold 0.1 M 1-methylimidazole, pH 7.0 (1 -MeIm7), is then added to a final concentration of 10 mM 1-MeIm7. A ssDNA solution is then dispensed into CovaLink NH strips (75 μ/l well) standing on ice.

[0422] Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM I-MeIn7, is made fresh and 25 μl added per well. The strips are incubated for 5 hours at 50° C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50° C.).

[0423] It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern & Maskos), incorporated herein by reference. This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3′-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support. The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support. Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.

[0424] An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed. For example, addressable laser-activated photodeprotection may be employed in the chemical synthesis of oligonucleotides directly on a glass surface, as described by Fodor et al. (1991) Science 251(4995), 767-73, incorporated herein by reference. Probes may also be immobilized on nylon supports as described by Van Ness et al. (1991) Nucleic Acids Res., 19(12) 3345-50; or linked to Teflon using the method of Duncan & Cavalier (1988) Anal. Biochem. 169(1), 104-8; all references being specifically incorporated herein.

[0425] To link an oligonucleotide to a nylon support, as described by Van Ness et al. (1991), requires activation of the nylon surface via alkylation and selective activation of the 5′-amine of oligonucleotides with cyanuric chloride.

[0426] One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al, (1994) Proc. Nat'l. Acad. Sci., USA 91(11), 5022-6, incorporated herein by reference). These authors used current photolithographic techniques to generate arrays of imrmobilized oligonucleotide probes (DNA chips). These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5′-protected N-acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies. A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.

[0427] 4.21 Preparation of Nucleic Acid Fragments

[0428] The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC inserts, and RNA, including mRNA without any amplification steps. For example, Sambrook et al. (1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).

[0429] DNA fragments maybe prepared as clones in M13, plasmid or lambda vectors and/or prepared directly firom genomic DNA or cDNA by PCR or other amplification methods. Samples may be prepared or dispensed in multiwell plates. About 100-1000 ng of DNA samples may be prepared in 2-500 ml of final volume.

[0430] The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al. (1989), shearing by ultrasound and NaOH treatment.

[0431] Low pressure shearing is also appropriate, as described by Schriefer et al. (1990) Nucleic Acids Res. 18(24), 7455-6, incorporated herein by reference). In this method, DNA samples are passed through a small French pressure cell at a variety of low to intermediate pressures. A lever device allows controlled application of low to intermediate pressures to the cell. The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.

[0432] One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al. (1992) Nucleic Acids Res. 20(14) 3753-62. These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.

[0433] The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends. Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA fragments form the small molecule pUC19 (2688 base pairs). Fitzgerald et al. (1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUC19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector. Sequence analysis of 76 clones showed that CviJI** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.

[0434] As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 μg instead of 2-5 μg); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed).

[0435] Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization. This is achieved by incubating the DNA solution for 2-5 minutes at 80-90° C. The solution is then cooled quickly to 2° C. to prevent renaturation of the DNA fragments before they are contacted with the chip. Phosphate groups must also be removed from genoinic DNA by methods known in the art.

[0436] 4.22 Preparation of DNA Arrays

[0437] Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane. Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane. By offset printing, a density of dots higher than the density of the wells is achieved. One to 25 dots may be accommodated in 1 mm2, depending on the type of label used. By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed. Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones. Each of the subarrays may represent replica spotting of the same samples. In one example, a selected gene segment may be amplified from 64 patients. For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample). A plate for each of the 64 patients is prepared. By using a 96-pin device, all samples may be spotted on one 8×12 cm membrane. Subarrays may contain 64 samples, one from each patient. Where the 96 subarrays are identical, the dot span may be 1 mm2 and there may be a 1 mm space between subarrays.

[0438] Another approach is to use membranes or plates (available from NUNC, Naperville, Ill.) which may be partitioned by physical spacers e.g. a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips. A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.

[0439] The present invention is illustrated in the following examples. Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention. Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention. Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.

[0440] All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.

5.0 EXAMPLES

[0441] 5.1 Example 1

[0442] Novel Nucleic Acid Sequences Obtained from Various Libraries

[0443] A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBH sequence signature analysis and Sanger sequencing techniques. The inserts of the library were amplified with PCR using primers specific for the vector sequences which flank the inserts. Clones from cDNA libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences. The clones were clustered into groups of similar or identical sequences. Representative clones were selected for sequencing.

[0444] In some cases, the 5′ sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol. PCR products were purified and subjected to fluorescent dye terminator cycle sequencing. Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences.

[0445] 5.2 Example 2

[0446] Assemblage of Novel Nucleic Acids

[0447] The contigs or nucleic acids of the present invention, designated as SEQ ID NO: 249-330 were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST sequences, dbEST, gb pri, and UniGene, and exons from public domain genomnic sequences predicated by GenScan) that belong to this assemblage. The algorithm terminated when there were no additional sequences from the above databases that would extend the assemblage. Further, inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.

[0448] Table 8 sets forth the novel predicted polypeptides (including proteins, SEQ ID NO: 331-412) encoded by the novel polynucleotides (SEQ ID NO: 249-330) of the present invention, and their corresponding translation start and stop nucleotide locations to each of SEQ ID NO: 249-330. Table 8 also indicates the method by which the polypeptide was predicted. Method A refers to a polypeptide obtained by using a software program called FASTY (available from http://fasta.bioch.virginia,edu) which selects a polypeptide based on a comparison of the translated novel polynucleotide to known polynucleotides (W. R. Pearson, Methods in Enzymology, 183:63-98 (1990), herein incorporated by reference). Method B refers to a polypeptide obtained by using a software program called GenScan for human/vertebrate sequences (available from Stanford University, Office of Technology Licensing) that predicts the polypeptide based on aprobabilistic model of gene structure/compositional properties (C. Burge and S. Karlin, J. Mol. Biol., 268:78-94 (1997), incorporated herein by reference). Method C refers to a polypeptide obtained by using a Hyseq proprietary software program that translates the novel polynucleotide and its complementary strand into six possible amino acid sequences (forward and reverse frames) and chooses the polypeptide with the longest open reading frame.

[0449] 5.3 Example 3

[0450] Novel Nucleic Acids

[0451] The novel nucleic acids of the present invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases. The nucleic acids were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (Hyseq's database containing EST sequences, dbEST, gb pri, and UniGene) that belong to this assemblage. The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage. Inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.

[0452] Using PBRAP (Univ. of Washington) or CAP4 (Paracel), a full-length gene cDNA sequence and its corresponding protein sequence were generated from the assemblage. Any frame shifts and incorrect stop codons were corrected by hand editing. During editing, the sequences were checked using FASTY and/or BLAST against Genebank (i.e., dbEST, gb pri, UniGene, and Genpept) and the Geneseq (Derwent). Other computer programs which may have been used in the editing process were PhredPhrap and Consed (University of Washington) and ed-ready, ed-ext and cg-zip-2 (Hyseq, Inc.). The full-length nucleotide and amino acid sequences, including splice variants resulting from these procedures are shown in the Sequence Listing as SEQ ID NO: 1-124.

[0453] SEQ ID NO: 1-37 were determined to contain transmembrane regions using Neural Network SignalP V1.1 program (from Center for Biological Sequence Analysis, The Technical University of Deinark); and TMpred program (http://www.ch.embnet.org/software/TMPRED form.html).

[0454] SEQ ID NO: 38-124 were determined to be membrane-bound polypeptides using a proprietary algorithm, SeqLocm (Hyseq Inc.). SeqLoc™ classifies the proteins into three sets of locales: intracellular, membrane, or secreted. This prediction is calculated using maximum likelihood estimation of three characteristics of each polypeptide, 1) percentage of cysteine residues, 2) Kyte-Doolittle scores for the first 20 amino acids of each protein (J. Mol Biol, 157, pp. 105-31 (1982), incorporated herein by reference), and 3) Kyte-Doolittle scores to calculate the longest hydrophobic stretch (LHS) of the said protein (J. Mol Biol, 157, pp. 105-31 (1982), incorporated herein by reference). The LHS is calculated by finding the stretch of 20 amino acid residues in the protein that have the highest sum of Kyte-Doolittle hydrophobicity values.

[0455] Table 1 shows the various tissue sources of SEQ ID NO: 1-124.

[0456] The homologs for polypeptides SEQ ID NO: 125-248, that correspond to nucleotide sequences SEQ ID NO: 1-124 were obtained by a BLASTP version 2.0al 19MP-WashU searches against current Genpept release using BLAST algorithm. The results showing homologues for SEQ ID NO: 125-248 from Genpept 124 are shown in Table 2.

[0457] Using eMatrix software package (Stanford University, Stanford, Calif.) (Wu et al., J. Comp. Biol., Vol. 6, 219-235 (1999), http://motif.stanford.edu/ematrix-search/herein incorporated by reference), all the polypeptide sequences were examined to determine whether they had identifiable signature regions. Scoring matrices of the eMatrix software package are derived from the BLOCKS, PRINTS, PFAM, PRODOM, and DOMO databases. Table 3 shows the accession number of the homologous eMatrix signature found in the indicated polypeptide sequence, its description, and the results obtained which include accession number subtype; raw score; p-value; and the position of signature in amino acid sequence.

[0458] Using the Pfam software program (Sonnhammer et al., Nucleic Acids Res., Vol. 26(1) pp. 320-322 (1998) herein incorporated by reference) all the polypeptide sequences were examined for domains with homology to certain peptide domains. Table 4 shows the name of the Pfam model found, the description, the product of their e-value, the Pfam score for the identified model within the sequence, number of domains found in the polypeptide sequence, and position(s) of the Pfam domain. Further description of the Pfam models can be found at http://pfam.wustl.edu/.

[0459] The GeneAtlas™ software package (Molecular Simulations Inc. (MSI), San Diego, Calif.) was used to predict the three-dimensional structure models for the polypeptides encoded by SEQ ID NO 1-125 (i.e. SEQ ID NO: 125-248). Models were generated by (1) PSI-BLAST which is a multiple alignment sequence profile-based searching developed by Altschul et al, (Nucl. Acids. Res. 25, 3389-3408 (1997)), (2) High Throughput Modeling (HTM) (Molecular Simulations Inc. (MSI) San Diego, Calif.) which is an automated sequence and structure searching procedure (http://www.msi.com/), and (3) SeqFold™ which is a fold recognition method described by Fischer and Eisenberg (J. Mol. Biol. 209, 779-791 (1998)). This analysis was carried out, in part, by comparing the polypeptides of the invention with the known NMR (nuclear magnetic resonance) and x-ray crystal three-dimensional structures as templates. Table 5 shows: “PDB ID”, the Protein DataBase (PDB) identifier given to template structure; “Chain ID”, identifier of the subcomponent of the PDB template structure; “Compound Information”, information of the PDB template structure and/or its subcomponents; “PDB Function Annotation” gives function of the PDB template as annotated by the PDB files (http:/www.rcsb.orgPDB/); start and end amino acid position of the protein sequence aligned; PSI-BLAST score, the verify score, the SeqFold score, and the Potential(s) of Mean Force (PMF). The verify score is produced by GeneAtlas™ software (MSI), is based on Dr. Eisenberg's Profile-3D threading program developed in Dr. David Eisenberg's laboratory (U.S. Pat. No. 5,436,850 and Luthy, Bowie, and Eisenberg, Nature, 356:83-85 (1992)) and a publication by R. Sanchez and A. Sali, Proc. Natl. Acad. Sci. USA, 95:13597-12502. The verify score produced by GeneAtlas normalizes the verify score for proteins with different lengths so that a unified cutoff can be used to select good models as follows:

Verify score (normalized)=(raw score−½ high score)/(½ high score)

[0460] The PMF score, produced by GeneAtlas™ software (MSI), is a composite scoring function that depends in part on the compactness of the model, sequence identity in the alignment used to build the model, pairwise and surface mean force potentials (MFP). As given in table 5, a verify score between 0 to 1.0, with 1 being the best, represents a good model. Similarly, a PMF score between 0 to 1.0, with 1 being the best, represents a good model. A SeqFold™ score of more than 50 is considered significant. A good model may also be determined by one of skill in the art based all the information in Table 5 taken in totality.

[0461] Table 6 shows the position of the signal peptide for polypeptides of the present invention and the maximum score and the mean score associated with that signal peptide using Neural Network SignalP V1.1 program (from Center for Biological Sequence Analysis, The Technical University of Denmark). The process for identifying prokaryotic and eukaryotic signal peptides and their cleavage sites are also disclosed by Henrik Nielson, Jacob Engelbrecht, Soren Brunak, and Gunnar von Heijne in the publication “Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites” Protein Engineering, Vol. 10, no. 1, pp. 1-6 (1997), incorporated herein by reference. A maximum S score and a mean S score, as described in the Nielson et al reference, was obtained for the polypeptide sequences.

[0462] Table 7 correlates each of SEQ ID NO: 1-124 to a specific chromosomal location.

[0463] Table 10 shows number of transmembrane regions, position of transmembrane 30 regions and score for each of the transmembrane region detected using Neural Network SignalP V1.1 program (from Center for Biological Sequence Analysis, The Technical University of Demnark);and TMPred program (http://www.ch.embnet.org/software/TMPRED form.html).

[0464] Table 9 is a correlation table of the novel polynucleotide sequences SEQ ID NO: 1-124, their corresponding polypeptide sequences SEQ ID NO: 125-248, their corresponding priority contig nucleotide sequences SEQ ID NO: 249-330, their corresponding priority contig polypeptide sequences SEQ ID NO: 331-412, and the US serial number of the priority application in which the contig sequence was filed.

TABLE 1
	RNA	Library
Tissue Origin	Source	Name	SEQ ID NO:
adult brain	GIBCO	AB3001	112
adult brain	GIBCO	ABD003	3-4 10 16 33 60 67-68 71 77 110 114-116 121-122
adult brain	Clontech	ABR001	3 102
adult brain	Clontech	ABR006	7 9 30 55 59-60 70 75 83 90 96 102 107 114-116
adult brain	Clontech	ABR008	2-3 5 7 9-12 21-22 25 30 34 37-39 43 45-47 58 60 62 71-72 78 83
			87 90 100 103 107 120-122 124
adult brain	BioChain	ABR012	60 122
adult brain	BioChain	ABR013	102
adult brain	Invitrogen	ABR014	75 102 122 124
adult brain	Invitrogen	ABR015	11 33 62 71 75 102 122
adult brain	Invitrogen	ABR016	71 102
adult brain	Invitrogen	ABT004	3 7 16 20 33 37 63 74 78 102 106
cultured	Stratagene	ADP001	10 12 55 71 102 122 124
preadipocytes
adrenal gland	Clontech	ADR002	5 23 33 38-39 45 60 63 71 79 94 101 106 112
adult heart	GIBCO	AHR001	1 3 10 14 33 47 59 62-66 71 73-74 78 81 87 91 102-103 114-116
			124
adult kidney	GIBCO	AKD001	3 10-13 21 29-30 33-34 36 52 55-56 58 60 62 68 71 74 91 102-103
			110 114-116 122 124
adult kidney	Invitrogen	AKT002	9 11 30 36 53 63 71 84 102 104 114-115 124
adult lung	GIBCO	ALG001	3 5 30 33 71 74
lymph node	Clontech	ALN001	12 58 71 74 85 122
young liver	GIBCO	ALV001	3 10 30 33 55 68 70-71 103
adult liver	Invitrogen	ALV002	3-4 11-12 14-15 25 33 56 58 63 69 71-72 79 102-103 122 124
adult liver	Clontech	ALV003	36 71 103
adult ovary	Invitrogen	AOV001	3 5 10 20 33-36 45 52-53 55 57-58 60 63 67-69 71 74 79 87 89 91
			102 106 112-113 116 122 124
adult placenta	Clontech	APL001	71
placenta	Invitrogen	APL002	17 63 106 124
adult spleen	GIBCO	ASP001	4 10-12 36 42 62-63 71 102 116 122 124
adult testis	GIBCO	ATS001	3 30 33 36 45 67-69 71 74 89 124
adult bladder	Invitrogen	BLD001	3 71 96
bone marrow	Clontech	BMD001	3 5 10 12 19 33 55 60 63-66 71 74 83 87 91-93 112 123
bone marrow	Clontech	BMD002	5 10 12 14 23 30-31 33 38-39 42-43 58-60 63-66 69 71-72 74 78
			92-93 96 102 107 109 116 124
adult colon	Invitrogen	CLN001	3 5 7 24 44 106 116
mixture of 16	various	CTL016	12
tissues/mRNAs	vendors
adult cervix	BioChain	CVX001	5 10 13 17 30 36 38-39 54-56 59-60 63 68 71 74 91 93 102 116 122
endothelial	Stratagene	EDT001	3 10-11 20 29 33 43 53 55 58-59 62 67 71 80 90-91 102 116 122
cells			124
fetal brain	Clontech	FBR001	58 75
fetal brain	Clontech	FBR004	90 100 105
fetal brain	Clontech	FBR006	3 5 7 10-12 25 30 37 45 58 60 62-63 69 103 107 112 118 121
fetal brain	Invitrogen	FBT002	5 10-11 30 33 38-39 45 90 102
fetal heart	Invitrogen	FHR001	11-12 14 18 34 59-60 69 71 103 105 112 117
fetal kidney	Clontech	FKD001	62-63 71
fetal kidney	Clontech	FKD002	3 5 12 30 38-39 55 59 62 71 103
fetal kidney	Invitrogen	FKD007	38-39
fetal lung	Clontech	FLG001	36 52 71 113
fetal lung	Invitrogen	FLG003	3 11 18 27 30 62-63 69 71 96 112
fetal liver-	Columbia	FLS001	3-5 10 12 25 29 33-34 38-39 43 52-53 55-63 67 70-71 74 87 91
spleen	University		102-104 106 110 113 116 119 121-122 124
fetal liver-	Columbia	FLS002	4 10-11 20 25 33 44-45 50-51 55-57 61-63 70 87 91 100 103 106-107
spleen	University		109 113 116 121-122
fetal liver-	Columbia	FLS003	43 55 63 71 87 96 103 107 124
spleen	University
fetal liver	Invitrogen	FLV001	3 20 25 30 33 47 56 58 71 124
fetal liver	Clontech	FLV002	58 70-71 83
fetal liver	Clontech	FLV004	3 5 11 33 35-36 45 52 55-56 71-72 79 100 102-103 105 122
fetal muscle	Invitrogen	FMS001	3 14 47 60 71 102 122
fetal muscle	Invitrogen	FMS002	4-5 14 55 71-72 80
fetal skin	Invitrogen	FSK001	3 10-11 14 17 27-28 30 36 44 54 57-58 61 63 69 71 105 112 124
fetal skin	Invitrogen	FSK002	3-4 11 18 38-39 43-45 53 69 71 79 105 107 120
umbilical cord	BioChain	FUC001	3 18 34-35 48-49 55 60 62 67 71 74 91 102 104 106 112-113 116
			122
fetal brain	GIBCO	HFB001	3-6 10 33 55 60 62 67-68 71 74-75 87 102 114-115 122 124
macrophage	Invitrogen	HMP001	3 53 63 72-73
infant brain	Columbia	IB2002	3-4 7 10 16 25 30 45 55 58 63 84 90 102 106 110 113
	University
infant brain	Columbia	IB2003	3 6-7 10-11 30 55 74 87 90 106 110
	University
infant brain	Columbia	IBM002	124
	University
infant brain	Columbia	IBS001	7 30 100 120
	University
lung, fibroblast	Stratagene	LFB001	3 10-11 53 67 71 111
lung tumor	Invitrogen	LGT002	10 12 15 30 33 52 62 70-71 74 87-88 91 94 98 102 110 113-115
			122
lymphocytes	ATCC	LPC001	3 15 24 31 47 52 55 58 63-66 68 72 102 108-109 112-113
leukocyte	GIBCO	LUC001	3-5 10-13 15 24 30-31 36 41 52 55 60 62-66 68-69 71-72 74 87 92-93
			101-102 112 116 122
leukocyte	Clontech	LUC003	20 62-63 71 116
melanoma	Clontech	MEL004	5 36 71 99 113 122
from-cell-line-
ATCC-#CRL-
1424
mammary	Invitrogen	MMG001	3 5 10-12 30 33 36 38-39 44 55 58 63 69 71 74 87 95-96 102 116
gland			124
induced	Stratagene	NTD001	33 55 71 84 102 110 114-115
neuron-cells
retinoic acid-	Stratagene	NTR001	5 55 59 69
induced-
neuronal-cells
neuronal cells	Stratagene	NTU001	10 55 71 106-107
pituitary gland	Clontech	PIT004	3 68 71 122
placenta	Clontech	PLA003	4 17 57 69 113 121
prostate	Clontech	PRT001	11 18 64-67 71 74 113
rectum	Invitrogen	REC001	3 12 29 35 44 58
salivary gland	Clontech	SAL001	10-12 15 67 71 82 116 122
skin fibroblast	ATCC	SFB002	122
small intestine	Clontech	SIN001	3 18 38-39 44 53 55 59 62 64-66 71 100 102 116 122 124
skeletal muscle	Clontech	SKM001	71 73-74 87 91 112 114-115
spinal cord	Clontech	SPC001	3 33 59 63 68 71 75 80 102 105 110 116 122 124
adult spleen	Clontech	SPLc01	11-12 18 23 38-39 63 71
stomach	Clontech	STO001	10-11 44 71
thalamus	Clontech	THA002	36 58 71 78 124
thymus	Clontech	THM001	3 5 10 30 33 55 64-67 71 91 100 106 116 124
thymus	Clontech	THMc02	5 11 23-24 36 38-39 43 45 47 55 59-60 63 71-72 93 113
thyroid gland	Clontech	THR001	9-11 23 25 33 38-39 55 63 67 69 71 74 82 85 91 93 105 122-123
trachea	Clontech	TRC001	5 60 71
uterus	Clontech	UTR001	3 10 71 102

[0465] The 16 tissue/mRNAs and their vendor sources are as follows: 1) Normal adult brain mRNA (Invitrogen), 2) Normal adult kidney mRNA (Invitrogen), 3) Normal fetal brain mRNA (Invitrogen), 4) Normal adult liver mRNA (Invitrogen), 5) Normal fetal kidney mRNA (Invitrogen), 6) Normal fetal liver mRNA (Invitrogen), 7) normal fetal skin mRNA (Invitrogen), 8) human adrenal gland mRNA (Clontech), 9) Human bone marrow mRNA (Clontech), 10) Human leukemia lymphoblastic rnRNA (Clontech), 11) Human thymus rnRNA (Clontech), 12) human lymph node mRNA (Clontech), 13) human sospinal cord mRNA (Clontech), 14) human thyroid inRNA (Clontech), 15) human esophagus mRNA (BioChainl), 16) human conceptional umbilical cord mRNA (BioChain).

TABLE 2
SEQ ID NO:	Accession No.	Species	Description	Score	% identity
125	AAY27616	Homo sapiens	Human secreted protein encoded by	562	99
			gene No. 50.
125	gi12957417	Casuarius	ATPase subunit 8	62	35
		bennetti
125	gi332009	Murine	p15-gag protein	57	27
		leukemia virus
126	gi15822827	Homo sapiens	mRNA for pendrin-like protein 1,	1154	39
			complete cds.
126	gi13344999	Homo sapiens	solute carrier family 26 member 6	1300	37
			(SLC26A6) mRNA, complete cds.
126	AAY71067	Homo sapiens	Human membrane transport protein,	1297	37
			MTRP-12.
127	AAY57945	Homo sapiens	Human transmembrane protein	780	100
			HTMPN-69.
127	AAY76141	Homo sapiens	Human secreted protein encoded by	780	100
			gene 18.
127	AAB24037	Homo sapiens	Human PRO 1555 protein sequence	356	47
			SEQ ID NO:49.
128	AAY59672	Homo sapiens	Secreted protein 108-006-5-0-E6-FL.	553	83
128	gi10435214	Homo sapiens	cDNA FLJ13263 fis, clone	549	82
			OVARC1000924.
128	AAB94543	Homo sapiens	Human protein sequence SEQ ID	549	82
			NO:15290.
129	AAY92710	Homo sapiens	Human membrane-associated protein	704	97
			Zsig24.
129	AAY87250	Homo sapiens	Human signal peptide containing	566	99
			protein HSPP-27 SEQ ID NO:27.
129	AAG00627	Homo sapiens	Human secreted protein, SEQ ID	260	100
			NO:4708.
130	AAY99452	Homo sapiens	Human PRO 1693 (UNQ803) amino	1670	63
			acid sequence SEQ ID NO:385.
130	AAB87587	Homo sapiens	Human PRO 1693.	1670	63
130	AAY66713	Homo sapiens	Membrane-bound protein PR01309.	1204	47
131	gi14572521	Homo sapiens	NEPH1 (NEPH1) mRNA, complete	1512	51
			cds.
131	AAB37996	Homo sapiens	Human secreted protein encoded by	1164	92
			gene 13 clone HIBEU15.
131	gi10434261	Homo sapiens	cDNA FLJ12646 fis, clone	1035	41
			NT2RM4001987, weakly similar to
			NEURAL CELL ADHESION
			MOLECULE 1, LARGE ISOFORM
			PRECURSOR.
132	gi29806	Homo sapiens	Human mRNA for CD59, an LY-6-	710	100
			like protein regulating complement
			membrane attack.
132	gi825637	Homo sapiens	H.sapiens gene for CD59 protein,	710	100
			exon 2.
132	gi29815	Homo sapiens	Human mRNA for CD59 antigen.	710	100
133	gi6841140	Homo sapiens	HSPG100 mRNA, partial cds.	498	100
133	gi2828808	Bacillus	glucose transporter	111	25
		subtilis
133	gi9106658	Xylella	glucose/galactose transporter	140	23
		fastidiosa 9a5c
134	AAB56632	Homo sapiens	Human prostate cancer antigen	3377	99
			protein sequence SEQ ID NO:1210.
134	gi13097708	Homo sapiens	ribophorin II, clone MGC: 1817	3152	100
			IMAGE: 3546673, mRNA, complete
			cds.
134	gi5834424	Homo sapiens	RIBIIR gene (partial), exon 1 and	3152	100
			joined CDS.
135	gil3182757	Homo sapiens	HTPAP mRNA, complete cds.	598	100
135	AAG89279	Homo sapiens	Human secreted protein, SEQ ID	598	100
			NO:399.
135	AAB70690	Homo sapiens	Human hDPP protein sequence SEQ	598	100
			ID NO:7.
136	gi2276448	Homo sapiens	Human MHC class I HLA-A (HLA-	1794	93
			A-0302-new allele) mRNA, complete
			cds.
136	gi6815812	Homo sapiens	MHC class I antigen heavy chain	1794	93
			(HLA-A) mRNA, HLA-A*0302
			allele, complete cds.
136	gi1245460	Homo sapiens	Human MHC class I HLA-A allele	1786	92
			(HLA-A) mRNA, complete cds.
137	AAB95392	Homo sapiens	Human protein sequence SEQ ID	567	78
			NO:17743.
137	AAB29645	Homo sapiens	Human membrane-associated protein	548	70
			HUMAP-2.
137	AAB95049	Homo sapiens	Human protein sequence SEQ ID	396	78
			NO:16845.
138	gi14017773	Musmusculus	Cgl0671-like	1517	96
138	gi14017764	Musmusculus	CG10671-like	1517	96
138	gi16198091	Drosophila	LD30661p	184	30
			melanogaster
139	AAG81431	Homo sapiens	Human AEP protein sequence SEQ	503	97
			ID NO:380.
139	gi6707026	Monodelphis	immunoglobulin light chain kappa	108	26
		domestica
139	gi6653413	Oryctolagus	immunoglobulin light chain VJ	102	27
		cuniculus	kappa region
140	gi12836893	Gallus gallus	IPR328-like protein	158	29
140	gi3093433	Homo sapiens	Chromosome 16 BAC clone	151	29
			CIT987SK-625P11, complete
			sequence.
140	gi4558766	Homo sapiens	neuronal voltage gated calcium	151	29
			channel gamma-3 subunit mRNA,
			complete cds.
141	gi4337100	Homo sapiens	M5H55 gene, partial cds; and	400	100
			CLIC1, DDAH, G6b, G6c, G5b,
			G6d, G6e, G6f, BAT5, G5b, CSK2B,
			BAT4, G4, Apo M, BAT3, BAT2,
			AIF-1, 1C7, LST-1, LTB, TNF, and
			LTA genes, complete cds.
141	gi5304878	Homo sapiens	genes encoding RNCC protein,	400	100
			DDAH protein, Ly6-C protein, Ly6-
			D protein and immunoglobulin
			receptor.
141	AAY27597	Homo sapiens	Human secreted protein encoded by	400	100
			gene No. 31.
142	AAB88325	Homo sapiens	Human membrane or secretory	912	99
			protein clone PSEC0020.
142	AAB53257	Homo sapiens	Human colon cancer antigen protein	859	99
			sequence SEQ ID NO:797.
142	gi13325409	Homo sapiens	clone IMAGE:3845253, mRNA,	774	100
			partial cds.
143	gi1234787	Xenopus	up-regulated by thyroid hormone in	917	61
		laevis	tadpoles; expressed specifically in
			the tail and only at metamorphosis;
			membrane bound or extracellular
			protein; C-terminal basic region
143	gi10435980	Homo sapiens	cDNA FLJ13840 fis, clone	812	62
			THYRO 1000783, moderately similar
			to Xenopus laevis tail-specific
			thyroid hormone up-regulated (gene
			5) mRNA.
143	AAB94773	Homo sapiens	Human protein sequence SEQ ID	812	62
			NO:15860.
144	gi4099139	Homo sapiens	Human P2X4 purinoreceptor gene,	2014	100
			exons 9, 10, 11 and 12 and complete
			cds.
144	gi4099121	Homo sapiens	Human P2X4 purinoreceptor mRNA,	2014	100
			complete cds.
144	AAW47066	Homo sapiens	Human brain P2X-1 receptor	2014	100
			polypeptide.
145	AAE03560	Homo sapiens	Human differentially expressed	1020	99
			kidney cDNA 22360 encoded
			protein.
145	gi15637151	Beta vulgaris	glycine decarboxylase subunit P	62	36
145	gi5824822	Caenorhabditis	Y53F4A.2	62	25
		elegans
146	gi972946	Mus musculus	ZP1 precursor	2217	67
146	gi1113794	Mus musculus	zona pellucida	2210	67
146	gi2804566	Rattus	zona pellucida 1 glycoprotein	2200	67
			norvegicus
147	gi15779156	Homo sapiens	Similar to RIKEN cDNA	1858	100
			1810073N04 gene, clone
			MGC:15523 IMAGE:3028844,
			mRNA, complete cds.
147	gi13097045	Mus musculus	Similar to RIKEN cDNA	1719	91
			1810073N04 gene
147	gi603254	Saccharomyces	Ye1064cp	319	27
		cerevisiae
148	AAW03516	Homo sapiens	Prostaglandin DP receptor.	1467	100
148	gi940379	Homo sapiens	Human DP prostanoid receptor	1467	100
			(PTGDR) gene, 5′ region and partial
			cds.
148	gi4567038	Rattus	prostaglandin D2 receptor	1127	77
		norvegicus
149	gi2811122	Xenopus	NaDC-2	1274	56
		laevis
149	gi1098557	Homo sapiens	Human renal sodium/dicarboxylate	1618	55
			cotransporter (NADC1) mRNA,
			complete cds.
149	gi3168585	Rattus	sodium-dependent dicarboxylate	1614	54
		norvegicus	transporter
150	gi3036840	Homo sapiens	mRNA for cystinosm.	1686	88
150	gi3036851	Homo sapiens	GTNS gene, exon 3, flanking intronic	1686	88
			regions and joined CDS.
150	gi7239176	Homo sapiens	vanilloid receptor gene, partial	1686	88
			sequence; CARKL and CTNS genes,
			complete cds; TIP1 gene, partial cds;
			P2X5b and P2X5a genes, complete
			cds; and HUMINAE gene, partial
			cds.
151	gi41077	Escherichia	cal protein precursor (aa 1-51)	63	42
		coli
151	gi6474978	Schizosaccharomyces	Amino acid permease	62	27
		pombe
151	AAB40157	Homo sapiens	Human secreted protein sequence	60	27
			encoded by gene 7 SEQ ID NO:67.
152	AAY36071	Homo sapiens	Extended human secreted protein	1252	92
			sequence, SEQ lD NO.456.
152	gi15990604	Homo sapiens	RAE-1-like transcript 4 mRNA,	1022	97
			complete cds.
152	AAG00501	Homo sapiens	Human secreted protein, SEQ ID	533	95
			NO:4582.
153	gi14290560	Homo sapiens	Similar to transmembrane 7	1548	98
			superfamily member 2, clone
			MGC:9286 IMAGE:3874367,
			mRNA, complete cds.
153	gi15277509	Homo sapiens	Similar to transmembrane 7	1548	97
			superfamily member 2, clone
			MGC:17157 IMAGE:4214662,
			mRNA, complete cds.
153	gi3211722	Homo sapiens	lamin B receptor homolog TM7SF2	1132	77
			(TM7SF2) mRNA, complete cds.
155	AAE06611	Homo sapiens	Human protein having hydrophobic	1552	99
			domain, HP03696.
155	gi13676372	Homo sapiens	clone MGC:4595 IMAGE:3345729,	469	50
			mRNA, complete cds.
155	AAY41690	Homo sapiens	Human PRo329 protein sequence.	469	50
156	AAG72119	Homo sapiens	Human olfactory receptor	1036	181
			polypeptide, SEQ ID NO:1800.
156	gi3769616	Rattus	olfactory receptor	887	81
		norvegicus
156	gi12054453	Homo sapiens	6M1-18*01 gene for olfactory	547	42
			receptor, cell line BM28.7.
157	gi7106778	Homo sapiens	HSPC194	530	95
157	AAW64547	Homo sapiens	Human stomach cancer cell clone	530	95
			HP1017S protein.
157	AAY35949	Homo sapiens	Extended human secreted protein	530	95
			sequence, SEQ ID NO. 198.
158	gi402185	Homo sapiens	H.sapiens ALK-2 mRNA.	1572	100
158	gi338219	Homo sapiens	Human novel serine kinase receptor	1572	100
			mRNA, complete cds.
158	AAR85206	Homo sapiens	Human ALK-2.	1572	100
159	gi4128041	Homo sapiens	claudin-9 (CLDN9) gene.	227	35
159	AAB64401	Homo sapiens	Amino acid sequence of human	227	35
			intracellular signalling molecule
			TNTRA33.
159	gi4325296	Mus musculus	claudin-9	214	34
160	gi1405893	Homo sapiens	H.sapiens MICA gene.	1896	93
160	AAW60043	Homo sapiens	Human MHC class I chain-related	1896	93
			gene A (MICA) polypetide.
160	gi508492	Homo sapiens	Human MHC class I-related protein	1838	90
			mRNA, complete cds.
161	gi15292437	Drosophila	LP10272p	444	39
		melanogaster
161	gi4877582	Homo sapiens	lipoma HMGIC fusion partner	221	28
			(LHFP) mRNA, complete cds.
161	AAY87336	Homo sapiens	Human signal peptide containing	221	28
			protein HSPP-113 SEQ ID NO:113.
162	AAB58289	Homo sapiens	Lung cancer associated polypeptide	1338	100
			sequence SEQ ID 627.
162	AAY29332	Homo sapiens	Human secreted protein clone	1338	100
			pe584 2 protein sequence.
162	AAB75295	Homo sapiens	Human secreted protein sequence	1247	100
			encoded by gene 7 SEQ ID NO:114.
163	AAB58289	Homo sapiens	Lung cancer associated polypeptide	1338	100
			sequence SEQ ID 627.
163	AAY29332	Homo sapiens	Human secreted protein clone	1338	100
			pe584 2 protein sequence.
163	AAB75295	Homo sapiens	Human secreted protein sequence	1247	100
			encoded by gene 7 SEQ ID NO:114.
164	AAE04780	Homo sapiens	Human vesicle trafficking protein-23	864	100
			(VETRP-23) protein.
164	AAB28629	Homo sapiens	Human B11Ag1 antigen splice	546	39
			isoform B11C-8.
164	AAB28630	Homo sapiens	Human B11Ag1 antigen splice	546	39
			isoform B11C-9-16.
165	gi15811373	Mus musculus	G protein coupled receptor affecting	1269	83
			testicular descent
165	gi10441730	Homo sapiens	leucine-rich repeat-containing G	1004	62
			protein-coupled receptor 7 (LGR7)
			mRNA, complete cds.
165	AAY42170	Homo sapiens	Human LGR7 long form protein	1004	62
			sequence.
166	gi13544043	Homo sapiens	clone IMAGE:3627317, mRNA,	1257	52
			partial cds.
166	gi14249892	Homo sapiens	spinster-like protein, clone	1257	52
			MGC: 15767 IMAGE: 3501826,
			mRNA, complete cds.
166	gi12003980	Homo sapiens	spinster-like protein mRNA,	1257	52
			complete cds.
167	AAB85029	Homo sapiens	Protein encoded by BAP28 cDNA	1618	68
			consisting of exons 1 to 45.
167	AAW54099	Homo sapiens	Homo sapiens BAP28 sequence.	1617	67
167	gi7022341	Homo sapiens	cDNA FLJ10359 fis, clone	1588	92
			NT2RM2001243.
168	gi13491841	Rattus	gamma-glutamyltranspeptidase-like	209	34
		norvegicus	protein
168	AAG75266	Homo sapiens	Human colon cancer antigen protein	217	100
			SEQ ID NO:6030.
168	gi57806	Rattus sp.	gamma-glutamyltranspeptidase (AA	186	33
			1-568)
169	gi5262646	Homo sapiens	mRNA; cDNA DKLFZp434I091	2917	100
			(from clone DKFZp43 41091); partial
			cds,
169	gi6807820	Homo sapiens	mRNA; cDNA DKFZp434A2372	629	100
			(from clone DKFZp434A2372);
			partial cds.
169	gi1408182	Homo sapiens	Human LGN protein mRNA,	282	31
			complete cds.
170	gi4878022	Homo sapiens	acyl-coenzyme A: cholesterol	930	98
			acyltransferase mRNA, complete
			cds.
170	AAR53079	Homo sapiens	Acetyl coenzyme A: cholesterol	925	98
			acetyltransferase (ACAT).
170	AAW38416	Homo sapiens	Human acyl-coenzyme A: cholesterol	925	98
			acyltransferase I.
171	gi458938	Saccharomyces	Yhr186cp	1004	58
		cerevisiae
171	gi5921144	Schizosacchar	mip1	2049	52
		omyces pombe
171	gi9366720	Trypanosoma	possible t06o11.22 protein.	277	45
		brucei
172	gi402187	Homo sapiens	H.sapiens ALK-3 mRNA.	1664	99
172	AAR55368	Homo sapiens	Human Activin receptor-like kinase 3	1664	99
			(hALK-3).
172	AAR85207	Homo sapiens	Human ALK-3.	1664	99
173	gi609354	Xenopus	BMP receptor	1485	90
		laevis
173	gi2446992	Xenopus	‘BMP receptor’	1483	89
		laevis
173	gi3551073	Danio rerio	type I serin/threonine kinase receptor	1451	87
174	AAW90873	Homo sapiens	Human brain-specific dysferlin	1340	53
			protein.
174	gi3600028	Homo sapiens	dysferlin mRNA, complete cds.	1340	53
174	AAY82643	Homo sapiens	Human dysferlin protein sequence	1340	53
			SEQ ID NO:2.
175	gi3600028	Homo sapiens	dysferlin mRNA, complete cds.	1866	49
175	AAY82643	Homo sapiens	Human dysferlin protein sequence	1866	49
			SEQ ID NO:2.
175	AAW90868	Homo sapiens	Human dysferlin protein.	1866	49
176	AAY92321	Homo sapiens	Human alpha-2-delta-D calcium	5881	99
			channel subunit.
176	AAB62262	Homo sapiens	Human calcium channel alpha2delta	5745	99
			subunit.
176	AAY92323	Homo sapiens	Human alpha-2-delta-D polypeptide	4976	99
			from splice variant 1.
177	gi2104689	Mus musculus	alpha glucosidase II, alpha subunit	1796	55
177	gi1890664	Sus scrofa	glucosidase II	1792	55
177	gi7672977	Homo sapiens	glucosidase II alpha subunit mRNA,	1783	55
			complete cds.
178	AAY01143	Homo sapiens	Secreted protein encoded by gene 9	238	100
			clone HSIDY06.
178	gi6692409	Otus	cytochrome b	64	38
		longicornis
178	gi10312185	Otus watsonii	cytochrome b	61	43
179	gi13477285	Homo sapiens	structure specific recognition protein	3683	100
			1, clone MGC: 1608
			IMAGE: 3536048, mRNA, complete
			cds.
179	gi184242	Homo sapiens	Human high mobility group box	3683	100
			(SSRP1) mRNA, complete cds.
179	AAR38744	Homo sapiens	Human SSRP.	3683	100
180	gi177814	Homo sapiens	Human alpha-1-antitrypsin-related	1925	90
			protein gene, exons 3, 4 and 5.
180	AAP50132	Homo sapiens	Sequence of the predominant form of	828	59
			human alpha-1-antitrypsin(AT).
180	gi15990507	Homo sapiens	Similar to serine (or cysteine)	1409	66
			proteinase inhibitor, dade A (alpha-1
			antiproteinase, antitrypsin), member
			1, clone MGC: 23330
			IMAGE: 4644658, mRNA, complete
			cds.
181	AAB56819	Homo sapiens	Human prostate cancer antigen	1054	100
			protein sequence SEQ ID NO:1397.
181	gi15981490	Yersinia pestis	protease	137	28
181	gi9654995	Vibrio	protease DegS	135	29
		cholerae
182	gi13543976	Homo sapiens	clone IMAGE:3603998, mRNA,	1523	100
			partial cds.
182	gi15930240	Homo sapiens	Similar to CAP-binding protein	1523	100
			complex interacting protein 2, clone
			MGC:9962 IMAGE: 3878011,
			mRNA, complete cds.
182	AAY57946	Homo sapiens	Human transmembrane protein	1128	100
			HTMPN-70.
183	AAY53031	Homo sapiens	Human secreted protein clone	590	93
			dd426_1 protein sequence SEQ ID
			NO:68.
183	AAY71062	Homo sapiens	Human membrane transport protein,	158	26
			MTRP-7.
183	gi15529155	Arabidopsis	AT3830390/T6J22_16	135	22
		thaliana
184	gi4959568	Homo sapiens	nuclear pore complex interacting	1650	94
			protein NPIP (NPIP) mRNA,
			complete cds.
184	gi2342743	Homo sapiens	Human Chromosome 16 BAC clone	1627	93
			CIT987SK-A-589H1, complete
			sequence.
184	AAY10912	Homo sapiens	Amino acid sequence of a human	760	88
			secreted peptide.
185	gi7022118	Homo sapiens	cDNA FLJ10213 fis, clone	1074	99
			HEMBA1006474, weakly similar to
			40 KD PROTEIN.
185	AAB92609	Homo sapiens	Human protein sequence SEQ ID	1074	99
			NO:10874.
185	gi456886	Borna disease	p40	396	41
		virus
186	gi38432	Homo sapiens	H.sapiens gene for mitochondrial	612	90
			ATP synthase c subunit (P2 form).
186	gi285910	Homo sapiens	P2 mRNA for ATP synthase subunit	612	90
			c, complete cds.
186	AAB43694	Homo sapiens	Human cancer associated protein	612	90
			sequence SEQ ID NO:1139.
187	gi897827	Homo sapiens	Human iron-responsive element-	4968	99
			binding protein/iron regulatory
			protein 2 (IRE-BP2/IRP2) mRNA,
			partial cds.
187	gi897581	Homo sapiens	Human iron-regulatory protein 2	4909	99
			(IRP2) mRNA, partial cds.
187	gi897583	Rattus	iron-regulatory protein 2	4700	93
		norvegicus
188	gi5732908	Homo sapiens	BPAG1n3 (BPAG1) mRNA, partial	75	32
			cds.
188	AAY87302	Homo sapiens	Human signal peptide containing	61	35
			protein HSPP-79 SEQ ID NO:79.
188	AAY76213	Homo sapiens	Human secreted protein encoded by	61	35
			gene 90.
189	gi5732908	Homo sapiens	BPAG1n3 (BPAG1) mRNA, partial	75	32
			cds.
189	AAY87302	Homo sapiens	Human signal peptide containing	61	35
			protein HSPP-79 SEQ ID NO:79.
189	AAY76213	Homo sapiens	Human secreted protein encoded by	61	35
			gene 90.
190	gi5732908	Homo sapiens	BPAG1n3 (BPAG1) mRNA, partial	75	32
			cds.
190	AAY87302	Homo sapiens	Human signal peptide containing	61	35
			protein HSPP-79 SEQ ID NO:79.
190	AAY76213	Homo sapiens	Human secreted protein encoded by	61	35
			gene 90.
191	AAY86234	Homo sapiens	Human secreted protein HNTNC20,	88	31
			SEQ ID NO:149.
191	gi5430769	Arabidopsis	Similar to somatic embryogenesis	88	32
		thaliana	receptor-like kinase
191	AAB24074	Homo sapiens	Human PRO1153 protein sequence	79	22
			SEQ ID NO:49.
192	gi13447199	Homo sapiens	spbingosine-1-phosphate	1931	98
			phosphatase mRNA, complete cds.
192	gi9623190	Mus musculus	sphingosine-1-phosphate	1692	83
			phosphohydrolase
192	gi15778670	Mus musculus	sphingosine-1-phosphate	1692	83
			phosphatase
193	gi12052824	Homo sapiens	mRNA; cDNA DKFZp564H1562	1544	100
			(from clone DKFZp564H1562);
			complete ods.
193	gi5326797	Homo sapiens	junctional adhesion molecule	1544	100
			(JAM1) mRNA, complete cds.
193	gi5731339	Homo sapiens	junctional adhesion molecule-1	1544	100
			mRNA, complete cds.
194	gi296636	Homo sapiens	Human apoC-II gene for	506	100
			preproapolipoprotein C-II.
194	gi757915	Homo sapiens	Human mRNA for lipoprotein	506	100
			apoCII.
194	gi178836	Homo sapiens	APOC2 gene, complete sequence;	506	100
			and apolipoprotein C-II (APOC2)
			gene, complete cds.
195	gi13097159	Homo sapiens	tumor protein, translationally-	794	97
			controlled 1, clone MGC: 5308
			IMAGE: 2899964, mRNA, complete
			cds.
195	gi7573519	Homo sapiens	TPT1 gene for translationally	794	97
			controlled tumor protein (TCTP),
			exons 1-6.
195	gi37496	Homo sapiens	Human mRNA for translationally	794	97
			controlled tumor protein.
196	gi12082725	Mus musculus	B cell phosphoinositide 3-kinase	3523	84
			adaptor
196	gi12082723	Gallus gallus	B cell phosphoinositide 3-kinase	2821	69
			adaptor
196	AAB43816	Homo sapiens	Human cancer associated protein	1257	98
			sequence SEQ ID NO:1261.
197	gi10177622	Arabidopsis	gene_id: K6M13.11˜	201	39
			thaliana
197	gi10437414	Homo sapiens	cDNA: FLJ21330 fis, clone	165	34
			COL02466.
197	gi499199	Schizosacchar	uvi22	155	33
		omyces pombe
198	gi13436446	Homo sapiens	myosin regulatory light chain, clone	881	99
			MGC: 4405 IMAGE: 2906108,
			mRNA, complete cds.
198	gi829623	Homo sapiens	Human myosin regulatory light chain	881	99
			mRNA, complete cds.
198	gi15076511	Homo sapiens	LC-2 mRNA for nonmuscle	881	99
			myosin light chain 2, complete cds.
199	gi5305502	Mus musculus	phospholemman precursor	153	45
199	gi1916012	Rattus	phospholemman chloride channel	142	53
		norvegicus
199	gi1916010	Homo sapiens	Human phospholemman chloride	133	47
			channel mRNA, complete cds.
200	gi13272522	Homo sapiens	transcription factor NYD-sp10	1344	90
			mRNA, complete cds.
200	gi14278918	Homo sapiens	mRNA for transcription factor	1166	82
			RFX4, complete cds.
200	gi583352	synthetic	does not include the start ot stop	162	29
		construct	codon
201	AAB47296	Homo sapiens	PR04401 polypeptide.	1062	58
201	AAY22496	Homo sapiens	Human secreted protein sequence	1062	58
			clone cn621 8.
201	gi14042441	Homo sapiens	cDNA FLJ14724 fis, clone	400	43
			NT2RP3001716.
202	gi15341863	Homo sapiens	Similar to RIKEN cDNA	758	98
			2900052H21 gene, clone
			MGC: 21625 IMAGE: 4214683,
			mRNA, complete cds.
202	AAY33297	Homo sapiens	Human membrane spanning protein	758	98
			MSP-4.
202	AAB61149	Homo sapiens	Human NOV18 protein.	758	98
203	gi11125139	Homo sapiens	Novel human gene mapping to	476	89
			chomosome 22.
203	AAY94914	Homo sapiens	Human secreted protein clone	476	89
			pw337_6 protein sequence SEQ ID
			NO:34.
203	gi602584	Methanosarcina	cytochrome b	75	33
		mazei
204	AAG72267	Homo sapiens	Human olfactory receptor	1281	100
			polypeptide, SEQ ID NO:1948.
204	AAG72407	Homo sapiens	Human OR-like polypeptide query	1281	100
			sequence, SEQ ID NO:2088.
204	AAG72270	Homo sapiens	Human olfactory receptor	997	73
			polypeptide, SEQ ID NO:1951.
205	gi12002782	Homo sapiens	olfactory receptor-like protein JCG2	1538	100
			(JCG2) mRNA, partial cds.
205	gi12002784	Homo sapiens	olfactory receptor-like protein JCG2	1538	100
			(JCG2) gene, complete cds.
205	AAE04555	Homo sapiens	Human G-protein coupled receptor-	1538	100
			11 (GCREC-11) protein.
206	gi5802817	Homo sapiens	endogenous retrovirus HERV-K104	479	77
			long terminal repeat, complete
			sequence; and Gag protein (gag) and
			envelope protein (env) genes,
			complete cds.
206	gi1469243	Human	pol/env	466	77
		endogenous
		retrovirus K
206	gi3150438	Human	pol-env	466	77
		endogenous
		retrovirus K
207	AG89341	Homo sapiens	Human secreted protein, SEQ ID	501	99
			NO:461.
207	gi6651037	Mus nmsculus	similar to RNA binding protein	411	96
		domesticus
207	AAG02095	Homo sapiens	Human secreted protein, SEQ ID	167	55
			NO:6176.
208	AAB20155	Homo sapiens	Secreted protein SECP1.	3983	51
208	gi3080663	Homo sapiens	PAC clone RP5-1168D11 from	1408	47
			7p21-p22, complete sequence.
208	gi2897863	Homo sapiens	BAC clone GS1-164B5 from 7p21-	1340	50
			p22, complete sequence.
209	gi32329	Homo sapiens	Human HMG-17 gene for non-	429	94
			histone chromosomal protein HMG-
			17.
209	gi306864	Homo sapiens	Human non-histone chromosomal	429	94
			protein HMG-17 mRNA, complete
			cds.
209	AAB28199	Homo sapiens	Human HMG-17 non histone	429	94
			chromosomal protein.
210	gi13905022	Homo sapiens	Similar to interferon induced	444	69
			transmembrane protein 3 (1-8U),
			clone MGC: 5225 IMAGE: 2986145,
			mRNA, complete cds.
210	gi14250038	Homo sapiens	Similar to interferon induced	436	68
			transmembrane protein 3 (1-8U,
			clone MGC: 14565 IMAGE: 4075453,
			mRNA, complete cds.
210	gi23398	Homo sapiens	Human 1-8U gene from interferon-	435	67
			inducible gene family.
211	g17019933	Homo sapiens	cDNA FLJ20071 fis, clone	2163	100
			COL01887.
211	AAB36618	Homo sapiens	Human FLEXHT-40 protein	1051	100
			sequence SEQ ID NO:40.
211	AAW88957	Homo sapiens	Polypeptide fragment encoded by	902	100
			gene 128.
212	AAB60112	Homo sapiens	Human transport protein TPPT-32.	775	100
212	gi11558029	Homo sapiens	boct gene for organic cation	382	48
			transporter.
212	gi9663117	Homo sapiens	mRNA for organic cation transporter.	382	48
213	AAR28120	Homo sapiens	NKG2 transmembrane protein-D.	727	95
213	gi2980865	Homo sapiens	NKG2D gene, exons 2-5 and joined	724	94
			mRNA and CDS.
213	gi35063	Homo sapiens	Human mRNA for NKG2-D gene.	724	94
214	gi7767239	Homo sapiens	nectin-like protein 2 (NECL2)	612	39
			mRNA, complete cds.
214	gi4519602	Homo sapiens	IGSF4 gene, exon 10 and complete	609	38
			cds.
214	AAY45092	Homo sapiens	Human lymphoid derived dendritic	609	38
			cell adhesion molecule.
215	gi7020365	Homo sapiens	cDNA FLJ20336 fis, clone	4316	99
			HEP11722.
215	gi10435830	Homo sapiens	cDNA FLJ13727 fis, clone	3079	99
			PLACE3000103.
215	AAB94738	Homo sapiens	Human protein sequence SEQ ID	3079	99
			NO:15776.
216	AAB75594	Homo sapiens	Human secreted protein sequence	678	99
			encoded by gene 37 SEQ ID
			NO:148.
216	AAB75542	Homo sapiens	Human secreted protein sequence	294	100
			encoded by gene 37 SEQ ID NO:96.
216	gi1864011	Homo sapiens	mRNA for SHPS-1, complete cds.	261	43
217	gi7020372	Homo sapiens	cDNA FLJ20340 fis, clone	1692	99
			HEP12374.
217	gi4098525	Prochlorothrix	CytM	80	31
		hollandica
217	gi324932	Influenza A	PA polymerase	67	38
		virus
218	gi7023403	Homo sapiens	cDNA FLJ11006 fis, clone	499	59
			PLACE1003045.
218	AA393412	Homo sapiens	Human protein sequence SEQ ID	499	59
			NO:12616.
218	gi13542919	Mus musculus	Similar to mucolipin 1	432	61
219	gi15488920	Homo sapiens	Similar to PJKEN cDNA	107	42
			2010107G23 gene, clone MGC: 9596
			IMAGE: 3896656, mRNA, complete
			cds.
219	AAW74777	Homo sapiens	Human secreted protein encoded by	74	40
			gene 48 clone H7FCAI74.
219	gi1304441	Pseudorabies	Rsp40	69	32
		virus
220	gi10119918	Homo sapiens	brain otoferlin short isoform (OTOF)	1315	49
			mRNA, complete cds.
220	gi10119916	Homo sapiens	brain otoferlin long isoform (OTOF)	1315	49
			mRNA, complete cds.
220	gi4588470	Homo sapiens	otoferlin (OTOF) mRNA, complete	2214	43
			cds.
221	gi1006665	Homo sapiens	H.sapiens mRNA for transcript	442	98
			associated with monocyte to
			macrophage differentiation.
221	gi15155898	Agrobacterium	AGR_C_1653p	167	31
		tumefaciens
221	gi15023850	Clostridium	Predicted membrane protein,	117	44
		acetobutylicum	hemolysin III homolog
222	AAG71803	Homo sapiens	Human olfactory receptor	1494	92
			polypeptide, SEQ ID NO:1484.
222	AAG71805	Homo sapiens	Human olfactory receptor	1205	92
			polypeptide, SEQ ID NO:1486.
222	AAG71807	Homo sapiens	Human olfactory receptor	1178	70
			polypeptide, SEQ ID NO:1488.
223	AAY70455	Homo sapiens	Human membrane channel protein-5	609	91
			(MECHP-5).
223	AAV83992_aa	Homo sapiens	Nucleic acid encoding a protein with	608	92
	1		water channel activity.
223	gi2317274	Homo sapiens	mRNA for aquaporin adipose,	608	92
			complete cds.
224	gi3319326	Homo sapiens	protein associated with Myc mRNA,	111	33
			complete cds.
225	gi2463632	Homo sapiens	monocarboxylate transporter	2574	97
			homologue MCT6 mRNA, complete
			cds.
225	gi10880482	Mus musculus	monocarboxylate transporter 4	393	39
225	gi2463634	Homo sapiens	monocarboxylate transporter (MCT3)	394	40
			mRNA, complete cds.
226	gi13528675	Homo sapiens	ATPase, H+ transporting, lysosomal	705	94
			(vacuolar proton pump) 16kD, clone
			MGC: 3723 IMAGE: 3618755,
			mRNA, complete cds.
226	gi13938484	Homo sapiens	ATPase, H+ transporting, lysosomal	705	94
			(vacuolar proton pump) 16kD, clone
			MGC: 16271 IMAGE: 3831016,
			mRNA, complete cds.
226	gi14043553	Homo sapiens	ATPase, H+ transporting, lysosomal	705	94
			(vacuolar proton pump) 16kD, clone
			MGC: 12873 IMAGE: 4127653,
			mRNA, complete cds.
227	gi15080314	Homo sapiens	Similar to RIKEN cDNA	514	100
			0610010D20 gene, clone
			MGC: 20590 IMAGE: 4310241,
			mRNA, complete cds.
227	gi10580053	Halobacterium	dihydrodipicolinate synthase; DapA	379	33
		sp. NRC-1
227	gi1590977	Methanococcus	dihydrodipicolinate synthase (dapA)	336	29
		jannaschii
228	AAE06614	Homo sapiens	Human protein having hydrophobic	1394	100
			domain, HP03974.
228	gi520469	Oryctolagus	597 aa protein related to Na/glucose	1231	85
		cuniculus	cotransporters
228	gi338055	Homo sapiens	Human Na+/glucose cotransporter 1	705	57
			mRNA, complete cds.
229	gi6708478	Mus musculus	formin-like protein	1571	66
229	gi4101720	Mus musculus	lymphocyte specific formin related	1543	65
			protein
229	gi1914849	Mus musculus	WW domain binding protein 3;	299	54
			WBP3
231	gi12052738	Homo sapiens	mRNA; cDNA DKFZp564H1322	1755	96
			(from clone DKFZpS64H1322);
			complete cds.
231	gi10434632	Homo sapiensc	DNA FLJ12886 fis, clone	1755	96
			NT2RP2004041, weakly similar to
			SYNAPSINS IA AND lB.
231	AAB94358	Homo sapiens	Human protein sequence SEQ ID	1755	96
			NO:14883.
232	AAW54370	Homo sapiens	G-protein coupled receptor	1815	100
			HLTEX11.
232	AAB64854	Homo sapiens	Human secreted protein sequence	1792	100
			encoded by gene 36 SEQ ID
			NO:140.
232	AAW70504	Homo sapiens	Leukocyte seven times membrane-	821	46
			penetrating type receptor protein
			JEG18.
233	gi15278128	Mus musculus	chemokine-like factor 2 variant 2	412	49
233	AAB51648	Homo sapiens	Human secreted protein sequence	410	100
			encoded by gene 29 SEQ ID NO:88.
233	AAE03929	Homo sapiens	Human gene 32 encoded secreted	410	100
			protein HTLIF 12, SEQ ID NO:92.
235	gi13477335	Homo sapiens	vitamin A responsive; cytoskeleton	777	95
			related, clone MGC: 1917
			IMAGE: 3510436, mRNA, complete
			cds.
235	gi3746652	Homo sapiens	JWA protein mRNA, complete cds.	777	95
235	gi6563260	Homo sapiens	jmx protein mRNA, complete cds.	777	95
236	gi2970431	Florometra	NADH dehydrogenase subunit 4	94	31
		serratissima
236	gi15042530	Chilo	450L	70	24
		iridescent
		virus
236	AAY87197	Homo sapiens	Human secreted protein sequence	90	27
			SEQ ID NO:236.
237	AAB93562	Homo sapiens	Human protein sequence SEQ ID	2402	100
			NO:12957.
237	gi7023538	Homo sapiens	cDNA FLJ11091 fis, clone	860	100
			PLAGE1005313.
237	AAB93489	Homo sapiens	Human protein sequence SEQ ID	860	100
			NO:12790.
239	gi10438431	Homo sapiens	cDNA: FLJ22155 fis, clone	1995	100
			HRC00205.
239	gi10437336	Homo sapiens	cDNA: FLJ2 1267 fis, clone	1776	99
			COL01717.
239	gi7020065	Homo sapiens	cDNA FLJ20152 fis, clone	705	100
			C0L08515.
240	gi12654159	Homo sapiens	interferon induced transmembrane	569	93
			protein 1 (9-27), clone MGC: 5195
			IMAGE: 3464598, mRNA, complete
			cds.
240	gi1177476	Homo sapiens	ILsapiens mRNA for interferon-	569	93
			induced 17kDa membrane protein.
240	gi177802	Homo sapiens	Human interferon-inducible protein	563	92
			9-27 mRNA, complete cds.
241	AAG72230	Homo sapiens	Human olfactory receptor	1615	100
			polypeptide, SEQ ID NO:1911.
241	AAG72382	Homo sapiens	Human OR-like polypeptide query	1615	100
			sequence, SEQ ID NO:2063.
241	gi15293613	Homo sapiens	clone OR5C1 olfactory receptor	1097	100
			gene, partial cds.
242	gi784997	Homo sapiens	H.sapiens mRNA for tumour	5025	95
			suppressor protein, HUGL.
242	gi1944491	Homo sapiens	Human LLGL mRNA, complete cds.	4797	91
242	gi854124	Homo sapiens	H.sapiens mRNA for human giant	2837	58
			larvae homolog.
243	AAB95830	Homo sapiens	Human protein sequence SEQ ID	219	72
			NO:18850.
243	gi7959889	Homo sapiens	PR02221	137	49
243	gi2072969	Homo sapiens	Human L1 element L1.24 p40 gene,	133	48
			complete cds.
244	gi15277644	Homo sapiens	amino acid transporter (SLC7A10)	2487	100
			gene, exon 11 and complete cds.
244	gi9309293	Homo sapiens	hasc-1 mRNA for asc-type amino	2487	100
			acid transporter 1, complete cds.
244	gi7415938	Mus musculus	asci	2329	91
245	gi6760373	Homo sapiens	ODZ3 (ODZ3) mRNA, partial cds.	2323	100
245	gi4760780	Mus musculus	Ten-m3	2248	96
245	gi6010049	Gallus gallus	teneurin-2 protein	878	62
246	gi14286298	Homo sapiens	clone MGC: 3593 IMAGE: 2963628,	630	99
			mRNA, complete cds.
246	gi4877285	Homo sapiens	mRNA for prenylated Rab acceptor 1	630	99
246	gi6563192	Homo sapiens	prenylated rab acceptor 1 mRNA,	630	99
			complete cds.
247	gi1780976	Human	protease	915	58
		endogenous
		retrovirus K
247	gi5802824	Homo sapiens	endogenous retrovirus HERV-K109,	909	59
			complete sequence.
247	g19558703	Homo sapiens	tandemly repeated human	905	59
			endogenous retrovirus HERV-K
			(HML-2.HOM), complete sequence.
248	gi13111941	Homo sapiens	vesicle-associated soluble NSF	804	91
			attachment protein receptor (v-
			SNARE; homolog of S.cerevisiae
			VTI1), clone MGC: 3767
			IMAGE: 2958320, mRNA, complete
			cds.
248	gi3861488	Homo sapiens	vesicle soluble NSF attachment	804	91
			protein receptor VTI2 mRNA,
			complete cds.
248	AAY73339	Homo sapiens	HTRM clone 2056042 protein	804	91
			sequence.

[0466]

TABLE 3
	Accession
SEQ ID NO:	No.	Description	Results*
126	BL01130	Sulfate transporters proteins.	BL01130A 21.63 7.407e−25 331-385
			BL01130B 23.34 2.286e−23 429-481
126	DM01292	ESICULAR LUMEN DOMAIN.	DM01292I 12.82 9.400e−10 148-190
			DM01292I 12.82 9.400e−10 591-633
130	PR00019	LEUCINE-RICH REPEAT	PR00019B 11.36 1.000e−10 114-128
		SIGNATURE	PR00019A 11.19 8.826e−10 117-131
			PR00019B 11.36 4.600e−09 258-272
			PR00019B 11.36 4.960e−09 186-200
131	PD02327	GLYCOPROTEIN ANTIGEN	PD02327B 19.84 5.574e−10 169-191
		PRECURSOR IMMUNOGLO.
131	PD02365	CHAIN FACTOR INTERLEUKIN-12	PD02365C 7.89 4.196e−09 365-395
		BETA PRECURSOR IL-1.
132	BL00983	Ly-6/u-PAR domain proteins.	BL00983C 12.69 3.500e−15 142-158
			BL00983B 8.19 1.643e−12 84-94
			BL00983A 5.84 7.261e−10 74-83
136	BL00290	Immunoglobulins and major	BL00290B 13.17 6.400e−22 281-299
		histocompatibility complex proteins.	BL00290A 20.89 4.600e−16 34-57
			BL00290A 20.89 2.080e−10 224-247
140	BL01221	PMP-22/EMP/MP20 family proteins.	BL01221B 13.29 6.745e−09 54-68
141	BL00983	Ly-6/u-PAR domain proteins.	BL00983C 12.69 4.981e−09 46-62
141	BL00272	Snake toxins proteins.	BL00272C 8.27 8.326e−09 50-62
143	BL00420	Speract receptor repeat proteins domain	BL00420B 22.67 4.627e−30 723-778
		proteins.	BL00420C 11.90 9.100e−13 809-820
143	PR00258	SPERACT RECEPTOR SIGNATURE	PR00258B 9.63 3.813e−15 738-750
			PR00258E 13.33 2.047e−12 808-821
			PR00258C 9.05 2.837e−10 753-764
143	BL00514	Fibrinogen beta and gamma chains C-	BL00514G 15.98 4.326e−09 542-572
		terminal domain proteins.
144	BL01212	ATP P2X receptors proteins.	BL01212A 34.89 1.000e−40 41-94
			BL01212E 24.87 1.000e−40 225-280
			BL01212G 11.86 3.700e−34 309-337
			BL01212D 11.42 9.609e−27 182-206
			BL01212B 19.25 8.393e−21 126-151
			BL01212F 10.12 2.421e−15 290-301
			BL01212C 8.40 2.500e−14 158-169
145	PR00920	SPUMAVIRUS ASPARTIC PROTEASE	PR00920C 13.24 7.310e−09 149-171
		(A9) SIGNATURE
146	BL00682	ZP domain proteins.	BL00682C 20.71 1.706e−12 439-464
146	BL00025	P-type ‘Trefoil’ domain proteins.	BL00025 17.17 5.645e−09 231-252
148	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 4.273e−14 98-138
148	PR00854	PROSTAGLANDIN D RECEPTOR	PR00854E 10.50 4.649e−26 236-260
		SIGNATURE	PR00854B 7.30 8.154e−21 41-59
			PR00854G 10.66 1.783e−18 341-358
			PR00854D 9.41 2.500e−18 185-201
			PR00854A 15.24 9.077e−18 6-21
			PR00854H 14.71 6.203e−17 369-390
			PR00854C 12.92 1.643e−12 93-105
			PR00854F 12.83 9.682e−11 321-333
148	PR00856	PROSTACYCLIN (PROSTANOID IP)	PR00856E 9.82 1.724e−09 178-195
		RECEPTOR SIGNATURE
149	BL01271	Sodium: sulfate symporter family	BL01271D 25.26 1.000e−40 480-535
		proteins.	BL01271B 12.02 6.400e−24 208-233
			BL01271A 8.06 7.955e−23 132-152
			BL01271C 13.62 7.429e−20 407-429
151	PF00798	Arenavirus glycoprotein.	PF00798I 18.55 8.811e−09 53-90
153	BL01017	Ergosterol biosynthesis ERG4/ERG24	BL01017D 20.82 1.000e−40 232-278
		family proteins.	BL01017F 23.34 9.196e−35 291-344
			BL01017C 15.91 7.324e−23 181-207
			BL01017B 12.69 9.419e−17 166-181
154	BL00874	Bacterial type II secretion system protein	BL00874B 29.89 9.724e−09 414-469
		F proteins.
155	PD01270	RECEPTOR FC IMMUNOGLOBULIN	PD01270C 19.54 2.895e−16 43-72
		AFFIN.
155	DM00179	w KINASE ALPHA ADHESION T-	DM00179 13.97 8.435e−09 183-193
		CELL.
156	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 3.455e−14 77-117
156	PR00237	RHODOPSIN-LIKE GPCR	PR00237C 15.69 1.257e−10 91-114
		SUPERFAMILY SIGNATURE	PR00237E 13.03 9.100e−10 175-199
156	PR00245	OLFACTORY RECEPTOR	PR00245A 18.03 9.581e−18 46-68
		SIGNATURE	PR00245C 7.84 4.780e−13 214-230
			PR00245E 12.40 6.741e−09 267-282
156	PR00534	MELANOCORTIN RECEPTOR	PR00534A 11.49 9.229e−09 38-51
		FAMILY SIGNATURE
158	BL00107	Protein kinases ATP-binding region	BL00107A 18.39 5.909e−15 409-440
		proteins.	BL00107B 13.31 4.214e−11 484-500
158	PR00109	TYROSINE KINASE CATALYTIC	PR00109E 14.41 4.353e−09 549-572
		DOMAIN SIGNATURE
160	BL00290	Immunoglobulins and major	BL00290A 20.89 4.789e−13 222-245
		histocompatibility complex proteins.
161	PR00308	TYPE I ANTIFREEZE PROTEIN	PR00308C 3.83 8.892e−10 4-14
		SIGNATURE	PR00308C 3.83 8.892e−10 5-15
			PR00308C 3.83 8.013e−09 3-13
161	PR00698	C. ELEGANS SRG FAMILY	PR00698E 14.43 8.714e−09 111-137
		INTEGRAL MEMBRANE PROTEIN
		SIGNATURE
164	PF00023	Ank repeat proteins.	PF00023A 16.03 7.000e−11 69-85
			PF00023B 14.20 2.636e−09 131-141
164	PD00078	REPEAT PROTEIN ANK NUCLEAR	PD00078B 13.14 6.087e−09 128-141
		ANKYR.
164	PR00806	VINCULIN SIGNATURE	PR00806C 11.07 8.839e−09 350-368
164	PF00791	Domain present in ZO-1 and Unc5-like	PF00791B 28.49 9.505e−09 135-190
		netrin receptors.	PF00791B 28.49 9.835e−09 69-124
165	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 5.610e−11 174-214
			BL00237C 13.19 4.176e−10 317-344
165	PR00237	RHODOPSIN-LIKE GPCR	PR00237F 13.57 7.677e−11 322-347
		SUPERFAMILY SIGNATURE	PR00237E 13.03 6.100e−10 276-300
			PR00237A 11.48 8.839e−09 103-128
166	BL00216	Sugar transport proteins.	BL00216B 27.64 1.831e−09 139-189
168	BL00462	Gamma-glutamyltranspeptidase proteins.	BL00462A 20.89 4.000e−20 108-151
			BL00462D 23.07 7.256e−12 356-396
			BL00462B 17.88 9.153e−12 183-220
169	BL00115	Eukaryotic RNA polymerase II	BL00115Z 3.12 2.125e−09 1363-1412
		heptapeptide repeat proteins.	BL00115Z 3.12 6.096e−09 1349-1398
172	BL00272	Snake toxins proteins.	BL00272C 8.27 9.182e−10 109-121
172	BL00107	Protein kinases ATP-binding region	BL00107A 18.39 3.348e−14 366-397
		proteins.	BL00107B 13.31 4.176e−09 441-457
172	PR00653	ACTIVIN TYPE II RECEPTOR	PR00653D 13.25 7.200e−09 385-407
		SIGNATURE
172	PR00109	TYROSINE KINASE CATALYTIC	PR00109E 14.41 6.727e−11 535-558
		DOMAIN SIGNATURE	PR00109D 17.04 7.609e−09 442-465
172	BL00983	Ly-6/u-PAR domain proteins.	BL00983C 12.69 9.135e−09 105-121
173	BL00272	Snake toxins proteins.	BL00272C 8.27 9.182e−10 109-121
173	BL00107	Protein kinases ATP-binding region	BL00107A 18.39 3.348e−14 428-459
		proteins.	BL00107B 13.31 4.176e−09 503-519
173	PR00653	ACTIVIN TYPE II RECEPTOR	PR00653D 13.25 7.200e−09 447-469
		SIGNATURE
173	PR00109	TYROSINE KINASE CATALYTIC	PR00109E 14.41 6.727e−11 597-620
		DOMAIN SIGNATURE	PR00109D 17.04 7.609e−09 504-527
173	BL00983	Ly-6/u-PAR domain proteins.	BL00983C 12.69 9.135e−09 105-121
174	PR00541	MUSCARINIC M4 RECEPTOR	PR00541C 8.06 7.726e−09 486-507
		SIGNATURE
175	PR00541	MUSCARINIC M4 RECEPTOR	PR00541C 8.06 7.726e−09 755-776
		SIGNATURE
176	PD01101	INHIBITOR HEAVY CHAIN	PD01101B 21.53 3.318e−22 343-396
		CHANNEL IN.
177	BL00129	Glycosyl hydrolases family 31 proteins.	BL00129A 26.21 2.400e−28 114-160
			BL00129D 16.76 6.806e−26 364-408
			BL00129C 15.12 5.295e−24 326-354
			BL00129E 22.60 4.857e−23 428-464
			BL00129B 19.19 4.436e−15 225-252
			BL00129F 26.19 2.500e−13 544-582
179	PR00887	STRUCTURE-SPECIFIC	PR00887A 11.39 1.643e−22 343-360
		RECOGNITION PROTEIN	PR00887F 12.74 2.000e−22 498-516
		SIGNATURE	PR00887B 9.94 3.250e−22 365-382
			PR00887C 13.16 4.000e−22 388-405
			PR00887E 10.36 5.200e−22 480-499
			PR00887H 11.84 8.313e−22 537-556
			PR00887G 14.17 9.438e−20 521-538
			PR00887D 15.12 8.313e−17 453-467
179	PR00886	HIGH MOBILITY GROUP	PR00886C 11.84 8.500e−13 696-715
		(HMG1/HMG2) PROTEIN	PR00886A 10.08 3.192e−10 710-733
		SIGNATURE
179	PD02448	TRANSCRIPTION PROTEIN DNA-	PD02448A 9.37 5.576e−10 686-725
		BINDIN.
179	BL00353	HMG1/2 proteins.	BL00353B 11.47 8.244e−24 664-714
			BL00353A 9.60 2.549e−09 674-723
180	BL00284	Serpins proteins.	BL00284C 28.56 4.000e−25 472-514
			BL00284D 16.34 5.655e−17 578-605
			BL00284A 15.64 2.742e−15 341-365
			BL00284E 19.15 4.818e−15 659-684
			BL00284B 17.99 3.667e−14 445-466
			BL00284A 15.64 2.600e−11 375-399
181	PR00839	V8 SERINE PROTEASE FAMILY	PR00839B 11.20 8.119e−10 357-375
		SIGNATURE
186	BL00605	ATP synthase c subunit proteins.	BL00605 27.67 3.172e−33 79-133
186	PR00124	ATP SYNTHASE C SUBUNIT	PR00124C 12.42 6.400e−18 113-139
		SIGNATURE	PR00124A 8.81 8.054e−14 75-95
			PR00124B 14.66 6.897e−12 96-112
187	BL00450	Aconitase family proteins.	BL00450B 42.34 8.393e−30 386-441
			BL00450D 21.14 2.800e−18 665-689
			BL00450E 16.34 8.875e−13 710-725
			BL00450B 42.34 6.400e−12 446-501
			BL00450A 13.76 2.406e−11 351-365
			BL00450C 11.95 6.657e−10 612-622
187	PR00415	ACONITASE FAMILY SIGNATURE	PR00415D 12.72 5.696e−16 390-406
			PR00415I 13.62 4.115e−15 675-689
			PR00415G 14.24 8.105e−15 548-563
			PR00415C 13.34 7.828e−14 376-390
			PR00415E 10.04 7.828e−14 452-466
			PR00415F 11.66 7.273e−13 466-480
			PR00415H 12.39 9.700e−13 613-625
			PR00415A 11.15 1.621e−10 323-337
			PR00415B 8.14 9.036e−09 347-356
193	DM00179	w KINASE ALPHA ADHESION T-	DM00179 13.97 1.000e−11 139-149
		CELL.
193	BL00240	Receptor tyrosine kinase class III	BL00240B 24.70 4.255e−09 85-109
		proteins.
195	BL01002	Translationally controlled tumor protein.	BL01002C 21.97 6.143e−26 79-110
			BL01002A 13.19 1.360e−24 1-24
			BL01002B 7.39 3.118e−14 48-62
196	PF00997	Kappa casein.	PF00997D 9.95 8.306e−09 513-548
198	BL00018	EF-hand calcium-binding domain	BL00018 7.41 1.391e−09 42-55
		proteins.
199	BL01310	ATP1G1/PLM/MAT8 family proteins.	BL01310 14.74 8.981e−24 99-135
201	PR00764	COMPLEMENT C9 SIGNATURE	PR00764B 13.56 2.250e−11 122-143
201	PR00261	LOW DENSITY LIPOPROTEIN (LDL)	PR00261E 11.08 6.308e−09 127-149
		RECEPTOR SIGNATURE	PR00261F 11.57 7.152e−09 127-149
204	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 4.273e−14 188-228
204	PR00245	OLFACTORY RECEPTOR	PR00245A 18.03 3.250e−19 157-179
		SIGNATURE	PR00245B 10.38 1.918e−09 275-290
204	PR00237	RHODOPSIN-LIKE GPCR	PR00237C 15.69 4.150e−09 202-225
		SUPERFAMILY SIGNATURE
205	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 2.658e−12 163-203
205	PR00245	OLFACTORY RECEPTOR	PR00245A 18.03 9.325e−19 132-154
		SIGNATURE	PR00245C 7.84 4.073e−15 311-327
			PR00245B 10.38 5.500e−13 250-265
			PR00245E 12.40 7.618e−13 364-379
			PR00245D 10.47 4.673e−09 347-359
205	PR00237	RHODOPSIN-LIKE GPCR	PR00237C 15.69 6.400e−10 177-200
		SUPERFAMILY SIGNATURE	PR00237G 19.63 5.814e−09 345-372
208	PD01719	PRECURSOR GLYCOPROTEIN	PD01719A 12.89 7.955e−13 969-997
		SIGNAL RE.	PD01719A 12.89 8.111e−09 305-333
209	BL00355	HMG14 and HMG17 proteins.	BL00355 5.97 1.692e−37 18-49
209	PR00925	NONHISTONE CHROMOSOMAL	PR00925A 5.47 2.800e−19 18-33
		PROTEIN HMG17 FAMILY	PR00925B 3.73 3.400e−16 34-47
		SIGNATURE	PR00925D 6.56 2.200e−13 66-77
			PR00925C 5.57 8.235e−09 47-58
213	BL00615	C-type lectin domain proteins.	BL00615A 16.68 4.240e−11 210-228
214	PD02327	GLYCOPROTEIN ANTIGEN	PD02327B 19.84 2.091e−09 191-213
		PRECURSOR IMMUNOGLO.
214	DM00179	w KINASE ALPHA ADHESION T-	DM00179 13.97 7.652e−09 338-348
		CELL.
216	PD02870	RECEPTOR INTERLEUKIN-1	PD02870D 15.74 8.755e−09 96-131
		PRECURSOR.
222	PR00245	OLFACTORY RECEPTOR	PR00245A 18.03 8.364e−14 122-144
		SIGNATURE	PR00245C 7.84 9.280e−13 300-316
			PR00245B 10.38 4.600e−11 240-255
			PR00245E 12.40 7.623e−10 353-368
222	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 5.371e−13 153-193
			BL00237D 11.23 7.750e−10 344-361
222	PR00237	RHODOPSIN-LIKE GPCR	PR00237G 19.63 6.063e−12 334-361
		SUPERFAMILY SIGNATURE	PR00237C 15.69 6.175e−09 167-190
223	BL00221	MIP family proteins.	BL00221B 10.22 1.871e−11 141-152
			BL00221D 12.33 2.174e−11 240-255
			BL00221E 8.47 9.710e−11 307-318
			BL00221A 6.39 5.935e−09 92-103
223	PR00783	MAJOR INTRINSIC PROTEIN	PR00783B 15.98 4.130e−15 127-152
		FAMILY SIGNATURE	PR00783F 12.33 9.156e−14 308-329
			PR00783A 12.72 7.462e−12 88-108
			PR00783E 16.78 8.263e−10 128-151
			PR00783C 13.54 1.340e−09 164-184
			PR00783E 16.78 6.754e−09 226-249
225	PD02886	GLYCOPROTEIN PRECURSOR	PD02886C 21.92 7.907e−10 112-151
		IMMUNOGLOBULIN FOL.
226	PR00122	VACUOLAR ATP SYNTHASE 16 KD	PR00122C 8.20 1.000e−33 104-131
		SUBUNIT SIGNATURE	PR00122B 8.60 2.125e−28 56-81
			PR00122D 9.97 4.375e−28 131-155
			PR00122A 11.44 6.053e−19 30-55
226	BL00605	ATP synthase c subunit proteins.	BL00605 27.67 1.778e−10 94-148
226	PR00124	ATP SYNTHASE C SUBUNIT	PR00124C 12.42 2.161e−10 128-154
		SIGNATURE
227	BL00665	Dihydrodipicolinate synthetase proteins.	BL00665B 30.33 8.265e−12 52-105
			BL00665D 14.76 1.000e−11 164-187
			BL00665C 25.58 5.832e−11 105-156
227	PR00146	DIHYDRODIPICOLINATE	PR00146D 16.26 2.525e−10 163-181
		SYNTHASE SIGNATURE
228	BL00456	Sodium:solute symporter family proteins.	BL00456C 24.55 4.886e−28 165-220
			BL00456A 22.59 3.127e−27 27-82
			BL00456B 18.94 1.220e−17 103-133
228	BL00415	Synapsins proteins.	BL00415O 3.44 6.270e−09 514-552
228	BL00136	Serine proteases, subtilase family,	BL00136B 9.63 7.796e−09 773-786
		aspartic acid proteins.
230	BL00310	Lysosome-associated membrane	BL00310F 23.26 4.162e−09 194-249
		glycoproteins duplicated domain proteins.
232	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 4.115e−18 126-166
			BL00237C 13.19 7.545e−15 263-290
			BL00237D 11.23 8.962e−11 324-341
232	PR00237	RHODOPSIN-LIKE GPCR	PR00237G 19.63 7.120e−15 314-341
		SUPERFAMILY SIGNATURE	PR00237F 13.57 2.565e−14 268-293
			PR00237C 15.69 6.667e−12 140-163
			PR00237A 11.48 8.125e−11 63-88
			PR00237B 13.50 1.563e−10 96-118
			PR00237E 13.03 3.118e−09 226-250
233	PR00049	WILM'S TUMOR PROTEIN	PR00049D 0.00 2.068e−09 7-22
		SIGNATURE
234	BL01159	WW/rsp5/WWP domain proteins.	BL01159 13.85 1.310e−14 387-402
234	PR00403	WW DOMAIN SIGNATURE	PR00403B 12.19 6.906e−15 387-402
			PR00403A 16.82 5.200e−11 373-387
234	BL01179	Phosphotyrosine interaction domain	BL01179A 12.63 8.286e−11 394-406
		proteins (PID) profile.	BL01179B 15.18 7.968e−10 667-682
236	BL00594	Aromatic amino acids permeases	BL00594A 16.75 3.851e−09 107-151
		proteins.
237	PR00399	SYNAPTOTAGMIN SIGNATURE	PR00399B 14.27 1.305e−09 242-256
237	PR00360	C2 DOMAIN SIGNATURE	PR00360B 13.61 6.318e−09 279-293
239	BL00291	Prion protein.	BL00291A 4.49 8.241e−09 21-56
241	BL00237	G-protein coupled receptors proteins.	BL00237A 27.68 6.447e−12 210-250
241	PR00237	RHODOPSIN-LIKE GPCR	PR00237G 19.63 3.512e−09 392-419
		SUPERFAMILY SIGNATURE	PR00237C 15.69 4.825e−09 224-247
241	PR00245	OLFACTORY RECEPTOR	PR00245A 18.03 1.500e−20 179-201
		SIGNATURE	PR00245B 10.38 3.571e−16 297-312
			PR00245E 12.40 1.000e−12 411-426
			PR00245D 10.47 1.000e−10 394-406
			PR00245C 7.84 6.727e−09 358-374
242	PR00962	LETHAL(2) GIANT LARVAE	PR00962B 11.98 2.800e−28 310-333
		PROTEIN SIGNATURE	PR00962G 15.71 5.655e−28 609-634
			PR00962D 10.40 1.225e−27 451-475
			PR00962F 12.39 6.786e−23 568-588
			PR00962H 13.32 9.710e−23 639-659
			PR00962I 11.68 3.829e−22 708-728
			PR00962C 8.00 4.250e−22 362-383
			PR00962A 13.28 7.612e−22 17-36
			PR00962E 8.81 1.628e−20 531-550
242	PR00320	G-PROTEIN BETA WD-40 REPEAT	PR00320A 16.74 9.122e−09 454-469
		SIGNATURE
244	BL00218	Amino acid permeases proteins.	BL00218D 21.49 2.038e−10 385-430
			BL00218E 23.30 6.400e−10 466-506
			BL00218B 21.44 5.790e−09 217-249
244	BL00341	Surfactant associated polypeptide SP-C	BL00341B 8.70 7.895e−09 54-88
		palmitoylation site proteins.
247	PR00783	MAJOR INTRINSIC PROTEIN	PR00783C 13.54 1.474e−17 31-51
		FAMILY SIGNATURE
247	BL00221	MIP family proteins.	BL00221B 10.22 1.643e−14 8-19
247	PD00302	PROTEASE POLYPROTEIN	PD00302B 9.52 1.360e−14 261-277
		HYDROLASE ASP.	PD00302A 6.33 3.323e−11 198-209
247	PF00692	dUTPase.	PF00692B 8.14 3.613e−11 113-124
247	DM00892	3 RETROVIRAL PROTEINASE.	DM00892C 23.55 4.818e−13 292-326
			DM00892B 9.78 1.000e−08 264-270
*Results show Accession No., subtype, e-value, and position of signature in the sequence.

[0467]

TABLE 4
			E-value		No. of
SEQ ID NO:	Pfam Model	Description	(product)	Score	Domains	Position
126	Sulfate_transp	Sulfate transporter	4.3e−103	355.9	2	2-284: 441-751
		family
126	STAS	STAS domain	4.8e−20	80.0	1	774-987
127	ubiguitin	Ubiquitin family	1.4e−09	39.6	1	55-126
130	LRR	Leucine Rich Repeat	9.6e−40	145.5	10	44-67: 68-91:
						92-115: 116-139:
						140-163: 164-187:
						188-211: 212-235:
						236-259: 260-283
131	ig	Immunoglobulin	1.2e-30	103.8	5	62-129: 163-229:
		domain				264-316: 349-400:
						433-501
132	UPAR_LY6	u-PAR/Ly-6 domain	9.1e−59	208.7	1	63-190
136	MHC_I	Class I	3.2e−147	502.5	1	25-203
		Histocompatibility
		antigen, domains
136	ig	Immunoglobulin	0.057	11.4	1	220-285
		domain
139	ig	Immunoglobulin	2.3e−09	35.2	1	38-110
		domain
140	PMP22_Claud	PMP-	0.0019	−4.7	1	4-194
	in	22/EMP/MP20/Claud
		in family
143	SRCR	Scavenger receptor	6.2e−25	96.3	1	722-820
		cysteine-rich domain
144	P2X_receptor	ATP P2X receptor	9.3e−302	1015.9	1	13-388
146	zona_pellucida	Zona pellucida-like	1.1e−80	281.5	1	268-538
		domain
146	trefoil	Trefoil (P-type)	0.02	9.1	1	+111 224-262
		domain
147	Aa_trans	Transmembrane	9.4e-09	42.5	1	30-389
		amino acid
		transporter protein
148	7tm_1	7 transmembrane	2.1e−13	44.8	1	33-280
		receptor (rhodopsin
		family)
149	Na_sulph—	Sodium: sulfate	1.2e−143	490.7	1	16-554
	symp	symporter
		transmembrane
153	ERG4_ERG24	Ergosterol	1.1e−103	357.8	1	7-350
		biosynthesis
		ERG4/ERG24 family
155	ig	Immunoglobulin	4.7e−16	56.8	3	42-95: 135-192:
		domain				231-288
156	7tm_1	7 transmembrane	2.3e−33	108.1	1	28-266
		receptor (rhodopsin
		family)
158	pkinase	Protein kinase	4.9e−68	239.4	1	298-578
		domain
158	Activin_recp	Activin types I and II	1.6e−27	104.8	1	20-107
		receptor domain
159	PMP22_Claud	PMP-	0.00018	13.2	1	3-177
	in	22/EMP/MP20/Claud
		in family
160	MHC_I	Class I	4.4e−14	55.1	1	24-196
		Histocompatibility
		antigen, domains
160	ig	Immunoglobulin	2.8e−07	28.5	1	218-284
		domain
162	sugar_tr	Sugar (and other)	0.028	−126.7	1	48-528
		transporter
163	sugar_tr	Sugar (and other)	0.028	−126.7	1	136-616
		transporter
164	ank	Ankrepeat	1.7e−45	164.6	6	31-63: 64-96:
						97-129: 130-162:
						163-195: 196-228
165	7tm_1	7 transmembrane	5.6e−12	40.2	1	178-349
		receptor (rhodopsin
		family)
166	sugar_tr	Sugar (and other)	0.0032	−100.1	1	46-470
		transporter
168	G_glu—	Gamma-	2.8e−05	−144.9	1	122-500
	transpept	glutamyltranspeptidase
169	TPR	TPR Domain	2.3e−19	77.8	5	28-61: 68-101:
						108-141: 148-181:
						188-221
170	ACAT	Sterol O-	1.9e−32	121.3	1	300-406
		acyltransferase
171	WD40	WD domain,G-beta	2.3e−16	67.8	7	1015-1050: 1059-
		repeat				1097: 1115-1151:
						1158-1194: 1203-
						1240: 1246-1281:
						1293-1329
172	pkinase	Protein kinase	4.9e−57	202.9	2	248-492: 537-564
		domain
172	Activin_recp	Activin types I and II	3.1e−36	133.8	1	26-127
		receptor domain
173	pkinase	Protein kinase	4.9e−57	202.9	2	310-554: 599-626
		domain
173	Activin_recp	Activin types I and II	3.1e−36	133.8	1	26-127
		receptor domain
175	C2	C2 domain	1.7e−06	35.0	1	233-316
176	Cache	Cache domain	1.5e−25	96.2	2	557-650: 960-985
177	Glyco_hydro—	Glycosyl hydrolases	4.9e−268	903.8	2	1-92: 114-636
	31	family 31
179	HMG_box	HMG (high mobility	3.8e−32	120.2	1	681-749
		group) box
180	serpin	Serpin (serine	3.1e−195	662.0	1	315-683
		protease inhibitor)
181	trypsin	Trypsin	0.0044	12.4	1	406-526
183	Aa_trans	Transmembrane	0.0042	−25.4	1	141-551
		amino acid
		transporter protein
186	ATP-synt_C	ATP synthase subunit C	3.3e−18	73.9	1	72-140
187	aconitase	Aconitase family	1.4e−198	651.7	2	162-241: 321-744
		(aconitate hydratase)
187	Aconitase_C	Aconitase C-terminal	8.9e−72	251.9	1	872-1043
		domain
192	PAP2	PAP2 superfamily	6.3e−15	63.0	1	89-236
193	ig	Immunoglobulin	1.4e−20	71.3	2	80-148: 183-251
		domain
195	TCTP	Translationally	3.5e−93	323.0	1	1-166
		controlled tumor
		protein
198	efhand	EF hand	1.2e−13	58.8	3	33-61: 102-130:
						138-166
199	ATP1G1—	ATP1G1/PLMIMAT	1.8e−13	58.2	1	92-146
	PLM_MAT8	8 family
201	ldl_recepta	Low-density	0.00073	26.3	1	115-153
		lipoprotein receptor
		domain
201	CUB	CUB domain	0.002	−3.5	1	9-109
204	7tm_1	7 transmembrane	3.9e−21	69.3	1	139-317
		receptor (rhodopsin
		family)
205	7tm_1	7 transmembrane	1.4e−24	80.3	3	2-28: 114-275:
		receptor (rhodopsin				348-363
		family)
208	tsp_1	Thrombospondin	4.5e−38	139.9	10	149-198: 306-364:
		type 1 domain				571-626: 631-696:
						707-761: 841-889:
						970-1021: 1099-1148:
						1219-1269: 1342-1398
209	HMG14_17	HMG14 and HMG17	1.3e−34	128.4	1	2-86
214	ig	Immunoglobulin	4.7e−20	69.7	3	84-153: 185-255:
		domain				292-347
216	ig	Immunoglobulin	1.6e−10	38.9	1	42-112
		domain
220	C2	C2 domain	5.7e−19	76.5	2	167-257: 667-750
222	7tm_1	7 transmembrane	6.9e−29	93.9	1	104-352
		receptor (rhodopsin
		family)
223	MIP	Major intrinsic	3.9e-40	125.5	3	80-189: 197-262:
		protein				308-325
225	sugar_tr	Sugar (and other)	0.024	−124.9	1	23-504
		transporter
226	ATP-synt_C	ATP synthase subunit C	3.3e−35	130.4	2	14-79: 90-155
227	DHDPS	Dihydrodipicolinate	4.4e−32	120.0	1	34-325
		synthetase family
228	SSF	Sodium: solute	1.5e−48	174.7	2	50-461: 569-953
		symporter family
232	7tm_1	7 transmembrane	2.2e−50	162.2	1	78-332
		receptor (rhodopsin
		family)
234	PID	Phosphotyrosine	1.9e−94	327.2	2	488-627: 661-782
		interaction domain
		(PTB/PID)
234	WW	WW domain	2.5e−08	41.1	1	373-401
237	C2	C2 domain	2.1e−30	114.4	2	87-165: 240-320
241	7tm_1	7 transmembrane	9.6e−31	99.8	1	161-410
		receptor (rhodopsin
		family)
242	WD40	WD domain, G-beta	0.013	22.1	4	26-62: 71-109:
		repeat				236-271: 430-467
244	aa_perrneases	Amino acid permease	5.6e−06	−179.9	1	193-613
247	dUTPase	dUTPase	5.1e−29	109.8	1	46-167
247	MIP	Major intrinsic	3.8e−28	88.8	1	2-56
		protein
247	rvp	Retroviral aspartyl	2.1e−22	85.1	1	179-280
		protease
247	G-patch	G-patch domain	0.00095	25.9	1	285-329

[0468]

TABLE 5
SEQ ID NO:	PDB ID	Chain ID	Start AA	End AA	PSI-BLAST	Verify Score	PMF Score	SeqFold Score	Compound	PDB Annotation
130	1a4y	A	29	355	9.8e−16	0.19	0.12		RIBONUCLEASE INHIBITOR;	COMPLEX (INHIBITOR/NUCLEASE)
									CHAIN: A, D; ANGIOGENIN;	COMPLEX (INHIBITOR/NUCLEASE),
									CHAIN: B, E;	COMPLEX (RI-ANG), HYDROLASE 2
										MOLECULAR RECOGNITION,
										EPITOPE MAPPING, LEUCINE-RICH 3
										REPEATS
130	1a4y	A	42	493	8.4e−11			71.45	RIBONUCLEASE INHIBITOR;	COMPLEX (INHIBITOR/NUCLEASE)
									CHAIN: A, D; ANGIOGENIN;	COMPLEX (INHIBITOR/NUCLEASE),
									CHAIN: B, E;	COMPLEX (RI-ANG), HYDROLASE 2
									MOLECULAR RECOGNITION,
									EPITOPE MAPPING, LEUCINE-RICH 3
									REPEATS
130	1a4y	A	46	293	1.7e−34	0.24	0.95		RIBONUCLEASE INHIBITOR;	COMPLEX (INHIBITOR/NUCLEASE)
									CHAIN: A, D; ANGIOGENIN;	COMPLEX (INHIBITOR/NUCLEASE),
									CHAIN: B, E;	COMPLEX (RI-ANG), HYDROLASE 2
									MOLECULAR RECOGNITION,
									EPITOPE MAPPING, LEUCINE-RICH 3
									REPEATS
130	1a9n	A	122	276	5.1e−27	0.42	0.54		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	A	170	293	5.1e−23	0.36	0.31		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	A	193	304	1.4e−18	0.20	0.36		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	A	214	311	2.8e−06	0.45	0.11		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	A	50	197	3.4e−26	0.25	0.84		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	A	74	213	1.2e−27	0.34	0.68		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	122	276	1e−26	0.41	0.52		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	170	293	1.7e−22	0.17	0.28		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	193	304	1e−18	0.20	0.33		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	214	311	2.8e−06	0.45	−0.02		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTETN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	48	200	6.8e−27	0.11	0.59		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	74	232	5.1e−28	0.15	−0.05		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A′; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1a9n	C	98	251	1.7e−25	0.59	0.48		U2 RNA HAIRPIN IV; CHAIN: Q,	COMPLEX (NUCLEAR PROTEIN/RNA)
									R; U2 A″; CHAIN: A, C; U2 B″;	COMPLEX (NUCLEAR PROTEIN/RNA),
									CHAIN: B, D;	RNA, SNRNP, RIBONUCLEOPROTEIN
130	1d0b	A	138	311	5.6e−21	0.42	0.88		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	24	122	8.4e−13	0.21	1.00		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	43	178	1.4e−24	0.71	1.00		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	53	270	1.7e−33	0.36	1.00		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	75	297	1.7e−33			65.89	INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	87	266	1.1e−24	0.29	1.00		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1d0b	A	95	304	1.2e−27	0.39	0.99		INTERNALIN B; CHAIN: A;	CELL ADHESION LEUCINE RICH
										REPEAT, CALCIUM BINDING, CELL
										ADHESION
130	1dce	A	214	332	1.4e−09	0.42	0.83		RAB	TRANSFERASE CRYSTAL
									GERANYLGERANYLTRANSFER	STRUCTURE, RAB
									ASE ALPHA SUBUNIT; CHAIN:	GERANYLGERANYLTRANSFEPASE
									A, C; RAB	2.0 A 2 RESOLUTION, N-
									GERANYLGERANYLTRANSFER	FORMYLMETHIONINE, ALPHA
									ASE BETA SUBUNIT; CHAIN: B, D	SUBUNIT, BETA SUBUNIT
130	1ds9	A	48	192	1.7e−18	−0.61	0.06		OUTER ARM DYNEIN; CHAIN:	CONTRACTILE PROTEIN LEUCINE-
									A;	RICH REPEAT, BETA-BETA-ALPHA
										CYLINDER, DYNEIN, 2
										CHLAMYDOMONAS, FLAGELIA
130	1ds9	A	55	175	2.8e−13	−0.16	0.00		OUTER ARM DYNEIN; CHAIN:	CONTRACTILE PROTEIN LEUCINE-
									A;	RICH REPEAT, BETA-BETA-ALPHA
										CYLINDER, DYNEIN, 2
										CULAMYDOMONAS, FLAGELLA
130	1ds9	A	93	282	1e−23	−0.28	0.04		OUTER ARM DYNEIN; CHAIN:	CONTRACTILE PROTEIN LEUCINE-
									A;	RICH REPEAT, BETA-BETA-ALPHA
										CYLINDER, DYNEIN, 2
										CHLAMYDOMONAS, FLAGELLA
130	1fo1	A	233	295	9.8e−07	−0.14	0.04		NUCLEAR RNA EXPORT	RNA BINDING PROTEIN TAP (NFX1);
									FACTOR 1; CHAIN: A, B;	RIBONUCLEOPROTEIN (RNP, RBD OR
										RRM) AND LEUCINE-RICH-REPEAT 2
										(LRR)
130	1fo1	A	257	332	5.6e−05	0.06	0.48		NUCLEAR RNA EXPORT	RNA BINDING PROTEIN TAP (NEX1);
									FACTOR I; CHAIN: A, B;	RIBONUCLEOPROTEIN (RNP,RBD OR
										RRM) AND LEUCINE-RICH-REPEAT 2
										(LRR)
130	1fo1	B	233	295	9.8e−07	0.04	0.07		NUCLEAR RNA EXPORT	RNA BINDING PROTEIN TAP (NFX1);
									FACTOR 1; CHAIN: A, B;	RIBONUCLEOPROTEIN (RNP,RBD OR
										RRM) AND LEUCINE-RICH-REPEAT 2
										(LRR)
130	1fo1	B	257	332	5.6e−05	0.04	−0.02		NUCLEAR RNA EXPORT	RNA BINDING PROTEIN TAP (NFX1);
									FACTOR 1; CHAIN: A, B;	RIBONUCLEOPROTEIN (RNP,RBD OR
										RRM) AND LEUCINE-RICH-REPEAT 2
										(LRR)
130	1fqv	A	87	293	8.5e−17	0.08	−0.06		SKP2; CHAIN: A, C, E, G, I, K, M,	LIGASE CYCLIN A/CDK2-
									O; SKP1; CHAIN: B, D, F, H, J, L,	ASSOCIATED PROTEIN P45; CYCLIN
									N, P;	A/CDK2-ASSOCIATED PROTEIN P19;
										SKP1, SKP2, F-BOX, LRR, LEUCINE
										RICH REPEAT, SCF, UBIQUITIN, 2 E3,
										UBIQUIITIN PROTEIN LIGASE
130	1fs2	A	11	262	1.2e−13	−0.20	0.06		SKP2; CHAIN: A, C; SKP1;	LIGASE CYCLIN A/CDK2-
									CHAIN: B, D;	ASSOCIATED P45; CYCLIN A/CDK2-
										ASSOCIATED P19; SKP1, SKP2, F-BOX,
										LRRS, LEUCINE-RICH REPEATS, SCF,
										2 UBIQUITIN, E3, UBIQUITIN PROTEIN
										LIGASE
130	1fs2	A	92	285	8.5e−16	0.35	0.36		SKP2; CHAIN: A, C; SKP1;	LIGASE CYCLIN A/CDK2-
									CHAIN: B, D;	ASSOCIATED P45; CYCLIN A/CDK2-
										ASSOCIATED P19; SKP1, SKP2, F-BOX,
										LRRS, LEUCINE-RICH REPEATS, SCF,
										2 UBIQUITIN, E3, UBIQUITIN PROTEIN
										LIGASE
130	1ft8	A	233	295	9.8e−07	−0.19	0.09		TIP ASSOCIATING PROTEIN;	RNA BINDING PROTEIN TAP;
									CHAIN: A, B, C, D, E;	RIBONUCLEOPROTEIN (RNP, RRM,
										RBD) AND LEUCINE-RICH-REPEAT 2
										(LRR) DOMAINS
130	1ft8	A	257	332	5.6e−05	0.02	0.17		TIP ASSOCIATING PROTEIN;	RNA BINDING PROTEIN TAP;
									CHAIN: A, B, C, D, E;	RIBONUCLEOPROTEIN (RNP, RRM,
										RED) AND LEUCINE-RICH-REPEAT 2
										(LRR) DOMAINS
130	1yrg	A	48	271	6.8e−29	−0.07	0.06		GTPASE-ACTIVATING PROTEIN	TRANSCRIPTION RNA1P; RANGAP;
									RNA1_SCHPO; CHAIN: A, B;	GTPASE-ACTIVATING PROTEIN FOR
										SPI1, GTPASE-ACTIVATING PROTEIN,
										GAP, RNA1P, RANGAP, LRR,
										LEUCINE-2 RICH REPEAT PROTEIN,
										TWINNING, HEMIHEDRAL
										TWINNING, 3 MEROHEDRAL
										TWINNING, MEROHEDRY
130	2bnh		40	293	3.4e−35	0.19	0.99		RIBONUCLEASE INHIBITOR;	ACETYLATION RNASE INHIBITOR,
									CHAIN: NULL;	RIBONUCLEASE/ANGIOGENIN
										INHIBITOR ACETYLATION, LEUCINE-
										RICH REPEATS
130	2bnh		66	443	4.2e−21	−0.17	0.00		RIBONUCLEASE INHIBITOR;	ACETYLATION RNASE INHIBITOR,
									CHAIN: NULL;	RIBONUCLEASE/ANGIOGENIN
										INHIBITOR ACETYLATION, LEUCINE-
										RICH REPEATS
131	12e8	H	336	518	5.6e−51	—0.05	0.10		2E8 (IGG1 = KAPPA =)	IMMUNOGLOBULIN
									ANTIBODY; CHAIN: L, H, M, P;	IMMUNOGLOBULIN
131	1a31	H	336	515	4.2e−50	0.02	0.19		IMMUNOGLOBULINFAB 13G5;	IMMUNOGLOBULIN DIELS-ALDER,
									CHAIN: L, H;	DISFAVORED REACTION,
										CATALYTIC ANTIBODY, 2
										IMMUNOGLOBULIN
131	1adq	L	51	240	8.4e−32	−0.11	0.18		IGG4 REA; CHAIN: A; RF-AN	COMPLEX
									IGM/LAMBDA; CHAIN: H, L;	(IMMUNOGLOBULIN/AUTOANTIGEN)
										COMPLEX
										(IMMUNOGLOBULIN/AUTOANTIGEN),
										RHEUMATOID FACTOR 2 AUTO-
										ANTIBODY COMPLEX
131	1afv	H	336	517	5.6e−51	0.17	0.10		HUMAN IMMUNODEFICIENCY	COMPLEX (VIRAL
									VIRUS TYPE 1 CAPSID CHAIN:	CAPSID/IMMUNOGLOBULIN) HIV-1
									A, B; ANTIBODY FAB25.3	CA, HIV CA, HIV P24, P24; FAB, FAB
									FRAGMENT; CHAIN: H, K, L, M;	LIGHT CHAIN, FAB HEAVY CHAIN
										COMPLEX (VIRAL
										CAPSID/IMMUNOGLOBULIN), HIV,
										CAPSID PROTEIN, 2 P24
131	1bih	A	149	506	2.8e−27	0.13	0.87		HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
131	1bih	A	150	515	8.5e−45	0.37	0.80		HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
131	1bih	A	46	417	3.4e−48			130.68	HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
131	1bih	A	50	417	3.4e−48	0.15	1.00		HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
131	1bm3	H	336	519	1.3e−50	0.14	0.09		IMMUNOGLOBULIN OPG2 FAB,	IMMUNE SYSTEM
									CONSTANT DOMAIN; CHAIN:	IMMUNOGLOBULIN
									L; IMMUNOGLOBULIN OPG2
									FAB, VARIABLE DOMAIN;
									CHAIN: H;
131	1c5c	H	336	519	2.8e−51	0.10	0.06		CHIMERIC DECARBOXYLASE	IMMUNE SYSTEM
									ANTIBODY 21D8; CHAIN: L;	IMMUNOGLOBULIN, CATALYTIC
									CHIMERIC DECARBOXYLASE	ANTIBODY, CHIMERIC FAB, 2
									ANTIBODY 21D8; CHAIN: II;	DECARBOXYLASE, HAPTEN
										COMPLEX
131	1cic	B	336	515	5.6e−51	−0.00	−0.02		IG HEAVY CHAIN V REGIONS;	IMMUNOGLOBULIN
									CHAIN: A; IG HEAVY CHAIN V	IMMUNOGLOBULIN, FAB COMPLEX,
									REGIONS; CHAIN: B; IG HEAVY	IDIOTOPE, ANTI-IDIOTOPE
									CHAIN V REGIONS; CHAIN: C;
									IG HEAVY CHAIN V REGIONS;
									CHAIN: D;
131	1cic	B	48	244	2.8e−72	0.16	−0.06		IG HEAVY CHAIN V REGIONS;	IMMUNOGLOBULIN
									CHAIN: A; IG HEAVY CHAIN V	IMMUNOGLOBULIN, FAB COMPLEX,
									REGIONS; CHAIN: B; IG HEAVY	IDIOTOPE, ANTI-IDIOTOPE
									CHAIN V REGIONS; CHAIN: C;
									10 HEAVY CHAIN V REGIONS;
									CHAIN: D;
131	1c17	I	434	519	7e−25	0.08	0.09		IGG1_ANTIBODY 1696 (LIGHT	IMMUNE SYSTEM
									CHAIN); CHAIN: L; IGG1	IMMUNOGLOBULIN, IGG1;
									ANTIBODY 1696 (VARIABLE	IMMUNOGLOBULIN, IGG1;
									HEAVY CHAIN); CHAIN: H;	IMMUNOGLOBULIN, IGG1 FAB
									IGG1 ANTIBODY 1696	FRAGMENT, CROSS-REACTIVITY,
									(CONSTANT HEAVY CHAIN);	HIV1 PROTEASE, ENZYME 2
									CHAIN: I;	INHIBITION, IMMUNOGLOBULIN
131	1cqk	A	418	516	1.4e−25	0.23	−0.11		CH3 DOMAIN OF MAK33	IMMUNE SYSTEM CONSTANT
									ANTIBODY; CHAiN: A, B;	DOMAIN, C1-SUBSET,
										IMMUNOGLOBULIN, IMMUNE
										SYSTEM
131	1cs6	A	135	515	3.4e−46	0.31	0.62		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
131	1cs6	A	149	517	1.4e−35	0.19	0.77		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
131	1cs6	A	244	602	1.1e−34	0.11	0.46		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
131	1cs6	A	43	418	1.7e−56			125.44	AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
131	1cs6	A	50	416	1.7e−56	−0.10	0.71		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
131	1dgi	R	151	416	5.1e−28	−0.23	0.47		POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
131	1dgi	R	49	331	3.4e−43			112.84	POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
131	1dgi	R	52	331	3.4e−43	−0.28	0.05		POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VPI; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
131	1dn2	A	250	415	1.3e−35	−0.05	0.07		IMMUNOGLOBULIN LAMBDA	IMMUNE SYSTEM FC IGG PHAGE
									HEAVY CHAIN; CHAIN: A, B;	DISPLAY PEPTIDE
									ENGINEERED PEPTIDE; CHAIN:
									E, F;
131	1e4k	A	244	415	1.4e−36	0.26	0.06		LOW AFFINITY	COMPLEX CD16; IGG1-FC COMPLEX,
									IMMUNOGLOBULIN GAMMA	FC FRAGMENT, IGG, FC, RECEPTOR,
									FC RECEPTOR CHAIN: C; FC	CD16, GAMMA
									FRAGMENT OF HUMAN IGG1;
									CHAIN: A, B;
131	1e4x	H	336	518	4.2e−51	0.32	0.27		TAB2; CHAIN: L, M; TAB2;	COMPLEX (ANTIBODY/ANTIGEN)
									CHAIN: H, I; CYCLIC PEPTIDE;	CROSS-REACTIVITY PROTEIN-
									CHAIN: P, Q	PEPTIDE RECOGNITION
131	1e4x	H	48	247	1.4e−74	0.08	−0.11		TAB2; CHAIN: L, M; TAB2;	COMPLEX (ANTIBODY/ANTIGEN)
									CHAIN: H, I; CYCLIC PEPTIDE;	CROSS-REACTIVITY, PROTEIN-
									CHAIN: P, Q	PEPTIDE RECOGNITION
131	1eap	B	49	241	1.1e−65	−0.06	0.29		CATALYTIC ANTIBODY 17E8
									COMPLEXED WITH PHENYL [1-
									(1-N-
									SUCCINYLMINO)PENTYL]
									1EAP 3 PHOSPHONATE 1EAP 4
131	1ejo	H	51	244	1.1e−65	0.05	0.00		IGG2A MONOCLONAL	IMMUNE SYSTEM FMDV, ANTIGENIC-
									ANTIBODY (LIGHT CHAIN);	ANTIBODY INTERACTIONS, RGD
									CHAIN: L; IGG2A	MOTIF, G-H LOOP 2 OF VP1.
									MONOCLONAL ANTIBODY
									(HEAVY CHAIN); CHAIN: H;
									FMDV PEPTIDE CHAIN: P;
131	1evt	C	247	416	8.5e−27	0.27	0.88		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 1; CHAIN: A, B;	RECEPTOR FGF1; FGFR1;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG) LIKE
									FACTOR RECEPTOR 1; CHAIN:	DOMAINS BELONGING TO THE I-SET
									C, D;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
131	1f2q	A	250	420	1.2e−26	0.13	0.87		HIGH AFFINITY	IMMUNE SYSTEM FC-EPSILON RI-
									IMMUNOGLOBULIN EPSILON	ALPHA; IMMUNOGLOBULIN FOLD,
									RECEPTOR CHAIN: A;	GLYCOPROTEIN, RECEPTOR, IGE-
										BINDING 2 PROTEIN
131	1f6a	A	246	420	5.1e−31	0.06	0.72		HIGH AFFINITY	IMMUNE SYSTEM HIGH AFFINITY
									IMMUNOGLOBULIN EPSILON	IGE-FC RECEPTOR, FC(EPSILON) IGE-
									RECEPTOR CHAIN: A; IG	FC; IMMUNGLOBULIN FOLD,
									EPSILON CHIAN C REGION;	GLYCOPRTEIN, RECRPTOR, IGE-
									CHAIN: B, D;	BINDING 2 PROTEIN, IGE ANTIBODY,
										IEC-FC
131	1fai	H	48	241	8.4e−68	0.07	−0.05		IMMUNOGLOBULIN FAB
									FRAGMENT FROM A
									MONOCLONAL ANTI-
									ARSONATE ANTIBODY, R19.9
									1FAI3 (IGG2B, KAPPA) 1FAI4
131	1fbi	H	48	244	1.1e−72	0.05	−0.17		COMPLEX
									ANTIBODY/ANTIGEN FAB
									FRAGMENT OF THE
									MONOCLONAL ANTIBODY
									F9.13.7 (IGG1) 1FBI 3
									COMPLEXED WITH LYSOZYME
									(E.C.3.2.1.17) 1FBI4
131	1fc2	D	250	415	7e−36	0.07	0.06		IMMUNOGLOBULIN
									IMMUNOGLOBULLN PC AND
									FRAGMENT B OF PROTEIN A
									COMPLEX IFC2 4
131	1fgn	H	337	514	7e−51	0.11	0.48		IMMUNOGLOBULLN FAB 5G9;	IMMUNOGLOBULIN FAB, FAB LIGHT
									CHAIN: L, H;	CHAIN, FAB HEAVY CHAIN;
										ANTIBODY, FAB, ANTI-TF,
										MONOCLONAL, MURINE,
										IMMUNOGLOBULIN
131	1fh5	H	54	244	8.4e−66	0.14	0.07		MONOCLONAL ANTIBODY	IMMUNE SYSTEM FAB, BIP, CRYSTAL
									MAK33; CHAIN: L;	STRUCTURE
									MONOCLONAL ANTIBODY
									MAK33; CHAIN: H;
131	1fl3	A	51	243	7e−66	−0.02	0.06		BLUE FLUORESCENT	IMMUNE SYSTEM
									ANTIBODY (19G2)-HEAVY	IMMUNOGLOBULIN FOLD
									CHAIN; CHAIN: H, A; BLUE
									FLUORESCENT ANTIBODY
									(19G2)-LIGHT CHAIN; CHAIN: L,
									B;
131	1for	H	50	244	4.2e−72	0.03	−0.06		IMMUNOGLOBULIN IGG2A
									FAD FRAGMENT (FAB17-IA)
									(ORTHORHOMBIC CRYSTAL
									FORM) 1FOR 3
131	1fsk	C	336	519	1.4e−50	0.11	0.01		MAJOR POLLEN ALLERGEN	IMMUNE SYSTEM BET V I-A, BETVI
									BET V 1-A; CHAIN: A, D, G, I;	ALLERGEN; BV16 FAB-FRAGMENT,
									IMMUNOGLOBULIN KAPPA	KAPPA MOPC21 CODING SEQUENCE;
									LIGHT CHAIN; CHAIN: B, E, H,	HEAVY CHAIN OF THE
									K; ANTIBODY HEAVY CHAIN	MONOCLONAL ANTIBODY MST2;
									FAB; CHAIN: C, F, I, L;	BET V 1, BV16 FAB FRAGMENT,
										ANTIBODY ALLERGEN COMPLEX
131	1fsk	C	48	244	2.8e−72	0.05	−0.14		MAJOR POLLEN ALLERGEN	IMMUNE SYSTEM BET V I-A, BETVI
									BET V 1-A; CHAIN: A, D, G, J;	ALLERGEN; BV16 FAR-FRAGMENT,
									IMMUNOGLOBULIN KAPPA	KAPPA MOPC21 CODING SEQUENCE;
									LIGHT CHAIN; CHAIN: B, E, H,	HEAVY CHAIN OF THE
									K; ANTIBODY HEAVY CHAIN	MONOCLONAL ANTIBODY MST2;
									FAB; CHAIN: C, F, I, L;	BET V 1, BV16 FAR FRAGMENT,
										ANTIBODY ALLERGEN COMPLEX
131	1hi6	B	50	246	1.1e−70	0.29	0.22		IGG2A KAPPA ANTIBODY CB41	COMPLEX (ANTIBODY/PEPTIDE)
									(LIGHT CHAIN); CHAIN: A;	POLYSPECIFICITY,
									IGG2A KAPPA ANTIBODY CB41	CROSSREACTIVITY, FAB-FRAGMENT,
									(HEAVY CHAIN); CHAIN: B;	PEPTIDE, 2 HIV-1
									PEPTIDE 5; CHAIN: C;
131	1hzh	H	163	521	4.2e−63	0.12	0.55		IMMUNOGLOBULIN HEAVY	IMMUNE SYSTEM IGG;
									CHAIN; CHAIN: H, K;	IMMUNOGLOBULIN, ANTIBODY, B12
									IMMUNOGLOBULIN LIGHT
									CHAIN; CHAIN: L, M;
131	1hzh	H	48	418	0	0.28	0.55		IMMUNOGLOBULIN HEAVY	IMMUNE SYSTEM IGG;
									CHAIN; CHAIN: H, K;	IMMUNOGLOBULIN, ANTIBODY, B12
									IMMUNOGLOBULIN LIGHT
									CHAIN; CHAIN: L, M;
131	lhzh	H	4	320	1.4e−51	−0.22	0.81		IMMUNOGLOBULIN HEAVY	IMMUNE SYSTEM IGG;
									CHAIN; CHAIN: H, K;	IMMUNOGLOBULIN, ANTIBODY, B12
									IMMUNOGLOBULIN LIGHT
									CHAIN; CHAIN: L, M;
131	1i1c	A	251	415	7e−30	0.07	−0.11		IGGAMMA-2A CHAIN C	IMMUNE SYSTEM IGG2A; IGG, FC
									REGION; CHAIN: A, B;
131	1ibg	H	49	241	5.6e−67	0.10	0.13		IMMUNOGLOBULIN IGG FAB
									(IGG2B, KAPPA) FRAGMENT
									(40-50 FAB) COMPLEXED WITH
									1IBG 3 OUABAIN 1IBG 4
131	ligt	B	160	517	9.8e−61	−0.03	0.54		IGG2A INTACT ANTIBODY-	IMMUNOGLOBULIN INTACT
									MAB231; CHAIN: A, B, C, D	IMMUNOGLOBULIN V REGION C
										REGION, IMMUNOGLOBULIN
131	1igt	B	49	415	0	0.10	0.66		IGG2A INTACT ANTIBODY-	IMMUNOGLOBULIN INTACT
									MAB231; CHAIN: A, B, C, D	IMMUNOGLOBULIN V REGION C
										REGION, IMMUNOGLOBULIN
131	1igt	B	51	475	0			102.57	IGG2A INTACT ANTIBODY-	IMMUNOGLOBULIN INTACT
									MAB231; CHAIN: A, B, C, D	IMMUNOGLOBULIN V REGION C
										REGION, IMMUNOGLOBULIN
131	1igt	B	5	318	2.8e−48	−0.12	0.28		IGG2A INTACT ANTIBODY-	IMMUNOGLOBULIN INTACT
									MAB231; CHAIN: A, B, C, D	IMMUNOGLOBULIN V REGION C
										REGION, IMMUNOGLOBULIN
131	1igy	B	160	516	5.6e−61	0.04	0.64		IGG1 INTACT ANTIBODY	IMMUNOGLOBULIN INTACT
									MAB61.1.3; CHAIN: A, B, C, D	IMMUNOGLOBULIN, V REGION, C
										REGION, HINGE REGION
131	1igy	B	49	415	0	−0.03	0.31		IGG1 INTACT ANTIBODY	IMMUNOGLOBULIN INTACT
									MAB61.1.3; CHAIN: A, B, C, D	IMMUNOGLOBULIN, V REGION, C
										REGION, HINGE REGION
131	1i11	A	50	244	7e−68	0.06	−0.02		MONOCLONAL ANTIBODY G3-	IMMUNE SYSTEM FAB, BETA SHEET
									519 (HEAVY CHAIN); CHAIN: A;	STRUCTURE, ANTIBODY
									MONOCLONAL ANTIBODY G3-
									519 (LIGHT CHAIN); CHAIN: B;
131	1itb	B	261	517	1e−36	0.15	0.71		INTERLEUKIN-1 BETA; CHAIN:	COMPLEX
									A; TYPE 1 INTERLEUKIN-1	(IMMUNOGLOBULIN/RECEPTOR)
									RECEPTOR; CHAIN: B;	IMMUNOGLOBULIN FOLD,
										TRANSMEMBRANE, GLYCOPROTEIN,
										RECEPTOR, 2 SIGNAL, COMPLEX
										(IMMUNOGLOBULIN/RECEPTOR)
131	1kb5	H	49	244	2.8e−72	0.10	0.06		KB5-C20 T-CELL ANTIGEN	COMPLEX
									RECEPTOR; CHAIN: A, B;	(IMMUNOGLOBULIN/RECEPTOR) TCR
									ANTIBODY DESIRE-1; CHAIN:	VAPLHA VBETA DOMAIN; T-CELL
									L, H;	RECEPTOR, STRAND SWITCH, FAB,
										ANTICLONOTYPIC, 2
										(IMMUNOGLOBULIN/RECEPTOR)
131	1mco	H	189	516	1.1e−67	0.05	0.01		IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION 1MCO3
131	1mco	H	48	415	0	0.05	0.66		IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION 1MCO3
131	1mco	H	49	475	0			106.26	IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION 1MCO 3
131	1mco	H	5	320	2.8e−55	−0.30	0.09		IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION 1MCO 3
131	1mcp	H	49	231	1.1e−48	−0.07	0.11		IMMUNOGLOBULIN
									IMMUNOGLOBULIN FAB
									FRAGMENT (MC/PC$603) 1MCP
									4
131	1m1b	B	336	519	1.4e−50	0.16	0.07		IMMUNOGLOBULIN FAB D44.1
									(IGG1, KAPPA) (BALB/C MOUSE,
									MONOCLONAL ANTIBODY)
									1MLE 5
131	1pfc		417	520	2.8e−23	0.02	−0.13		IMMUNOGLOBULIN
									$P/F$C(PRIME) FRAGMENT OF
									ANIG*G1 1PFC4
131	1plg	H	48	243	4.2e−73	0.17	−0.05		IGG2A = KAPPA =; 1PLG 4 CHAIN:	IMMUNOGLOBULIN
									L, H; 1PLG 5
131	1psk	H	49	240	1.4e−61	−0.17	0.04		ANTIBODY; CHAIN: L, H;	IMMUNOGLOBULIN FAB, GD2-
										GANGLIOSIDE, CARBOHYDRATE,
										MELANOMA, IMMUNOGLOBULIN
131	1qfu	H	336	518	1.3e−50	0.30	0.28		HEMAGGLUTININ (HA1	VIRALPROTEIN/IMMUNE SYSTEM
									CHAIN); CHAIN: A;	COMPLEX
									HEMAGGLUTININ (HA2	(HEMAGGLUTININ/IMMMUNOGLOBU
									CHAIN); CHAIN: B;	LIN), HEMAGGLUTININ, 2
									IMMUNOGLOBULIN IGG1-	IMMUNOGLOBULIN, VIRAL
									KAPPA ANTIBODY (LIGHT	PROTEIN/IMMUNE SYSTEM
									CHAIN); CHAIN: L;
									IMMUNOGLOBULIN IGG1-
									KAPPA ANTIBODY (HEAVY
									CHAIN); CHAIN: H;
131	1qfu	H	48	244	1.4e−72	0.10	−0.11		HEMAGGLUTININ (HA1	VIRAL PROTEIN/IMMUNE SYSTEM
									CHAIN); CHAIN: A	COMPLEX
									HEMAGGLUTININ(HA2	(HEMAGGLUTININ/IMMMUNOGLOBU
									CHAIN); CHAIN: B;	LIN), HEMAGGLUTININ, 2
									IMMUNOGLOBULIN IGG1-	IMMUNOGLOBULIN, VIRAL
									KAPPA ANTIBODY (LIGHT	PROTEIN/IMMUNE SYSTEM
									CHAIN); CHAIN: L;
									IMMUNOGLOBULIN IGG1-
									KAPPA ANTIBODY (HEAVY
									CHAIN); CHAIN: H;
131	1vge	H	51	244	1.4e−66	−0.10	0.18		TR1.9 FAP; CHAIN: L, H;	IMMUNOGLOBULIN TR1.9, ANTI-
										THYROID PEROXIDASE,
										AUTOANTIBODY, 2
										IMMUNOGLOBULIN
131	1wej	H	336	520	8.4e−51	0.24	0.27		E8 ANTIBODY; CHAIN: L, H;	COMPLEX (ANTIBODY/ELECTRON
									CYTOCHROME C; CHAIN: F;	TRANSPORT) FAB E8; CYT C,
										ANTIGEN; IMMUNOGLOBULIN, IGG1
										KAPPA, FAB FRAGMENT, HORSE 2
										CYTOCHROME C, COMPLEX
										(ANTIBODY/ELECTRON TRANSPORT)
131	1yej	H	50	244	8.4e−69	0.18	−0.01		IG ANTIBODY D2.3 (LIGHT	IMMUNE SYSTEM ABZYME,
									CHAIN); CHAIN: L; IG	TRANSITION STATE ANALOG,
									ANTIBODY D2.3 (HEAVY	IMMUNE SYSTEM
									CHAIN); CHAIN: H;
131	25c8	H	336	515	1.4e−51	0.11	0.16		IGG 5C8; CHAIN: L, H;	CATALYTIC ANTIBODY CATALYTIC
										ANTIBODY, FAD, RING CLOSURE
										REACTION
131	2fbj	H	49	231	7e−51	−0.03	0.04		IMMUNOGLOBULIN IG*A FAD
									FRAGMENT (J539) (GALACTAN-
									BINDING) 2FBJ 3
131	2fcb	A	249	419	3.4e−28	0.11	0.74		FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										FC, CD32, IMMUNE SYSTEM
131	3fct	B	336	518	4.2e−50	0.22	0.09		METAL CHELATASE	IMMUNE SYSTEM METAL
									CATALYTIC ANTIBODY;	CHELATASE, CATALYTIC ANTIBODY,
									CHAIN: A, C; METAL	FAB FRAGMENT, IMMUNE 2 SYSTEM
									CHELATASE CATALYTIC
									ANTIBODY; CHAIN: B, D;
132	1cdq		88	164	8.4e−20	0.59	1.00		COMPLEMENT REGULATORY
									PROTEIN CD59 (NMR, 20
									STRUCTURES) 1CDQ3
132	1cdq		88	164	8.4e−20			142.11	COMPLEMENT REGULATORY
									PROTEIN CD59 (NMR, 20
									STRUCTURES) 1CDQ 3
132	1erg		88	157	2.8e−19	0.41	1.00		COMPLEMENT FACTOR
									HUMAN COMPLEMENT
									REGULATORY PROTEIN CD59
									(EXTRACELLULAR 1ERG 3
									REGION, RESIDUES 1-70)
									(NMR, RESTRAINED
									MINIMIZED 1ERG 4 AVERAGE
									STRUCTURE) 1ERG 5
132	1erg		88	157	2.8e−19			131.94	COMPLEMENT FACTOR
									HUMAN COMPLEMENT
									REGULATORY PROTEIN CD59
									(EXTRACELLULAR 1ERG 3
									REGION, RESIDUES 1-70)
									(NMR, RESTRAINED
									MINIMIZED IERG 4 AVERAGE
									STRUCTURE) 1ERG 5
136	1a1n	A	11	199	0			232.06	B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE) B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBILITY
										ANTIGEN, MHC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGEN/PEPTIDE)
136	1a1n	A	25	299	0			410.38	B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE) B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBILITY
										ANTIGEN, MHC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGENIPEPTIDE)
136	1a1n	A	25	300	0	0.83	1.00		B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE) B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBILITY
										ANTIGEN, MHC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGEN/PEPTIDE)
136	1agd	A	11	199	0				233.86	B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHC
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILITY
									(GGKKXYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
136	1agd	A	25	299	0			411.64	B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHC
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILLTY
									(GGKKKYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
136	1agd	A	25	300	0	0.79	1.00		B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHG
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILITY
									(GGKKKYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
136	1efx	A	25	302	0	0.87	1.00		HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
136	1efx	A	25	302	0			420.37	HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHG, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
136	1hsa	A	11	199	0			232.10	HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN 1HSA 3/HLA-
									B(ASTERISK)2705$ 1HSA 4
136	1hsa	A	25	299	0			410.78	HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN 1HSA 3/HLA-
									B(ASTERISK)2705$ 1HSA 4
136	1hsa	A	25	300	0	0.82	1.00		HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN 1HSA 3/HLA-
									B(ASTERJSK)2705$ 1HSA 4
136	1hsb	A	11	199	0			257.74	HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
136	1hsb	A	25	294	0	0.86	1.00		HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
136	1hsb	A	25	294	0			414.03	HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
136	1i4f	A	11	199	1.4e−100			263.59 HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
136	1i4f	A	25	299	0	0.83	1.00		HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
136	1i4f	A	25	299	0			435.50	HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATlBILITY	MAJOR HiSTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
136	1qqd	A	12	199	0			232.33	HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
136	1qqd	A	26	298	0	0.87	1.00		HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
136	1qqd	A	26	298	0			407.96	HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (LG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
136	1tmc	A	11	185	2.8e−94			284.63	HISTOCOMPATIBILITY
									ANTIGEN TRUNCATED HUMAN
									CLASS 1 HISTOCOMPATIBILITY
									ANTIGEN HLA-AW68 1TMC 3
									COMPLEXED WITH A
									DECAMERIC PEPTIDE
									(EVAPPEYHRK) 1TMC 4
137	1efx	A	11	199	0			241.21	HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTORIMHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
137	2ebo	A	12	88	4.2e−18	−0.74	0.29		EBOLA VIRUS ENVELOPE	ENVELOPE GLYCOPROTEIN
									GLYCOPROTEIN; CHAIN: A, B,	ENVELOPE GLYCOPROTEIN,
									C;	FILOVIRUS, EBOLA VIRUS, GP2,
										COAT 2 PROTEIN
139	1cdy		32	133	3.4e−07	0.40	0.19		T-CELL SURFACE	T-CELL SURFACE GLYCOPROTEIN
									GLYCOPROTEIN CD4; CHAIN:	IMMUNOGLOBULIN FOLD,
									NULL;	TRANSMEMLBRANE, GLYCOPROTEIN,
										T-CELL, 2 MHC, LIPOPROTEIN, T-
										CELL SURFACE GLYCOPROTEIN
139	1dgi	R	25	127	2.8e−29	0.41	0.46		POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
139	1dr9	A	32	126	8.5e−10	0.33	0.06		T LYMPHOCYTE ACTIVATION	IMMUNE SYSTEM B7-1 (CD80); IG
									ANTIGEN; CHAIN: A;	SUPERFAMILY
139	1eaj	A	33	127	1.7e−07	0.41	−0.03		CONSACKIE VIRUS AND	VIRUS/VIRAL PROTEIN RECEPTOR
									ADENOVIRUS RECEPTOR;	COXSACKIE VIRUS B-ADENO VIRUS
									CHAIN: A, B;	RECEPTOR, HCAR, VIRUS/VIRAL
										PROTEIN RECEPTOR,
										IMMUNOGLOBULIN V DOMAIN
										FOLD, 2 SYMMETRIC DIMER
139	1hxm	B	20	123	1.5e−06	0.36	0.06		GAMMA-DELTA T-CELL	IMMUNE SYSTEM T-CELL RECEPTOR
									RECEPTOR; CHAIN: A, C, E, D;	DELTA CHAIN; T-CELL RECEPTOR
									GAMMA-DELTA T-CELL	GAMMA CHAIN; IG DOMAIN, T CELL
									RECEPTOR; CHAIN: B, D, F, H;	RECEPTOR, TCR, GDTCR
139	1i81	C	33	120	8.5 e−06	0.12	0.80		TLYMPHOCYTE ACTIVATION	IMMUNE SYSTEM ACTIVATION B7-1
									ANTIGEN CD80; CHAIN: A, B;	ANTIGEN, CTLA-4 COUNTER-
									CYTOTOXIC T-LYMPHOCYTE	RECEPTOR CTLA-4, CYTOTOXIC T-
									PROTEIN 4; CHAIN: C, D;	LYMPHOCYTE-ASSOCIATED
										ANTIGEN RECEPTORS, INHIBITORY
										COMPLEX
139	1ii1	G	32	131	7e−06	0.21	−0.03		HEPARIN-BINDING GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2, HBGF-2, BASIC
									FIBROBLAST GROWTH	FIBROBLAST GROWTH FACTOR,
									FACTOR RECEPTOR 2; CHAIN:	FGFR2, KERATINOCYTE GROWTH
									E, F, 0, H;	FACTOR RECEPTOR;
										IMMUNOGLOBULIN LIKE DOMAIN, B-
										TREFOIL
139	1neu		27	128	6.8e−11	0.56	0.13		MYELIN P0 PROTEIN; CHAIN:	STRUCTURAL PROTEIN MYELIN,
									NULL;	STRUCTURAL PROTEIN,
										GLYCOPROTEIN, TRANSMEMBRANE,
										PHOSPHORYLATION,
										IMMUNOGLOBULIN FOLD, SIGNAL,
										MYELIN 2 MEMBRANE ADHESION
										MOLECULE
139	2cd0	A	29	127	8.4e−06	0.35	0.31		BENCE-JONES PROTEIN WIL, A	IMMUNE SYSTEM
									VARIABLE DOMAIN FROM	IMMUNOGLOBULIN, BENCE-JONES
									CHAIN: A, B;	PROTEIN, LAMBDA-6
141	1tgx	A	55	98	0.0031	−0.49	0.01		CYTOTOXIN TOXIN GAMMA
									(CARDIOTOXIN) 1TGX 3
141	2crs		55	98	0.0023	−0.25	0.00		CARDIOTOXIN CARDIOTOXIN
									III (NMR, 13 STRUCTURES)
									2CRS 3
143	1a5e		117	272	8.4e−20			74.90	TUMOR SUPPRESSOR	ANTI-ONCOGENE CELL CYCLE, ANTI-
									P16INK4A; CHAIN: NULL;	ONCOGENE, REPEAT, ANK REPEAT
143	1awc	B	95	244	7e−38			75.28	GA BINDING PROTEIN ALPHA;	COMPLEX (TRANSCRIPTION
									CHAIN: A; GA BINDING	REGULATION/DNA) GABPALPHA;
									PROTEIN BETA 1; CHAIN: B;	GABPBETA1; COMPLEX
									DNA; CHAIN: D, E;	(TRANSCRIPTION
										REGULATION/DNA), DNA-BINDING, 2
										NUCLEAR PROTEIN, ETS DOMAIN,
										ANKYRIN REPEATS, TRANSCRIPTION
										3 FACTOR
143	1bd8		93	247	4.2e−31			71.99	P19INK4D CDK4/6 INHIBITOR;	TUMOR SUPPRESSOR TUMOR
									CHAIN: NULL;	SUPPRESSOR, CDK4/6 INHIBITOR,
										ANKYRIN MOTIF
143	1blx	B	95	250	2.8e−31			71.23	CYCLIN-DEPENDENT KINASE	COMPLEX (INHIBITOR
									6; CHAIN: A; P19INK4D; CHAIN:	PROTEIN/KINASE) INHIBITOR
									B;	PROTEIN, CYCLIN-DEPENDENT
										KINASE, CELL CYCLE 2 CONTROL,
										ALPHA/BETA, COMPLEX (INHIBITOR
										PROTEIN/KINASE)
143	1bu9	A	91	255	4.2e−33			80.55	CYCLIN-DEPENDENT KINASE 6	HORMONE/GROWTH FACTOR P18-
									INHIBITOR; CHAIN: A;	INK4C; CELL CYCLE INHIBITOR,
										P18INK4C, TUMOR, SUPPRESSOR,
										CYCLIN-2 DEPENDENT KINASE,
										HORMONE/GROWTH FACTOR
143	1by2		1	113	8.4e−44			114.47	MAC-2 BINDING PROTEIN;	EXTRACELLULAR MODULE TUMOR-
									CHAIN: NULL;	ASSOCIATED ANTIGEN 90K;
										EXTRACELLULAR MODULE,
										SCAVENGER RECEPTOR, TUMOUR-
										ASSOCIATED 2 ANTIGEN,
										EXTEACELLULAR MATRIX,
										GLYCOSYLATED PROTEIN
143	1by2		711	824	7e−44			113.40	MAC-2 BINDING PROTEIN;	EXTRACELLULAR MODULE TUMOR-
									CHAIN: NULL;	ASSOCIATED ANTIGEN 90K;
										EXTRACELLULAR MODULE,
										SCAVENGER RECEPTOR, TUMOUR-
										ASSOCIATED 2 ANTIGEN,
										EXTRACELLULAR MATRIX,
										GLYCOSYLATED PROTRIN
143	1by2		714	822	7e−44	0.79	1.00		MAC-2 BINDING PROTEIN;	EXTRACELLULAR MODULE TUMOR-
									CHAIN: NULL;	ASSOCIATED ANTIGEN 90K;
										EXTRACELLULAR MODULE,
										SCAVENGER RECEPTOR, TUMOUR-
										ASSOCIATED 2 ANTIGEN,
										EXTRACELLULAR MATRIX,
										GLYCOSYLATED PROTEIN
143	1cru	A	217	709	1.4e−74			146.51	SOLUBLE QUINOPROTEIN	OXIDOREDUCTASE BETA-
									GLUCOSE DEHYDROGENASE;	PROPELLER, SUPERBARREL,
									CHAIN: A, B;	COMPLEX WITH THE COFACTOR PQQ
										2 AND THE INHIBITOR
										METHYLHYDRAZINE,
										OXIDOREDUCTASE
143	1cru	A	218	645	1.4e−74	0.34	0.92		SOLUBLE QUINOPROTEIN	OXIDOREDUCTASE BETA-
									GLUCOSE DEHYDROGENASE;	PROPELLER, SUPERBARREL,
									CHAIN: A, B;	COMPLEX WITH THE COFACTOR PQQ
										2 AND THE INHIBITOR
										METHYLHYDRAZINE,
										OXIDOREDUCTASE
143	1d9s	A	2	129	2.8e−07			51.72	CYCLIN-DEPENDENT KINASE4	SIGNALING PROTEIN HELIX-TURN-
									INHIBITOR B; CHAIN: A;	HELIX, ANKYRIN REPEAT
143	1ihb	A	96	246	4.2e−33			78.44	CYCLIN-DEPENDENTKINASE 6	CELL CYCLE INHIBITOR P18-
									INHIBITOR; CHAIN: A, B;	INK4C(INK6); CELL CYCLE
										INHIBITOR, P18-INK4C(INK6),
										ANKYRIN REPEAT, 2 CDK 4/6
										INHIBITOR
143	1ikn	D	95	296	2.8e−38			80.27	NP-KAPPA-B P65 SUBUNIT;	TRANSCRIPTION FACTOR P65; PSOD;
									CHAIN: A; NF-KAPPA-B P50D	TRANSCRIPTION FACTOR, IKB/NFKB
									SUBUNIT; CHAIN: C; I-KAPPA-	COMPLEX
									B-ALPHA; CHAIN: D;
143	1myo		127	244	1.3e−26			72.80	MYOTROPHIN; CHAIN: NULL	ANK-REPEAT MYOTROPHIN,
										ACETYLATION, NMR, ANK-REPEAT
143	1nfi	E	87	292	5.6e−38			75.42	NE-KAPPA-B P65; CHAIN: A, C;	COMPLEX (TRANSCRIPTION
									NF-KAPPA-B P50; CHAIN: B, D;	REG/ANK REPEAT) COMPLEX
									I-KAPPA-B-ALPHA; CHAIN: E, F;	(TRANSCRIPTION REGULATION/ANK
										REPEAT), ANKYRIN 2 REPEAT HELIX
146	1e9t	A	220	269	1 .3e−11	0.15	−1202.08		INTESTINAL TREFOIL FACTOR;	CELL MOTILITY FACTOR HITF;
									CHAIN: A;	INTESTINAL TREFOIL FACTOR,
										SOLUTION STRUCTURE, TREFOIL 2
										DOMAIN, NMR SPECTROSCOPY, CELL
										MOTILITY FACTOR
146	1hi7	A	222	275	7.5e−16	0.26	−1202.08		PS2 PROTEIN; CHAIN: A, B;	GROWTH FACTOR PNR-
										2,PS2,TFF1 ,BREAST CANCER
										ESTROGEN INDUCIBLE GROWTH
										FACTOR, CELL MOTILITY, TUMOR
										SUPPRESSOR, TREFOIL 2 DOMAIN,
										SIGNAL
146	2psp	A	223	269	1.5e−11	0.35	−1202.08		PORCINE PANCREATIC	TREFOIL FAMILY OF PEPTIDES PSP
									SPASMOLYTIC POLYPEPTIDE;	REPEAT, GROWTH FACTOR, SIGNAL
									CHAIN: A, B;
152	1aln	A	29	255	0	0.27	−1202.08	B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE) B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBILITY
										ANTIGEN, MIIC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGENIPEPTIDE)
152	1a6z	A	22	227	1.1e−68			53.05	HFE; CHAIN: A, C; BETA-2-	MHC CLASS I COMPLEX HFE,
									MICROGLOBULIN; CHAIN: B, D	HEREDITARY HEMOCHROMATOSIS,
										MHC CLASS I
152	1a6z	A	29	255	1.4e−68			59.25	HFE; CHAIN: A, C; BETA-2-	MHC CLASS I COMPLEX HFE,
									MICROGLOBULIN; CHAIN: B, D	HEREDITARY HEMOCHROMATOSIS,
										MHC CLASS I
152	1agd	A	29	255	0	0.36	−1202.08		B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHC
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILITY
									(GGKKKYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
152	1c16	A	29	255	2.8e−67			50.68	MHC-LIKE PROTEIN T22;	IMMUNE SYSTEM NON-CLASSICAL
									CHAIN: A, C, E, G; BETA-2-	MHC-LIKE, MAJOR
									MICROGLOBULIN; CHAIN: B, D,	HISTOCOMPATIBILITY, BETA2- 2
									F, H	MICROGLOBULIN
152	1d2v	C	118	585	0			522.22	MYELOPEROXIDASE; CHAIN:	OXIDOREDUCTASE HEME-PROTEIN,
									A, B; MYELOPEROXIDASE;	PEROXIDASE, OXIDOREDUCTASE,
									CHAIN: C, D;	PEROXIDASE-2 BROMIDE COMPLEX
152	1ed3	A	29	255	0	0.40	−1202.08		CLASS I MAJOR	IMMUNE SYSTEM MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX,
									ANTIGEN RTl-AA; CHAIN: A, D;	RAT MINOR 2 HISTOCOMPATIBILITY
									BETA-2-MICROGLOBULIN;	COMPLEX, MIC, IMMUNOLOGY,
									CHAIN: B, E; PEPTIDE MTF-E	PEPTIDE 3 ANTIGEN PRESENTATION,
									(13N3E); CHAIN: C, F;	CELLULAR IMMUNITY, CELL
										SURFACE 4 RECEPTOR, T CELL
										RECEPTOR LIGAND
152	1ed3	A	29	255	0			58.49	CLASS I MAJOR	IMMUNE SYSTEM MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX,
									ANTIGEN RTl-AA; CHAIN: A, D;	RAT MINOR 2 HISTOCOMPATIBILITY
									BETA-2-MICROGLOBULIN;	COMPLEX, MHC, IMMUNOLOGY,
									CHAIN: B, E; PEPTIDE MTF-E	PEPTIDE 3 ANTIGEN PRESENTATION,
									(13N3E); CHAIN: C, F;	CELLULAR IMMUNITY, CELL
										SURFACE 4 RECEPTOR, T CELL
										RECEPTOR LIGAND
152	1efx	A	29	255	0	0.44	−1020.08		HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
152	1efx	A	29	255	0			57.25	HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
152	1fzk	A	29	255	5.6e−98			58.77	H-2 CLASS I	IMMUNE SYSTEM SEV9; MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX
									ANTIGEN, K-B CHAIN: A;	PEPTIDE-MHC
									BETA-2-MICROGLOBULIN;
									CHAIN: B; NUCLEOCAPSID
									PROTEIN; CHAIN: P;
152	1hoc	A	29	255	2.8e−98			50.16	HISTOCOMPATIBILITY
									ANTIGEN MURINE CLASS I
									MAJOR HISTOCOMPATIBILITY
									COMPLEX CONSISTING 1HOC 3
									OF H-2D==B=, B2-
									MICROGLOBULIN, AND A9-
									RESIDUE PEPTIDE 1HOC 4
152	1hsa	A	29	255	0	0.24	−1202.08		HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN IHSA 3 /HLA-
									B(ASTERISK)2705$ 1HSA 4
152	1hsb	A	29	255	0	0.40	−1202.08		HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILIlIY
									ANTIGEN AW68.1 (LEUCOCYTE
									IHSB 3 ANTIGEN) 1HSB 4
152	1hsb	A	29	255	0			52.66	HISTOCOMPATIIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
152	1hyr	C	21	227	8.4e−55			52.26	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2 A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
152	1hyr	C	28	255	1.4e−53			67.13	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2 A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
152	1i4f	A	29	255	0	0.47	−1202.08		HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
152	1i4f	A	29	255	0			60.36	HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
152	11d9	A	29	254	0			56.90	MHC CLASS I H-2LD HEAVY	MAJOR HISTOCOMPATIBILITY
									CHAIN; CHAIN: A; BETA-2	COMPLEX LD; MAJOR
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY COMPLEX, LD
									NANO-PEPTIDE; CHATN: C;
152	11d9	A	29	255	0	0.20	−1202.08		MHC CLASS I H-2LD HEAVY	MAJOR HISTOCOMPATIBILITY
									CHAIN; CHAIN: A; BETA-2	COMPLEX LD; MAJOR
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY COMPLEX, LD
									NANO-PEPTIDE; CHAIN: C;
152	1qo3	A	30	255	0	0.46	−1202.08		MHC CLASS I H-2DD HEAVY	COMPLEX (NK RECEPTOR/MHC
									CHAIN; CHAIN: A; BETA-2-	CLASS 1)H-2 CLASS I
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY ANTIGEN,
									HIV ENVELOPE	B2M; NK-CELL SURFACE
									GLYCOPROTEIN 120 PEPTIDE;	GLYCOPROTEIN YE1/48, NK CELL,
									CHAIN: P; LY49A; CHAIN: C, D;	INHIBITORY RECEPTOR, MHC-I, C-
										TYPE LECTIN-LIKE, 2
										HISTOCOMPATIBILLTY, B2M, LY49,
										LY-49
152	1qo3	A	30	255	0			54.24	MHC CLASS I H-2DD HEAVY	COMPLEX (NK RECEPTOR/MHC
									CHAIN; CHAIN: A; BETA-2-	CLASS I) H-2 CLASS I
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY ANTIGEN,
									HIV ENVELOPE	B2M; NK-CELL SURFACE
									GLYCOPROTEIN 120 PEPTIDE;	GLYCOPROTEIN YE1/48, NK CELL,
									CHAIN: P; LY49A; CHAIN: C, D;	INHIBITORY RECEPTOR, MHC-I, C-
										TYPE LECTIN-LIKLE, 2
										HISTOCOMPATIBILITY, B2M, LY49,
										LY-49
152	1qqd	A	30	255	0	0.20	−1202.08		HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUXOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
152	1qqd	A	30	255	0			53.86	HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
152	1tmc	A	22	192	9.8e−79			68.60	HISTOCOMPATIBILITY
									ANTIGEN TRUNCATED HUMAN
									CLASS I HISTOCOMPATIBILFIY
									ANTIGEN HLA-AW68 1TMC 3
									COMPLEXED WITH A
									DECAMERIC PEPTIDE
									(EVAPPEYHRK) 1TMC 4
152	1zag	A	29	255	5.6e−62			55.36	ZINC-ALPHA-2-	LIPID MOBILIZATION FACTOR ZN-
									GLYCOPROTEIN; CHAIN: A, B,	ALPHA-2-GLYCOPROTEIN, ZAG LIPID
									C, D;	MOBILIZATION FACTOR, SECRETED
										MUC CLASS I HOMOLOG
154	1eqj	A	71	336	4.2e−29	0.11	−1202.08		PHOSPHOGLYCERATE	ISOMERASE ALPHAIBETA-TYPE
									MUTASE; CHAIN: A;	STRUCTURE
155	12e8	H	2	227	8.4e−09			59.62	2E8 (IGG1=KAPPA=)	IMMUNOGLOBULIN
									ANTIBODY; CHAIN: L, H, M, P;	IMMUNOGLOBULIN
155	1bih	A	29	376	1.1e−29			78.69	HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
155	1bih	A	30	346	1.1e−29	0.07	−1202.08		HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
155	1cs6	A	20	376	2.8e−35			85.17	AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
155	1cvs	D	122	302	7e−31	0.12	−1202.08		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
155	1cvs	D	37	208	2.8e−23	0.25	−1202.08		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
155	1dgi	R	12	303	9e−22			63.55	POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
155	1ev2	G	132	308	4.2e−30	0.09	−1202.08		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2; FGFR2;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG)LIKE
									FACTOR RECEPTOR 2; CHAIN:	DOMAINS BELONGING TO THE I-SET
									E, F, G, H;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
155	levt	C	37	208	2.8e−22	0.16	−1202.08	FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 1; CHAIN: A, B;	RECEPTOR FGF1; FGFR1;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG) LIKE
									FACTOR RECEPTOR 1; CHAIN:	DOMAINS BELONGING TO THE I-SET
									C, D;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
155	1f2q	A	121	308	8.4e−23	0.18	−1202.08	HIGH AFFINITY	IMMUNE SYSTEM PC-EPSILON RI-
									IMMUNOGLOBULIN EPSILON	ALPHA; IMMUNOGLOBULIN FOLD,
									RECEPTOR CHAIN: A;	GLYCOPROTEIN, RECEPTOR, IGE-
										BINDING 2 PROTEIN
155	1f2q	A	26	214	4.2e−28			66.45	HIGH AFFINITY	IMMUNE SYSTEM PC-EPSILON RI-
									IMMUNOGLOBULIN EPSILON	ALPHA; IMMUNOGLOBULIN FOLD,
									RECEPTOR CHAIN: A;	GLYCOPROTEIN, RECEPTOR, IGE-
										BINDING 2 PROTEIN
155	1f2q	A	28	214	4.2e−28	0.23	−1202.08		HIGH AFFINITY	IMMUNE SYSTEM FC-EPSILON RI-
									IMMUNOGLOBULIN EPSILON	ALPHA; IMMUNOGLOBULIN FOLD,
									RECEPTOR CHAIN: A;	GLYCOPROTEIN, RECEPTOR, IGE-
										BINDING 2 PROTEIN
155	1f42	A	21	325	1.2e−08			63.76	INTERLEUKIN-12 BETA CHAIN;	CYTOKINE CYTOKINE
									CHAIN: A;
155	1f6a	A	24	213	1.4e−29			75.69	HIGH AFFINITY	IMMUNE SYSTEM HIGH AFFINITY
									IMMUNOGLOBULIN EPSILON	IGE-FC RECEPTOR, FC(EPSILON) IGE-
									RECEPTOR CHAIN: A; IG	FC; IMMUNOGLOBULIN FOLD,
									EPSILON CHAIN C REGION;	GLYCOPROTEIN, RECEPTOR, IGE-
									CHAIN: B, D;	BINDING 2 PROTEIN, 1GB ANTIBODY,
										IGE-FC
155	1f6a	A	24	214	1.4e−29	0.42	−1202.08		HIGH AFFINITY	IMMUNE SYSTEM HIGH AFFINITY
									MMUNOGLOBULIN EPSILON	IGE-FC RECEPTOR, FC(EPSILON) IGE-
									RECEPTOR CHAIN: A; IG	FC; IMMUNOGLOBULIN FOLD,
									EPSILON CHAIN C REGION;	GLYCOPROTEIN, RECEPTOR, IGB-
									CHAIN: B, D;	BINDING 2 PROTEIN, IGE ANTIBODY,
										IGE-FC
155	1f8t	H	2	227	4.2e−08			66.69	ANTIBODY FAB FRAGMENT	IMMUNE SYSTEM MONOCLONAL
									(LIGHT CHAIN); CHAIN: L;	ANTIBODY, ANTIGEN-BINDING
									ANTIBODY FAB FRAGMENT	FRAGMENT, INTERLEUKIN-22, X-
									(HEAVY CHAIN); CHAIN: H	RAY ANALYSIS, CRYSTAL
155	1f97	A	101	309	1.4e−29			72.64	JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
155	1fcg	A	120	305	3e−23	0.14	−1202.08		FC RECEPTOR	IMMUNE SYSTEM, MEMBRANE
									FC(GAMMA)RIIA; CHAIN: A;	PROTEIN CD32; FC RECEPTOR,
										IMMUNOGLOULIN, LEUKOCYTE,
										CD32
155	1fcg	A	23	210	8.4e−28			78.62	FC RECEPTOR	IMMUNE SYSTEM, MEMBRANE
									FC(GAMMA)RIIA; CHAIN: A;	PROTEIN CD32; FC RECEPTOR,
										IMMUNOGLOULIN, LEUKOCYTE,
										CD32
155	1fu1	A	117	307	1.5e−23	0.05	−1202.08		LOW AFFINITY	IMMUNE SYSTEM RECEPTOR BETA
									IMMUNOGLOBULIN GAMMA	SANDWICH, IMMUNOGLOBULIN-
									FC REGION CHAIN: A;	LIKE, RECEPTOR
155	1fn1	A	22	211	7e−27			73.09	LOW AFFINITY	IMMUNE SYSTEM RECEPTOR BETA
									IMMUNOGLOBULIN GAMMA	SANDWICH, IMMUNOGLOBULIN-
									FC REGION CHAIN: A;	LIKE, RECEPTOR
155	1ful	A	28	212	7e−27	0.17	−1202.08		LOW AFFINITY	IMMUNE SYSTEM RECEPTOR BETA
									IMMUNOGLOBULIN GAMMA	SANDWICH, IMMUNOGLOBULIN-
									FC REGION CHAIN: A;	LIKE, RECEPTOR
155	1g0x	A	118	310	2.8e−22			72.43	LEUCOCYTE	IMMUNE SYSTEM LEUKOCYTE
									IMMUNOGLOBULIN-LIKE	INHIBITORY RECEPTOR-1;
									RECEPTOR-1; CHAIN: A;	LEUKOCYTE IMMUNOGLOBULIN
										FOLD, 3-10 HELIX
155	1g0x	A	120	297	9e−22	0.18	−1202.08		LEUCOCYTE	IMMUNE SYSTEM LEUKOCYTE
									IMMUNOGLOBULIN-LIKE	INHIBITORY RECEPTOR-1;
									RECEPTOR-1; CHAIN: A;	LEUKOCYTE IMMUNOGLOBULIN
										FOLD, 3-10 HELIX
155	1g0x	A	120	306	2.8e−22	0.21	−1020.08		LEUCOCYTE	IMMUNE SYSTEM LEUKOCYTE
									IMMUNOGLOBULIN-LIKE	INHIBITORY RECEPTOR-1;
									RECEPTOR-1; CHAIN: A;	LEUKOCYTE IMMUNOGLOBULIN
										FOLD, 3-10 HELIX
155	1gOx	A	28	210	5.6e−26	0.21	−1020.08		LEUCOCYTE	IMMUNE SYSTEM LEUKOCYTE
									IMMUNOGLOBULIN-LIKE	INHIBITORY RECEPTOR-1;
									RECEPTOR-1; CHAIN: A;	LEUKOCYTE IMMUNOGLOBULIN
										FOLD, 3-10 HELIX
155	1igy	B	3	376	8.4e−09			65.38	IGG1 INTACT ANTIBODY	IMMUNOGLOBULIN INTACT
									MAB61.1.3; CHAIN: A, B, C, D	IMMUNOGLOBULIN, V REGION, C
										REGION, HINGE REGION
155	1mco	H	2	376	5.6e−10			74.55	IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION IMCO 3
155	1nkr		29	211	9.8e−26	0.21	−1202.08		P58-CL42 KIR; CHAIN: NULL;	INHIBITORY RECEPTOR KILLER CELL
										INHIBITORY RECEPTOR; INHIBITORY
										RECEPTOR, NATURAL KILLER CELLS,
										IMMUNOLOGICAL 2 RECEPTORS,
										IMMUNOGLOBULIN FOLD
155	1nkr		31	211	5.6e−33			71.40	P58-CL42 KIR; CHAIN: NULL;	INHIBITORY RECEPTOR KILLER CELL
										INHIBITORY RECEPTOR; INHIBITORY
										RECEPTOR, NATURAL KILLER CELLS,
										IMMUNOLOGICAL 2 RECEPTORS,
										IMMUNOGLOBULIN FOLD
155	2dli	A	119	304	2.8e−32	0.16	−1202.08		MHC CLASS INK CELL	IMMUNE SYSTEM P58 NATURAL
									RECEPTOR PRECURSOR;	KILLER CELL RECEPTOR; KIR,
									CHAIN: A;	NATURAL KILLER RECEPTOR,
										INHIBITORY RECEPTOR, 2
										IMMUNOGLOBULIN
155	2dli	A	216	331	9.8e−09	0.06	−1202.08		MHC CLASS INK CELL	IMMUNE SYSTEM P58 NATURAL
									RECEPTOR PRECURSOR;	KILLER CELL RECEPTOR; KIR,
									CHAIN: A;	NATURAL KILLER RECEPTOR,
										INHIBITORY RECEPTOR, 2
										IMMUNOGLOBULIN
155	2dli	A	29	210	1.1e−24	0.43	−1202.08		MHC CLASS INK CELL	IMMUNE SYSTEM P58 NATURAL
									RECEPTOR PRECURSOR;	KILLER CELL RECEPTOR; KIR,
									CHAIN: A;	NATURAL KILLER RECEPTOR,
										INHIBITORY RECEPTOR, 2
										IMMUNOGLOBULIN
155	2dli	A	31	213	2.8e−32			74.62	MHC CLASS I NK CELL	IMMUNE SYSTEM P58 NATURAL
									RECEPTOR PRECURSOR;	KILLER CELL RECEPTOR; KIR,
									CHAIN: A;	NATURAL KILLER RECEPTOR,
										INHIBITORY RECEPTOR, 2
										IMMUNOGLOBULIN
155	2fcb	A	120	306	3e−23	0.14	−1202.08		FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										PC, CD32, IMMUNE SYSTEM
155	2fcb	A	23	214	1.4e−29			81.15	FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										PC, CD32, IMMUNE SYSTEM
155	2fcb	A	24	213	1.4e−29	0.12	−1202.08		FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										FC, CD32, IMMUNE SYSTEM
155	2nmb	A	1	141	5.6e−33			52.09	NUMB PROTEIN; CHAIN: A;	CELL CYCLE/GENE REGULATION
									GPPY PEPTIDE; CHAIN: B;	COMPLEX, SIGNAL TRANSDUCTION,
										PHOSPHOTYROSINE BINDING 2
										DOMAIN (PTB), ASYMETR IC CELL
										DIVISION
155	32c2	B	2	225	9.8e−09			60.00	IGG1 ANTIBODY 32C2; CHAIN:	IMMUNE SYSTEM FAB, ANTIBODY,
									A; IGG1 ANTIBODY 32C2;	AROMATASE, P450
									CHAIN: B;
156	1hx2	A	8	64	2.8e−16			54.02	BSTI; CHAIN: A;	HYDROLASE INHIBITOR BOMBINA
										SKIN TRYPSIN INHIBITOR BETA-
										SHEET DISULFIDE-RICH
158	1b6c	B	1	299	0			340.18	FK506-BINDING PROTEIN;	COMPLEX (ISOMERASE/PROTEIN
									CHAIN: A, C, E, G; TGF-B	KINASE) EKEP 12;
									SUPERFAMILY RECEPTOR	SERINE/THREONINE-PROTEIN
									TYPE I; CHAIN: B, D, F, H;	KINASE RECEPTOR R4; COMPLEX
										(ISOMERASE/PROTEIN KINASE),
										RECEPTOR 2 SERINE/THREONINE
										KINASE
158	1b6c	B	253	586	0			351.53	FK506-BINDING PROTEIN;	COMPLEX (ISOMERASE/PROTEIN
									CHAIN: A, C, E, G; TGF-B	KINASE) FKBP12;
									SUPERFAMILY RECEPTOR	SERINE/THREONINE-PROTEIN
									TYPE I; CHAIN: B, D, F, H;	KINASE RECEPTOR R4; COMPLEX
										(ISOMERASE/PROTEIN KINASE),
										RECEPTOR 2 SERINE/THREONINE
										KINASE
158	1b6c	B	264	581	0	0.64	−1202.08		FK506-BINDING PROTEIN;	COMPLEX (ISOMERASE/PROTEIN
									CHAIN: A, C, E, G; TGF-B	KINASE) FKBP 12;
									SUPERFAMILY RECEPTOR	SERINE/THREONINE-PROTEIIN
									TYPE I; CHAIN: B, D, F, I-I;	KINASE RECEPTOR R4; COMPLEX
										(ISOMERASE/PROTEIN KIN ASE),
										RECEPTOR 2 SERINE/THREONINE
										KINASE
158	1es7	B	33	108	1.4e−12	0.14	−1202.08	BONE MORPHOGENETIC	CYTOKINE BMP-2; ALK-3; PROTEIN-
									PROTEIN-2; CHAIN: A, C; BONE	PROTEIN COMPLEX, THREE FINGER
									MORPHOGENETIC PROTEIN	TOXIN FOLD, RECEPTOR-2 LIGAND
									RECEPTOR 1A; CHAIN: B, D;	COMPLEX, CYTOKINE RECEPTOR,
										TGF BETA SUPERFAMILY
160	1aln	A	24	299	0			166.47	B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE)B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBLLITY
										ANTIGEN, MHC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGEN/PEPTIDE)
160	1aln	A	26	298	0	0.49	−1202.08		B*3501; CHAIN: A, B; PEPTIDE	COMPLEX (ANTIGEN/PEPTIDE)B35;
									VPLRPMTY; CHAIN: C;	MAJOR HISTOCOMPATIBILITY
										ANTIGEN, MHC, HLA, HLA-B3501,
										HIV, 2 NEF, COMPLEX
										(ANTIGEN/PEPTIDE)
160	1agd	A	24	299	0			169.42	B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHC
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILITY
									(GGKKKYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
160	1agd	A	26	298	0	0.41	−1202.08		B*0801; CHAIN: A; BETA-2	HISTOCOMPATIBILITY COMPLEX B8;
									MICROGLOBULIN; CHAIN: B;	B2M; PEPTIDE HLA B8, HIV, MHC
									HIV-1 GAG PEPTIDE	CLASS I, HISTOCOMPATIBILITY
									(GGKKKYKL-INDEX	COMPLEX
									PEPTIDE); CHAIN: C;
160	1c16	A	24	299	5.6e−89			139.27	MHC-LIKE PROTEIN T22;	IMMUNE SYSTEM NON-CLASSICAL
									CHAIN: A, C, E, G; BETA-2-	MHC-LIKE, MAJOR
									MICROGLOBULIN; CHAIN: B, D,	HISTOCOMPATIBILITY, BETA2- 2
									F, H	MICROGLOBULIN
160	1ed3	A	24	300	0			157.88	CLASS I MAJOR	IMMUNE SYSTEM MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX,
									ANTIGEN RT1-AA; CHAIN: A, D;	RAT MINOR 2 HISTOCOMPATIBILITY
									BETA-2MICROGLOBULIN;	COMPLEX, MHC, IMMUNOLOGY,
									CHAIN: B, E; PEPTIDE MTF-E	PEPTIDE 3 ANTIGEN PRESENTATION,
									(13N3E); CHAIN: C, F;	CELLULAR IMMUNITY, CELL
										SURFACE 4 RECEPTOR, T CELL
										RECEPTOR LIGAND
160	1ed3	A	26	298	0	0.52	−1202.08		CLASS I MAJOR	IMMUNE SYSTEM MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX,
									ANTIGEN RT1-AA; CHAIN: A, D;	RAT MINOR 2 HISTOCOMPATIBILITY
									BETA-2-MICROGLOBULIN;	COMPLEX, MHC, IMMUNOLOGY,
									CHAIN: B, E; PEPTIDE MTF-E	PEPTIDE 3 ANTIGEN PRESENTATION,
									(13N3E); CHAIN: C, F;	CELLULAR IMMUNITY, CELL
										SURFACE 4 RECEPTOR, T CELL
										RECEPTOR LIGAND
160	1efx	A	24	300	0			163.46	HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
160	1efx	A	26	298	0	0.64	−1202.08		HLA-CW3 (HEAVY CHAIN);	IMMUNE SYSTEM MHC, HLA, CLASS
									CHAIN: A; BETA-2-	I, KIR, NK CELL RECEPTOR,
									MICROGLOBULIN; CHAIN: B;	IMMUNOGLOBULIN 2 FOLD,
									PEPTIDE FROM IMPORTIN	RECEPTOR/MHC COMPLEX
									ALPHA-2; CHAIN: C; NATURAL
									KILLER CELL RECEPTOR
									KIR2DL2; CHAIN: D, E;
160	1fzk	A	24	296	0			167.88	H-2 CLASS I	IMMUNE SYSTEM SEV9; MAJOR
									HISTOCOMPATIBILITY	HISTOCOMPATIBILITY COMPLEX
									ANTIGEN, K-B CHAIN: A;	PEPTIDE-MHC
									BETA-2-MICROGLOBULIN.
									CHAIN: B; NUCLEOCAPSID
									PROTEIN; CHAIN: P;
160	1hoc	A	24	295	0			172.82	HISTOCOMPATIBILITY
									ANTIGEN MURINE CLASS I
									MAJOR HISTOCOMPATIBILITY
									COMPLEX CONSISTING 1HOC 3
									OF H-2D═B═, B2-
									MICROGLOBULIN, AND A 9-
									RESIDUE PEPTIDE 1HOC 4
160	1hsa	A	24	299	0			167.79	HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN 1HSA 3 /HLA-
									B(ASTERISK)2705$ 1HSA 4
160	1hsa	A	26	298	0	0.49	−1202.08		HISTOCOMPATIBILITY
									ANTIGEN HUMAN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN 1HSA 3 /HLA-
									B ASTERISK 2705$ 1HSA 4
160	1hsb	A	24	293	0			166.59	HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
160	1hsb	A	26	293	0	0.46	−1202.08		HISTOCOMPATIBILITY
									ANTIGEN CLASS I
									HISTOCOMPATIBILITY
									ANTIGEN AW68.1 (LEUCOCYTE
									1HSB 3 ANTIGEN) 1HSB 4
160	1hyr	C	10	193	2.8e−53			236.94	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2 A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
160	1hyr	C	23	297	6e−93			439.85	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
160	1i4f	A	24	298	0			168.36	HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
160	1i4f	A	26	298	0	0.49	−1202.08		HLA CLASS I	IMMUNE SYSTEM MAGE-4 ANTIGEN;
									HISTOCOMPATIBILITY	MAJOR HISTOCOMPATIBILITY
									ANTIGEN, A-2 CHAIN: A; BETA-	COMPLEX, HUMAN LEUKOCYTE
									2-MICROGLOBULIN; CHAIN: B;	ANTIGEN, 2 MELANOMA-
									MELANOMA-ASSOCIATED	ASSOCIATED ANTIGEN
									ANTIGEN 4; CHAIN: C;
160	11d9	A	24	291	0			166.41	MHC CLASS I H-2LD HEAVY	MAJOR HISTOCOMPATIBILITY
									CHAIN; CHAIN: A; BETA-2	COMPLEX LD; MAJOR
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY COMPLEX, LD
									NANO-PEPTIDE; CHAIN: C;
160	1mhc	A	24	299	0			156.53	MHC CLASS I ANTIGEN H2-M3;	HISTOCOMPATIBILITY
									1MHC 6 CHAIN: A, B, D, E;	ANTIGEN/PEPTIDE MAJOR
									1MHC 7 NONAPEPTIDE FROM	HISTOCOMPATIBILITY COMPLEX;
									RAT NADH DEHYDROGENASE;	1MHC 8 ND1; 1MHC 15
									1MHC 12 CHAIN: C, F; 1MHC 13
160	1mhe	A	25	296	0			170.11	HLA CLASS I	MAJOR HISTOCOMPATIBILITY
									HISTOCOMPATIBILITY	COMPLEX MHC NONCLASSICAL
									ANTIGEN HLA-E; CHAIN: A, C;	CHAIN, MHC-E, HLA-E, MHC CLASS
									BETA-2-MICROGLOBULIN;	HLA-E, HLAE, MAJOR
									CHAIN: B, D; PEPTIDE	HISTOCOMPATIBILITY COMPLEX,
									(VMAPRTVLL); CHAIN: P, Q;	MHC, HLA, 2 BETA 2
										MICROGLOBULIN, PEPTIDE, LEADER
										PEPTIDE, 3 NON-CLASSICAL MHC,
										CLASS LB MHC
160	1mhe	A	26	297	0	0.53	−1202.08		HLA CLASS I	MAJOR HISTOCOMPATIBILITY
									HISTOCOMPATIBILITY	COMPLEX MHC NONCLASSICAL
									ANTIGEN LILA-B; CHAIN: A, C;	CHAIN, MHC-E, HLA-E, MHC CLASS
									BETA-2-MICROGLOBULIN;	HLA-E, HLA E, MAJOR
									CHAIN: B, D; PEPTIDE	HISTOCOMPATIBILITY COMPLEX,
									(VMAPRTVLL); CHAIN: P, Q;	MHC, HLA, 2 BETA 2
										MICROGLOBULIN, PEPTIDE, LEADER
										PEPTIDE, 3 NON-CLASSICAL MHC,
										CLASS IB MHC
160	1qo3	A	25	298	0			177.20	MHC CLASS I H-2DD HEAVY	COMPLEX (NK RECEPTOR/MHC
									CHAIN; CHAIN: A; BETA-2-	CLASS I) H-2 CLASS I
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY ANTIGEN,
									HIV ENVELOPE	B2M; NK-CELL SURFACE
									GLYCOPROTEIN 120 PEPTIDE;	GLYCOPROTEIN YE1/48, NK CELL,
									CHAIN: P; LY49A; CHAIN: C, D;	INHIBITORY RECEPTOR, MHC-I, C-
										TYPE LECTIN-LIKE, 2
										HISTOCOMPATIBILITY, B2M, LY49,
										LY-49
160	1qo3	A	26	298	0	0.42	−1202.08		MHC CLASS I H-2DD HEAVY	COMPLEX (NK RECEPTOR/MHC
									CHAIN; CHAIN: A; BETA-2-	CLASS I) H-2 CLASS I
									MICROGLOBULIN; CHAIN: B;	HISTOCOMPATIBILITY ANTIGEN,
									HIV ENVELOPE	B2M; NK-CELL SURFACE
									GLYCOPROTEIN 120 PEPTIDE;	GLYCOPROTEIN YE1/48, NK CELL,
									CHAIN: P; LY49A; CHAIN: C, D;	INHIBITORY RECEPTOR, MHC-I, C-
										TYPE LECTIIN-LIKE, 2
										HISTOCOMPATIBILITY, B2M, LY49,
										LY-49
160	1qqd	A	25	296	0			173.19	HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
160	1qqd	A	26	297	0	0.43	−1202.08		HISTOCOMPATIBILITY	IMMUNE SYSTEM
									LEUKOCYTE ANTIGEN (HLA)-	IMMUNOGLOBULIN (IG)-LIKE
									CW4 CHAIN: A; BETA-2	DOMAIN, ALPHA HELIX, BETA
									MICROGLOBULIN; CHAIN: B;	SHEET, 2 IMMUNE SYSTEM
									HLA-CW4 SPECIFIC PEPTIDE;
									CHAIN: C;
160	1tmc	A	11	185	8.4e−80			83.62	HISTOCOMPATIBILITY
									ANTIGEN TRUNCATED HUMAN
									CLASS I HISTOCOMPATIBILITY
									ANTIGEN HLA-AW68 1TMC 3
									COMPLEXED WITH A
									DECAMERIC PEPTIDE
									(EYAPPEYHRK) 1TMC 4
160	2fb4	H	212	305	1.1e−07	0.84	−1202.08		IMMUNOGLOBULIN
									IMMUNOGLOBULIN FAB 2FB4
									4
160	2fgw	H	186	305	4.2e−08	0.18	−1202.08	IMMUNOGLOBULIN FAB
									FRAGMENT OF A HUMANIZED
									VERSION OF THE ANTI-CD 18
									2FGW 3 ANTIBODY ‘H52’
									(HUH52-OZ FAB) 2FGW 4
176	1aox	A	356	548	4.2e−32	0.32	0.96		INTEGRIN ALPHA 2 BETA;	INTEGRIN INTEGRIN, CELL
									CHAIN: A, B;	ADHESION, GLYCOPROTEIN
176	1atz	A	358	516	4.2e−12	0.23	0.81		VON WILLEBRAND FACTOR;	COLLAGEN-BINDING COLLAGEN-
									CHAIN: A, B;	BINDING, HEMOSTASIS,
										DINUCLEOTIDE BINDING FOLD
176	1auq		345	552	4.2e−54	0.16	0.16		A1 DOMAIN OF VON	WILLEBRAND WILLEBRAND, BLOOD
									WILLEBRAND FACTOR; CHAIN:	COAGULATION, PLATELET,
									NULL;	GLYCOPROTEIN
176	1ck4	A	361	545	1.4e−31	0.37	0.42		INTEGRIN ALPHA-1; CHAIN: A,	STRUCTURAL PROTEIN I-DOMAIN,
									B;	METAL BINDING, COLLAGEN,
										ADHESION
176	1dzi	A	358	534	3.4e−14	0.10	0.55		INTEGRIN; CHAIN: A;	INTEGRIN INTEGRIN, COLLAGEN
									COLLAGEN; CHAIN: B, C, D;
176	1dzi	A	361	534	1.4e−28	0.23	1.00		INTEGRIN; CHAIN: A;	INTEGRIN INTEGRIN, COLLAGEN
									COLLAGEN; CHAIN: B, C, D;
176	1fns	A	355	549	7e−51	0.29	0.49		IMMUNOGLOBULIN NMC-4	IMMUNE SYSTEM VON WILLEBRAND
									IGG1; CHAIN: L;	FACTOR, GLYCOPROTEIN IBA
									IMMUNOGLOBULIN NMC-4	(A:ALPHA) BINDING, 2 COMPLEX
									IGG1; CHAIN: H; VON	(WILLEBRAND/IMMUNOGLOBULIN),
									WILLEBRAND FACTOR; CHAIN:	BLOOD COAGULATION TYPE 3 2B
									A;	VON WILLEBRAND DISEASE
176	1ido		361	542	4.2e−35	0.13	0.48		INTEGRIN; CHAIN: NULL;	CELL ADHESION PROTEIN A-DOMAIN
										INTEGRIN, CELL ADHESION
										PROTEIN, GLYCOPROTEIN,
										EXTRACELLULAR 2 MATRIX,
										CYTOSKELETON
176	1lfa	A	361	547	7e−32	−0.04	0.46		CD11A; 1LFA 5 CHAIN: A, B;	CELL ADHESION LFA-1, ALPHA-
									1LFA 6	L\, BETA-2 INTEGRIN, A-DOMAIN;
										1LFA 8
176	1qc5	A	361	543	5.6e−30	0.33	0.77		ALPHA1 BETA1 INTEGRIN;	CELL ADHESION INTEGRIN, CELL
									CHAIN: A; ALPHAI BETA1	ADHESION
									INTEGRIN; CHAIN: B;
177	1ciu		6	675	1.4e−77			82.96	CYCLODEXTRIN	GLYCOSIDASE CGTASE; 1CIU 8
									GLYCOSYLTRANSFERASE;	THERMOSTABLE 1CIU 14
									1CIU 6 CHAIN: NULL; 1CIU 7
177	1e43	A	9	484	9.8e−17			79.59	ALPHA-AMYLASE; CHAIN: A;	HYDROLASE HYDROLASE,
										AMYLASE, FAMILY 13
177	1gcy	A	1	397	5.6e−18			74.07	GLUCAN 1,4-ALPHA-	HYDROLASE BETA-ALPHA-BARREL,
									MALTOTETRAHYDROLASE;	BETA SHEET
									CHAIN: A;
177	1hx0	A	5	488	5.6e−43			66.82	ALPHA AMYLASE (PPA);	HYDROLASE ALPHA-AMYLASE,
									CHAIN: A;	INHIBITOR, CARBOHYDRATE,
										PANCREAS
177	1qho	A	12	671	4.2e−70			81.19	ALPHA-AMYLASE; CHAIN: A;	HYDROLASE “MALTOGENIC” ALPHA
										AMYLASE; AMYLASE, GLYCOSIDE
										HYDROLASE, STARCH
										DEGRADATION
177	1uok		110	675	0			90.36	OLIGO-1,6-GLUCOSIDASE;	GLUCOSIDASE GLUCOSIDASE,
									CHAIN: NULL;	SUGAR DEGRADATION, HIYDROLASE,
										TIM-BARREL 2 GLYCOSIDASE,
										HYDROLASE
177	1uok		7	543	0			74.70	OLIGO-1,6-GLUCOSIDASE;	GLUCOSIDASE GLUCOSIDASE,
									CHAIN: NULL;	SUGAR DEGRADATION, HYDROLASE,
										TIM-BARREL 2 GLYCOSIDASE,
										HYDROLASE
179	1aab		675	754	1.4e−17	0.90	1.00		HIGH MOBILITY GROUP	DNA-BINDING HMGA DNA-BINDING
									PROTEIN; 1AAB 5 CHAIN:	HMG-BOX DOMAIN A OF RAT HMG1;
									NULL; 1AAB 6	1AAB 8 HMG-BOX 1AAB 20
179	1aab		676	754	1.7e−23	0.83	1.00		HIGH MOBILITY GROUP	DNA-BINDING HMGA DNA-BINDING
									PROTEIN; 1AAB 5 CHAIN:	HMG-BOX DOMAIN A OF RAT HMG1;
									NULL; 1AAB 6	1AAB 8 HMG-BOX 1AAB 20
179	1cg7	A	669	751	4.2e−25	0.51	1.00		NON HISTONE PROTEIN 6 A;	DNA BINDING PROTEIN HMG BOX,
									CHAIN: A;	DNA BENDING, DNA RECOGNITION,
										CHROMATIN, NMR, DNA 2 BINDING
										PROTEIN
179	1ckt	A	680	748	1.4e−14	0.29	1.00		HIGH MOBILITY GROUP 1	GENE REGULATION/DNA HMG-1,
									PROTEIN; CHAIN: A; DNA (5′-	AMPHOTERIN, HEPARIN-BINDING
									D(*CP*CP*(IDO) CHAIN: B; DNA	PROTEIN P30; HIGH-MOBILITY
									(5′-CHAIN: C;	GROUP DOMAIN, BENT DNA,
										PROTEIN-DRUG-DNA 2 COMPLEX,
										GENE REGULATION/DNA
179	1ckt	A	681	748	3.4e−20	0.47	1.00		HIGH MOBILITY GROUP 1	GENE REGULATION/DNA HMG-1,
									PROTEIN; CHAIN: A; DNA (5′-	AMPHOTERIN, HEPARIN-BINDING
									D(*CP*CP*(IDO) CHAIN: B; DNA	PROTEIN P30; HIGH-MOBILITY
									(5′-CHAIN: C;	GROUP DOMAIN, BENT DNA,
										PROTEIN-DRUG-DNA 2 COMPLEX,
										GENE REGULATION/DNA
179	1hme		676	751	5.6e−29	0.50	1.00		DNA-BINDING HIGH MOBILITY
									GROUP PROTEIN FRAGMENT-B
									(HMGB) (DNA-BINDING 1HME 3
									HMG-BOX DOMAIN B OF RAT
									HMG1) (NMR, 1 STRUCTURE)
									1HME4
179	1hsm		679	752	2.8e−27	0.68	1.00		DNA-BINDING HIGH MOBILITY
									GROUP PROTEIN 1 (HMG1) BOX
									2, COMPLEXED WITH 1HSM 3
									MERCAPTOETHANOL (NMR,
									MINIMIZED AVERAGE
									STRUCTURE) 1HSM 4
179	1qrv	A	678	752	1.4e−17	0.65	1.00		DNA 5′-	GENE REGULATION/DNA HMG-D;
									D(*GP*CP*GP*AP*TP*AP*TP*C	PROTEIN-DNA COMPLEX, HMG
									P*GP*C)-3~); CHAIN: C, D; HIGH	DOMAIN, NON-SEQUENCE SPECIFIC 2
									MOBILITY GROUP PROTEIN D;	CHROMOSOMAL PROTEIN HMG-D
									CHAIN: A, B;
180	1d5s	B	342	382	5.6e−13			61.26	P1-ARG ANTIThYPSIN; CHAIN:	HYDROLASE INHIBITOR SERPIN
									A; P1-ARG ANTITRYPSIN;	FOLD, RCL CLEAVAGE, A BETA
									CHAIN: B;	SHEET POLYMERISATION
180	1d5s	B	646	686	1.2e−14	−0.81	0.75		P1-ARG ANTITRYPSIN; CHAIN:	HYDROLASE INHIBITOR SERPIN
									A; P1-ARG ANTITRYPSIN;	FOLD, RCL CLEAVAGE, A BETA
									CHAIN: B;	SHEET POLYMERISATION
180	1d5s	B	646	686	9.8e−13	−0.81	0.75		P1-ARG ANTITRYPSIN; CHAIN:	HYDROLASE INHIBITOR SERPIN
									A; PI-ARG ANTITRYPSIN;	FOLD, RCL CLEAVAGE, A BETA
									CHAIN: B;	SHEET POLYMERISATION
180	1ezx	A	12	346	0			370.31	ALPHA-1-ANTITRYPSIN;	HYDROLASE/HYDROLASE INHIBITOR
									CHAIN: A; ALPHA-1-	PROTEASE-INHIBITOR COMPLEX,
									ANTITRYPSIN; CHAIN: B;	SERPIN, ALPHA-1-ANTITRYPSIN, 2
									TRYPSIN; CHAIN: C;	TRYPSIN
180	1ezx	A	316	650	0			366.89	ALPHA-1-ANTITRYPSIN;	HYDROLASE/HYDROLASE INHIBITOR
									CHAIN: A; ALPHA-1-	PROTEASE-INHIBITOR COMPLEX,
									ANTITRYPSIN; CHAIN: B;	SERPIN, ALPHA-1-ANTITRYPSIN, 2
									TRYPSIN; CHAIN: C;	TRYPSIN
180	1ezx	A	317	650	0	0.69	1.00		ALPHA-1-ANTITRYPSIN;	HYDROLASE/HYDROLASE INHIBITOR
									CHAIN: A; ALPHA-1-	PROTEASE-INHIBITOR COMPLEX,
									ANTITRYPSIN; CHAIN: B;	SERPIN, ALPHA-1-ANTITRYPSIN, 2
									TRYPSIN; CHAIN: C;	TRYPSIN
180	1ezx	B	651	686	1.1e−11	−0.78	0.30		ALPHA-1-ANTITRYPSIN;	HYDROLASE/HYDROLASE INHIBITOR
									CHAIN: A; ALPHA-1-	PROTEASE-INHIBITOR COMPLEX,
									ANTITRYPSIN; CHAIN: B;	SERPIN, ALPHA-1-ANTITRYPSIN, 2
									TRYPSIN; CHAIN: C;	TRYPSIN
180	1ezx	B	651	686	3.4e−12	−0.78	0.30		ALPHA-1-ANTITRYPSIN;	HYDROLASE/HYDROLASE INHIBITOR
									CHAIN: A; ALPHA-1-	PROTEASE-INHIBITOR COMPLEX,
									ANTITRYPSIN; CHAIN: B;	SERPIN, ALPHA-1-ANTITRYPSIN, 2
									TRYPSIN; CHAIN: C;	TRYPSIN
180	1qlp	A	11	382	0			424.42	ALPHA-1-ANTITRYPSIN;	SERINE PROTEASE INHIBITOR
									CHAIN: A;	ALPHA-1-PROTEINASE INHIBITOR,
										ALPHA-1-ANTIPROTEINASE; SERINE
										PROTEASE INHIBITOR, SERPIN,
										GLYCOPROTEIN, SIGNAL, 2
										POLYMORPHISM, EMPHYSEMA,
										DISEASE MUTATION, ACUTE PHASE
180	1glp	A	315	686	0			424.95	ALPHA-1-ANTITRYPSTN;	SERINE PROTEASE INHIBITOR
									CHAIN: A;	ALPHA-1-PROTEINASB INHIBITOR,
										ALPHA-1-ANTIPROTEINASE; SERINE
										PROTEASE INHIBITOR, SERPIN,
										GLYCOPROTEIN, SIGNAL, 2
										POLYMORPHISM, EMPHYSEMA,
										DISEASE MUTATION, ACUTE PHASE
180	1qlp	A	317	686	0	0.82	1.00		ALPHA-1-ANTITRYPSIN;	SERINE PROTEASE INHIBITOR
									CHAIN: A;	ALPHA-1-PROTEINASE INHIBITOR,
										ALPHA-1-ANTIPROTEINASE; SERINE
										PROTEASE INHIBITOR, SERPIN,
										GLYCOPROTEIN, SIGNAL, 2
										POLYMORPHISM, EMPHYSEMA,
										DISEASE MUTATION, ACUTE PHASE
180	1qmb	B	341	382	1.4e−12			61.02	ALPHA-1-ANTITRYPSIN;	SERINE PROTEASE INHIBITOR
									CHAIN: A, B;	ALPHA-1-PROTEINASE INHIBITOR,
										ALPHA-1-PI; SERPIN, ANTITRYPSIN,
										POLYMER, CLEAVED
180	1qmb	B	645	686	2.8e−12	−0.81	0.90		ALPHA-1-ANTITRYPSIN;	SERINE PROTEASE INHIBITOR
									CHAIN: A, B;	ALPHA-1-PROTEINASE INHIBITOR,
										ALPHA-1-PI; SERPIN, ANTITRYPSIN,
										POLYMER, CLEAVED
180	1qmb	B	645	686	5.1e−14	−0.81	0.90		ALPHA-1-ANTITRYPSIN;	SERINE PROTEASE INHIBITOR
									CHAIN: A, B;	ALPHA-1-PROTEINASE INHIBITOR,
										ALPHA-1-PI; SERPIN, ANTITRYPSIN,
										POLYMER, CLEAVED
181	1a0j	A	330	536	1.4e−69	0.19	0.65		TRYPSIN; CHAIN: A, B, C, D;	SERINE PROTEASE SERINE
										PROTEINASE, TRYPSIN, HYDROLASE
181	1a01	A	330	530	1.4e−67	0.07	0.76		BETA-TRYPTASE; CHAIN: A, B,	SERINE PROTELNASE TRYPSIN-LIKE
									C, D;	SERINE PROTEINASE, TETRAMER,
										HEPARIN, ALLERGY, 2 ASTHMA
181	1bru	P	330	536	2.8e−69	0.21	0.49		ELASTASE; CHAIN: P;	SERINE PROTEASE PPE; SERINE
										PROTEASE, HYDROLASE
181	1ddj	A	328	536	7e−70	0.32	0.93		PLASMINOGEN; CHAIN: A, B, C,	BLOOD CLOTTING PLASMINOGEN,
									D;	CATALYTIC DOMAIN
181	1dle	A	339	430	2.8e−17	0.39	−0.09		COMPLEMENT FACTOR B;	HYDROLASE SERINE PROTEASE,
									CHAIN: A, B;	COMPLEMENT SYSTEM, FACTOR B,
										PROTEIN-2 PROTEIN INTERACTION,
										ACTIVATION MECHANISM, BETA-
										BARREL FOLD,
181	1dle	A	476	534	1.3e−07	−0.21	0.21		COMPLEMENT FACTOR B;	HYDROLASE SERINEPROTEASE,
									CHAIN: A, B;	COMPLEMENT SYSTEM, FACTOR B,
										PROTEIN-2PROTEIN INTERACTION,
										ACTIVATION MECHANISM, BETA-
										BARREL FOLD,
181	1elv	A	352	497	0.0034	0.17	0.89		COMPLEMENT C1S	HYDROLASETRYPSIN-LIKE SERIN
									COMPONENT; CHAIN: A;	PROTEASE, CCP (OR SUSHI OR
										SCR)MODULE
181	1f7z	A	330	536	1.4e−67	0.34	0.95		TRYPSIN II, ANIONIC; CHAIN:	HYDROLASE/HYDROLASE INHIBITOR
									A; PANCREATIC TRYPSIN	BPTISERINE PROTEASE, TRYPSIN
									INHIBITOR; CHAIN: I;	PRECURSOR
181	1fn8	A	331	497	0.0017	0.66	0.84		TRYPSIN; CHAIN: A; GLY-ALA-	HYDROLASE BETA BARREL
									ARG; CHAIN: B;
181	1fni	A	330	536	1.3e−71	0.09	0.77		TRYIPSIN; CHAIN: A;	HYDROLASE SERINE PROTEASE,
										HYDROLASE
181	1qtf	A	357	532	3.4e−09	0.41	0.19		EXFOLIATIVE TOXIN B;	HYDROLASE, TOXIN
									CHAIN: A;	EPIDERMOLYTIC TOXIN B; SEPJNE
										PROTEASE, SUPERANTIGEN,
										HYIDROLASE, TOXIN
181	1s1w	B	330	536	5.6e−67	0.29	0.60		ECOTIN; CHAIN: A; ANIONIC	COMPLEX (SERINE
									TRYPSIN; CHAIN: B;	PROTEASE/INHIBITOR) TRYPSIN
										INHIBITOR; SERINE PROTEASE,
										INHIBITOR, COMPLEX, METAL
										BINDING SITES, 2 PROTEIN
										ENGINEERING, PROTEASE-
										SUBSTRATE INTERACTIONS, 3
										METALLOPROTEINS
181	1trn	A	330	536	1.4e−70	0.30	0.43		HYDROLASE(SERINE
									PROTEIINASE) TRYPSIN
									(E.C.3.4.21.4) COMPLEXED
									WITH THE INHIBITOR 1TRN 3
									DUSOPROPYL-
									FLUOROPHOSPHOFLUORIDAT
									E(DFP)ITRN 4 HUMAN
									TRYPSIN, DFP INHIBITED 1TRN
									6
181	2sfa		357	532	1.7e−13	0.47	0.62		SERINEPROTEINASE; CHAIN:	HYDROLASE HYDROLASE, SERINE
									NULL;	PROTIFSASE
181	2sta	E	330	534	1.4e−68	0.17	0.76		TRYPSIN; CHAIN: E; TRYPSIN	HYDROLASE/HYDROLASE INHIBITOR
									INHIBITOR; CHAIN: I	SERINE PROTEINASE, TRYPSIN
										INHIBITOR
181	5ptp		330	536	2.8e−65	0.09	0.51		BETA TRYPSIN; CHAIN: NULL;	SERINE PROTEASE HYDROLASE,
										SERINE PROTEASE, DIGESTION,
										PANCREAS, 2 ZYMOGEN, SIGNAL
192	1d2t	A	27	242	3.4e−39	0.45	0.78		ACID PHOSPHATASE; CHAIN:	HYDROLASE ALL ALPHA
									A;
193	1cdq		36	112	2.8e−21			142.48	COMPLEMENT REGULATORY
									PROTEiN CD59 (NMR, 20
									STRUCTURES) 1CDQ 3
193	1cdy		59	166	1e−08	0.23	−0.14		T-CELL SURFACE	T-CELL SURFACE GLYCOPROTEIN
									GLYCOPROTEIN CD4; CHAIN:	IMMUNOGLOBULIN FOLD,
									NULL;	TRANSMEMBRANE, GLYCOPROTEIN,
										T-CELL, 2 MHC, LIPOPROTEIN, T-
										CELL SURFACE GLYCOPROTEIN
193	1erg		36	105	1.4e−20			132.21	COMPLEMENT FACTOR
									HUMAN COMPLEMENT
									REGULATORY PROTEIN CD59
									(EXTRACELLULAR 1ERG 3
									REGION, RESIDUES 1-70)
									(NMR, RESTRAINED
									MINIMIZED 1ERG 4 AVERAGE
									STRUCTURE) 1ERG 5
193	1f97	A	1	89	1.4e−33			54.30	JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
193	P97	A	65	274	8.4e−52			269.92	JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
193	1f97	A	67	272	8.4e−52	0.92	1.00		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
193	1f97	A	67	274	3.4e−51	0.90	1.00		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
193	1wio	A	75	312	6.8e−28	0.01	−0.18		T-CELL SURFACE	GLYCOPROTEIN CD4;
									GLYCOPROTEIN CD4; CHAIN:	IMMUNOGLOBULIN FOLD,
									A, B;	TRANSMEMBRANE, GLYCOPROTEIN,
										T-CELL, 2 MHC LIPOPROTEIN,
										POLYMORPHISM
194	1i5j	A	20	86	1.4e−29			87.22	AVOLIPOPROTEIN CII; CHAIN:	LIPID TRANSPORT APOC-Il; PROTEIN-
									A;	LIPID INTERACTION, AMPHIPATHIC
										ALPHA HELIX
194	1iSj	A	71	137	1.2e−30	−0.93	0.77		APOLIPOPROTEIN CII; CHAIN:	LIPID TRANSPORT APOC-Il; PROTEIN-
									A;	LIPID INTERACTION, AMPHIPATHIC
										ALPHA HELIX
194	1i5j	A	71	137	1.2e−30			86.49	APOLIPOPROTEIN CII; CHAIN:	LIPID TRANSPORT APOC-II; PROTEIN-
									A;	LIPID INTERACTION, AMPHIPATHIC
										ALPHA HELIX
194	1i5j	A	71	137	7e−29	−0.93	0.77		APOLIPOPROTEIN CII; CHAIN:	LIPID TRANSPORT APOC-II; PROTEIN-
									A;	LIPID INTERACTION, AMPHIPATHIC
										ALPHA HELIX
195	1h6q	A	1	159	2.8e−60	0.40	1.00		TRANSLATIONALLY	TUMOR-ASSOCIATED PROTEIN TCTP,
									CONTROLLED TUMOR	P23FYP; TUMOR-ASSOCIATED
									PROTEIN; CHAIN: A;	PROTEIN, FUNCTION UNKNOWN
195	1h6q	A	1	160	1.7e−58	0.37	1.00		TRANSLATIONALLY	TUMOR-ASSOCIATED PROTEIN TCTP,
									CONTROLLED TUMOR	P23FYP; TUMOR-ASSOCIATED
									PROTEIN; CHAIN: A;	PROTEIN, FUNCTION UNKNOWN
196	1awc	B	300	393	0.00051	−0.29	0.29		GA BINDING PROTEIN ALPHA;	COMPLEX (TRANSCRIPTION
									CHAIN: A; GA BINDING	REGULATION/DNA) GABPALPHA;
									PROTEIN BETA 1; CHAIN: B;	GABPBETAI1 COMPLEX
									DNA; CHAIN: D, E;	(TRANSCRIPTION
										REGULATION/DNA), DNA-BINDING, 2
										NUCLEAR PROTEIN, ETS DOMAIN,
										ANKYRIN REPEATS, TRANSCRIPTION
										3 FACTOR
196	1b1x	B	337	411	0.00034	−0.03	0.09		CYCLIN-DEPENDENT KINASE	COMPLEX (INHIBITOR
									6; CHAIN: A; P19INK4D; CHAIN:	PROTEIN/KINASE) INhIBITOR
									B;	PROTEIN, CYCLIN-DEPENDENT
										KINASE, CELL CYCLE 2 CONTROL,
										ALPHAIBETA, COMPLEX (INHIBITOR
										PROTEIN/KINASE
196	1dcq	A	337	397	0.00051	0.15	0.64		PYK2-ASSOCIATED PROTEIN	METAL BINDING PROTEIN ZINC-
									BETA; CHAIN: A;	BINDING MODULE, ANKYRIN
										REPEATS, METAL BINDING PROTEIN
196	1ikn	D	337	394	0.00085	−0.47	0.55		NF-KAPPA-B P65 SUBUNIT;	TRANSCRIPTION FACTOR P65; P50D;
									CHAIN: A; NF-KAPPA-B P50D	TRANSCRIPTION FACTOR, IXBINFKB
									SUBUNIT; CHAIN: C; I-KAPPA-	COMPLEX
									B-ALPHA; CHAIN: D;
196	1myo		337	394	0.00068	0.18	0.11		MYOTROPHIN; CHAIN: NULL	ANK-REPEATMYOTROPHIN
										ACETYLATION, NMR, ANK-REPEAT
196	1ufi	E	345	398	0.001	−0.25	0.84		NP-KAPPA-B P65; CHAIN: A, C;	COMPLEX (TRANSCRIPTION
									NF-KAPPA-B P50; CHAIN: B, D;	REG/ANK REPEAT) COMPLEX
									I-KAPPA-B-AIPHA; CHAIN: E, F;	(TRANSCRIPTION REGULATION/ANK
										REPEAT), ANKYRIN 2 REPEAT HELIX
196	1ycs	B	337	423	0.00017	−0.05	0.03		P53; CHAIN: A; 53BP2; CHAIN:	COMPLEX (ANTI-
									B;	ONCOGENE/ANKYRIN REPEATS)
										P53BP2; ANKYRIN REPEATS, SH3, P53,
										TUMOR SUPPRESSOR, MULTIGENE 2
										PHOSPHORYLATION, DISEASE
										MUTATION, 3 POLYMORPHISM,
										COMPLEX(ANTI-
										ONCOGEN/ANKYRIN REPEATS)
197	1d2h	A	108	240	1.4e−18	−0.26	0.06		GLYCINE N-	TRANSFERASE
									METHYLTRANSFERASE;	METHYLTRANSFEPASE
									CHAIN: A, B, C, D;
198	1aj4		16	168	2.8e−26			99.38	TROPONIN C; CHAIN: NULL;	MUSCLE PROTEIN CTNC; CARDIAC,
										MUSCLE PROTEIN, REGULATORY,
										CALCIUM BINDING
198	1aj4		97	222	2.8e−26	0.11	0.46		TROPONIN C; CHAIN: NULL;	MUSCLE PROTEIN CTNC; CARDIAC,
										MUSCLE PROTEIN, REGULATORY,
										CALCIUM BINDING
198	1ak8		3	74	5.6e−32			59.57	CALMODULIN; CHAIN: NULL;	CALCIUM-BINDING PROTEIN
										CALMODULIN CERIUM TR1C-
										DOMAIN, RESIDUES 1-75; CERIUM-
										LOADED, CALCIUM-BINDING
										PROTEIN
198	1ap4		20	96	1.1e−18	0.79	1.00		CARDIAC N-TROPONIN C;	CALCIUM-BINDING CNTNC;
									CHAIN: NULL;	CALCIUM-BINDING, REGULATION,
										TROPONIN C, CARDIAC MUSCLE 2
										CONTRACTION
198	1aul	B	18	179	2.8e−16			75.78	SERINE/THREONINE	HYDROLASE CALCINEURIN;
									PHOSPHATASE 2B; CHAIN: A,	HYDROLASE, PHOSPHATASE,
									B;	IMMUNOSUPPRESSION
198	1avs	A	1	76	2.8e−28			54.68	TROPONIN C; CHAIN: A, B;	MUSCLE CONTRACTION MUSCLE
198	1b1q		1	78	8.4e−29			50.01	N-TROPONIN C; CHAIN: NULL;	CALCIUM-BINDING PROTEIN SNTNC;
										CALCIUM-BINDING, REGULATION,
										TROPONIN C, CARDIAC MUSCLE, 2
										CONTRACTION
198	1br1	B	26	166	1.3e−38	0.63	1.00		MYOSIN; CHAIN: A, B, C, D, E,	MUSCLE PROTEIN MDE; MUSCLE
									F, G, H;	PROTEIN
198	1br1	B	26	166	1.3e−38			92.46	MYOSIN; CHAIN: A, B, C, D, E,	MUSCLE PROTEIN MDE; MUSCLE
									F, G, H;	PROTEIN
198	1br1	B	97	209	1.4e−11	0.24	0.22		MYOSIN; CHAIN: A, B, C, D, E,	MUSCLE PROTEIN MDE; MUSCLE
									F, G, H;	PROTEIN
198	1cdm	A	102	209	1.3e−29	−0.08	0.19		CALCIUM-BINDING PROTEIN
									CALMODULIN COMPLEXED
									WITH CALMODULINBINDING
									DOMMNOF 1CDM3
									CALMODULIN-DEPENDENT
									PROTEIN KINASE II 1CDM 4
198	1cdm	A	26	164	8.4e−59	0.72	1.00		CALCIUM-BINDING PROTEIN
									CALMODULIN COMPLEXED
									WITH CALMODULIN-BINDING
									DOMAIN OF 1CDM 3
									CALMODULIN-DEPENDENT
									PROTEIN KINASE II 1CDM 4
198	1cdm	A	26	164	8.4e−59			118.25	CALCIUM-BINDING PROTEIN
									CALMODULIN COMPLEXED
									WITH CALMODULIN-BINDING
									DOMAIN OF 1CDM 3
									CALMODULIN-DEPENDENT
									PROTEIN KINASE II 1CDM 4
198	1cll		102	209	9.8e−36	−0.05	0.24		CALCIUM-BINDING PROTEIN
									CALMODULIN (VERTEBRATE)
									1CLL 3
198	1cll		15	91	1.4e−19	0.39	1.00		CALCIUM-BINDING PROTEIN
									CALMODULIN (VERTEBRATE)
									1CLL 3
198	1cll		1	86	1.4e−42			50.32	CALCIUM-BINDING PROTEIN
									CALMODULIN (VERTEBRATE)
									1CLL 3
198	1cll		26	164	5.6e−65	0.73	1.00		CALCIUM-BINDING PROTEIN
									CALMODULIN (VERTEBRATE)
									1CLL 3
198	1cll		26	165	5.6e−65			135.44	CALCIUM-BINDING PROTEIN
									CALMODULIN (VERTEBRATE)
									1CLL 3
198	1cmf		15	87	1.4e−05			70.55	CALMODULIN (VERTEBRATE);	CALCIUM-BINDING PROTEIN
									1CMF 6 CHAIN: NULL; 1CMF 7	CALMODULIN APO TR2C-DOMAIN;
										1CMF 9
198	1dgu	A	12	177	8.4e−16			64.07	CALCIUM-SATURATED CIB;	BLOOD CLOTTING HELICAL, EF-
									CHAIN: A	HANDS, BLOOD CLOTTING
198	1dtl	A	20	165	2.8e−26			91.37	CARDIAC TROPONIN C; CHAIN:	STRUCTURAL PROTEIN HELIX-TURN-
									A;	HELIX
198	1dtl	A	97	222	2.8e−26	0.36	0.63		CARDIAC TROPONIN C; CHAIN:	STRUCTURAL PROTEIN HELIX-TURN-
									A;	HELIX
198	1exr	A	102	209	2.8e−33	0.04	0.29		CALMODULIN; CHAIN: A;	METAL TRANSPORT CALMODULIN,
										HIGH RESOLUTION, DISORDER
198	1exr	A	15	90	4.2e−18	0.29	0.95		CALMODULIN; CHAIN: A;	METAL TRANSPORT CALMODULIN,
										HIGH RESOLUTION, DISORDER
198	1exr	A	24	163	1.4e−62	0.75	1.00		CALMODULIN; CHAIN: A;	METAL TRANSPORT CALMODULIN,
										HIGH RESOLUTION, DISORDER
198	1exr	A	24	165	1.4e−62			132.92	CALMODULIN; CHAIN: A;	METAL TRANSPORT CALMODULIN,
										HIGH RESOLUTION, DISORDER
198	1f4q	A	3	130	3.4e−10	−0.15	0.30		GRANCALCIN; CHAIN: A, B;	METAL TRANSPORT PENTA-EF-HAND
										PROTEIN, CALCIUM BINDING
										PROTEIN
198	1fpw	A	48	216	8.4e−19	−0.21	0.37		CALCIUM-BINDING PROTEIN	METAL BINDINGPROTEIN YEAST
									NCS-1; CHAIN: A;	FREQUENIN EF-HAND, CALCIUM
198	1fw4	A	20	84	1.4e−05			67.19	CALMODULIN; CHAIN: A;	METAL BINDING PROTEIN EF-HAIND,
										HELIX-LOOP-HELIX, FRAGMENT,
										CALCIUM, TR2C, C-2 TERMINAL
										DOMAIN, CALMODULIN
198	1g8i	A	6	180	7e−14			65.19	NEURONAL CALCIUM SENSOR	METAL BINDING PROTEIN
									1; CHAIN: A, B;	FREQUENIN; CALCIUM BINDING-
										PROTEIN, EF-HAND, CALCIUM ION
198	1ggw	A	28	166	7e−11			89.53	CDC4P; CHAIN: A;	CYTOKINE EF-HAND PROTEIN,
										MYOSIN LIGHT CHAIN; LiGHT
										CHAIN, CYTOKINESIS, CELL CYCLE,
										EF-HAND
198	1hqv	A	15	203	2.8e−23			60.78	PROGRAMMED CELL DEATH	APOPTOSIS PROBABLE CALCIUM-
									PROTEIN 6; CHAIN: A;	BINDING PROTEIN ALG-2; PENTA-EF-
										HAND PROTEIN, CALCIUM BINDING
										PROTEIN
198	1hqv	A	37	194	2.8e−23	0.19	0.24		PROGRAMMED CELL DEATH	APOPTOSIS PROBABLE CALCIUM-
									PROTEIN 6; CHAIN: A;	BINDING PROTEIN ALG-2; PENTA-EF-
										HAND PROTEIN, CALCIUM BINDING
										PROTEIN
198	1iku		5	191	5.6e−11			58.57	RECOVERIN; CHAIN: NULL;	CALCIUM-BINDING PROTEIN
										CALCIUM-MYRISTOYL SWITCH,
										CALCUIM-BINDING PROTEIN
198	1tcf		102	224	7e−30	0.06	0.40		TROPONIN C; CHAIN: NULL;	CALCIUM-REGULNED MUSCLE
										CONTRACTION MUSCLE
										CONTRACTION, CALCIUM-BINDlNG,
										TROPONIN, E-F HAND, 2 OPEN
										CONFORMATION REGULATORY
										DOMAIN, CALCIUM-REGULATED 3
										MUSCLE CONTRACTION
198	1tcf		17	165	7e−30			104.72	TROPONIN C; CHAIN: NULL;	CALCIUM-REGULATED MUSCLE
										CONTRACTION MUSCLE
										CONTRACTION, CALCIUM-BINDING,
										TROPONIN, E-F HAND, 2 OPEN
										CONFORMATION REGULATORY
										DOMAIN, CALCIUM-REGULATED 3
										MUSCLE CONTRACTION
198	1top		102	224	28e−30	0.15	0.87		CONTRACTILE SYSTEM
									PROTEIN TROPONIN C 1TOP 3
198	1top		13	168	2.8e−30			107.77	CONTRACTILE SYSTEM
									PROTEIN TROPONIN C 1TOP 3
198	1trc	A	19	86	1.4e−05			63.97	CALCIUM BINDING PROTEIN
									CALMODULIN (/TR=2=C$
									FRAGMENT COMPRISING
									RESIDUES 78-148 LTRC 3 OF
									THE INTACT MOLECULE) 1TRC
									4
198	1trf		5	76	2.3e−28			53.23	MUSCLE PROTEIN TROPONIN C
									(TR1C FRAGMENT) (APO
									FORM) (NMR, 1 STRUCTURE)
									1TRF 3
198	1vrk	A	102	209	2.8e−34	0.24	0.57		CALMODULIN; CHAIN: A; RS20;	CALMODULIN, CALCIUM BINDING,
									CHAIN: B;	HELIX-LOOP-HELIX, SIGNALLING, 2
										COMPLEX(CALCIUM-BINDING
										PROTEINYEPTIDE)
198	1vrk	A	15	93	1.1e−18	0.39	0.99		CALMODULIN; CHAIN: A; RS20;	CALMODULIN, CALCIUM BINDING,
									CHAIN: B;	HELIX-LOOP-HELIX, SIGNALLING, 2
										COMPLEX(CALCIUM-BINDING
										PROTEIN/PEPTIDE)
198	1vrk	A	23	166	9.8e−64	0.60	1.00		CALMODULIN; CHAIN: A; RS20;	CALMODULIN, CALCIUM BINDING,
									CHAIN: B;	HELIX-LOOP-HELIX, SIGNALLING, 2
										COMPLEX(CALCIUM-BINDING
										PROTEIN/PEPTIDE)
198	1vrk	A	24	166	9.8e−64			133.11	CALMODULIN; CHAIN: A; RS20;	CALMODULIN, CALCIUM BINDING,
									CHAIN: B;	HELIX-LOOP-HELIX, SIGNALLING, 2
										COMPLEX(CALCIUM-BINDING
										PROTEIN/PEPTIDE)
198	1wdc	B	1	89	7e−20			67.20	SCALLOP MYOSIN; CHAIN: A,	MUSCLE PROTEIN MYOSIN,
									B, C;	CALCIUM BINDING PROTEIN,
										MUSCLE PROTEIN
198	1wdc	B	26	168	1.7e−43			163.19	SCALLOP MYOSIN; CHAIN: A,	MUSCLE PROTEIN MYOSIN,
									B, C;	CALCIUM BINDING PROTEIN,
										MUSCLE PROTEIN
198	1wdc	B	26	168	5.6e−35	0.48	1.00		SCALLOP MYOSIN; CHAIN: A,	MUSCLE PROTEIN MYOSIN,
									B, C;	CALCIUM BINDING PROTEIN,
										MUSCLE PROTEIN
198	1wdc	B	28	166	1.7e−43	0.52	1.00		SCALLOP MYOSIN; CHAIN: A,	MUSCLE PROTEIN MYOSIN,
									B, C;	CALCIUM BINDING PROTEIN,
										MUSCLE PROTEIN
198	1wdc	C	26	169	1.3e−06			89.97	SCALLOP MYOSIN; CHAIN: A,	MUSCLE PROTEIN MYOSIN,
									B, C;	CALCIUM BINDING PROTEIN,
										MUSCLE PROTEIN
198	2mys	B	1	90	2.8e−18			51.56	MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	B	26	166	1.7e−38	−0.25	1.00		MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	B	26	169	1.7e−38			146.55	MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	B	7	78	5.6e−22			50.77	MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	B	96	198	5.6e−17	−0.25	0.05		MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	C	29	165	2.8e−35			87.97	MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
198	2mys	C	32	165	2.8e−35	−0.05	1.00		MYOSIN; CHAIN: A, B, C;	MUSCLE PROTEIN MUSCLE PROTEIN,
										MYOSIN SUBFRAGMENT-1, MYOSIN
										HEAD, 2 MOTOR PROTEIN
201	1ajj		116	151	5.1e−09	−0.28	0.13		LOW-DENSITY LIPOPROTEIN	RECEPTOR LR5; RECEPTOR, LDL
									RECEPTOR; CHAIN: NULL;	RECEPTOR, CYSTEINE-RICH
										MODULE, CALCIUM
201	1ajj		117	151	5.6e−09	0.06	0.01		LOW-DENSITY LIPOPROTEIN	RECEPTOR LR5; RECEPTOR, LDL
									RECEPTOR; CHAIN: NULL;	RECEPTOR, CYSTEINE-RICH
										MODULE, CALCIUM
201	1f8z	A	117	151	1.3e−07	−0.12	0.06		LOW-DENSITY LIPOPROTEIN	LIPID BINDING PROTEIN LDL
									RECEPTOR; CHAIN: A;	RECEPTOR, L1GANTJ-I3INDING
										DOMAIN, CALCIUM-BINDING, 2
										FAMILIAL
										HYPERCHOLESTEROLEMIA
201	1ldl		116	151	5.1e−07	0.29	0.33		LOW-DENSITY LIPOPROTEIN	BINDING PROTEIN LB1; 1LDL 7LDL
									RECEPTOR; 1LDL 4 CHAIN:	RECEPTOR CYSTEINE-RICH REPEAT
									NULL; 1LDL 5	1LDL 15
201	1sfp		1	113	8.4e−07	0.35	0.04		ASFP; CHAIN: NULL;	SPERMADHESIN ACIDIC SEMINAL
										PROTEIN; SPERMADHESIN, BOVINE
										SEMINAL PLASMA PROTEIN, ACIDIC
										2 SEMINAL FLUID PROTEIN, ASFP,
										CUB DOMAIN, X-RAY CRYSTAL 3
										STRUCTURE, GROWTH FACTOR
201	1sfp		26	114	1.7e−10	0.37	0.09		ASFP; CHAIN: NULL;	SPERMADHESIN ACIDIC SEMINAL
										PROTEIN; SPERMADHESIN, BOVINE
										SEMINAL PLASMA PROTEIN, ACIDIC
										2 SEMINAL FLUID PROTEIN, ASFP,
										CUB DOMAIN, X-RAY CRYSTAL 3
										STRUCTURE, GROWTH FACTOR
201	1spp	A	26	112	8.5e−09	0.35	0.30		MAJOR SEMINAL PLASMA	COMPLEX (SEMINAL PLASMA
									GLYCOPROTEIN PSP-I; CHAIN:	PROTEIN/SPP) SEMINAL PLASMA
									A; MAJOR SEMINAL PLASMA	PROTEINS, SPERMADHESINS, CUB
									GLYCOPROTEIN PSP-II; CHAIN:	DOMAIN 2 ARCHITECTURE,
									B	COMPLEX (SEMINAL PLASMA
										PROTEIN/SPP)
201	1spp	B	26	112	5.1e−10	0.17	0.11		MAJOR SEMINAL PLASMA	COMPLEX (SEMINAL PLASMA
									GLYCOPROTEIN PSP-I; CHAIN:	PROTElN/SPP) SEMINAL PLASMA
									A; MAJOR SEMINAL PLASMA	PROTEINS, SPERMADHESINS, CUB
									GLYCOPROTEIN PSP-II; CHAIN:	DOMAIN 2 ARCHITECTURE,
									B	COMPLEX (SEMINAL PLASMA
										PROTEIN/SPP)
208	1eis	A	277	354	9.8e−07	0.46	−0.09		AGGLUTININ ISOLBCTIN	SUGAR BINDING PROTEIN UDA;
									VI/AGGLUTININ ISOLECTIN V;	LECTIN, HEVEIN DOMAIN, UDA,
									CHAIN: A;	SUPERANTIGEN
208	9wga	A	485	655	4.2e−11	0.19	−0.19		LECTIN (AGGLUTININ) WHEAT
									GERM AGGLUTININ
									(ISOLECTIN 2) 9WGA 3
208	9wga	A	915	1107	1.4e−13	0.04	−0.19		LECTIN (AGGLUTLNIN) WHEAT
									GERM AGGLUTININ
									(ISOLECTIN 2) 9WGA 3
212	1e08	A	1	325	0			152.98	[FE]-HYDROGENASE (LARGE	HYDROGENASE HYDROGENASE,
									SUBUNIT); CHAIN: A; [FE]-	CYTOCUROME C553, ELECTRON
									HYDROGENASE (SMALL	TRANSFER COMPLEX
									SUBUNIT); CHAIN: D;
									CYTOCHROME C553; CHAIN: E
212	1hfe	L	1	325	0			137.95	FE-ONLY HYDROGENASE	HYDROGENASE FE-ONLY
									(SMALLER SUBUNIT); CHAIN:	HYDROGENASE, X-RAY
									5, T; FE-ONLY HYDROGENASE	CRYSTALLOGRAPHY, HYDROGENE 2
									(LARGER SUBUNIT); CHAIN: L,	METABOLISM, PERIPLASM
									M;
212	1jgj	A	8	217	0.0068			51.59	SENSORY RHODOPSIN II;	SIGNALING PROTEIN SENSORY
									CHAIN: A;	RHODOPSIN, MEMBRANE PROTEIN,
										PHOTOTAXIS RECEPTOR
213	1dv8	A	199	326	5.6e−34	−0.18	0.33		ASIALOGLYCOPROTEIN	SIGNALING PROTEIN HEPATIC
									RECEPTOR 1; CHAIN: A;	LECTIN H1; C-TYPE LECTIN CED
213	1hq8	A	194	308	5.6e−28			86.06	NKG2-D; CHAIN: A;	APOPTOSIS HOMODIMER, CIS-
										PROLINE
213	1hyr	A	193	315	2.8e−26			100.53	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2 A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
213	1hyr	A	48	163	1.4e−27			94.69	NKG2-D TYPE II INTEGRAL	IMMUNE SYSTEM NKG2D; MIC-A,
									MEMBRANE PROTEIN; CHAIN:	MIC, PERB11; ACTIVATING NK CELL
									B, A; MHC CLASS I CHAIN-	RECEPTOR, NKG2D, C-TYPE-LECTIN
									RELATED PROTEIN A; CHAIN:	LIKE, MIC-2 A, MHC-I, COMPLEX,
									C;	IMMUNE SYSTEM
214	12e8	L	71	269	9.8e−17			73.24	2E8 (IGG1=KAPPA=)	IMMUNOGLOBULIN
									ANTIBODY; CHAIN: L, H, M, P;	IMMUNOGLOBULIN
214	12e8	L	83	267	9.8e−17	0.28	0.75		2E8 (IGG1=KAPPA=)	IMMUNOGLOBULIN
									ANTIBODY; CHAIN: L, H, M, P;	IMMUNOGLOBULIN
214	1adq	L	72	258	2.8e−22	0.38	1.00		IGG4 REA; CHAIN: A; RF-AN	COMPLEX
									IGM/LAMBDA; CHAIN: H, L;	(IMMUNOGLOBULIN/AUTOANTIGEN)
										COMPLEX
										(IMMUNOGLOBULIN/AUTOANTIGEN),
										RHEUMATOID FACTOR 2 AUTO-
										ANTIBODY COMPLEX
214	1adq	L	72	271	2.8e−22			72.32	IGG4 REA; CHAIN: A; RF-AN	COMPLEX
									1GM/LAMBDA; CHAIN: H, L;	(IMMUNOGLOBULIN/AUTOANTIGEN)
										COMPLEX
										(IMMUNOGLOBULIN/AUTOANTIGEN)
										RHEUMATOID FACTOR 2 AUTO-
										ANTIBODY COMPLEX
214	1b2w	L	70	269	4.2e−20			73.56	ANTIBODY (LIGHT CHAIN),	IMMUNE SYSTEM
									CHAIN: L; ANTIBODY (HEAVY	IMMUNOGLOBULIN;
									CHAIN); CHAIN: H;	IMMUNOGLOBULIN ANTIBODY
										ENGINEERING, HUMANIZED AND
										CHIMERIC ANTIBODY, FAB, 2 X-RAY
										STRUCTURE, THREE-DIMENSIONAL
										STRYCTUHE, GAMMA-3
										INTERFERON, IMMUNE SYSTEM
214	1b6d	A	70	269	7e−21			73.38	IMMUNOGLOBULIN; CHAIN: A,	IMMUNOGLOBULIN
									B;	IMMUNOGLOBULIN, KAPPA LIGHT-
										CHAIN DIMER HEADER
214	1bih	A	2	362	1.3e−43	0.06	0.99		HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
214	1bih	A	2	364	1.3e−43			121.44	HEMOLIN; CHAIN: A, B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
214	1bih	A	73	386	5.1e−38	0.18	0.77		HEMOLIN; CHAIN: A,B;	INSECT IMMUNITY INSECT
										IMMUNITY, LPS-BINDING,
										HOMOPHILIC ADHESION
214	1bj1	J	76	267	1.4e−21	0.10	0.89		FAB FRAGMENT; CHAIN: L, H,	COMPLEX (ANTIBODY/ANTIGEN)
									J, K; VASCULAR ENDOTHELIAL	FAB-12; VEGF; COMPLEX
									GROWTH FACTOR; CHAIN: V,	(ANTIBODY/ANTIGEN), ANGIOGENIC
										FACTOR
214	1bql	H	84	268	9.8e−14	0.01	0.34		COMPLEX
									(ANTIBODY/ANTIGEN) HYHEL-
									5 FAB COMPLEXED WITH
									BOBWHITE QUAIL LYSOZYME
									1BQL3 1BQL 95
214	1bz7	A	70	265	4.2e−19			73.01	ANTIBODY R24 (LIGHT CHAIN);	IMMUNE SYSTEM ANTIBODY (FAB
									CHAIN: A; ANTIBODY R24	FRAGMENT), IMMUNE SYSTEM
									(HEAVY CHAIN); CHAIN: B;
214	1cic	A	83	267	5.6e−17	0.35	0.82		IG HEAVY CHAIN V REGIONS;	IMMUNOGLOBULIN
									CHAIN: A; IG HEAVY CHAIN V	IMMUNOGLOBULIN, FAB COMPLEX,
									REGIONS; CHAIN: B; IG HEAVY	IDIOTOPE, ANTI-IDIOTOPE
									CHAIN V REGIONS; CHAIN: C;
									IG HEAVY CHAIN V REGIONS;
									CHAIN: D;
214	1cs6	A	10	363	5.6e−41	0.10	0.86		AXONTN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
214	1cs6	A	15	364	1e−43			99.18	AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
214	1cs6	A	66	429	5.6e−40	0.19	0.76		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
214	1cs6	A	72	379	1e−43	0.09	0.16		AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
214	1cvs	C	169	362	4.2e−38	0.15	0.48		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
214	1cvs	C	6	167	8.4e−20	0.01	−0.09		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
214	1cvs−	C	81	270	4.2e−22	0.02	−0.05		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
214	1cvs	D	169	362	1.3e−39	0.32	0.80		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
214	1cys	D	6	167	2.8e−20	−0.26	0.06		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
214	1d5i	L	70	269	4.2e−21			72.82	CHIMERIC GERMLINE	IMMUNE SYSTEM IMMUNE SYSTEM
									PRECURSOR OF OXY-COPE
									CHAIN: L; CHIMERIC
									GERMLINE PRECURSOR OF
									OXY-COPE CHAIN: H;
214	1dfb−	L	70	269	8.4e−22			75.44	IMMUNOGLOBULIN 3D6 FAB
									1DFB3
214	1dfb	L	76	267	8.4e−22	0.36	0.99		IMMUNOGLOBULIN 3D6 FAB
									1DFB3
214	1dgi	R	58	362	3.4e−51			111.26	POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
214	1dgi	R	75	362	3.4e−51	−0.21	0.46		POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VP1; CHAIN: 1; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
214	1dgi	R	76	362	1.4e−39	−0.02	0.06		POLIOVIRUS RECEPTOR;	VIRUS/VIRAL PROTEIN, RECEPTOR
									CHAIN: R; VPI; CHAIN: I; VP2;	CD155, PVR, HUMAN POLIOVIRUS,
									CHAIN: 2; VP3; CHAIN: 3; VP4;	ELECTRON MICROSCOPY, 2
									CHAIN: 4;	POLIOVIRUS-RECEPTOR COMPLEX,
										VIRUS/VIRAL PROTEIN, RECEPTOR
214	1epf	A	165	352	1.7e−28	0.36	0.55		NEURAL CELL ADHESION	CELL ADHESION NCAM; NCAM,
									MOLECULE; CHAIN: A, B, C, D;	IMMUNOGLOBULIN FOLD,
										GLYCOPROTEIN
214	1epf	A	175	346	2.8e−19	0.37	0.94		NEURAL CELL ADHESION	CELL ADHESION NCAM; NCAM,
									MOLECULE; CHAIN: A, B, C, D;	IMMUNOGLOBULIN FOLD,
										GLYCOPROTEIN
214	1epf	A	3	152	2.8e−15	−0.07	0.00		NEURAL CELL ADHESION	CELL ADHESION NCAM; NCAM,
									MOLECULE; CHAIN: A, B, C, D;	IMMUNOGLOBULIN FOLD,
										GLYCOPROTEIN
214	1epf	A	72	272	4.2e−24	−0.00	0.16		NEURAL CELL ADHESION	CELL ADHESION NCAM; NCAM,
									MOLECULE; CHAIN: A, B, C, D;	IMMUNOGLOBULIN FOLD,
										GLYCOPROTEIN
214	1ev2	E	170	362	2.8e−34	0.04	0.23		FIBROBLAST GROWTH	GROWTH FACTORIGROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2; FGF2;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG) LIKE
									FACTOR RECEPTOR 2; CHAIN:	DOMAINS BELONGING TO THE I-SET
									E, F, G, H;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
214	1ev2	G	170	366	4.2e−37	0.03	0.70		FIBROBLAST GROWTH	GROWTH FACTORIGROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2; FGF2;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG) LIKE
									FACTOR RECEPTOR 2; CHAIN:	DOMAINS BELONGING TO THE I-SET
									E, F, G, H;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
214	1evt	C	169	362	2.8e−39	0.03	0.51		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 1; CHAIN: A, B;	RECEPTOR FGF1; FGFR1;
									FIBROBLAST GROWTH	IMMUNOGLOBULIN (IG) LIKE
									FACTOR RECEPTOR 1; CHAIN:	DOMAINS BELONGING TO THE I-SET
									C, D;	2 SUBGROUP WITHIN IG-LIKE
										DOMAINS, B-TREFOIL FOLD
214	1f2q	A	26	171	2.8e−12	−0.13	0.07		HIGH AFFINITY	IMMUNE SYSTEM FC-EPSILON RI-
									IMMUNOGLOBULIN EPSILON	ALPHA; IMMUNOGLOBULIN FOLD,
									RECEPTOR CHAIN: A;	GLYCOPROTEIN, RECEPTOR, IGB-
										BINDING 2 PROTEIN
214	1f6a	A	166	365	3.4e−27	0.26	0.18		HIGH AFFINITY	IMMUNE SYSTEM HIGH AFFINITY
									IMMUNOGLOBULIN EPSILON	IGE-FC RECEPTOR, FC(EPSILON) IGE-
									RECEPTOR CHAIN: A; IG	FC; IMMUNOGLOBULIN FOLD,
									EPSiLON CHAIN C REGION;	GLYCOPROTEIN, RECEPTOR, IGE-
									CHAIN: B, D;	BINDING 2 PROTEIN, IGE ANTIBODY,
										IGE-FC
214	1f6a	A	171	346	1.4e−14	0.40	0.99		HIGH AFFINITY	IMMUNE SYSTEM HIGH AFFINITY
									IMMUNOGLOBULIN EPSILON	IGE-FC RECEPTOR, FC(EPSILON) IGE
									RECEPTOR CHAIN: A; IG	FC; IMMUNOGLOBULIN FOLD,
									EPSILON CHAIN C REGION;	GLYCOPROTEIN, RECEPTOR, IGE
									CHAIN: B, D;	BINDING 2 PROTEIN, IGE ANTIBODY,
										IGE-EC
214	1f97	A	181	362	5.1e−26	0.27	0.11		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
214	1f97	A	5	158	2.8e−12	−0.05	0.09		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
214	1f97	A	77	265	4.2e−30	0.09	0.86		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
214	1fcg	A	170	362	8.5e−28	0.14	0.39		FC RECEPTOR	IMMUNE SYSTEM, MEMBRANE
									FC(GAMMA)RIIA; CHAIN: A;	PROTEIN CD32; FC RECEPTOR,
										IMMUNOGLOULIN, LEUKOCYTE,
										CD32
214	1fhg	A	272	362	1.5e−17	0.48	0.74		TELOKIN; CHAIN: A	CONTRACTILE PROTEIN
										IMMUNOGLOBULIN FOLD, BETA
										BARREL
214	1fhg	A	275	362	2.8e−17	0.38	0.72		TELOKIN; CHAIN: A	CONTRACTILE PROTEIN
										IMMUNOGLOBULIN FOLD, BETA
										BARREL
214	1fhg	A	78	167	5.6e−13	0.02	0.33		TELOKIN; CHAIN: A	CONTEACTILE PROTEIN
										IMMUNOGLOBULIN FOLD, BETA
										BARREL
214	1fnl	A	167	362	3.4e−26	0.21	0.01		LOW AFFINITY	IMMUNE SYSTEM RECEPTOR BETA
									IMMUNOGLOBULIN GAMMA	SANDWICH, IMMUNOGLOBULIN-
									FC REGION CHAIN: A;	LIKE, RECEPTOR
214	1fnl	A	273	375	1.7e−16	0.34	−0.06		LOW AFFINITY	IMMUNE SYSTEM RECEPTOR BETA
									IMMUNOGLOBULIN GAMMA	SANDWICH, IMMUNOGLOBULIN-
									PC REGION CHAIN: A;	LIKE, RECEPTOR
214	1g0x	A	167	356	6.8e−24	0.23	0.05		LEUCOCYTE	IMMUNE SYSTEM LEUKOCYTE
									IMMUNOGLOBULIN-LIKE	INHIBITORY RECEPTOR-1;
									RECEPTOR-1; CHAIN: A;	LEUKOCYTE IMMUNOGLOBULIN
										FOLD, 3-10 HELIX
214	1iai	L	83	267	9.8e−15	0.12	0.27		IDIOTYPIC FAB 730.1.4 (IGG1)	COMPLEX (IMMUNOGLOBULIN
									OF VIRUS 1IAI 5 CHAIN: L, H;	IGG1/IGG2A)
									1IAI 7 ANTI-IDIOTYPIC FAB
									409.5.3 (IGG2A); 1IAI9 CHAIN:
									M, I 1IAI 10
214	1ie5	A	269	362	8.4e−18	−0.11	0.45		NEURAL CELL ADHESION	CELL ADHESION N-CAM;
									MOLECULE; CHAIN: A;	INTERMEDIATE IMMUNOGLOBULIN
										FOLD
214	1ie5	A	272	363	6.8e−18	0.01	0.51		NEURAL CELL ADHESION	CELL ADHESION N-CAM;
									MOLECULE; CHAIN: A;	INTERMEDIATE IMMUNOGLOBULIN
										FOLD
214	1iil	G	164	366	6.8e−27	0.24	0.46		HEPARIN-BINDING GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2, HBGF-2, BASIC
									FIBROBLAST GROWTH	FIBROBLAST GROWTH FACTOR,
									FACTOR RECEPTOR 2; CHAIN:	FGFR2, KERATINOCYTE GROWTH
									B, F, G, H;	FACTOR RECEPTOR;
										IMMUNOGLOBULIN LIKE DOMAIN, B-
										TREFOIL
214	1iil	G	170	366	1.4e−36	0.38	0.53		HEPARIN-BINDING GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2, HBGF-2, BASIC
									FIBROBLAST GROWTH	FIBROBLAST GROWTH FACTOR,
									FACTOR RECEPTOR 2; CHAIN:	FGFR2, KERATINOCYTE GROWTH
									B, F, G, H;	FACTOR RECEPTOR;
										IMMUNOGLOBULIN LIKE DOMAIN, B-
										TREFOIL
214	1iil	G	275	365	1.5e−16	0.61	0.55		HEPARIN-BINDING GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B, C, D;	RECEPTOR FGF2, HBGF-2, BASIC
									FIBROBLAST GROWTH	FIBROBLAST GROWTH FACTOR,
									FACTOR RECEPTOR 2; CHAIN:	FGFR2, KERATINOCYTE GROWTH
									B, F, G, H;	FACTOR RECEPTOR;
										IMMUNOGLOBULIN LIKE DOMAIN, B-
										TREFOIL
214	1itb	B	79	366	3.4e−37			82.33	INTERLEUKIN-1 BETA; CHAIN:	COMPLEX
									A; TYPE 1 TNTERLEUKIN-1	(IMMUNOGLOBULIN/RECEPTOR)
									RECEPTOR; CHAIN: B;	IMMUNOGLOBULIN FOLD,
										TRANSMEMBRANE, GLYCOPROTEIN
										RECEPTOR, 2 SIGNAL, COMPLEX
										(IMMUNOGLOBULIN/RECEPTOR)
214	1mco	H	1	363	9.8e−19			78.42	IMMUNOGLOBULIN
									IMMUNOGLOBULIN G1 (IGG1)
									(MCG) WITH A HINGE
									DELETION 1MCO 3
214	1nfd	E	74	267	1.1e−21	0.32	0.96		N15 ALPHA-BETA T-CELL	COMPLEX
									RECEPTOR; CHAIN: A, B, C, D;	(IMMUNORECEPTOR/IMMUNOGLOBU
									H57 FAB; CHAIN: B, F, G, H	LIN) COMPLEX
										(IMMUNORECEPTOR/IMMUNOGLOBU
										LIN)
214	1osp	L	70	269	1.1e−17			75.72	FAD 184.1; CHAIN: L, H; OUTER	COMPLEX
									SURFACE PROTEIN A; CHAIN:	(IMMUNOGLOBULIN/LIPOPROTEIN)
									O;	OSPA; COMPLEX
									N		(IMMUNOGLOBULIN/LIPOPROTEIN),
										OUTER SURFACE 2 PROTEIN A
										COMPLEXED WITH FAD 184.1,
										BORRELIA BURGDORFERI 3 STRAIN
										B31
214	1vca	A	73	278	8.5e−27	0.57	0.93		HUMAN VASCULAR CELL	CELL ADHESION PROTEIN VCAM-
									ADHESION MOLECULE-1; 1VCA	D1, 2; 1VCA 6 IMMUNOGLOBULIN
									4 CHAIN: A, B; 1VCA 5	SUPERFAMILY, INTEGRIN-BINDING
										1YCA 15
214	1wio	A	76	442	1.5e−35			89.83	T-CELL SURFACE	GLYCOPROTEIN CD4;
									GLYCOPROTEIN CD4; CHAIN:	IMMUNOGLOBULIN FOLD,
									A, B;	TRANSMEMBRANE, GLYCOPROTEIN,
										T-CELL, 2 MHC LIPOPROTEIN,
										POLYMORPHISM
214	2dli	A	167	354	8.5e−23	0.17	0.00		MHC CLASS INK CELL	IMMUNE SYSTEM P58 NATURAL
									RECEPTOR PRECURSOR;	KILLER CELL RECEPTOR; KIR,
									CHAIN: A;	NATURAL KILLER RECEPTOR,
										INHIBITORY RECEPTOR, 2
										IMMUNOGLOBULIN
214	2fcb	A	170	365	1.5e−27	−0.16	0.75		FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										FC, CD32, IMMUNE SYSTEM
214	2fcb	A	278	375	1.5e−16	0.17	0.03		FC GAMMA RIIB; CHAIN: A;	IMMUNE SYSTEM CD32; RECEPTOR,
										FC, CD32, IMMUNE SYSTEM
214	2fgw	L	76	267	1.1e−21	0.30	0.99		IMMUNOGLOBULIN FAB
									FRAGMENT OF A HUMANIZED
									VERSION OF ThE ANTI-CD18
									2FGW 3 ANTIBODY ′h52′
									(HUH52-OZ FAJ3) 2FGW 4
214	2ncm		282	363	1.5e−17	0.42	0.29		NEURAL CELL ADHESION	CELL ADHESION NCAM DOMAIN 1;
									MOLECULE; CHAIN: NULL;	CELL ADHESION, GLYCOPROTEIN,
										HEPARIN-BINDING, GPI-ANCHOR, 2
										NEURAL ADHESION MOLECULE,
										IMMUNOGLOBULIN FOLD, SIGNAL
214	3fct	A	73	269	1.4e−20			77.03	METAL CHELATASE	IMMUNE SYSTEM METAL
									CATALYTIC ANTIBODY;	CHELATASE, CATALYTIC ANTIBODY,
									CHAIN: A, C; METAL	FAB FRAGMENT, IMMUNE 2 SYSTEM
									CHELATASE CATALYTIC
									ANTIBODY; CHAIN: B, D;
214	8fab	A	73	268	5.6e−23			74.31	IMMUNOGLOBULIN FAB
									FRAGMENT FROM HUMAN
									IMMUNOGLOBULIN IGG1
									(LAMBDA, HIL) 8FAB 3
214	8fab	A	75	258	5.6e−23	0.42	1.00		IMMUNOGLOBULIN FAB
									FRAGMENT FROM HUMAN
									IMMUNOGLOBULIN IGG1
									(LAMBDA, HIL) 8FAB 3
215	1b3u	A	22	571	4.5e−18	0.11	−1202.08		PROTEIN PHOSPHATASE PP2A;	SCAFFOLD PROTEIN SCAFFOLD
									CHAIN: A, B;	PROTEIN, PP2A, PHOSPHORYLATION,
										HEAT REPEAT
215	1ee4	A	389	777	4.5e−21	0.35	−1202.08		KARYOPHERIN ALPHA; CHAIN:	TRANSPORT PROTEIN SHRINE-RICH
									A, B; MYC PROTO-ONCOGENE	RNA POLYMERASE I SUPPRESSOR
									PROTEIN; CHAIN: C, D, E, F;	PROTEIN; ARM REPEAT
215	1g3j	C	462	799	3e−15	0.02	−1202.08		BETA-CATENIN ARMADILLO	TRANSCRIPTION BETA-
									REPEAT REGION; CHAIN: A, C;	CATENIN,TCF-3, PROTEIN-PROTEIN
									TCF3-CBD (CATENIN BINDING	COMPLEX
									DOMAIN); CHAIN: B, D;
215	1i7w	A	462	915	1.5e−21	0.09	−1202.08		BETA-CATENIN; CHAIN: A, C;	CELL ADHESION E-CADHERIN; E-
									EPITHELIAL-CADHERlN;	CADHERIN, CELL ADHESION, BETA-
									CHAIN: B, D;	CATENIN, PROTEIN-PROTEIN 2
										COMPLEX, EXTENDED INTERFACE,
										ARMADILLO REPEAT,
										PHOSPHOSERINE
215	1ial	A	456	901	1.5e−18	0.14	−1202.08		IMPORTIN ALPHA; CHAIN: A;	NUCLEAR IMPORT RECEPTOR
										KARYOPHERIN ALPHA; NUCLEAR
										IMPORT RECEPTOR, NUCLEAR
										LOCALIZATION SIGNAL, 2
										ARMADILLO REPEATS,
										AUTOINHIBITION, INTRASTERIC
										REGULATION
215	3bct		412	787	6e−17	0.11	−1202.08		BETA-CATENIN; CHAIN: NULL;	ARMADILLO REPEAT ARMADILLO
										REPEAT, BETA-CATENIN,
										CYTOSKELETON
216	1a7q	L	27	132	0.00012			60.18	MONOCLONAL ANTIBODY	IMMUNOGLOBULIN
									D1.3; CHAIN: L, H;	IMMUNOGLOBULIN, VARIANT
216	1aif	A	27	211	0.0015			61.80	ANTI-IDIOTYPIC FAB 409.5.3	IMMUNOGLOBULIN
									(IGG2A) FAB; CHAIN: A, B, L, H	IMMUNOGLOBULIN, C REGION, V
										REGION
216	1bww	A	25	133	0.00045			61.39	IG KAPPA CHAIN V-I REGION	IMMUNE SYSTEM REIV, STABILIZED
									REI; CHAIN: A, B;	IMMUNOGLOBULIN FRAGMENT,
										BENCE-JONES 2 PROTEIN, IMMUNE
										SYSTEM
216	1cdy		35	136	1.5e−09	0.41	−1202.08		T-CELL SURFACE	T-CELL SURFACE GLYCOPROTEIN
									GLYCOPROTEIN CD4; CHAIN:	IMMUNOGLOBULIN FOLD,
									NULL;	TRANSMEMBRANE, GLYCOPROTEIN,
										T-CELL, 2 MHC, LIPOPROTEIN, T-
										CELL SURFACE GLYCOPROTEIN
216	1cs6	A	26	159	6e−08	0.25	−1202.08	AXONIN-1; CHAIN: A;	CELL ADHESION NEURAL CELL
										ADHESION
216	1cvs	C	9	112	1.5e−11	0.04	−1202.08		FIBROBLAST GROWTH	GROWTH FACTOR/GROWTH FACTOR
									FACTOR 2; CHAIN: A, B;	RECEPTOR FGF, FGFR,
									FIBROBLAST GROWTH	IMMUNOGLOBULIN-LIKE, SIGNAL
									FACTOR RECEPTOR 1; CHAIN:	TRANSDUCTION, 2 DIMERIZATION,
									C, D;	GROWTH FACTOR/GROWTH FACTOR
										RECEPTOR
216	1dr9	A	37	134	4.5e−08	0.35	−1202.08		TLYMPHOCYTE ACTIVATION	IMMUNE SYSTEM B7-1 (CD80); IG
									ANTIGEN; CHAIN: A;	SUPERFAMILY
216	1eaj	A	28	132	7.5e−1 1	0.41	−1202.08		COXSACKIE VIRUS AND	VIRUS/VIRAL PROTEIN RECEPTOR
									ADENOVIRUS RECEPTOR;	COXSACKIEVIRUS B-ADENOVIRUS
									CHAIN: A, B;	RECEPTOR, HCAR, VIRUS/VIRAL
										PROTEIN RECEPTOR,
										IMMUNOGLOBULIN V DOMAIN
										FOLD, 2 SYMMETRIC DIMER
216	1epf	A	31	112	6e−10	0.47	−1202.08		NEURAL CELL ADHESION	CELL ADHESION NCAM; NCAM,
									MOLECULE; CHAIN: A, B, C, D;	IMMUNOGLOBULIN FOLD,
										GLYCOPROTEIN
216	1f97	A	30	112	1.5e−10	0.12	−1202.08		JUNCTION ADHESION	CELL ADHESION IMMUNOGLOBULIN
									MOLECULE; CHAIN: A;	SUPERFAMILY, BETA-SANDWICH
										FOLD
216	1g9m	L	27	210	3e−06			61.27	ENVELOPE GLYCOPROTEIN	VIRUS/VIRAL PROTEIN COMPLEX
									GP120; CHAIN: G; T-CELL	(HIV ENVELOPE PROTEIN/CD4/FAB),
									SURFACE GLYCOPROTEIN	HIV-1 EXTERIOR 2 ENVELOPE GPI2O
									CD4; CHAIN: C; ANTIBODY 17B,	FROM LABORATORY-ADAPTED
									LIGHT CHAIN; CHAIN: L;	ISOLATE, HXBC2, 3 SURFACE T-CELL
									ANTIBODY 17B, HEAVY	GLYCOPROTEIN CD4, ANTIGEN-
									CHAIN; CHAIN: H;	BINDING FRAGMENT 4 OF HUMAN
										IMMUNOGLOBULIIN 17B
216	1hxm	B	32	142	6e−10	0.32	−1202.08		GAMMA-DELTA T-CELL	IMMUNE SYSTEM T-CELL RECEPTOR
									RECEPTOR; CHAIN: A, C, B, G;	DELTA CHAIN; T-CELL RECEPTOR
									GAMMA-DELTA T-CELL	GAMMA CHAIN; IG DOMAIN, T CELL
									RECEPTOR; CHAIN: B, D, F, H;	RECEPTOR, TCR, GDTCR
216	1igm	L	27	140	7.5e−05			60.22	IMMUNOGLOBULIN
									IMMUNOGLOBULIN M (IG-M)
									FV FRAGMENT 1IGM 3
216	1neu		31	132	1.2e−09	0.36	−1202.08		MYBLIN P0 PROTEIN; CHAIN:	STRUCTURAL PROTEIN MYBLIN,
									NULL;	STRUCTURAL PROTEIN,
										GLYCOPROTEIN, TRANSMEMBRANE,
										PHOSPHORYLATION,
										IMMUNOGLOBULIN FOLD, SIGNAL,
										MYBLIN 2 MEMBRANE ADHESION
										MOLECULE
216	1nkr		29	148	1.5e−09	0.16	−1202.08		P58-CL42 KIR; CHAIN: NULL;	INHIBITORY RECEPTOR KILLER CELL
										INHIBITORY RECEPTOR; INHIBITORY
										RECEPTOR, NATURAL KILLER CELLS,
										IMMUNOLOGICAL 2 RECEPTORS,
										IMMUNOGLOBULIN FOLD
216	1vca	A	31	134	1.5e−10	0.22	−1202.08		HUMAN VASCULAR CELL	CELL ADHESION PROTEIN VCAM
									ADHESION MOLECULE-1; 1VCA	D1, 2; 1VCA 6 IMMUNOGLOBULIN
									4 CHAIN: A, B; IVCA 5	SUPERFAMILY, INTEGRIN-BINDING
										IVCA 15
220	1a25	A	648	768	1.4e−17	0.24	−1202.08		PROTEIN KINASE C (BETA);	CALCIUM-BINDING PROTEIN CALB;
									CHAIN: A, B;	CALCIUM++IPHOSPHOLIPID BINDING
										PROTEIN, 2 CALCIUM-BINDING
										PROTEIN
220	1a25−	A	667	754	1.5e−18	0.08	−1202.08		PROTEIN KINASE C (BETA);	CALCIUM-BINDING PROTEIN CALB;
									CHAIN: A, B;	CALCIUM++IPHOSPHOLIPID BINDING
										PROTEIN, 2 CALCIUM-BINDING
										PROTEIN
220	1byn	A	648	768	8.4e−23	0.21	−1202.08		SYNAPTOTAGMIN I; CHAIN: A;	ENDOCYTOSIS/EXOCYTOSIS
										SYNAPTOTAGMIN, C2-DOMAIN,
										EXOCYTOSIS, NEUROTRANSMI~LTER
										2 RELEASE,
										ENDOCYTOSIS/EXOCYTOSIS
220	1cjy	A	666	786	1.4e−08	0.16	−1202.08		CYTOSOLIC PHOSPHOLIPASE	HYDROLASE CPLA2;
									A2; CHAIN: A, B;	PHOSPHOLIPASE, LIPID-BINDING,
										HYDROLASE
220	1djx	B	845	1047	2.8e−12	0.01	−1202.08		PHOSPHOINOSITIDE-SPECIHC	LIPID DEGRADATION PLC-D1;
									PHOSPHOLIPASE C, CHAIN: A,	PHOSPHORIC DIESTER HYDROLASE,
									B;	HYDROLASE, LIPID DEGRADATION, 2
										TRANSDUCER, CALCIUM-BINDING,
										PHOSPHOLIPASE C, 3
										PHOSPHOINOSITIDE-SPECIFIC
220	1dsy	A	647	781	5.6e−21	0.23	−1202.08		PROTEIN KINASE C, ALPHA	TRANSFERASE CALCIUM++,
									TYPE; CHAIN: A;	PHOSPHOLIPID BINDING PROTEIN,
										CALCIUM-BINDING 2 PROTEIN,
										PHOSPHATIDYLSERINE, PROTEIN
										KINASE C
220	1rlw		664	754	4.5e−19	0.04	−1202.08		PHOSPHOLIPASE A2; CHAIN:	HYDROLASE CALB DOMAIN;
									NULL;	HYDROLASE, C2 DOMAIN, CALB
										DOMAIN
220	1rlw		666	765	2.8e−08	0.14	−1202.08		PHOSPHOLIPASE A2; CHAIN:	HYDROLASE CALB DOMAIN;
									NULL;	HYDROLASE, C2 DOMAIN, CALB
										DOMAIN
220	1rsy		619	754	3e−20	0.22	−1202.08		CALCIUM/PHOSPHOLIPID
									BINDING PROTEIN
									SYNAPTOTAGMIN I (FIRST C2
									DOMAIN) (CALB) IRSY 3
220	1rsy		648	768	8.4e−23	0.11	−1202.08		CALCIUM/PHOSPHOLIPID
									BINDING PROTEIN
									SYNAPTOTAGMIN I (FIRST C2
									DOMAIN) (CALB) lRSY 3
220	3rpb	A	650	779	9.8e−17	0.29	−1202.08	RABPHILIN 3-A; CHAIN: A;	ENDOCYTOSIS/EXOCYTOSIS C2-
										DOMAINS, C2B-DOMAIN, RABPHILIN,
										ENDOCYTOSIS/EXOCYTOSIS
222	1f88	A	54	378	1e−24			73.00	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
222	1f88	B	54	371	3e−18			70.57	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
222	1hMe		6	81	1.1 e−28			98.43	DNA-BINDING HIGH MOBILITY
									GROUP PROTEIN FRAGMENT-B
									(HMGB) (DNA-BINDING 1HME 3
									HMG-BOX DOMAIN B OF RAT
									HMG1) (NMR, 1STRUCTURE)
									1HMB 4
222	1hsM		9	87	1.1e−26			97.62	DNA-BINDING HIGH MOBILITY
									GROUP PROTEIN 1 (11MG 1) BOX
									2, COMPLEXED WITH IUSM 3
									MERCAPTOETHANOL (NMR,
									MINIMIZED AVERAGE
									STRUCTURE) 1HSM 4
223	1fx8	A	85	333	1.4e−47			73.96	GLYCEROL UPTAKE	MEMBRANE PROTEIN GLPF;
									FACILITATOR PROTEIN;	GLYCEROL-CONDUCTING
									CHAIN: A;	MEMBRANE CHANNEL PROTEIN
227	1914		1	104	9.8e−36			69.38	SIGNAL RECOGNITION	ALU DOMAIN SRP9/14, ALU BM, RBD;
									PARTICLE 9/14 FUSION	ALU DOMAIN, CRYSTAL
									PROTEIN; CHAIN: NULL;	STRUCTURE, RNA BINDING, SIGNAL
										2 RECOGNITION PARTICLE (SRP),
										TRANSLATION REGULATION
227	1dhp	A	35	327	1.4e−91	0.66	−1202.08		DIHYDRODIPICOLINATE	SYNTHASE DHDPS; SYNTHASE,
									SYNTHASE; CHAIN: A, B;	DIHYDRODIPICOLINATE
227	1dhp	A	35	327	1.4e−91			130.43	DIHYDRODIPICOLINATE	SYNTHASE DHDPS; SYNTHASE,
									SYNTHASE; CHAIN: A, B;	DIHYDRODIPICOLINATE
227	1f6k	A	10	304	1.4e−69			123.19	N-ACETYLNEURAMINATE	LYASE BETA BARREL, LYASE
									LYASE; CHAIN: A, C;
227	1f6k	A	33	327	3e−76			123.09	N-ACETYLNEURAMINATE	LYASE BETA BARREL, LYASE
									LYASE; CHAIN: A, C;
227	1f6k	A	34	318	3e−76	0.52	−1202.08		N-ACETYLNEURAMINATE	LYASE BETA BARREL, LYASE
									LYASE; CHAIN: A, C;
227	1f6k	A	34	323	5.6e−69	0.44	−1202.08		N-ACETYLNEURAMINATE	LYASE BETA BARREL, LYASE
									LYASE; CHAIN: A, C;
227	1nal	1	11	300	7e−64			121.57	N-ACETYLNEURAMINATE	LYASE
									LYASE; 1NAL 4 CHAIN:
									1, 2, 3, 4; INAL 5
227	1Nai	1	34	318	4.5 e−75	0.66	−1202.08		N-ACETYLNEURAMINATE	LYASE
									LYASE; 1NAL 4 CHAIN:
									1, 2, 3, 4; INAL 5
227	1nal	1	34	319	1.4e−63	0.61	−1202.08		N-ACETYLNEURAMINATE	LYASE
									LYASE; iNAL 4 CHAIN:
									1, 2, 3, 4; 1NAL 5
227	1nal	1	34	323	4.5e−75			121.46	N-ACETYLNEUIRAMINATE	LYASE
									LYASE; LNAL4 CHAIN:
									1, 2, 3, 4; 1NAL 5
229	1hci	A	363	478	1.5e−08	0.04	−1202.08		ALPHA-ACTININ 2; CHAIN: A,	TRIPLE-HELIX COILED COIL ALPHA
									B;	ACTININ SKELETAL MUSCLE
										ISOFORM 2, TRIPLE-HELIX COILED
										COIL, CONTRACTILE PROTEIN,
										MUSCLE, 2 Z-LINE, ACTIN-BINDiNG
										PROTEIN
231	1dx5	I	176	284	1.4e−10	0.44	−1202.8		THROMBIN LIGHT CHAIN;	SERINE PROTEINASE COAGULATION
									CHAIN: A, B, C, D; THROMBIN	FACTOR II; COAGULATION FACTOR
									HEAVY CHAIN; CHAIN: M, N, O,	II; FETOMODULIN, TM, CD141
									P; THROMBOMODULIN; CHAIN:	ANTIGEN; EOR-CMK SERINE
									I, J, K, L; THROMBIN lNHIBITOR	PROTEINASE, EGF-LIKE DOMAINS,
									L-GLU-L-GLY-L-ARM; CHAIN:	ANTICOAGULANT COMPLEX, 2
									E, F, G, H;	ANTIFIBRINOLYTIC COMPLEX
231	1Dx5	I	252	353	5.6e−14	0.33	−1202.08		THROMBIN LIGHT CHAIN;	SERINE PROTEINASE COAGULATION
									CHAIN: A, B, C, D; THROMBIN	FACTOR II; COAGULATION FACTOR
									HEAVY CHAIN; CHAIN: M, N, O,	II; FETOMODULIN, TM, CD 141
									P; THROMBOMODULIN; CHAIN:	ANTIGEN; EGR-CMK SERINE
									I, J, K, L; THROMBIN INHIBITOR	PROTEINASE, EGF-LIKE DOMAINS,
									L-GLU-L-GLY-L-ARM; CHAIN:	ANTICOAGULANT COMPLEX, 2
									E, F, G, H;	ANTIFIBRINOLYTIC COMPLEX
231	1dx5	I	320	427	5.6e−12	0.33	−1202.08		THROMBIN LIGHT CHAIN;	SERINE PROTEINASE COAGULATION
									CHAIN: A, B, C, D; THROMBIN	FACTOR II; COAGULATION FACTOR
									HEAVY CHAIN; CHAIN: M, N, O,	II; FETOMODULIN, TM, CDl4I
									P; THROMBOMODULIN; CHAIN:	ANTIGEN; EGR-CMK SERINE
									I, I, K, L; THROMBIN INHIBITOR	PROTEINASE, EGF-LIKE DOMAINS,
									L-GLU-L-GLY-L-ARM; CHAIN:	ANTICOAGULANT COMPLEX, 2
									E, F, G, H;	ANTIHBRINOLYTIC COMPLEX
231	1hj7	A	214	288	1 .4e−09	0.33	−1202.08		LDL RECEPTOR; CHAIN: A;	CELL-SURFACE RECEPTOR CELL-
										SURFACE RECEPTOR, CALCIUM-
										BINDING, EGF-LIKE DOMAIN, 2
										MODULE, APO-E, APO-B, LDL, VLDL
231	1hj7	A	368	427	1.3e−09	0.02	−1202.08		LDL RECEPTOR; CHAIN: A;	CELL-SURFACE RECEPTOR CELL-
										SURFACE RECEPTOR, CALCIUM-
										BINDING, EGF-LIKE DOMAIN, 2
										MODULE, APO-E, APO-B, LDL, VLDL
231	1kLO		163	288	5.6e−09	0.18	−1202.08		LAMININ; CHAIN: NULL;	GLYCOPROTEIN GLYCOPROTEIN
231	1pfx	L	250	327	8.4e−09	0.09	−1202.08		FACTOR IXA; CHAIN: C, L,; D-	COMPLEX (BLOOD
									PHE-PRO-ARG; CHAIN: I;	COAGULATION/INHIBITOR)
										CHRISTMAS FACTOR; COMPLEX,
										INHIBITOR, HEMOPHILIAIEGF,
										BLOOD COAGULATION, 2 PLASMA,
										SERINE PROTEASE, CALCIUM-
										BINDING, HYDROLASE, 3
										GLYCOPROTEIN
231	9wga	A	290	462	7e−15	0.01	−1202.08		LECTIN (AGGLUTININ) WHEAT
									GERM AGGLUTININ
									(ISOLECTIN 2) 9WGA 3
231	9wga	A	98	263	2.8e−15	−0.00	−1202.08		LECTIN (AGGLUTININ) WHEAT
									GERM AGGLUTININ
									(ISOLECTIN 2) 9WGA 3
232	1f88	A	1	275	7e−82			58.80	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
232	1188	A	25	366	1.4e−90			95.22	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
232	1f88	B	23	352	2.8e−82			66.80	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
234	1aqc	A	661	780	6e−23	0.03	−1202.08		X11; CHAIN A, B; PEPTIDE;	COMPLEX (PEPTIDE BINDING
									CHAIN. C, D	MODULE/PEPTIDE), PEPTIDE
										BINDING 2 MODULE, PTB DOMAIN
234	1ddm	A	484	618	1.5e−13	0.11	−1202.08		NUMB PROTEIN; CHAIN: A;	SIGNALING PROTEIN/TRANSFERASE
									NUMB ASSOCIATE KINASE;	NAK; COMPLEX, SIGNAL
									CHAIN: B;	TEANSDUCTION, PHOSPHOTYROSINE
										BINDING 2 DOMAIN (PTE),
										ASYMMETRIC CELL DIVISION
234	1ddm	A	661	778	4.5 e−25	0.45	−1202.08		NUMB PROTEIN; CHAIN: A;	SIGNALING PROTEINITRANSFERASE
									NUMB ASSOCIATE KINASE;	NAK; COMPLEX, SIGNAL
									CHAIN: B;	TRANSDUCTION, PHOSPHOTYROSINE
										BINDING 2 DOMAIN (PTB),
										ASYMMETRIC CELL DIVISION
234	1shc	A	477	620	9e−21	0.42	−1202.08		SHC; CHAIN: A; TRKA	COMPLEX (SIGNAL
									RECEPTOR PHOSPHOPEPTIDE;	TRANSDUCTION/PEPTIDE) COMPLEX
									CHAIN: B;	(SIGNAL TRANSDUCTIONIPEPTIDE),
										PHOSPHOTYROSINE 2 BINDING
										DOMAIN (PTB)
234	1x11	A	661	782	3e−23	0.20	−1202.08	X11; CHAIN: A, B; 13-MER	COMPLEX (PEPTIDE BINDING
									PEPTIDE; CHAIN: C, D;	MODULE/PEPTIDE), PTE DOMAIN
234	2nMb	A	661	786	7.5e−26	0.28	−1202.08		NUMB PROTEIN; CHAIN: A;	CELL CYCLE/GENE REGULATION
									GPPY PEPTIDE; CHAIN: B;	COMPLEX, SIGNAL TRANSDUCTION,
										PHOSPHOTYROSINE BINDING 2
										DOMAIN (PTB), ASYMETR IC CELL
										DIVISION
237	1a25	A	224	347	4.2e−24	0.06	−1202.08		PROTEIN KINASE C (BETA);	CALCIUM-BINDING PROTEIN CALB;
									CHAIN: A, B;	CALCIUM++/PHOSPHOLIPID BINDING
										PROTEIN, 2 CALCIUM-BINDING
										PROTEIN
237	1a25	A	72	191	4.2e−24	0.15	−1202.08		PROTEIN KINASE C (BETA);	CALCIUM-BINDING PROTEIN CALB;
									CHAIN: A, B;	CALCIUM++/PHOSPHOLIPID BINDING
										PROTEIN, 2 CALCIUM-BINDING
										PROTEIN
237	1byn	A	69	185	8.4e−30	0.21	−1202.08		SYNAPTOTAGMIN I; CHAIN: A;	ENDOCYTOSIS/EXOCYTOSIS
										SYNAPTOTAGMIN, C2-DOMAIN,
										EXOCYTOSIS, NEUROTRANSMITTER
										2 RELEASE,
										ENDOCYTOSIS/EXOCYTOSIS
237	1djx	A	255	356	2.8e−21	0.32	−1202.08		PHOSPHOINOSITIDE-SPECIFIC	LIPID DEGRADATION PLC-D1;
									PHOSPHOLIPASE C, CHAIN: A,	PHOSPHORIC DIESTER HYDROLASE,
									B;	HYDROLASE, LIPID DEGRADATION, 2
										TRANSDUCER, CALCIUM-I3INDING,
										PHOSPHOLIPASE C, 3
										PHOSPHOINOSITIDE-SPECIFlC
237	1djx	B	115	355	1e−31	0.00	−1202.08		PHOSPHOINOSITIDE-SPECIFIC	LIPID DEGRADATION PLC-D1;
									PHOSPHOLIPASE C, CHAIN: A,	PHOSPHORIC DIESTER HYDROLASE,
									B;	HYDROLASE, LIPID DEGRADATION, 2
										TRANSDUCER, CALCIUM-BINDING,
										PHOSPHOLIPASE C, 3
										PHOSPHOlNOSITIDE-SPECIFIC
237	1dix	B	255	356	2.8e−21	0.38	−1202.08		PHOSPHOINOSITIDE-SPECIFIC	LIPID DEGRADATION PLC-D1;
									PHOSPHOLIPASE C, CHAIN: A,	PHOSPHORIC DIESTER HYDROLASE,
									B;	HYDROLASE, LIPID DEGRADATION, 2
										TRANSDUCER, CALCIUM-BINDING,
										PHOSPHOLIPASE C, 3
										PHOSPHOlNOSITIDE-SPECIFIC
237	1dsy	A	70	194	4.2E−26	0.20	−1202.08		PROTEIN KINASE C, ALPHA	TRANSFERASE CALCIUM++,
									TYPE; CHAIN: A;	PHOSPHOLIPID B1NDING PROTEIN,
										CALCIUM-BINDING 2 PROTEIN,
										PHOSPHATIDYLSERINE, PROTEIN
										KINASE C
237	1r1w		240	331	1.5E−22	0.20	−1202.08		PHOSPHOLIPASE A2; CHAIN:	HYDROLASE CALB DOMAIN;
									NULL;	HYDROLASE, C2 DOMAIN, CALB
										DOMAIN
237	1r1w		90	181	8.4e−16	0.21	−1202.08		PHOSPHOLIPASE A2; CHAIN:	HYDROLASE CALB DOMAIN;
									NULL;	HYDROLASE, C2 DOMAIN, CALB
										DOMAIN
237	3rpb	A	227	340	6e−24	0.05	−1202.08		RABPHILIN 3-A; CHAIN: A;	ENDOCYTOSIS/EXOCYTOSIS C2-
										DOMAINS, C2B-DOMAIN, RABPHIL1N,
										ENDOCYTOSIS/EXOCYTOSIS
237	3rpb	A	72	191	4.2e−20	0.10	−1202.08		RABPHILIN 3-A; CHAIN: A;	ENDOCYTOSIS/EXOCYTOSIS C2-
										DOMAINS, C2B-DOMAIN, RABPHILIN,
										ENDOCYTOSIS/EXOCYTOSLS
238	1cex		8	53	0.0006	1.11	−1202.08		CUTINASE; CHAIN: NULL;	SERINE ESTERASE HYDROLASE,
										SERINE ESTERASE, GLYCOPROTEIN
238	1kap	P	8	53	0.0015	1.00	−1202.08		ALKALINE PROTEASE; 1KAP 4	ZINC METALLOPROTEASE P.
									CHAIN: P; 1KAP 5	AERUGINOSA ALKALINE PROTEASE;
									TETRkPEPTIDE (GLY SER ASN	1KAP 6 CALCIUM BINDING PROTEIN
									SER); IKAP9CHAIN:I; 1KAP 10	1KAP 19
238	1qq4	A	24	53	0.003	2.03	−1202.08		ALPHA-LYTIC PROTEASE;	HYDROLASE DOUBLE BETA BARREL,
									CHAIN: A;	BACTERIAL SER1NE PROTEASE
238	1tal		3	53	3e−05	1.40	−1202.08		ALPHA-LYTIC PROTEASE;	SERINE PROTEASE SERINE
									CHAIN: NULL;	PROTEASE, LOW TEMPERATURE,
										HYDROLASE, 2 SERINE PROTELNASE
238	1tal		3	70	0.003	0.91	−1202.08		ALPHA-LYTIC PROTEASE;	SERINE PROTEASE SERJNE
									CHAIN: NULL;	PROTEASE, LOW TEMPERATURE,
										HYDROLASE, 2 SERINE PROTEINASE
238	1tal		8	63	0.00045	1.19	−1202.08		ALPHA-LYTIC PROTEASE;	SERINE PROTEASE SERINE
									CHAIN: NULL;	PROTEASE, LOW TEMPERATURE,
										HYDROLASE, 2 SERINE PROTEINASE
239	1cex		8	67	9e−06	1.25	−1202.08		CUTINASE; CHAiN: NULL;	SERINEESTERASE HYDROLASE,
										SERINE ESTERASE, GLYCOPROTEIN
239	1ga6	A	8	67	0.0006	0.92	−1202.08		SERIN-CARBOXYL	HYDROLASE PSCP,
									PROTEINASE; CHAIN: A;	PSEUDOMONAPEPSIN, PEPSTATIN-
									FRAGMENT OF TYROSTATIN;	INSENSITIVE SERINE-CARBOXYL
									CHAIN: I;	PROTEINASE
239	1qq4	A	24	53	0.003	2.03	−1202.08		ALPHA-LYTIC PROTEASE;	HYDROLASE DOUBLE BETA BARREL,
									CHAIN: A;	BACTERIAL SERINE PROTEASE
239	1tal		24	67	3e−05	1.57	−1202.08		ALPHA-LYTIC PROTEASE;	SERINE PROTEASE SERINE
									CHAIN: NULL;	PROTEASE, LOW TEMPERATURE,
										HYDROLASE, 2 SERINE PROTEINASE
239	1tal		3	63	3e−07	1.27	−1202.08		ALEHA-LYTIC PROTEASE;	SERINE PROTEASE SERINE
									CHAIN: NULL;	PROTI3ASE, LOW TEMPERATURE,
										HYDROLASE, 2 SERINE PROTEINASE
241	1f88	A	107	436	1.5e−15			61.82	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
241	1f88	B	107	434	4.5e−13			68.15	RHODOPSIN; CHAIN: A, B	SIGNALING PROTEIN
										PHOTORECEPTOR, G PROTEIN-
										COUPLED RECEPTOR, MEMBRANE
										PROTEIN, 2 RETINAL PROTEIN,
										VISUAL PIGMENT
242	1erj	A	24	362	5.6e−52	0.54	−1202.08		TRANSCRIPTIONAL	TRANSCRIPTION INHIBITOR BETA-
									REPRESSOR TUP1; CHAIN: A, B,	PROPELLER
									C;
242	1erj	A	480	761	1.4e−55	0.10	−1202.08		TRANSCRIPTIONAL	TRANSCRIPTION INHIBITOR BETA-
									REPRESSOR TUPI; CHAIN: A, B,	PROPELLER
									C;
242	1erj	A	725	931	2.Se−21	0.11	−1202.08		TRANSCRIPTIONAL	TRANSCRIPTION INHIBITOR BETA-
									REPRESSOR TUPI; CHAIN: A, B,	PROPELLER
									C;
242	1erj	A	72	431	4.2e−50	0.16	−1202.08		TRANSCRIPTIONAL	TRANSCRIPTION INHIBITOR BETA-
									REPRESSOR TUPi; CHAIN: A, B,	PROPELLER
									C;
242	1got	B	17	363	1.4e−58	0.36	−1202.08		GT-ALPHA/GI-ALPHA	COMPLEX (GTP-
									CHIMERA; CHAIN: A; GT-BETA;	BINDING/TRANSDUCER) BETA1,
									CHAIN: B; GT-GAMMA; CHAIN:	TRANSDUCIN BETA SUBUNIT;
									G;	GAMMAI, TRANSDUCIN GAMMA
										SUBUNIT; COMPLEX (GTP-
										BINDING/TRANSDUCER), G PROTEIN,
										HETEROTRIMER 2 SIGNAL
										TRANSDUCTION
242	1got	B	513	802	1.1 e−43	0.10	−1202.08		GT-ALPHA/GI-ALPHA	COMPLEX (GTP-
									CHIMERA; CHAIN: A; GT-BETA;	BINDING/TRANSDUCER) BETA1,
									CHAIN: B; GT-GAMMA; CHAIN:	TRANSDUCIN BETA SUBUNIT;
									G;	GAMMAI, TRANSDUCIN GAMMA
										SUBUNIT; COMPLEX (GTP-
										BINDING/TRANSDUCER), G PROTEIN,
										HETEROTRIMER 2 SIGNAL
										TRANSDUCTION
242	1got	B	552	887	4.2e−34	0.10	−1202.08		GT-ALPHA/GI-ALPHA	COMPLEX (GTP-
									CHIMERA; CHAIN: A; GT-BETA;	BINDING/TRANSDUCER) BETA1,
									CHAIN: B; GT-GAMMA; CHAIN:	TRANSDUC1N BETA SUBUNIT;
									G;	GAMMAl, TRANSDUCIN GAMMA
										SUBUNIT; COMPLEX (GTP-
										BINDING/TRANSDUCER), G PROTEIN,
										HETEROTRIMER 2 SIGNAL
										TRANSDUCTION
242	1got	B	644	936	2.8e−28	0.31	−1202.08		GT-ALPHA/GI-ALPHA	COMPLEX (GTP-
									CHIMERA; CHAIN: A; GT-BETA;	BINDING/TRANSDUCER) BETA1,
									CHAIN: B; GT-GAMMA; CHAIN:	TRANSDUCIN BETA SUBUNIT;
									G;	GAMMAI, TRANSDUCIN GAMMA
										SUBUNIT; COMPLEX (GTP-
										BINDING/TRANSDUCER), G PROTEIN,
										HETEROTRIMER 2 SIGNAL
										TRANSDUCTION
247	1b61	A	176	280	4.2e−57	0.22	−1202.08		RETROPEPSIN; CHAIN: A, B;	HYDROLASE/HYDROLASE INHIBITOR
										HIV-1 PR; COMPLEX (ACID
										PROTEINASE/PEPTIDE)
247	1bai	A	162	279	2.8e−17			55.92	ROUS SARCOMA VIRUS	COMPLEX (PROTEASE/INHIBITOR)
									PROTEASE; CHAIN: A, B;	HUMAN IMMUNODEFIClENCY ViRUS
									INHIBITOR; CHAIN: C;	PROTEASE, ROUS SARCOMA VIRUS 2
										PROTEASE, CRYSTAL STRUCTURES,
										PROTEIN-MEDIATED INTERACTION, 3
										VIRAL MATURATION, COMPLEX
										(PROTEASE/INHIBITOR) HEADER
247	1bai	A	1	111	1.4e−24			52.01	ROUS SARCOMA VIRUS	COMPLEX (PROTEASE/INHIBITOR)
									PROTEASE; CHAIN: A, B;	HUMAN IMMUNODEFICIENCY VIRUS
									INHIBITOR; CHAIN: C;	PROTEASE, ROUS SARCOMA VIRUS 2
										PROTEASE, CRYSTAL STRUCTURES,
										PROTEIN-MEDIATED INTERACTION, 3
										VIRAL MATURATION, COMPLEX
										(PROTEASE/INHIBITOR) HEADER
247	1bwb	A	176	280	1.4e−60	0.15	−1202.08		HIV-1 PROTEASE; CHAIN: A, B;	HYDROLASE HIV-1 PROTEASE,
										HYDROLASE
247	1c6x	A	176	280	2.8e−60	0.42	−1202.08		PROTEASE; CHAIN: A, B;	HYDROLASE HYDROLASE
247	1daz	C	176	280	5.6e−58	0.29	−1202.08		PEPTIDE INHIBITOR; CHAIN: A,	HYDROLASE HIV-1 PROTEASE,
									B; HIV-1 PROTEASE	MUTANT, DIMER, INHIBITOR,
									(RETROPEPSIN); CHAIN: C, D;	OCCUPANCY
247	1dun		44	161	7.5e−23			57.26	DEOXYURIDINE 5′-	HYDROLASE DUTPASE, DUTP
									TEIPHOSPHATE	PYROPHOSPHATASE; HYDROLASE,
									NUCLEODITOHYDROLASE;	DUTPASE, EIAV, TRIMERIC ENZYME,
									CHAIN: NULL;	ASPARTYL PROTEASE
247	1dun		58	150	7.5 e−23	0.91	−1202.08		DEOXYURIDINE 5′-	HYDROLASE DUTPASE, DUTP
									TRIPHOSPHATE	PYROPHOSPHATASE; HYDROLASE,
									NUCLEODITOHYDROLASE;	DUTPASE, EIAV, TRIMERIC ENZYME,
									CHAIN: NULL;	ASPARTYL PROTEASE
247	1dun		9	126	1.4e−18			56.78	DEOXYURIDINE 5′-	HYDROLASE DUTPASE, DUTP
									TRIPHOSPHATE	PYROPHOSPHATASE; HYDROLASE,
									NUCLEODITOHYDROLASE;	DUTPASE, EIAV, TRIMERIC ENZYME,
									CHAIN: NULL;	ASPARTYL PROTEASE
247	1euw	A	1	125	7e−22			61.05	DEOXYURIDINE 5′-	HYDROLASE DUTPASE; JELLY ROLL,
									TRIPHOSPHATE	MERCURY DERIVATIVE
									NUCLEOTIDOHYDROLASE;
									CHAIN: A;
247	1euw	A	32	160	4.Se−18			62.42	DEOXYURIDINE 5′-	HYDROLASE DUTPASE; JELLY ROLL,
									TRIPHOSPHATE	MERCURY DERIVATIVE
									NUCLEOTIDOHYDROLASE;
									CHAIN: A;
247	1euw	A	58	150	4.5e−18	0.76	−1202.08		DEOXYURIDINE 5′-	HYDROLASE DUTPASE; JELLY ROLL,
									TRIPHOSPHATE	MERCURY DERIVATIVE
									NUCLEOTIDOHYDROLASE;
									CHAIN: A;
247	1f7d	A	43	157	1.2e−22			62.82	POL POLYPROTEIN; CHAIN: A,	VIRUS/VIRAL PROTEIN EIGHT
									B;	STRANDED BETA-BARREL
247	1f7d	A	58	150	1.2e−22	0.83	−1202.08		POL POLYPROTEIN; CHAIN: A,	VIRUS/VIRAL PROTEIN EIGHT
									B;	STRANDED BETA-BARREL
247	1F7d	A	8	122	1.4e−21			62.45	POL POLYPROTEIN; CHAIN: A,	VIRUS/VIRAL PROTEIN EIGHT
									B;	STRANDED BETA-BARREL
247	1f7r	A	43	180	1.5e−24			73.37	POLPOLYPROTEIN; CHAIN: A;	VIRUS/VIRAL PROTEIN EIGHT
										STRANDED BETA BARREL PROTEIN
247	1f7r	A	58	166	1.5e−24	0.29	−1202.08		POLPOLYPROTEIN; CHAIN: A;	VIRUS/VIRAL PROTEIN EIGHT
										STRANDED BETA BARREL PROTEIN
247	1f7r	A	8	136	2.8e−26			71.47	POL POLYPROTEIN CHAIN: A;	VIRUS/VIRAL PROTEIN EIGHT
										STRANDED BETA BARREL PROTEIN
247	1fmb		176	280	2.8e−13			51.30	EIAV PROTEASE; CHAIN:	HYDROLASE (ACID PROTEINASE)
									NULL;	HYDROLASE (ACID PROTEINASE),
										RNA-DIRECTED DNA POLYMERASE,2
										ASPARTYL PROTEASE,
										ENDONUCLEASE, POLYPROTEIN
247	1g61	A	170	280	2.8e−63	−0.00	−1202.08		HIV-1 PROTEASE; CHAIN: A;	HYDROLASE HYDROLASE
247	1g61	A	93	280	2.8e−63			53.13	HIV-1 PROTEASE; CHAIN: A;	HYDROLASE HYDROLASE
247	1hvc		148	280	1.4e−63	0.13	−1202.08	HYDROLASE(ACID PROTEASE)
									HIV-1 PROTEASE (TETHERED
									DIMER LINKED BY 1HVC 3
									GLY-GLY-SER-SER-GLY)
									COMPLEXED WITH A-76928
									1HVC 4
247	1hvc		60	280	1.4e−63			54.32	HYDROLASE(ACID PROTEASE)
									HIV-1 PROTEASE (TETHERED
									DIMER LINKED BY 1HVC 3
									GLY-GLY-SER-SER-GLY)
									COMPLEXED WITH A-76928
									1HVC 4
247	1ida	A	176	279	2.8e−37	0.08	−1202.08		HYDROLASE(ACID
									PROTEINASE) HUMAN
									IMMUNODEFICIENCY VIRUS
									TYPE 2 (HIV-2) PROTEASE lIDA
									3 COMPLEXED WITH THE
									INHIBITOR BILA 1906
									CONTAINING THE 1IDA 4
									HYDROXYETHYLAMVINE
									DIPEPTIDE ISOSTERE 1IDA 5
247	1sip		176	280	1.4e−39	0.29	−1202.08		HYDROLASE(ACID
									PROTEINASE) SIMIAN
									IMMUNODEFICIENCY VIRUS
									(SIV) PROTEINASE 1SIP 3 (SIV
									MAC251-32H ISOLATE)
									(E.C.3.4.23.-) 1SIP 4

[0469]

TABLE 6
SEQ
ID NO:	Position of Signal Peptide	Maximum score	Mean score
125	1-31	0.921	0.630
126	1-36	0.972	0.563
127	1-39	0.976	0.551
128	1-26	0.937	0.703
129	1-74	0.991	0.543
130	1-19	0.983	0.965
131	1-23	0.945	0.797
132	1-16	0.977	0.506
133	1-21	0.967	0.759
134	1-22	0.861	0.539
135	1-27	0.934	0.682
136	1-18	0.983	0.962
137	1-22	0.827	0.517
138	1-34	0.980	0.703
139	1-15	0.987	0.955
140	1-28	0.995	0.945
141	1-18	0.995	0.977
142	1-25	0.935	0.739
143	1-19	0.976	0.950
144	1-49	0.933	0.538
145	1-22	0.918	0.723
146	1-25	0.972	0.902
147	1-52	0.981	0.622
148	1-75	0.969	0.541
149	1-75	0.979	0.817
150	1-22	0.957	0.756
151	1-45	0.978	0.852
152	1-29	0.984	0.954
153	1-36	0.994	0.713
154	1-34	0.914	0.608
155	1-25	0.986	0.952
156	1-38	0.990	0.909
157	1-54	0.908	0.565
158	1-20	0.870	0.708
159	1-27	0.985	0.856
160	1-23	0.966	0.812
161	1-54	0.967	0.524

[0470]

TABLE 7
SEQ ID NO: Chromosomal Location
1          13q12-q14
2          13q12-q14
3          20q12
4          4
5          4
6          9q33-q34
7          9q33-q34
8          2
9          2
10         2
11         13q12-q14
12         13q12-q14
13         13q12-q14
14         13q12-q14
15         13q12-q14
16         17
17         6p21.3
18         13q12-q14
19         13q12-q14
20         13q12-q14
21         13q12-q14
22         13q12-q14
23         13q12-q14
24         13q12-q14
25         13q12-q14
26         13q12-q14
27         13q12-q14
28         13q12-q14
29         13q12-q14
30         13q12-q14
31         13q12-q14
32         2
33         2
34         19q13.3-q13.4
35         19q13.3-q13.4
36         19q13.3-q13.4
37         19q13.3-q13.4
38         4
39         4
40         9q33-q34
41         13q12-q14
42         13q12-q14
43         13q12-q14
44         13q12-q14
45         22q12.1-12.3
46         13q12-q14
47         13q12-q14
48         13q12-q14
49         13q12-q14
50         13q12-q14
51         13q12-q14
52         8q
53         20q12
54         20q12
55         4
56         4
57         4
58         9q33-q34
59         9q33-q34
60         9q33-q34
61         3
62         9q33-q34
63         9q33-q34
64         9q33-q34
65         9q33-q34
66         9q33-q34
67         9q33-q34
68         9q33-q34
69         2
70         2
71         13q12-q14
72         13q12-q14
73         13q12-q14
74         13q12-q14
75         13q12-q14
76         13q12-q14
77         13q12-q14
78         13q12-q14
79         13q12-q14
80         13q12-q14
81         13q12-q14
82         13q12-q14
83         13q12-q14
84         13q12-q14
85         13q12-q14
86         13q12-q14
87         13q12-q14
88         13q12-q14
89         13q12-q14
90         19q13
91         13q12-q14
92         13q12-q14
93         13q12-q14
94         13q12-q14
95         13q12-q14
96         13q12-q14
97         13q12-q14
98         13q12-q14
99         13q12-q14
100        13q12-q14
101        13q12-q14
102        13q12-q14
103        13q12-q14
104        13q12-q14
105        13q12-q14
106        13q12-q14
107        13q12-q14
108        13q12-q14
109        13q12-q14
110        13q12-q14
111        13q12-q14
112        13q12-q14
113        13q12-q14
114        5
115        5
116        19q13.3-q13.4
117        19q13.3-q13.4
118        19q13.3-q13.4
119        19q13.3-q13.4
120        19q13.3-q13.4
121        19q13.3-q13.4
122        19q13.3-q13.4
123        19q13.3-q13.4
124        19q13.3-q13.4

[0471]

TABLE 8
				Amino acid sequence (A = Alanine, C = Cysteine,
				D = Aspartic Acid, E = Glutamic Acid,
				F = Phenylalaaine, G = Glycine, H = Histidine,
			Predicted	I = Isoleucine, K = Lysine, L = Leucine,
			location of first	M = Methionine, N = Asparagine, P = Proline,
			nucleotide of	Q = Glutamine, R = Arginine, S = Serine,
SEQ ID		Predicted nucleotide	codon corresp.	T = Threonine, V = Valine, W = Tryptophan,
NO: of		location corresp. to	to last residue	Y = Tyrosine, X = Unknown, * = Stop codon, / = possible
peptide		first residue of	of peptide	nucleotide deletion, = possible nucleotide
sequence	Method	peptide sequence	sequence	insertion)
331	A	3	438	VSFLSSFFLSLPYGVAVGVAFSVLVVVFQ
				TQFRNGYALAQVMDTDIYVNPKTYNRAQ
				DIQGIKIITYCSPLYFANSEIFRQKVIAKTG
				MDPQKVLLAKQKYLKKQEKRRMRPTQQ
				RRSLFMKTKTVSLQELQQDFENAPPTDPMY
332	A	1608	663	SGLFSVDPASSQAMELSDVTLIEGVGNEV
				MVVAGVVVLILALVLAWLSTYVADSGSN
				QLLGAIVSAGDTSVLHLGHVDHLVAGQG
				NPEPTELPHPSEGNDEKAEEAGEGRGDST
				GEAGAGGGVEPSLEHLLDIQGLPKRQAG
				AGSSSPEAPLRSEDSTCLPPSPGLITVRLKF
				LNDTEELAVARPEDTVGALKSKYFPGQES
				QMKLIYQGRLLQDPARTLRSLNITDNCVI
				HCHRSPPGSAVPGPSASLAPSATEPPSLGV
				NVGSLMVPVFVVLLGVVWYFRINYRQFF
				TAPATVSLVGVTVFFSFLVFGMYGR
333	C	163	245	MLAQYYGIQGLSHMNQPGKPIPIAQEG
334	A	841	1209	SPARGKSNRTDVMITAPKNKKMTENLAA
				PEALDSSTHSSSTATQSRAKMNTPAPTPST
				VPAIPRGGSGGPPPCAPHDRVSSVLQCDT
				QAMDHKTESSHSVVEFLFKRTKTPSPFHP
				AVRENRN
335	A	3	522	FPRLFNLRSIYLQWNRISISQGLTWTWSS
				LHNLDLSGNDIQGIEPGTFKCLPNLQKLNL
				DSNKLTNISQETVNAWISLISITLSGNMWE
				CSRSICPLFYWLKNFKGNKESTMICAGPK
				HIQGEKVSDAVETYNICSEVQVVNTERSH
				LVPQTPQKPLIIPRPTIFKPITPHP
336	A	245	574	EQAVCVGWLQIPRGTKRPKPPGGTHGRT
				DGRREPERTGGG*APRAAKEEKLTTAKLP
				RRLSFAALRNETLPARSALRLLLPLQSRA
				GPPEERMLSGAGLHGQGQVSENE
337	A	3	420	KNERQTTDISVHVCCQILKRGSHYSNTQS
				QPQEGGTQHQGGEPPQLAPGPTALPG/EPP
				PPPAPAHSPPGPPPAGAAAPQPGARPHGA
				PPLTPARRLRRSRLAAAALLSRTSGAPRR
				ALAPTPGTGVPPG\PPPSGPPGNE
338	A	2411	325	NSSWPAEPAASPWRPLWRALGATFPSGS
				QPAARTPAGPCIGGMAPPGFKHVSSMLA\
				LTIIAST\WALTPTHYLTKHDVERLKASLD
				RPFTNLESAFYS\IVGLSSLG\AQVP\DAKK
				ACTYI\RSNLDP\SNV\DSLFYGWPRASQ\A
				LSGM*RSLFSNE\TKDLAFGQLFS*GTSSV
				YPRSYHAS/VAALKWALGLPLASQEALSA
				LTARLSKEETVLATVQALQTASHLSQQAD
				LRSIVEEIEDLVARLDELGGVYLQ\FEEGL
				ETTAL\FVAATYKA/LMDH\VGTE\PSIKE\D
				QVIQLMN\AIF\SKKNFE\SLSEAFSV\ASAA
				AVLSHNRYHVPVVVVPEGSASDTHEQAIL
				RLQVTNVLSQPLTQATVKLEHAKSVAS\R
				ATVLQKTSFTP\VGIVFELNFMN\VKFS\SG
				Y\YDFLGRKLKGDNRYIS\NTVELRVQDPP
				TEVGITNVDLSTV\DKDQSIAP\QTTRVTYP
				\AKAKGTFIADSHQNFALFFQL\VGVNTGA
				ELTPHQTFVRLHNQKTGQ\EVVFVAEPDN
				KNVYKFELDTSERKGLNLTSRSGTYTFY\L
				IIGDATLKNPILWNVADVVIKFPEEEAPST
				VLSQNLFTPKQEIQHLFREPEKRPPTVVSN
				TFTALILSPLLLLFALWIRIGANVSNFTFAP
				STIIFHLGHAAMLGLMYVYWTQLNMFQT
				LKYLAILGSVTFLAGNRMLAQQAVKRTAH
339	A	2083	1152	SLIIGQYCIAREGKGFTHPVGQLSCLGQKL
				YNGTTKTVTWWSSNYTEKNPFSKFPKLQ
				TVWAHPELHWDWTAPTGLYWVCGHRA
				YAKLPDQWTGSCVIGTIKPSFFLVPIKTGK
				LLGFPVCASCEK*SIAIGDWKDDEWPPEKI
				LQYYGPATWSQDVSWGYGTPIYMLNRII
				WLQAVLEIITNKTTQALTVLAWQETLMR
				NAIYQNRLALDYLLAAEGGVCEKFDLTN
				YCLHIDDQGQVVEDIVKDITKLAHAPVQV
				WHGLNLGAMFGNWFPAIGGFKTLIIRVIIV
				IGTCLLLPCLIPVFLQMIKNFVA
340	A	2	885	EHGAGAGGGGRTGGRGPYPGTAGLPAQG
				AALGGLCLAVLWKRTGRPPSGQPLLTAPL
				PCLAGSSGHLWAASAVPCQPSDYLRQPR
				QLLQ\QKFVNSAWGWTCTFLGGFVLLVV
				FLATRRVAVTARHLSRLVVGAAVWRGA
				GRAFLLIEDLTGSCFEPLPQGLLLHELPDR
				RSCLAAGHQWRGYTVSSHTFLLTFCCLL
				MAEEAAVFAKYLAHGLPAGAPLRLVFLL
				NVLLLGLWNFLLLCTVIYFHQYTHKVVG
				AAVGTFAWYLTYGSWYHQPWSPGSPGH
				GLFPRPHSSRKHN
341	A	319	492	MQGVRVSFGWAMGLAWGSCALEAFSGT
				LLLSAAWTLSLSPPICGHLSPQQVGGRGG
				D*
342	A	2	440	PYRPEFPGSAAGVATILRTLAMKALMLLT
				LSVLLCWVSADIRCHSCYKVPVLGCVDR
				QSCRLEPGQQCLTTHAYLGKMWVFSNLR
				CGTPEEPCQEAFNQTNRKLGLTYNTTCCN
				KDNCNSAGPRPTPALGLVFLTSLAGLGLW
				LLH
343	A	3	1234	EFGNRFDVNNCSICYHWVTSRPQEPAVFS
				ADYRGCHVLEKDGRFHLRVFMEAVLPNG
				RVDVAQDATLICPKPDPSRTLDSQLAPPA
				MFSVSIPQTLSFLPTSGHTSQGSGHAFPSPL
				DPGHSSVHPTPALPSPGPGPTLATLAQPH
				WGTLEHWDVNKRDYIGTHLSQEQCQVAS
				GHLPCIVRRTSKEACQQAGCCYDNTREVP
				CYYGNTATVQCFRDGYFVLVVSQEMALT
				HRITLANIHLAYAPTSCSPTQHTEAFVVFY
				FPLTHCGTTMQVAGDQLIYENWLVSGIHI
				QKGPQGSITRDSTFQLHVRCVFNASGFLPI
				QASIFPPPSPAPMTQPGPLRLELRIAKDETF
				SSYYGEDDYPIVRLLREPVHVEVRLLQRT
				DPNLVLLLHQCWGAPSANPFQQPQWPILSD
344	A	1	665	AAAASNWGLITNIVNSIVGVSVLTMPFCF
				KQCGIVLGALLLVFCSWMTHQSCMFLVK
				SASLSKRRTYAGLAFHAYGKAGKMLVET
				SMIGLMLGTCIAFYVVIGDLGSNFFARLFG
				FQVGGTFRMFLLFAVSLCIVLPLSLQRNM
				MASIQSFSAMALLFYTVFMFVIVLSSLKH
				GLFSGQWLRRVSYVRWEGVFRCIPIFGMS
				FACQSQVLPTYDSLDEPSV
345	A	2	1200	PRVRLLRPSRSRSCRGLLSTRAPGPSPFRS
				LHSSPLLPHAMKSPFYRCQNTTSVEKGNS
				AVMGGVLFSTGLLGNLLALGLLARSGLG
				WCSRRPLRPLPSVFYMLVCGLTVTDLLGK
				CLLSPVVLAAYAQNRSLRVLAPALDNSLC
				QAFAFFMSFFGLSSTLQLLAMALECWLSL
				GHPFFYRRHITLRLGALVAPVVSAFSLAFC
				ALPFMGFGKFVQYCPGTWCFIQMVHEEG
				SLSVLGYSVLYSSLMALLVLATVLCNLGA
				MRNLYAMHRRLQRHPRSCTRDCAEPRAD
				GREASPQPLEELDHLLLLALMTVLFTMCS
				LPVIYRAYYGAFKDVKEKNRTSEEAEDLR
				ALRFLSVISIVDPWIFIIFRSPVFRIFFHKIFI
				RPLRYRSRCSNSTNMESSL
346	A	2	1149	CSEAEYTSAATEAGLELVDKGKAKELPGS
				QVIFEGPTLGQQEDQERKRLCKAMTLCIC
				YAASIGGTATLTGTGPNVVLLGQMNELFP
				DSKDLVNFASWFAFAFPNMLVMLLFAWL
				WLQFVYMRFNFKKSWGCGL*SKKNEKA
				ALKVLQEEYRKLGPLSFAEINVLICFFLLVI
				LWFSRDPGFMPGWLTVAWVEGETKYVS
				DATVAIFVATLLFIVPSQKPKFNFRSQTEE
				ERKTPFYPPPLLDWKVTQEKVPWGIVLLL
				GGGFALAKGSEASGLSVWMGKQMEPLH
				AVPPAAITLILSLLVAVFTECTSNVATTTL
				FLPIFASMSRSIGLNPLYIMLPCTLSASFAF
				MLPVATPPNAIVFTYGHLKVADMVTQLF
				LFTPVGL
347	A	292	1442	ELARRPKQQSSEKSRNMIRNWLTIFILFPL
				KLVEKCESSVSLTVPPVVKLENGSSTNVS
				LTLRPPLNATLVITFEITFRSKNITILELPDE
				VVVPPGVTNSSFQVTSQNVGQLTVYLHG
				NHSNQTGPRIRFLVIRSSAISIINQVIGWIYF
				VAWSISFYPQVIMNWRRKSVIGLSFDFVA
				LNLTGFVAYSVFNIGLLWVPYIKEQFLLK
				YPNGVNPVNSNDVFFSLHAVVLTLIIIVQC
				CLYERGGQRVSWPAIGFLVLAWLFAFVT
				MIVAAVGVITWLQFLFCFSYIKLAVTLVK
				YFPQAYMNFYYKSTEGWSIGNVLLDFTG
				GSFSLLQMFLQSYNNDQWTLIFGDPTKFG
				LGVFSIVFDVVFFIQHFCLYRKRPGYDQLN
348	A	3	816	IRNLNSPALLEDSVIRQAKAAGKRIVFYG
				DETWVKLFPKHFVEYDGTTSFFVSDYTEV
				DNNVTRHLDKVLKRGDWDILILHYLGLD
				HIGHISGPNSPLIGQKLSEMDSVLMKIHTS
				LQSKERETPLPNLLVLCGDHGMSETGSHG
				ASSTEEGNTPLILISSAFERKPGDIRHPKHV
				QQTDVAATLAIALGLPIPKDSVGSLLFPVV
				EGRPMREQLRFLHLNTVQLIKLLQENVPS
				YEKDPGFEQFKMSKRLHGNWIKLYLEEK
				HSEVLFNL
349	A	424	1	EVRVQAPVSRPVLTLHHGPADPAVGDMV
				QLLCEAQRGSPPILYSFYLDEKIVGNHSAP
				CGGTTSLLFPVKSEQDAGNYSCEAENSVS
				RERSEPKKLSLKGSQVLFTPASNWLVPWH
				IVGTALHLELWVVSGMEGAQLFSRI
350	A	315	679	SPVWTEKRKMQDTGSVVPLHWFGFGYA
				ALVASGGIIGYVKAGSVPSLAAGLLFGSL
				AGLGAYQLSQDPRNVWVFLATSGTLAGI
				MGMRFYHSGKFMPAGLIAGASLLMVAK
				VGVSMFNRPH
351	A	1	1017	MGLGPVFLLLAGIFPFAPPGAAAEPHSLR
				YNLTVLSWDGSVQSGFLAEVHLDGQPFL
				RYDRQKCRAKPQGQWAEDVLGNKTWDR
				ETRDLTGNGKDLRMTLAHIKDQKEGLHS
				LQEIRVCEIHEDNSTRSSQHFYYDGELFLS
				QNLETEEWTVPQSSRAQTLAMNVRNFLK
				EDAMKTKTHYHAMHADCLQELRRYLES
				GVVLRRTVPPMVNVTRSEASEGNITVTCR
				ASSFYPRNIILTWRQDGVSLSHDTQQWGD
				VLPDGNGTYQTWVATRICRGEEQRFTCY
				MEHSGNHSTHPVPSELVSLQVLDQHPVGT
				SDHRDATQLGFQPLMSALGSTGSTEGT
352	A	2	462	EFQEAAKLYHTNYVRNSRAIGVLWAIFTI
				CFAIVNVVCFIQPYWIGDGVDTPQAGYFG
				LFHYCIGNGFSRELTCRGSFTDFSTLPSGA
				FKAASFFIGLSMMLIIACIICFTLFFFCNTAT
				VYKICAWMQLTSAACLVLGCMIFPDGWD
				SDEVN
353	A	170	619	AWSRRRSWRRRRRRSPRRE/LMPEKRAG
				AQAAGSTWLQGFGPPSVYHAAIVIFLEFF
				AWGLLTTPMLTVLHETFSQHTFLMNGLIQ
				GVKGLLSFLSAPLIGALSDVWGRKPFLLG
				TVFFTCFPIPLMRISPCLCKYRIRDKRPYN
				MIFGMN
354	A	170	619	AWSRRRSWRRRRRRSPRRE/LMPEKRAG
				AQAAGSTWLQGFGPPSVYHAAIVIFLEFF
				AWGLLTTPMLTVLHETFSQHTFLMNGLIQ
				GVKGLLSFLSAPLIGALSDVWGRKPFLLG
				TVFFTCFPIPLMRISPCLCKYRIRDKRPYN
				MIFGMN
355	A	337	642	FAFPHYYIKPYHLKRIHRAVLRGNLEKLK
				YLLLTYYDANKRDRKERTALHLACATGQ
				PEMVHLLVSRRCELNLCDREDRTPLIKAV
				QLRQEACATLLLQNGA
356	A	609	6	PLGVNGLAFLIMVFLIGVCCVPFKEPALQP
				TEVRNCFGREVAVANRFFFIVFSDAICWIP
				VFVVKILSLFRVEIPGQSLLSFPSIIHRAFLR
				PSFDKARVFQRNISLNYHPCMKIPSQELRN
				PGERLWHLSSRTPSTYGGSRTAPEPGPCL
				MDQGIRHKSPLISHQGSLPKDSSSKPAHRP
				RQLFQPESLNRQIVTGFPC
357	A	164	517	PGPGMQGPPPITPTSWSLPPWRAYVAAAV
				LCYINLLNYMNWFIIAGVLLDIQEVFQISD
				NHAGLLQTVFVSCLLLSAPVFGYLGDRHS
				RKATMSFGILLWSGAGLSSSFISPRYSWLF
358	A	113	1089	KMTSLAQQLQRLALPQSDASLLSRDEVAS
				LLFDPKEAATIDRDTAFAIGCTGLEELLGI
				DPSFEQFEAPLFSQLAKTLERSVQTKAVN
				KQLDENISLFLIHLSPYFLLKPAQKCLEWL
				IHRFHIHLYNQDSLIACVLPYHETRIFVRVI
				QLLKINNSKHRWFWLLPVKQSGVPLAKG
				TLITHCYKDLGFMDFICSLVTKSVKVFAE
				YPGSSAQLRVLLAFYASTIVSALVAAEDV
				SDNIIAKLFSYIQKGLKSSLPDYRAATYMII
				CQISVKVTMENTFVNSLASQIIKTLTKIPSL
				IKDGLSCLIVLLQRQKPESLGKKYVQLN
359	A	1	724	VEVPSAVPRPTLDTSRAATCAPGHAVHHP
				QSLSWPRTAGTVGGSPALRGAHP*PLPTV
				PADCCEP*EQCPGRRGQQRLCAPSHLLAQ
				LLLWLCTPVPKHWGSAQQPGGQVYH*CL
				GLPPHPPWQPG*HRG*CVGACGFRDP*CG
				QGHDSHPTQASGSKAPYPGPAPASGSART
				NRASQHLWPRDPAPGGSPHRARPCLQCPP
				CLLPLPGVLTGWGWVWQKAELFEAWGQ
				EQSRHSSNGVCT
360	A	3	4047	SSNSQLYRASALFETIRHEAQLSTDYKLSL
				FDLQTSSYQALQRVLVSLGHHDEALAVA
				ERGRTRAFADLLVERQTGQQDSDPYSPVT
				IDQILEMVNGQRGLVLYYSLAAGYLYSW
				LLAPGAGIVKLFHEHYLGENTVENSSDFQA
				SSSVTLPTATGSALEQHIASVREALGVESH
				YSRACASSETESEAGDIMDQQFEEMNNKL
				NSVTDPTGFLRMVRRNNLFNRSCQSMTSL
				FSNTVSPTQDGTSSLPRRQSSFAKPPLRAL
				YDLLIAPMEGGLMHSSGPVGRHRQLILVL
				EGELYLIPFALLKGSSSNEYLYERFGLLAV
				PSIRSLSVQSKSHLRKNPPTYSSSTSMAAV
				IGNPKLPSAVMDRWLWGPMPSAEEEAYM
				VSELLGCQPLVGSVATKERVMSALTQAE
				CVHFATHISWKLSALVLTPSMDGNPASSK
				SSFGHPYTIPESLRVQDDASDGESISDCPPL
				QELLLTAADVLDLQLPVKLVVLGSSQESN
				SKVAADGVIALTRAFLAAGAQCVLVSLW
				PVPVAAFKMFIHAFYSSLLNGLKASAALG
				EAMKVVQSSKAFSHPSNWAGFMLIGSDV
				KLNSPSSLIGQALTEILQHPERARDALRVL
				LHLVEKSLQRIQNGQRNAMYTSQQSVEN
				KVGGIPGWQALLTAVGFRLDPPTSGLPAA
				VFFPTSDPGDRLQQCSSTLQSLLGLPNPAL
				QALCKLITASETGEQLISRAVKNMVGMLH
				QVLVQLQAGEKEQDLASAPIQVSISVQLW
				RLPGCHEFLAALGFDLCEVGQEEVILKTG
				KQANRRTVHFALQSLLSLFDSTELPKRLS
				LDSSSSLESLASAQSVSNALPLGYQQPPFS
				PTGADSIASDAISVYSLSSIASSMSFVSKPE
				GGSEGGGPGGRQDHDRSKNAYLQRSTLP
				RSQLPPQTRPAGNKDEEEYEGFSIISNEPL
				ATYQENRNTCFSPDHKQPQPGTAGGMRV
				SVSSKGSISTPNSPVKMTLIPSPNSPFQKVG
				KLASSDTGESDQSSTETDSTVKSQEESNPK
				LDPQELAQKILEETQSHLIAVERLQRSGGQ
				VSKSNNPEDGVQAPSSTAVFRASETSAFS
				RPVLSHQKSQPSPVTVKPKPPARSSSLPKV
				SSGYSSPTTSEMSIKDSPSQHSGRPSPGCD
				SQTSQLDQPLFKLKYPSSPYSAHISKSPRN
				MSPSSGHQSPAGSAPSPALSYSSAGSARSS
				PADAPDIDKLKMAAIDEKVQAVHNLKMF
				WQSTPQHSTGPMKIFRGAPGTMTSKRDV
				LSLLNLSPRPNKKEEGVDKLELKELSLQQ
				HDGAPPKAPPNGHWRTETTSLGSLPLPAG
				PPATAPARPLRLPSGNGYKFLSPGRFFPSS
				KC
361	A	36	835	KRGSVRKLKAPNP*LR/DWRMKDRMNTV
				SVALVLCLNVGVDPPDVVKTTPCARLEC
				WIDPLSMGPQKALGTIGANLQKQYENWQ
				PRARYKQSLDPTVDEVKKLCTSLRRNAK
				EERVLFHYNGHGVPRPTVNGEVWVFNKN
				YTQYIPLSIYDLQTWMGSPSIFVYDCSNA
				GLIVKSFKQFALQREQELEVAAINPNHPL
				AQMPLPPSMKNCIQLAACEATELLPMIPD
				LPADLFTSCLTTPIKIALRWFCMQKCVSLV
				PGVTLDLIEK
362	A	1797	1484	IGISCPATIFVPMFSHSLIGIGEEYQLPYYN
				MVPSDPSYEDMREVVCVKRLRPIVSNRW
				NSDECLRAVLKLMSECWAHNPASRLTAL
				RIKKTLAKMVESQDVKI
363	A	1797	1484	IGISCPATIFVPMFSHSLIGIGEEYQLPYYN
				MVPSDPSYEDMREVVCVKRLRPIVSNRW
				NSDECLRAVLKLMSECWAHNPASRLTAL
				RIKKTLAKMVESQDVKI
364	A	47	520	AAGVQMKLEFLQRKFWAATRQCSTVDG
				PCTQSCEDSDLDCFVIDNNGFILISKRSRET
				GRFLGEVDGAVLTQLLSMGVFSQVTMYD
				YQAMCKPSSHHHSAAQPLVSPISAFLTAT
				RWLLQELVLFLLEWSVWGSWYDRGAEA
				KSCLPSLPQTQEAGPA
365	A	3	631	EYGTSQVGAYQPFFRGHATMNTKRRVPW
				LFGEEHTRLIREAIRERYGLLPYWYSLFYH
				AHVASQPVMRPLWVEFPDELKTFDMEDE
				YMLGSALLVHPVTEPKATTVDVFLPGSNE
				VWYDYKTFAHWEGGCTVKIPVALDTIPV
				FQRGGSVIPIKTTVGKSTGWMTESSYGLR
				VALSTKGSSVGELYLDDGHSFQYLHQKQ
				FLHRKFSFC
366	A	1773	3913	FEQNTKLDQAQQAPEDHYPISLLLPSHMA
				IGLLMAQEGHCKDSSAMGEEAHHPLTPA
				TPPFPPLSPDWGHMQPDFFVPVAVPAVFR
				GPPQLQCHGRRLFLNSPCAQKSSSGLVVE
				PGLSRTLLEMVKLTSMRGQFLEAQIPTGIS
				LTLQYQLYQKQTNKNMSYSFVLFLKWVA
				LGQGRRAGYPSLEDADSRRFNGSRSFLIT
				VIGITLTVEIVTSGMMKGTRVRWSGAGNE
				GMMGLEEGRNERSVKEAPPRRAVEAQPK
				DRTWDVGKGQGTEGEGRGLEVEGQQHQ
				GSEPGTIPFSVSWGVLLLAGLCCLVPSSLV
				EDPQEDAAQKTDTSHHDQGDWEDLACQ
				KISYNVTDLAFDLYK\SWLIYH\NQ\HVLV
				TPTSVAMAFAMLSLGTKADTRTEILEGLN
				VNLTETPEAKIHECFQQVLQALSRPDTRL
				QLTTGSSLFVNKSMKLVDTFLEDTKKLYH
				SEASSINFRDTEEAKEQINNYVEKRTGRK
				VVDLVKHLKKDTSLALVDYISFHGKWKD
				KFKAERIMVEGFHVDDKTIIRVPMINHLG
				RFDIHRDRELSSWVLAQHYVGNATAFFIL
				PDPKKMWQLEEKLTYSHLENIQRAFDIRSI
				NLHFPKLSISGTYKLKRVPRNLGITKIFSNE
				ADLSGVSQEAPLKLSKAVHVAVLTIDEKG
				TEATGAPHLEEKAWSKYQTVMFNRPFLVI
				IKEYITNFPLFIGKVVNPTQK
367	A	47	888	TLRARALQARPRTGSSCTAATWTS/SGAS
				QHSLRALSWRRLYLSRAKLKASSRTSALL
				SGFAMVAMVEVQLESDHEYPPGLLVAFS
				ACTTVLVAVHLFALMVSTCLLPHIEAVSN
				IHNLNSVHQSPHQRLHRYVELAWGFSTAL
				GTFLFLAEVVLVGWVKFVPIGAPLDTPTP
				MVPTSRVPGTLAPVATSLSPASNLPRSSAS
				AAPSQAEPACPPRQACGGGGAHGPGWQA
				AMASTAIMVPVGLVFVAFALHFYRSLVA
				HKTDRYKQELEELNRLQGELQAV
368	A	46	501	MIVYWVLMSNFLFNTGKFIFNFIHHINDT
				DTILSTNNSNPVICPSAGSGGHPDNSSMIF
				YANDTGAQQFEKWWDKSRTVPFYLVGL
				LLPLLNFKSPSFFSKFNILGINNQVILPGVT
				EMPGYCPFLLPVSTECCAVATSYTCFEEK
				NIGQCC
369	A	385	1605	TTTLDIQRATCCVLLICLFLGANAVWYGA
				VGDSAYSTGHVSRLSPLSVDTVAVGLVSS
				VVVYPVYLAILFLFRMSRSKVINTLADHR
				HRGTDFGGSPWLLIITVFLRSYKFAISLCTS
				YLCVSFLKTIFPSQNGHDGSTDVQQRARR
				SNRRRQEGIKIVLEDIFTLWRQVETKVRA
				KIRKMKVTTKVNRHDKINGKRKTAKEHL
				RKLSMKEREHGEKERQVSEAEENGKLDM
				KEIHTYMEMFQRAQALRRRAEDYYRCKI
				TPSARKPLCNRVRMAAVEHRHSSGLPYW
				PYLTAETLKNRMGHQPPPPTQQHSIIDNSL
				SLKTPSECLLTPLPPSALPSADDNLKTPAE
				CLLYPLPPSADDNLKTPPECLLTPLPPSAPP
				SADDNLKTPPECVCSLPFHPQRMIISRN
370	A	328	1146	NPNPSIGDIKDIKKAAKSMLDPAHKSHFH
				PVTPSLVFLCFIFDGLHQALLSVGVSKRSN
				TVVGNENEERGTPYASRFKDMPNFIALEK
				SSVLRHCCDLLIGVAAGSSDKICTSSLQVQ
				RRFKAMMASIGRLSHGESADLLISCNAES
				AIGWISSRPWVGELMFTFLFGDFESPLHKL
				RKSS*LPRKHR*QPINAVRMFLDQCMDGS
				IALRAIVSEIPVFEEKKNNG*KGIGEIF*VW
				GCTLPPHYWGAVTTNVPKLSNSGKLLGQ
				DEQPHIFG
371	B	139	13320	MMMVMMVVMVVVVVVVELRAIKMQM
				EDRWSNRPDTATALAGGAVMPELILYVAI
				TLSVAERLVGPAPHPLKMFACSKFVSTPS
				LVKSTSQLLSRPLSAVVLKRPEILTDESLS
				KLGSLMSPLTSTCLLNRKLPKPAPISKGTS
				NNSSPKFNWKLGLATSWGGWFLGLGLET
				VFGEPSSLGYARNPSLKQQLFSYAILGFAL
				SEAMGLFCLMVAFLILFAM
372	A	1	3044	FRAALAIFARACFLLSSLASLPVFLPVFPA
				RPPPSSPAGPLPGGIIWSPAMDAPKAGYAF
				EYLIETLNDSSHKKFFDVSKLGTKYDVLP
				YSIRVLLEAAVRNCDGFLMKKEDVMNIL
				DWKTKQSNVEVPFFPARVLLQDFTGIPAM
				VDFAAMREAVKTLGGDPEKVHPACPTDL
				TVDHSLQIDFSKCAIQNAPNPGGGDLQKA
				GKLSPLKVQPKKLPCRGQTTCRGSCDSGE
				LGRNSGTFSSQIENTPILCPFHLQPVPEPET
				VLKNQEVEFGRNRERLQFFKWSSRVFKN
				VAGIPPGTGMAHQINLEYLSRVVFEEKDL
				LFPDSVVGTDSHITMVNGLGILGWGVGGI
				ETEAVMLGLPVSLTLPEVVGCELTGSSNP
				FVTSIDVVLGITKHLRQVGVAGKFVEFFG
				SGVSQLSIVDRTTIANMCPEYGAILSFFPV
				DNVTLKHLEHTGFSKAKLESMETYLKAV
				KLFRNDQNSSGEPEYSQVIQINLNSIVPSV
				SGPKRPQDRVAVTDMKSDFQACLNEKVG
				FKGFQIAAEKQKDIVSIHYEGSEYKLSHGS
				VVIAAVISCTNNCNPSVMLAAGLLAKKA
				VEAGLRVKLPYIRTSLSPGSGMVTHYLSSS
				GVLPYLSKLGFEIVGYGCST*VGNTAPLS
				DAVLNAVKQGDLVTCGILSGNKNFEGRL
				CDCVRANYLASPPLVVAYAIAGTVNIDCQ
				TEPLGTDPTGKNIYLHDIWPSREEVHRVE
				EEHVILSMFKALKDKIEMGNKRWNSLEA
				PDSVLFPWDLKSTYIRCPSFFDKLTKEPIA
				LQA\IENAHVLLYLGDSVTT\DHISPA\KSIA
				RNSAAAKYLTNRGLTPREFNSYGARRGN
				DAVMTRGTFANIKLFNKFIGKPAPKTIHFP
				SGQTLDVFEAAELYQKEGIPLIILAGKKYG
				SGNSRDWAAKGPYLLGVKAVLAESYEKI
				HKDHLIGIGIAPLQFLPGENADSLGLSGRE
				TFSLTFPEELSPGITLNIQTSTGKVFSVIASF
				EDDVEITLYKHGGLLNFVARKFS
373	B	103	905	XTSKSWLHGSIFGDINSSPSEDNWLKGTR
				RLDTDHCNGNADDLDCSSLTDDWESGK
				MNAESVITSSSSHIISQPPGGNSHSLSLQSQ
				LTASERFQENSSDHSETRLLQEVFFQAILL
				AVCLIISACARWFMGEILASVFTCSLMITV
				AYVKSLFLSLASYFKTTACARFVKI
374	B	103	905	XTSKSWLHGSIFGDINSSPSEDNWLKGTR
				RLDTDHCNGNADDLDCSSLTDDWESGK
				MNAESVITSSSSHIISQPPGGNSHSLSLQSQ
				LTASERFQENSSDHSETRLLQEVFFQAILL
				AVCLIISACARWFMGEILASVFTCSLMITV
				AYVKSLFLSLASYFKTTACARFVKI
375	B	103	905	XTSKSWLHGSIFGDINSSPSEDNWLKGTR
				RLDTDHCNGNADDLDCSSLTDDWESGK
				MNAESVITSSSSHIISQPPGGNSHSLSLQSQ
				LTASERFQENSSDHSETRLLQEVFFQAILL
				AVCLIISACARWFMGEILASVFTCSLMITV
				AYVKSLFLSLASYFKTTACARFVKI
376	A	40	999	SRSCVCSQESFGGCCVSGLIAMGTKAQVE
				RKLLCLFILAILLCSLALGSVTVHSSEPEVR
				IPENNPVKLSCAYSGFSSPRVEWKFDQGD
				TTRLVCYNNKITASYEDRVTFLPTGITFKS
				VTREDTGTYTCMVSEEGGNSYGEVKVKL
				IVLVPPSKPTVNIPSSATIGNRAVLTCSEQD
				GSPPSEYTWFKDGIVMPTNPKSTRAFSNSS
				YVLNPTTGELVFDPLSASDTGEYSCEARN
				GYGTPMTSNAVRMEAVERNVGVIVAAVL
				VTLILLGILVFGIWFAYSRGHFDRTKKGTS
				SKKVIYSQPSARSEGEFKQTSSFLV
377	A	52	448	HPIVGLRRMGDFKACQFQEGEGRSVGGV
				SRSP*WPSLRASPLSPTSSDSIPSGHPAPPTP
				PQPPTQPLSEANSQSEGSLSLERRFPVT*P
				WGTSLPFLSPPTPSAVLLARTLAYTKDGG
				CGCGAELVLTPIK
378	B	102	431	MIIYRDLISHDEMFSDIYKIREIADGLCLEV
				EGKMVSRTEGNIDDSLIGGNASAEGPEGE
				GTESTVITGVDIVMNHHLQETSFTKEAYK
				KYIKDYMKSIKGKLEEQRPDR
379	B	14	419	MRHPHRLQPGCRGMVPVPADPVPVQSAE
				DLSLFLSTRCVVVLLSAELVQHFHKPALL
				PLLQRAFHPPHRVVRLLCGVRDSEEFLDF
				FPDWAHWQELTCDDTYVAAVKKAISEX
380	A	115	644	TTTMSSKKAKTKTTKKRPQRATSNVFAM
				FDQSQIQEFKEAFNMIDQNRDGFIDKEDL
				HDMLASLGKNPTDAYLDAMMNEAPGPIN
				FTMFLTMFGEKLNGTDPEDVIRNAF/ASCF
				DEEATGTIQEDYLRELLTTMGDRFTDEEV
				DELYREAPIDKKGNFNYIEFTRILKHGAK
				DKDD
381	A	384	722	PEETPLPTLPERGSLRTGWRRWGPSRAPG
				ALPGMSRPTHPKAGAAAPCCPSPGLGND
				DPPKSPSAPQTQGLRPPAPGIRESIPAQHPQ
				HPRVWPPCTSLSHPRRSVPLAPQCP
382	C	120	356	MMYRTHCQRILDTVIRANFDEVQSFLLHF
				WQGMPPHMLPVLGSSTVVNIVGVCDSIL
				YKAISGVLMPTVLQALPDSLT
383	A	1	1052	MPGTCKCTGAEASRIWKGEDVCEYWGQ
				RVVAFLAMVMGTHTYSHWPSCCPSKGQ
				DTSEELLRWSTVPVPPLEPARPNRHPESCR
				ASEDGPLNSRAISPWRYEPDKCRPHRLDR
				DLNRLPQDLYHARCLCPHCVSLQTGSHM
				DPRGNSELLYHNQTVFYRRPCHGEKGTH
				KGYCLERRLYRVSLACGAVLVGPTKMLS
				ARDRRDRHPEEGVVAELQGFAVDKAFLT
				SHKGILLETELALTLIIFICFTASISAYMAA
				ALLEFFITLAFLFLYATQYYQRFDRINWP
				WLDFLRCVSAIIIFLVVSFAAVTSRDGAAI
				AAFVFGIILVSIFAYDAFKIYRTEMAPGAS
				QGDQQ
384	A	1	381	SRYSRVDDFVAEPSSAAERLCRHGYTME
				RPDKAALNALQPPEFRNESSLASTLKTLLF
				FTALMITVPIGLYFTTKSYIFEGALGMSNR
				DSYFYAAIVAVVAVHVVLALFVYVAWN
				EGSRQWREGKQD
385	A	3	270	KADVKNLSGKNRPVNSKIHDIFKGWALQ
				PLDPDGRVKIWVYGVSGGAFLIMIFLIFTS
				YLVCKKPKPHQSTPPQQKPLTLSYDGDLDM
386	A	366	892	PCVYSQFPAGEQCLKLHSPAEASPPALEA
				SEAQTRKAPECGSGVPEVAGGSCPCLLLC
				LPRHQAVPTQGPGTYSPCTSHQPHIFPRPA
				APHHLGLLQNPHNAASCIQCLYPAGVATT
				MPRRKAEGDAEGD/KAKVKDEPQRRPAK
				LSAKPAPPNPEAKPKNAPGVTLSLRGTAT
				RF
387	A	1800	983	IILLILTEDDGFNRSIHEVILKNITWYSERV
				LTEISLGSLLILVVIRTIQYNMTRTRDKYL
				DTNCLAALANMSAQFRSLHQYAAQRIISL
				FSLLSKKHNKVLEQATQSLRGSLSSNDVP
				LPDYAQDLNVIEEVIRMMLEIINSCLTNSL
				HHNPNLVYALLYKRDLFEQFRTHPSFQDI
				MQNIDLVISFFSSRLLQAGAELSVERVLEII
				KQGVVALPKDRLKKFPELKFKYVEEEQPE
				EFFIPYVWSLVYNSASRPCTGIHRTSSCSP
				WIPD
388	A	148	449	NLPGWTVLFLSVLGLLASRAVSALSSLFA
				AEVFPTVIRGAGLGLVLGAGFLGQAAGPL
				DTLHGRQGFFLQQVVFASLAVLALLCVLL
				LPESRSRGLPQSL
389	A	641	1310	TCTYKYLMGWIRGRRSRHSWEMSEFHNY
				NLDLKKSDFSTRWQKQRCPVVKSKCREN
				ASPFFFCCFIAVAMGIRFIIMVAIWSAVFL
				NSLFNQEVQIPLTESYCGPCPKNWICYKN
				NCYQFFDESKNWYESQASCMSQNASLLK
				VYSKEDQDLLKLVKSYHWMGLVHIPTNG
				SWQWEDGSILSPNLLTIIEMQKGDCALYA
				SSFKGYIENCSTPNTYICMQRTV
390	A	642	290	VGERLTLPGLVSADNGTYTCEASNKHGH
				ARALYVLVVYDPGAVVEAQTSVPYAIVG
				GILALLVFLIICVLVGMVWCSVRQKGSYL
				THEASGLDEQGEAREAFLNGSDGHKRKE
				EFFI
391	A	182	703	CCCNVFNCFSLSLQTWALHSLSLIIDSAGP
				LYYVHVEPTLSLIIIVVVNVPPTHAEVHQS
				LGRCLNALITTLGPELQGNSTSISTLRTSCL
				LGCAVMQDNPDCLVQAQAISCLQQLHMF
				APRHVNLSSLVSCLCVNLCSPYLLLRRAV
				LACLRQLVQREAAEVSEHAVMLAKDS
392	A	221	858	EMSERWKRRGNSTRTSSLASGAGDPEPDL
				WIIQPQELVLGTTGDTVFLNCTVLGDGPP
				GPIRWFQGAGLSREAIYNFGGISHPKATA
				VQASNNDFSILLQNVSSEDAGTYYCVKFQ
				RKPNRQYLSGQGTSLKVKAKSTSSKEAEF
				TSEPATEMSPTGLLVVFAPVVLGLKAITL
				AALLLALATSRRSPGQEDVKTTGPAGAM
				NTLSWSKGQE
393	A	674	1228	APLESLKPPPNVPPSYELRVVIWNTEDVV
				LDDENPLTGEMSSDIYVKSWVKGLEHDK
				QETDVHFNSLTGEGNFNWRFVFRFDYLPT
				EREVSVWRRSGPFALEEAEFRQPAVLVLQ
				VWDYDRISANDFLGSLELQLPDMVRGAR
				GPELCSVQLARNGAGPRCNLFRCRRLRG
				WWPVVKLKEAEDVE
394	A	2522	1737	GPRARPPVLTRRSSWPPRRSRGSMRFKNR
				FQRFMNHRAPANGRYKPTCYEHAANCYT
				HAFLIVPAIVGSALLHRLSDDCWEKITAWI
				YGMGLCALFIVSTVFHIVSWKKSHLRTVE
				HCFHMCDRMVIYFFIAASYAPWLNLREL
				GPLASHMRWFIWLMAAGGTIYVFLYHEK
				YKGVELFFYLTMGFSPALVVTSMNNTDG
				LQELACGGLIYCLGVVFFKSDGIIPFAHAI
				WHLFVATAAAVHYYAIWKYLYRSPTDF
				MRHL
395	A	513	273	KTQETHIYISEHIFFPFLQGFGNLPICMAKT
				DLSLSHQPDKKGVPSDFILPISDVRASIGA
				GFIYPLVGTGSRESPLWL
396	A	1	2073	MKPCAHSWNAELSRNIIRHSFNLVMVAA
				SQVAVSQLLGSYEILLLVSIELMFCFGLGY
				FFIPMQEWPNTYGERVFVDVESSVFKWN
				HKCLHKTEAERDYTKKRLKLCGHKPGNA
				VGQQKLEEARNRFFTRAPGGSAALPTLRF
				QPSDTDFRLLASRTILTFETKNPSELAERL
				RSVCGNQSNAYARLLEYRLNALRGLWNA
				QRQLALEEQHERESSGDEETLALLKRQGL
				LQQPEQAPFTSRMGLLLVFPLIQSQSRTDP
				SLCNITAEVLLNCLRDCQPLSLTKEPADCL
				NGIETLLCSWLEETSDTGRHIPHKQKENA
				AAALVALACARGFVYCRNEELEPGWVAF
				GSGSLLHRPVSFDNKPHSLFQVIDQNTLQ
				VCQVVPMPANHLPIGSTMSTVHLSSDGTY
				FYWIWSPASLNEKTPKGHSVFMDIFELVT
				LKGKKAKGKKVAPAPAVVKKQEAKKVV
				NSLFEKR\DIQPKRELTYFVKW/PRYVRLQ
				QQRAILYKQLKVPPAINQFTQALNCQTVT
				QLLKLAHKYRPETKQEKKQRLLAQAEKK
				AAGKGGVPTKRPPALRAGVNTITTLVENK
				KAQLVVIAHDVDSIELVVFLPALCCKMGV
				PYCIIKGKARLGRLVHRKTCTTVAFTQVN
				LEDKGALAKLVEGIRTNDNDRYDEICCH
				WGGNILGPKSVACIAKLEKAKAKELATK
				LG
397	A	145	1752	SELLLTFSFRLRMTQNKLKLCSKANVYTE
				VPDGGWGWAVAVSFFFVEVFTYGIIKTFG
				VFFNDLMDSFNESNSRISWIISICVFVLTFS
				APLATVLSNRFGHRLVVMLGGLLVSTGM
				VAASFSQEVSHMYVAIGIISGLGYCFSFLP
				TVTILSQYFGKRRSIVTAVASTGECFAVFA
				FAPAIMALKERIGWRYSLLFVGLLQLNIVI
				FGALLRPIFIRGPASPKIVIQENRKEAQYM
				LENEKTRTSIDSIDSGVELTTSPKNVPTHT
				NLELEPKADMQQVLVKTSPRPSEKKAPLL
				DFSILKEKSFICYALFGLFATLGFFAPSLYII
				PLGISLGIDQDRAAFLLSTMAIAEVFGRIG
				AGFVLNREPIRKIYIELICVILLTVSLFAFTF
				ATEFWGLMSCSIFFGFMVGTIGG\LTFHCL
				LRMMSWALQKMSSAAGVYIFIQSIAGLA
				GPPLAGLLVDQSKIYSRAFYSCAAGMALA
				AVCLALVRPCKMGLCQHHHSGETKVVSH
				RGKTLQDIPEDFLEMDLAKNEHRVHVQM
				EPV
398	A	1	520	PPRAAELAPSPPADMFESKNGPEYASFFPV
				MGASAAMVFSALGPAYGTTKSGTGISAM
				SVIRPEQIMKSIIPVVMAGIIAISGLVVAVLI
				ANSLECSVYADDLEMSFLFPRMFIYKDLA
				CSCVSGTALVSQLFITLVRGSPCGFLLFRL
				PGWNRPPRRARGPARNCVPQSFWM
399	A	3	449	HASGFVVQGSNGEFPFLTSSERLEVVSRV
				RQAMPMNRLLLAGSGCESTQATVEMTVS
				MAQVGADAAMVVTPCYYRGRMSSAALI
				HHYTKVADLSPIPVVLYSVPANTGLDLPV
				DAVVTLSQHPNIVGMKDSGGDVTRIGLIV
				HKTQEA
400	A	35	637	MPIGLRGLMIAVMLAALMSSLTSIFNSSST
				LFTMDIWRRLRPRSGERELLLVGRLVIVA
				LIGVSVAWIPVLQDSNSGQLFIYMQSVTSS
				LAPPVTAVFVLGVFWRRANEQGAFWGLI
				AGLVVGATRLVLEFLNPAPPCGEPDTRPA
				VLGSIHYLHFAVALFALSGAVVVAGSLLT
				PPPQSVQIENLTWWTLAQDVPLGTKA
401	A	1	1128	YNRAMFHPHAVNKIALSLNNKNP\RSKVL
				FLELLAAVCLVRGGHKLFYLAFDNFKEV
				CGEKQRFEKLMEHFRNEDNNIDFMVASM
				QFINIVVHSVEDMNFRVHLQYEFTKLGLD
				EYLDKLKHTESDKL\QVQIQAYLDNVFDV
				GALLEDAETKNAALERVEELEENISHLSE
				KLQDTENEAMSKIVELEKQLMQRNKELD
				VVREIYKDANTQVHTLRKMVKEKEEAIQ
				RQSTLEKKIHELEKQGTIKIQKKGDGDIAI
				LPVVASGTLSMGSEVVAGNSVGPTMGAA
				SSGPLPPPPPPLPPSSDTPETVQNGPVTPPM
				PPPPTPPPPPPPPPPPPPPPPLPGPAAETVPA
				PPLAPPLPSAPPLPGTSSPTVVFNSGLA
402	A	53	1004	NSAKKNVSSPTSSNKEVVMRNDQNNGD
				MKPFQNFTTIPITQALNYNLSKEGHLEKEP
				WNAFSHHGPVNVSINGIPCILFWAKRIMIK
				FKNQTWLDLTDEPFGQKVTVDPDNSNCS
				EESARLSLKLGDAGNPRSLAIRFILTNYNK
				LSIQSWFSLRRVEIISNNSIQAVFNPTGVYA
				PSGYSYRCQRVGSLQQDQALLLPSDTDD
				GSSLWEVTFIDFQIQGFAIKGGRFTKAQDC
				ASSFSPAFLIGLAMSLILLLVLAYALHMLI
				YLRYLDQQYDLIASPAHFSQLKARDTAEE
				KELLRSQGAECYKLRSQQISKIYV
403	A	1660	657	RRGIRDSGIEYLLDQTDVLVVGVLGLQGT
				GKSMVMSLLSANTPEEDQRTYVFRAQSA
				EMKERGGNQTSGIDFFITQERIVFLDTQPIL
				SPSILDHLINNDRKLPPEYNLPHTYVEMQS
				LQIAAFLFTVCHVVIVVQDWFTDLSLYRF
				LQTAEMVKPSTPSPSHESSSSSGSDEGTEY
				YPHLVFLQNKARREDFCPRKLRQMHLMI
				DQLMAHSHLRYKGTLSMLQCNVFPGLPP
				DFLDSEVNLFLVPFMDSEAESENPPRAGP
				GSSPLFSLLPGYRGHPSFQSLVSKLRSQVM
				SMARPQLSHTILTEKNWFHYAARIWDGV
				RKSSALAEYSRLLA
404	A	2	479	IKIRSLGCLIAAMILLSSLTAHPILRLIITMEI
				SFFSFFILLYSFAIHRYIPFILWPIPDLFNDLI
				ACAFLVGAVVFAVRSRRSMNLHYLLAVI
				LIGAAGVFAFIDVCLQRNHFRGKKAKKH
				MLVPPPGKEKGPQQGKGPEPAKPPEPGKP
				PGPAKGKK*LGCLIAAMILLSSLTAHPILR
				LIITMEISFFSFFILLYSFAIHRYIPFILWPIPD
				LFNDLIACAFLVGAVVFAVRSRRSMNLH
				YLLAVILIGAAGVFAFIDVCLQRNHFRGK
				KAKKHMLVPPPGKEKGPQQGKGPEPAKP
				PEPGKPPGPAKGKK
405	A	1	1527	MAITLRELNGLSYEEIAAIMDCPALTIAGY
				WIRVLGMQKEQLSALMDGETLDSELLNE
				LAHNPEMQKTWESYHLIRDSMRGDTPEV
				LHFDISSRVMAAIEEEPVFLRDIICEYNCAS
				IPYERDRIMQSVTKIVNAQLIRIELAGKHTI
				DVLMERLSVRIALIKKLLRLFFPLSLRVRF
				LLATAAVVLVLSLAYGMVALIGYSVSFD
				KTTFRLLRGESNLFYTLAKWENNKLHVE
				LPENIDKQSPTMTLIYDENGQLLWAQRD
				MKGWTNECILVLSGDHSIQQQLQEVRED
				DDDAEMTHSVAVNVYPATSRMPKLTIVV
				VDTIPVELKSSYMGLCGQPTNKDVLRRM
				KKRYPTTFVMVVMLASYFLISMFGGVMV
				FVFGITFPLLCMEKIVSTKAILDKNTNQCK
				GMCKGIRTLKSCLCYLINGSSIVEVQDSW
				LMGAIKFQQESRLLHHRLLSAIRIKQKEEE
				ERNKKEKKDKELESIFPSYGPFHYFKSKTI
				KEWAPFYGYDFYPLVL
406	A	1	1148	TRYDPRVRRDRCGTSDPYVKFKLNGKTL
				YKSKVIYKNLNPVWDEIVVLPIQSLDQKL
				RVKVYDRDLTTSDFMGSAFVILSDLELNR
				TTEHILKLEDPNSLEDDMGVIVLNLNLVV
				KQGDFKRHRWSNRKRLSASKSSLIRNLRL
				SESLKKNQLWNGIISITLLEGKNVSGGSMT
				EMFVQLKLGDQRYKSKTLCKSANPQWQE
				QFDFHYFSDRMGILDIEVWGKDNKKHEE
				RLGTCKVDISALPLKQANCLELPLDSCLG
				ALLMLVTLTPCAGVSVSDLCVCPLADLSE
				RKQITQRYCLQNSLKDVKDVGILQVKVL
				KAADLLAADFSGKSDPFCLLELGNDRLQT
				HTVYKNLNPEWNKVFTFPIKDIHDVLEVT
				VFDEDGDK
407	A	1138	1735	LPSLSLRLLHNCAPLVLDKTISFIICIITRPSI
				MTEIR*YTLHGVNARNQNSRLAATKPSSV
				RSGLFQLSSSSARQP/TPQRPAPRAARLPRP
				PPGPRPPPPATPRPPPPQLPALPPPAAAALR
				GMPGAVAATAAPAPRRQEPGIPPRRAPEA
				PGSPSSAVLPGRDGAGRARGRAWVWVPP
				RAGRRWRQVPERGAHRGAQ
408	A	1138	1735	LPSLSLRLLHNCAPLVLDKTISFIICIITRPSI
				MTEIR*YTLHGVNARNQNSRLAATKPSSV
				RSGLFQLSSSSARQP/TPQRPAPRAARLPRP
				PPGPRPPPPATPRPPPPQLPALPPPAAAALR
				GMPGAVAATAAPAPRRQEPGIPPRRAPEA
				PGSPSSAVLPGRDGAGRARGRAWVWVPP
				RAGRRWRQVPERGAHRGAQ
409	A	2	376	EVSLSTVPASGHHSGPSLHAENHTSQTFT
				QHFLPQSQKMHKEEHEVAVLGAPPSTILP
				RSTVINIHSETSVPDHVVWSLFNTLFLNW
				CCLGFIAFAYSVKSMDRKMVGDVTGAQA
				YASTAKCLNI
410	A	1	794	RIVFEQDHAKLGTRAGTRRDSDMAGHTQ
				QPSGRGNPRPAPSPSPVPGTVPGASERVAL
				KKEIGLLSACTIIIGNIIGSGIFISPKGVLEHS
				GSVGLALFVWVLGGGVTALGSLCYAELG
				VAIPKSGGDYAYVTEIFGGLAGFLLLWSA
				VLIMYPTSLAVISMTFSNYVLQPVFPNCIP
				PTTASRVLSMACLMLLTWVNSSSVRWAT
				RIQDMFTGGKLLALSLIIGVGLLQIFQGHF
				EELRPSNAFAFWMTPSVGHLALAFLQGS
411	A	167	853	SMDVKERRPYCSLTKSRREKERRYTNSSA
				DNEECRVPTQKSYSSSETLKAFDHDSSRL
				LYGNRVKDLVHREADEFTRQGQNFTLRQ
				LGVCEPATRRGLAFCAEMGLPHRGYSISA
				GSDADTENEAVMSPEHAMRLWGRGVKS
				GRSSCLSSRSNSALTLTDTEHENKSDSENG
				KFSFWLYNVGIQCFCLFWLTPRGGDVFLS
				LFPLILLSLSFLSISFCFNVVELKKCP
412	A	905	177	SPSGLQLPQYSAAELQSPAAPGLRHVDSA
				GWGRRRAGPAGSSGYRAGYSSSTPHDAN
				MAAQKDQQKDAEAEGLSGTTLLPKLIPSG
				AGREWLERRRATIRPWSTFVDQQRFSRPR
				NLGELCQRLVRNVEYYQSNYVFVFLGLIL
				YCVVTSPMLLVALAVFFGACYILYLRTLE
				SKLVLFGREVSPAHQYALAGGISFPFFWL
				AGAGSAVFWVLGATLVVIGSHAAFHQIE
				AVDGEELQMEPV

[0472]

TABLE 9
SEQ ID NO:	SEQ ID NO:	SEQ ID NO:	SEQ ID NO:	Identification of Priority
of full-length	of full-length	of contig	of contig	Application that contig nucleotide
nucleotide	peptide	nucleotide	peptide	sequence was filed (Attorney
sequence	sequence	sequence	sequence	Docket No._SEQ ID NO.) *
1	125
2	126	249	331	789_2490
3	127	250	332	784_2340
4	128	251	333	790_2827
5	129	252	334	787_9834
6	130	253	335	784_1594
7	131	254	336	787_7563
8	132
9	133	255	337	784_969
10	134	256	338	788_13029
11	135
12	136
13	137	257	339	784_3978
14	138	258	340	784_3848
15	139
16	140	259	341	785_1465
17	141	260	342	787_7763
18	142
19	143
20	144
21	145
22	146	261	343	787_2258
23	147	262	344	787_2584
24	148	263	345	784_8266
25	149	264	346	784_1397
26	150	265	347	784_8164
27	151
28	152
29	153
30	154	266	348	784_2498
31	155	267	349	787_5189
32	156
33	157	268	350	787_10359
34	158
35	159
36	160	269	351	790_17261
37	161	270	352	784_9629
38	162	271	353	784_9102
39	163	272	354	784_9102
40	164	273	355	784_8867
41	165	274	356	787_3900
42	166	275	357	787_9753
43	167	276	358	787_4766
44	168	277	359	789_3521
45	169	278	360	784_8097
46	170
47	171	279	361	784_735
48	172	280	362	784_4418
49	173	281	363	784_4418
50	174
51	175
52	176	282	364	784_1006
53	177	283	365	787_3050
54	178
55	179
56	180	284	366	791_2053
57	181
58	182	285	367	788_6860
59	183	286	368	785_108
60	184	287	369	784_8348
61	185	288	370	784_8679
62	186	289	371	790_19249
63	187	290	372	784_5566
64	188	291	373	790_3027
65	189	292	374	790_3027
66	190	293	375	790_3027
67	191
68	192
69	193	294	376	784_7116
70	194	295	377	789_1658
71	195	296	378	790_26168
72	196	297	379	790_3240
73	197
74	198	298	380	784_6361
75	199	299	381	784_297
76	200	300	382	790_13930
77	201
78	202	301	383	790_29538
79	203
80	204
81	205
82	206
83	207	302	384	784_7603
84	208	303	385	787_5453
85	209	304	386	790_23838
86	210
87	211	305	387	784_5422
88	212	306	388	784_2530
89	213	307	389	787_7257
90	214	308	390	784_5473
91	215	309	391	784_1793
92	216	310	392	784_10027
93	217
94	218
95	219
96	220	311	393	787_732
97	221	312	394	784_8556
98	222
99	223	313	395	787_5766
100	224	314	396	790_4531
101	225	315	397	784_6708
102	226	316	398	790_19316
103	227	317	399	784_1784
104	228	318	400	785_470
105	229	319	401	787_1368
106	230	320	402	789_6192
107	231	321	403	784_4498
108	232
109	233	322	404	789_6042
110	234
111	235	323	405	790_4461
112	236
113	237	324	406	784_2675
114	238	325	407	789_4591
115	239	326	408	789_4591
116	240	327	409	790_13145
117	241
118	242
119	243
120	244	328	410	784_10141
121	245	329	411	784_10225
122	246	330	412	784_7722
123	247
124	248

[0473] 784_XXX=SEQ ID NO: XXX of Attorney Docket No. 784, U.S. Ser. No. 09/488,725 filed Jan. 21, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 784CIP, U.S. application Ser. No. 09/552,317, filed Apr. 25, 2000, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 784CIP3A/PCT, PCT Serial No. PCT/US00/35017 filed Dec. 22, 2000, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

[0474] 85_XXX=SEQ ID NO: XXX of Attorney Docket No. 785, U.S. Ser. No. 09/491,404 filed Jan. 25, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 785CIP3/PCT, PCT Serial No. PCT/US01/02623 filed Jan. 25, 2001, which is incorporated herein by reference in its entirety, including Tables, and Sequence Listing.

[0475] 787_XXX=SEQ ID NO: XXX of Attorney Docket No. 787, U.S. Ser. No. 09/496,914 filed Feb. 03, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 787CIP, U.S. application Ser. No. 09/560,875, filed Apr. 27, 2000, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 787CIP3/PCT, PCT Serial No. PCT/US01/03800 filed Feb. 5, 2001, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

[0476] 788_XXX=SEQ ID NO: XXX of Attorney Docket No. 788, U.S. Ser. No. 09/515,126 filed Feb. 28, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 788CIP, U.S. application Ser. No. 09/577,409, filed May 18, 2000, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 788CIP3/PCT, PCT Serial No. PCT/US01/04927 filed Feb. 26, 2001, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

[0477] 789_XXX=SEQ ID NO: XXX of Attorney Docket No. 789, U.S. Ser. No. 09/519,705 filed Mar. 07, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 789CIP, U.S. application Ser. No. 09/574,454, filed May 19, 2000, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 789CIP3/PCT, PCT Serial No. PCT/US01/04941 filed Mar. 5, 2001, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

[0478] 790 _XXX=SEQ ID NO: XXX of Attorney Docket No. 790, U.S. Ser. No. 09/540,217 filed Mar. 31, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 790CIP, U.S. application Ser. No. 09/649,167, filed Aug. 23, 2000, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 790CIP3/PCT, PCT Serial No. PCT/US01/08631 filed Mar. 30, 2001, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

[0479] 791_XXX=SEQ ID NO: XXX of Attorney Docket No. 791, U.S. Ser. No. 09/552,929 filed Apr. 18, 2000, the entire disclosure of which, including sequence listing, is incorporated herein by reference. This application is the parent application of a continuation-in-part application bearing Attorney Docket No. 791CIP, U.S. application Ser. No. 09/770,160, filed Jan. 26, 2001, which in turn is a parent application of continuation-in-part application bearing Attorney Docket No. 791CIP3/PCT, PCT Serial No. PCT/US01/8656 filed Apr. 8, 2001, both of which are incorporated herein by reference in their entirety, including Tables, and Sequence Listing.

	TABLE 10
		Number of	Position of
		Transmembrane	Transmembrane
	SEQ ID NO:	Regions	Region::Scores
	125	1	100-115:1952
	126	1	732-749:2593
	127	1	181-201:2410
	128	2	53-68:1828
			132-149:2533
	129	2	53-69:2959
			121-140:2878
	130	1	407-429:3163
	131	1	536-560:2906
	132	1	63-82:2545
	133	5	86-102:1766
			189-205:2721
			229-244:1878
			273-300:1714
			385-405:1946
	134	1	629-645:2430
	135	1	59-75:2149
	136	1	306-332:2773
	137	1	118-136:2329
	138	2	98-113:2861
			220-243:2391
	139	1	151-169:2618
	140	2	94-110:2524
			124-146:2138
	141	1	73-87:2180
	142	1	206-226:2584
	143	1	402-419:2096
	144	1	343-361:1953
	145	1	132-154:2199
	146	1	590-613:2402
	147	2	89-105:1748
			155-173:2433
	148	1	201-222:2190
	149	4	254-277:2256
			317-332:1771
			442-460:2005
			530-544:2110
	150	2	169-186:1866
			239-259:2042
	151	1	63-77:1794
	152	1	227-248:3456
	153	1	133-148:2558
	154	3	435-453:1849
			505-526:2495
			697-712:2057
	155	1	317-340:2214
	156	1	173-192:2637
	157	1	63-79:1933
	158	1	124-146:3384
	159	3	82-102:2213
			115-135:1769
			160-185:2317
	160	1	312-329:2354
	161	2	116-131:3056
			188-209:2254
	162	6	48-71:1708
			174-196:2300
			237-254:1918
			359-378:1887
			413-435:1864
			501-518:2625
	163	6	136-159:1708
			262-284:2300
			325-342:1918
			447-466:1887
			501-523:1864
			589-606:2625
	164	1	352-376:2946
	165	3	106-125:2854
			226-241:1973
			277-300:2759
	166	4	85-105:2047
			208-225:1907
			309-330:2122
			454-471:2461
	168	1	60-75:2189
	170	3	192-214:1705
			236-259:1933
			436-453:2349
	171	1	459-477:1896
	172	1	144-159:3028
	173	1	144-159:3028
	174	1	436-455:2525
	175	1	705-724:2525
	182	2	93-108:2014
			249-264:2324
	183	5	145-165:2633
			316-331:2180
			399-412:1770
			481-496:2328
			541-560:2589
	184	1	73-92:1951
	186	1	85-103:2195
	188	1	160-176:2085
	189	1	256-272:2085
	190	1	210-226:2085
	191	1	63-94:3259
	192	2	184-201:2183
			245-262:1812
	193	1	276-295:3080
	195	1	179-194:2620
	199	1	111-129:2519
	201	1	169-190:2680
	202	3	61-82:2141
			99-134:1715
			119-139:2765
	203	1	65-85:1713
	204	3	123-137:2644
			190-218:2074
			300-314:2588
	205	2	98-123:2354
			270-295:2148
	206	1	77-92:1791
	207	1	68-88:2672
	208	1	1524-1547:2939
	210	1	95-113:2958
	212	2	92-107:1923
			162-178:2760
	213	1	71-94:1835
	214	1	379-403:3221
	216	1	152-182:1795
	218	3	201-217:2437
			338-353:1761
			449-466:2589
	219	2	99-114:1754
			108-130:2731
	220	1	1177-1193:3038
	221	1	95-111:2301
	222	2	205-227:1715
			307-322:1735
	223	1	308-330:2431
	225	5	92-107:1734
			298-311:2063
			363-378:1720
			382-399:1988
			453-471:2040
	226	2	56-75:2481
			127-148:2269
	227	1	228-251:1822
	228	4	97-115:1903
			177-194:1919
			889-905:2063
			988-1008:2027
	230	1	223-242:2971
	232	3	63-86:2169
			177-194:1878
			271-288:2186
	233	2	116-136:2390
			179-194:2530
	235	2	66-82:2701
			110-126:1755
	236	2	74-106:2580
			139-156:1958
	237	1	522-544:2644
	238	2	83-97:2024
			200-216:2275
	239	1	200-216:2275
	240	1	92-109:2588
	241	2	145-169:1834
			317-346:1891
	244	4	64-83:2948
			218-232:2016
			452-480:1829
			535-553:1999
	245	1	311-330:2524
	246	1	78-111:2597
	248	1	163-180:2270

[0480]

Claims

1. An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-124.

2. An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide hybridizes to the polynucleotide of claim 1 under stringent hybridization conditions.

3. An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide has greater than about 99% sequence identity with the polynucleotide of claim 1.

4. The polynucleotide of claim 1 wherein said polynucleotide is DNA.

5. An isolated polynucleotide of claim 1 wherein said polynucleotide comprises the complementary sequences.

6. A vector comprising the polynucleotide of claim 1.

7. An expression vector comprising the polynucleotide of claim 1.

8. A host cell genetically engineered to comprise the polynucleotide of claim 1.

9. A host cell genetically engineered to comprise the polynucleotide of claim 1 operatively associated with a regulatory sequence that modulates expression of the polynucleotide in the host cell.

10. An isolated polypeptide, wherein the polypeptide is selected from the group consisting of: (a) a polypeptide encoded by any one of the polynucleotides of claim 1;(b) a polypeptide encoded by a polynucleotide hybridizing under stringent conditions with any one of SEQ ID NO: 1-124; and (c) a polypeptide of any one of SEQ ID NO: 125-248.

11. A composition comprising the polypeptide of claim 10 and a carrier.

12. An antibody directed against the polypeptide of claim 10.

13. A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide of claim 1 for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, the polynucleotide of claim 1 is detected.

14. A method for detecting the polynucleotide of claim 1 in a sample, comprising: a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to the polynucleotide of claim 1 under such conditions; b) amplifying a product comprising at least a portion of the polynucleotide of claim 1; and c) detecting said product and thereby the polynucleotide of claim 1 in the sample.

15. The method of claim 14, wherein the polynucleotide is an RNA molecule and the method further comprises reverse transcribing an amlealed RNA molecule into a cDNA polynucleotide.

16. A method for detecting the polypeptide of claim 19 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex; and b) detecting formation of the complex, so that if a complex formation is detected, the polypeptide of claim 10 is detected.

17. A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10 under conditions sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.

18. A method for identifying a compound that binds to the polypeptide of claim 10, comprising: a) contacting the compound with the polypeptide of claim 10, in a cell, under conditions sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.

19. A method of producing the polypeptide of claim 10, comprising, a) culturing a host cell comprising a polynucleotide sequence selected from the group consisting of any of the polynucleotides from SEQ ID NO: 1-124, under conditions sufficient to express the polypeptide in said cell; and b) isolating the polypeptide from the cell culture or cells of step (a).

20. Am isolated polypeptide comprising an amino acid sequence selected from the group consisting of any one of the polypeptides SEQ ID NO: 125-248.

21. The polypeptide of claim 20 wherein the polypeptide is provided on a polypeptide array.

22. A collection of polynucleotides, wherein the collection comprising of at least one of SEQ ID NO: 1-124.

23. The collection of claim 22, wherein the collection is provided on a nucleic acid array.

24. The collection of claim 23, wherein the array detects full-matches to any one of the polynucleotides in the collection.

25. The collection of claim 23, wherein the array detects mismatches to any one of the polynucleotides in the collection.

26. The collection of claim 22, wherein the collection is provided in a computer-readable format.