Engineered human-derived kunitz domains that inhibit human neutrophil elastase

Abstract

Certain Kunitz domain derived proteins which bind and inhibit human neutrophil elastase with a K.sub.i of less than 10 picomolar are described.

Description

The following related and commonly-owned applications are also incorporated by reference:

Robert Charles Ladner, Sonia Kosow Guterman, Rachel Baribault Kent, and Arthur Charles Ley are named as joint inventors on U.S. Ser. No. 07/293,980, filed Jan. 8, 1989, and entitled GENERATION AND SELECTION OF NOVEL DNA-BINDING PROTEINS AND POLYPEPTIDES. This application has been assigned to Protein Engineering Corporation. Robert Charles Ladner, Sonia Kosow Guterman, and Bruce Lindsay Roberts are named as a joint inventors on a U.S. Ser. No. 07/470,651 fled 26 Jan. 1990 (now abandoned), entitled "PRODUCTION OF NOVEL SEQUENCE-SPECIFIC DNA-ALTERING ENZYMES", likewise assigned to Protein Engineering Corp. Ladner, Guterman, Kent, Ley, and Markland, Ser. No. 07/558,011 is also assigned to Protein Engineering Corporation. Ladner filed an application on May 17, 1991, Ser. No. 07/715,834 that is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to novel proteins that inhibit human neutrophil elastase (hNE). A large fraction of the sequence of each of these proteins is identical to a known human protein which has very little or no inhibitory activity with respect to hNE.

Information Disclosure Statement

1. hNE, its natural inhibitors, and pathologies

Human Neutrophil Elastase (hNE, also known as Human Leukocyte Elastase (xhLE); EC 3.4.21.11) is a 29 Kd protease with a wide spectrum of activity against extracellular matrix components (CAMP82, CAMP88, MCWH89, and references therein). The enzyme is one of the major neutral proteases of the azurophil granules of polymorphonuclear leucocytes and is involved in the elimination of pathogens and in connective tissue restructuring (TRAV88). In cases of hereditary reduction of the circulating .alpha.-1-anti-protease inhibitor (API, formerly known as .alpha.1 antitrypsin), the principal systemic physiological inhibitor of hNE (HEID86), or the inactivation of API by oxidation ("smoker's emphysema"), extensive destruction of lung tissue may result from uncontrolled elastolytic activity of hNE (CANT89). Several human respiratory disorders, including cystic fibrosis and emphysema, are characterized by an increased neutrophil burden on the epithelial surface of the lungs (SNID91, MCEL91, GOLD86) and hNE release by neutrophils is implicated in the progress of these disorders (MCEL91, WEIS89). A preliminary study of aerosol administration of API to cystic fibrosis patients indicates that such treatment can be effective both in prevention of respiratory tissue damage and in augmentation of host antimicrobial defenses (MCEL91).

API presents some practical problems to large-scale routine use as a pulmonary anti-elastolytic agent. These include the relatively large size of the molecule (394 residues, 51 Kd), the lack of intramolecular stabilizing disulfide bridges, and specific post translational modifications of the protein by glycosylation at three sites. Perhaps of even greater importance is the sensitivity of API to oxidation, such as those released by activated neutrophils. Hence a small stable nontoxic highly efficacious inhibitor of hNE would be of great therapeutic value.

2. ITI domain 1 and ITI domain 2 as an initial protein binding domains (IPBD)

Inter-.alpha.-trypsin inhibitor (ITI) is a large (M.sub.r ca 240,000) circulating protease inhibitor found in the plasma of many mammalian species (for recent reviews see ODOM90, SALI90, GEBH90, GEBH86). The intact inhibitor is a glycoprotein and is currently believed to consist of three glycosylated subunits that interact through a strong glycosaminoglycan linkage (ODOM90, SALI90, ENGH89, SELL87). The anti-trypsin activity of ITI is located on the smallest subunit (ITI light chain, unglycosylated M.sub.r ca 15,000) which is identical in amino acid sequence to an acid stable inhibitor found in urine (UTI) and serum (STI) (GEBH86, GEBH90). The amino-acid sequence of the ITI light chain is shown in Table 400. The mature light chain consists of a 21 residue N-terminal sequence, glycosylated at Ser.sub.10, followed by two tandem Kunitz-type domains the first of which is glycosylated at Asn.sub.45 (ODOM90). In the human protein, the second Kunitz-type domain has been shown to inhibit trypsin, chymotrypsin, and plasmin (ALBR83a, ALBR83b, SELL87, SWAI88). The first domain lacks these activities but has been reported to inhibit leukocyte elastase (.apprxeq.1 .mu.M>K.sub.i >.apprxeq.1 nM) (ALBR83a,b, ODOM90). cDNA encoding the ITI light chain also codes for .alpha.-1-microglobulin (TRAB86, KAUM86, DIAR90); the proteins are separated post-translationally by proteolysis.

The two Kunitz domains of the ITI light chain (ITI-D1 and ITI-D2) possesses a number of characteristics that make them useful as IPBDs. ITI-D1 comprises at least residues 26 to 76 of the UTI sequence shown in FIG. 1 of GEBH86. The Kunitz domain could be thought of as comprising residues from as early as residue 22 to as far as residue 79. Residues 22 through 79 constitute a 58-amino-acid domain having the same length as BPTI and having the cysteines aligned. ITI-D2 comprises at least residues 82 through 132; residues as early as 78 and as later as 135 could be included to give domains closer to the classical 58-amino-acid length. As the space between the last cysteine of ITI-D1 (residue 76 of ITI light chain) and the first cysteine of ITI-D2 (residue 82 of ITI light chain) is only 5 residues, one can not assign 58 amino acids to each domain without some overlap. Unless otherwise stated, herein, we have taken the second domain to begin at residue 78 of the ITI light chain. Each of the domains are highly homologous to both BPTI and the EpiNE series of proteins described in U.S. Pat. No. 5,223,409. Although x-ray structures of the isolated domains ITI-D1 and ITI-D2 are not available, crystallographic studies of the related Kunltz-type domain isolated from the Alzheimer's amyloid .beta.-protein (AA.beta.P) precursor show that this polypeptide assumes a 3D structure almost identical to that of BPTI (HYNE90).

The three-dimensional structure of alpha-dendrotoxin from the green mamba venom has been determined (SKAR92) and the overall structure is highly similar to that of BPTI.

"The three-dimensional structure of alpha-dendrotoxin (alpha-DTX) from the green mamba (Dendroaspis angusticeps) venom has been determined crystallographically using the method of isomorphous replacement and refined at 2.2 A resolution using a restrained least-squares method. The crystallographic R-factor is 0.169 for all 3451 measured reflections between 7.0 and 2.2 A. Although the main-chain fold of alpha-DTX is similar to that of homologous bovine pancreatic trypsin inhibitor (BPTI), there are significant differences involving segments of the polypeptide chain close to the `antiprotease site` of BPTI. Comparison of the structure of alpha-DTX with the existing models of BPTI and its complexes with trypsin and kallikrein reveals structural differences that explain the inability of alpha-DTX to inhibit trypsin and chymotrypsin."

The structure of the black mamba K venom has been determined by NMR spectroscopy and has a 3D structure that is highly similar to that of BPTI despite 32 amino-acid sequence differences between residues 5 and 55 (the first and last cysteines)(BERN93). "The solution structure of Toxin K is very similar to the solution structure of the basic pancreatic trypsin inhibitor (BPTI) and the X-ray crystal structure of the alpha-dendrotoxin from Dendroaspis angusticeps (alpha-DTX), with r.m.s.d. values of 1.31 A and 0.92 A, respectively, for the backbone atoms of residues 2 to 56. Some local structural differences between Toxin K and BPTI are directly related to the fact that intermolecular interactions with two of the four internal molecules of hydration water in BPTI are replaced by intramolecular hydrogen bonds in Toxin K." Thus, it is likely that the solution 3D structure of either of the isolated ITI-D1 domain or of the isolated ITI-D2 domain will be highly similar to the structures of BPTI, AA.beta.P, and black mamba K venom. In this case, the advantages described previously for use of BPTI as an IPBD apply to ITI-D1 and to ITI-D2. ITI-D1 and ITI-D2 provide additional advantages as an IPBD for the development of specific anti-elastase inhibitory activity. First, the ITI-D1 domain has been reported to inhibit both leukocyte elastase (ALBR83a,b, ODOM90) and Cathepsin-G (SWAI88, ODOM90); activities which BPTI lacks. Second, ITI-D1 lacks affinity for the related serine proteases trypsin, chymotrypsin, and plasmin (ALBR83a,b, SWAI88), an advantage for the development of specificity in inhibition. ITI-D2 has the advantage of not being glycosylated. Additionally, ITI-D1 and ITI-D2 are human-derived polypeptides so that derivatives are anticipated to show minimal antigenicity in clinical applications.

3. Secretion of heterologous proteins from Pichia pastoris

Others have produced a number of proteins in the yeast Pichia pastoris. For example, Vedvick et al. (VEDV91) and Wagner et al. (WAGN92) produced aprotinin from the alcohol oxidase promoter with induction by methanol as a secreted protein in the culture medium at .apprxeq.1 mg/ml. Gregg et al. (GREG93) have reviewed production of a number of proteins in P. pastoris. Table 1 of GREG93 shows proteins that have been produced in P. pastoris and the yields.

No admission is made that any cited reference is prior art or pertinent prior art, and the dates given are those appearing on the reference and may not be identical to the actual publication date. The descriptions of the teachings of any cited reference are based on our present reading thereof, and we reserve the right to revise the description if an error comes to our attention, and to challenge whether the description accurately reflects the actual work reported. We reserve the right to challenge the interpretation of cited works, particularly in light of new or contradictory evidence. All references, including prior applications of any of the inventors, cited in this specification are hereby incorporated by reference.

SUMMARY OF THE INVENTION

The present invention describes a series of small potent proteinaceous inhibitors of human neutrophil elastase (hNE). One group of inhibitors are derived from one of two Kunitz-type inhibitory domain found in a protein of human origin, namely, the light chain of human Inter-.alpha.-trypsin inhibitor (ITI). The domains are designated ITI-D1 and ITI-D2. The present invention also comprises modifications to the ITI-D2 sequence that facilitate its production in the yeast Pichia pastoris and that are highly potent inhibitors of hNE. The invention also comprises derivatives of bovine pancreatic trypsin inhibitor that inhibit hNE. The invention also relates to methods of transferring segments of sequence from one Kunitz domain to another and to methods of production.

The invention is presented as a series of examples that describe discovery, production, and testing of actual inhibitors and additional examples describing how other inhibitors could be discovered.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a restriction map of plasmid pHIL-D2. Radial lines are drawn at 1000 base intervals. Two NotI sites, two BstBI sites, and a number of unique restriction sites are shown. The map shows genetic elements: a) aox1 5' segment (dark grey), b) a portion of the 3' region of aox1 (cross hatched) running clockwise from EcoRI, c) his4 (medium grey) running clockwise from near 3 o'clock to just after 6 o'clock, d) a second part of aox1 3' segment (cross hatched) running clockwise from just after the unique SphI to just before the unique AatII site (about 8 o'clock), e) bla (.beta. lactamase, to allow selection for the plasmid in E. coli) in light grey from about 8:30 to about 9:30, and f) the f1 origin of replication (hatched) from about 10 o'clock to about 10:30.

NOMENCLATURE AND ABBREVIATIONS

______________________________________Term Meaning______________________________________x::y Fusion of gene x to gene y in frame.X::Y Fusion protein expressed from x::y fusion gene..mu.M Micromolar, 10.sup.-6 molar.nM Namomolar, 10.sup.-9 molar.pM Picomolar, 10.sup.-12 molar.______________________________________

DESCRIPTION OF THE INVENTION

The invention is presented by the following Examples and Tables. The examples contain numerous examples of amino-acid sequences accompanied by DNA sequences that encode them. It is to be understood that the invention is not limited to the particular DNA sequence shown.

The present invention refers to sequences that are "substantially homologous". Typically, "substantially homologous" sequences are at least 50%, more preferably at least 80%, identical in sequence, at least over any regions known to be involved in the desired activity. Most preferably, no more than five residues, other than at the termini, are different. Preferably, the divergence in sequence, at least in the aforementioned regions, is in the form of "conservative modifications".

"Conservative modifications" are defined as:

a) conservative substitutions of amino acids as hereafter defined, and b) single or multiple insertions or deletions of amino acids at the termini, at interdomain boundaries, in loops or in other segments of relatively high mobility (as indicated, for example, by high temperature factors or lack of resolution in X-ray diffraction, neutron diffraction, or NMR). Preferably, except at the termini, no more than about five amino acids are inserted or deleted at a particular locus, and the modifications are outside regions known to contain binding sites important to activity.

"Conservative substitutions" are herein defined as exchanges within on of the following five groups:

I. Small aliphatic, nonpolar or slightly polar residues: [Ala, Ser, Thr, (Pro, Gly)], II. Acidic amino acids and their amides: [Asp, Glu, Asn, Gln], III. Polar, positively charged residues: [His, Lys, Arg], IV. Large, aliphatic nonpolar residues: [Met, Leu, Ile, Val, (Cys)], and V. Large, aromatic residues: [Phe, Tyr, Trp]

Residues Pro, Gly, and Cys are parenthesized because they have special conformational roles. Cys often participates in disulfide bonds; when not so doing, it is highly hydrophobic. Gly imparts flexibility to the chain; it is often described as a "helix breaker" although many .alpha. helices contain Gly. Pro imparts rigidity to the chain and is also described as a "helix breaker". Although Pro is most often found in turns, Pro is also found in helices and sheets. These residues may be essential at certain positions and substitutable elsewhere.

"Semi-conservative substitutions" are defined to be exchanges between two of groups (I)-(V) above which are limited either to the supergroup consisting of (I), (II), and (III) or to the supergroup consisting of (IV) and (V).

A protein sequence can be called an "aprotinin-like Kunitz domain" if it can be aligned, with four or fewer mismatches, to the pattern:

Cys-(Xaa).sub.6 -Gly-Xaa-Cys-(Xaa).sub.8 -[Tyr.linevert split.Phe]-(Xaa).sub.6 -Cys-(Xaa).sub.2 -Phe-Xaa-[Tyr.linevert split.Trp.linevert split.Phe]-Xaa-GlY-Cys-(Xaa).sub.4 -[Asn.linevert split.Gly]-Xaa-[Phe.linevert split.Tyr]-(Xaa).sub.5 -Cys-(Xaa).sub.3 -Cys. (The sequence having the most prevalent amino acid at each ambiguous position has SEQ ID NO. 234). For the above test, an insertion or deletion is counted as a single mismatch. By convention, the first Cys is numbered 5 and the last Cys is numbered 51. The probability that a random sequence will pass this test is about 4.7.times.10.sup.-11.

A protein that is a Kunitz domain would be substantially homologous to one of the proteins here disclosed if:

1) there is a Phe at position 18, 2) there is either Ile or Val at position 15, and 3) in the regions 10-21 and 30-42, there are six or fewer mismatches.

A protein would also be viewed as substantially homologous to the proteins of the present invention if it contains at least 50 amino acids and if a part of the sequence can be made to align with the specification in Table 790 with no more than about five mismatches. In making this alignment, insertions and deletions are counted as mismatches.

______________________________________ContentsItem page______________________________________SUMMARY OF THE INVENTION 6BRIEF DESCRIPTION OF THE DRAWINGS 6Example 1: Expression and display of BPTI, ITI-D1, and 14 other Kunitz DomainsExample 2: Fractination of MA-ITI-D1 phage bound to 15 agarose-immobilized protease beads.Example 3: Alteration of the P1 region of ITI-D1. 16Example 4: Fractionation of MA-ITI-D1E7 phage 17Example 5: Preparation of BITI-E7 Phage 18Table 10: Recovery of Display phage 20Example 6: Production and properties of MA-BITI-E7-1222 21 and MA-BITI-E7-141Example 7: Mutagenesis of BITI-E7-141 22Example 8: hNE-binding properties of mutagenized 24 MA-BITI-E7-141 display phageExample 9: Amino-acid sequences of EPI-HNE-3 and 27 EPI-HNE-4Example 10: Pichia pastoris production system 28Example 11: Protein Production 30Example 12: Purification of EPI-HNE-2 31Example 13: Purification of EPI-HNE-3 32Example 14: Tricine-PAGE Analysis of EPI-HNE-2 and 35 EPI-HNE-3Example 15: Measured K.sub.D.spsb.S of EPI-HNE proteins for 36EExample 16: Specificity of EPI-HNE proteins 37Example 17: Resistance to Oxidative Inactivation 38Example 18: pH Stability 38Table 14: Buffers used in stability studies 39Example 19: Temperature Stability 39Example 20: Relationship of various hNE-inhibiting 40 Kunitz DomainsExample 21: Substitution of Segments in Kunitz Domains 40Example 22: Point substitutions in Kunitz Domains 41Example 23: Libraries of Kunitz Domains 43Table 28: Sequences of EPI-HNE-7 and ITI-D1 in the 45 active siteTable 30: IIIs::bpti::mautreIII fusion gene 46Table 35: IIIsp::itiD1::matureIII fusion gene 50Table 40: Local sequences of Kunitz domains derived from 53 BPTI or ITI-D1Table 55: Affinity Classes of ITI-D1-derived hNE inhibitors 54Table 100: hNE-inhibiting Kunitz domains and their 55 parental domainsTABLE 208: SEQUENCES OF THE EpiNE CLONES IN THE 56 P1 REGIONTable 209: BPTI analogues selected for binding to Cathepsin 57Table 210: Derivatives of EpiNE7 Obtained by Variegation at 58 positions 34, 36, 39, 40 and 41TABLE 211: Effects of antisera on phage infectivity 60TABLE 212: Fractionation of EpiNE-7 and MA-ITI-D1 phage 61 on hNE beadsTABLE 213: Fractionation of EpiC-10 and MA-ITI-D1 phage 62 on Cat-G beadsTABLE 214: Abbreviated fractionation of display phage 63 on hNE beadsTABLE 215: Fractionation of EpiNE-7 and MA-ITI-D1E7 phage 64 on hNE beadsTABLE 216: Fractionation of MA-EpiNE-7, MA-BITI and 65 MA-BITI-E7 on hNE beadsTABLE 217: Fractionation of MA-BITI-E7 and 66 MA-BITI-E7-1222 on hNE beadsTABLE 218: Fractionation of MA-EpiNE7 and MA-BITI-E7-141 67 on hNE beadsTABLE 219: pH Elution Analysis of hNE Binding by 68 BITI-E7-141 Varient Display PhageTABLE 220: ITI-D1-derived hNE InhibitorsTable 221: Same sequences as in Table 220 showing only 70 changesTable 250: Plasmid pHIL-D2 71Table 251: pHIL-D2(MF.alpha.PrePro::EPI-HNE-3) 75Table 252: BstBI-AatII-EcoRI cassette for expression of 81 EPI-HNE-4Table 253: pD2pick(MF.alpha.PrePro::EPI-HNE-3) 82Table 254: restriction map of pD2pick(MF.alpha.PrePro::EPI- 87 HNE-3)Table 399: Number of amino-acid differences between some 89 Kunitz domainsTable 400: Amino-acid Sequence of ITI light chain 90Table 401: Kunitz-domain hNE inhibitors producible in 91 Pichia pastorisTABLE 601: Sequences of purified hNE inhibitors derived from 92 Kunitz domainsTABLE 602: Physical properties of hNE inhibitors derived from 93 Kunitz domainsTABLE 603: SUMMARY OF PURIFICATION OF EPI-HNE-2 94TABLE 604: SUMMARY OF PURIFICATION OF EPI-HNE-3 95TABLE 605: K.sub.1 VALUES OF EPI-HNE PROTEINS FOR 96 VARIOUS HUMAN SERUM SERINE PROTEASESTable 607: PEY-33 which produces EPI-HNE-2 97Table 608: PEY-43 Which produces EPI-HNE-3 98Table 610: Inhibitory properties of EPI-HNE-2 99Table 611: hNE inhibitory properties of EPI-HNE-3 100Table 612: pH stability of Kunitz-domain hNE inhibitors 101Table 620: Stability of hNE inhibitory proteins to oxidation 102 Chloramine-TTable 630: Temperature stability of EPI-HNE proteins 104Table 700: Kunitz domains in segments 105Table 701: Substitutions for Segment 1 (amino terminus to 109 residue 4) that are likely to give Kunitz Domains that could have very-high affinity for hNETable 702: Substitutions for Segment 3 (residues 10-13) that 109 are likely to give Knuitz Domains that could have very-high affinity for hNETable 703: Substitutions for Segment 5 (residues 15-21) that 110 are likely to give Kunitz Domains that could have very-high affinity for hNETable 704: Substitutions for Segment 7 (residues 31-35) that 111 are likely to give Kunitz Domains that could have very-high affinity for hNETable 705: Substitutions for Segment 9 (residues 39-41) that 112 are likely to give Kunitz Domains that could have very-high affinity for hNETable 706: Sample Candidate hNE inhibitor proteins 113Table 710: Cumulative collection of allowed amino acids 114Table 711: Mutations that are likely to improve the affinity 117 of a Kunitz domain for hNETable 720: M13.sub.-- III.sub.-- signal::Human.sub.-- LACI-D2:: 118 mature.sub.-- M13.sub.-- IIITable 725: Synthetic laci-d1 with sites for cloning into 119 display vectorTable 730: LACI-D1 hNE Library 120Table 735: LACI-D2 hNE Library 121Table 750: M13.sub.-- III.sub.-- signal::Human.sub.-- LACI-D3:: 122 mature.sub.-- M13.sub.-- IIITable 760: Variegation of LACI-D3 123Table 790: Amino acids allowed in hNE-inhibiting 124 Kunitz domainsTable 800: Amino-acid sequences of Kunitz domains 126Table 810: Frequency of amino-acid types at the positions in 133 BPTI-homologous Kunitz domains and identification of residues in five surface groupsCITATIONS 135CLAIMS 157______________________________________

EXAMPLE 1

Expression and display of BPTI, ITI-D1, and other Kunitz Domains.

Table 30 shows a display gene that comprises codons that encode: 1) the M13 III signal peptide, 2) BPTI, and 3) mature M13 III protein. Phage have been made in which this gene is the only iii-like gene so that all copies of III expressed are expected to be modified at the amino terminus of the mature protein. Substitutions in the BPTI domain can be made in the cassettes delimited by the AccIII, XhoI, PflMI, ApaI, BssHII, StuI, XcaI, EspI, SphI, or NarI sites. Tables 208 and 209 give sequences that may be substituted into BPTI to give hNE-binding or CatG-binding Kunitz domains. Table 100, Table 208, and Table 210 give amino-acid sequences of a number of hNE-binding Kunitz domains. Each of the sequences shown in Table 100, Table 208, and Table 210 can be expressed as an intact hNE-binding protein or can be incorporated into a larger protein as a domain. Proteins that comprise part of one of the sequences found in Table 100, Table 208, and Table 210 are expected to exhibit hNE-inhibitory activity. This is particularly true if the sequence beginning with the first cysteine and continuing through the last cysteine is retained.

Table 209 gives amino-acid sequences of Cathepsin-G-binding Kunitz domains. The sequences in Table 209 may be expressed as intact proteins or they may be incorporated into a larger protein as a Cathepsin-G-inhibitory domain. Proteins that comprise part of one of the sequences found in Table 209 are expected to exhibit Cathepsin-G-inhibitory activity. This is particularly true if the sequence beginning with the first cysteine and continuing through the last cysteine is retained.

ITI domain 1 is a Kunitz domain as discussed below. The ability of display phage to be retained on matrices that display hNE is related to the affinity of the particular Kunitz domain (or other protein) displayed on the phage. Expression of the ITI domain 1::iii fusion gene and display of the fusion protein on the surface of phage were demonstrated by Western analysis and phage titer neutralization experiments, data for which is given in Table 211.

Table 35 gives the sequence of a fusion gene comprising: a) the signal sequence of M13 III, b) ITI-D1, and c) mature III of M13. The displayed ITI-D1 domain can be altered by standard methods including: i) oligonucleotide-directed mutagenesis of single-stranded phage DNA, and ii) cassette mutagenesis of RF DNA using the restriction sites (BglI, EagI, NcoI, StyI, PstI, and KasI (two sites)) designed into the gene.

EXAMPLE 2

Fractionation of MA-ITI-D1 phage bound to agarose-immobilized protease beads.

To test if phage displaying the ITI-D1::III fusion protein interact strongly with the proteases human neutrophil elastase (hNE) or cathepsin-G, aliquots of display phage were incubated with agarose-immobilized hNE or cathepsin-G beads (hNE beads or Cat-G beads, respectively). The beads were washed and bound phage eluted by pH fractionation as described in U.S. Pat. No. 5,223,409. The pHs used in the step gradient were 7.0, 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, and 2.0. Following elution and neutralization, the various input, wash, and pH elution fractions were titered. Phage displaying ITI-D1 were compared to phage that display either EpiNE-7 or EpiC-10.

The results of several fractionations are summarized in Table 212 (EpiNE-7 or MA-ITI-D1 phage bound to hNE beads) and Table 213 (EpiC-10 or MA-ITI-D1 phage bound to Cat-G beads). For the two types of beads (hNE or Cat-G), the pH elution profiles obtained using the control display phage (EpiNE-7 or EpiC-10, respectively) were similar to those seen previously (U.S. Pat. No. 5,223,409). About 0.3% of the EpiNE-7 display phage applied to the hNE beads were eluted during the fractionation procedure and the elution profile had a maximum for elution at about pH 4.0. A smaller fraction, 0.02%, of the EpiC-10 phage applied to the Cat-G beads were eluted and the elution profile displayed a maximum near pH 5.5.

The MA-ITI-D1 phage show no evidence of great affinity for either hNE or cathepsin-G immobilized on agarose beads. The pH elution pro fries for MA-ITI-D1 phage bound to hNE or Cat-G beads show essentially monotonic decreases in phage recovered with decreasing pH. Further, the total fractions of the phage applied to the beads that were recovered during the fractionation procedures were quite low: 0.002% from hNE beads and 0.003% from Cat-G beads.

Published values of K.sub.i for inhibition neutrophil elastase by the intact, large (M.sub.r =240,000) ITI protein range between 60 and 150 nM and values between 20 and 6,000 nM have been reported for the inhibition of Cathepsin G by ITI (SWAI88, ODOM90). Our own measurements of pH fraction of display phage bound to hNE beads show that phage displaying proteins with low affinity (>1 .mu.M) for hNE are not bound by the beads while phage displaying proteins with greater affinity (nM) bind to the beads and are eluted at about pH 5. If the first Kunitz-type domain of the ITI light chain is entirely responsible for the inhibitory activity of ITI against hNE, and if this domain is correctly displayed on the MA-ITI-D1 phage, then it appears that the minimum affinity of an inhibitor for hNE that allows binding and fractionation of display phage on hNE beads is between 50 and 100 nM.

EXAMPLE 3

Alteration of the P1 region of ITI-D1.

We assume that ITI-D1 and EpiNE-7 have the same 3D configuration in solution as BPTI. The amino acid sequences of these proteins in the primary and secondary binding loops are shown in Table 28. (Table 810 (derived from Table 34 of U.S. Pat. No. 5,223,409) identifies several interaction surfaces of Kunitz domains. Table 810 also shows the frequency of each amino-acid type at each position in BPTI-homologous Kunitz domains.) Although EpiNE-7 and ITI-D1 are identical at positions 13, 17, 20, 32, and 39, they differ greatly in their affinities for hNE. To improve the affinity of lTI-D1 for hNE, the EpiNE-7 sequence Val.sub.15 -Ala.sub.16 -Met.sub.17 -Phe.sub.18 -Pro.sub.19 -Arg.sub.20 (bold, underscored amino acids are alterations) was incorporated into the ITI-D1 sequence by cassette mutagenesis between the EagI and StyI/NcoI sites shown in Table 35. Phage isolates containing the ITI-D1::III fusion gene with the EpiNE-7 changes around the P1 position are called MA-ITI-D1E7.

EXAMPLE 4

Fractionation of MA-ITI-D1E7 phage.

To test if the changes at positions 15, 16, 18, and 19 of the ITI-D1::III fusion protein (named ITI-D1E7) influence binding of display phage to hNE beads, abbreviated pH elution profiles were measured. Aliquots of EpiNE-7, MA-ITI-D1, and MA-ITI-D1E7 display phage were incubated with hNE beads for three hours at room temperature. The beads were washed and phage were eluted as described in U.S. Pat. No. 5,223,409, except that only three pH elutions were performed: pH 7.0, 3.5, and 2.0. The results of these elutions are shown in Table 214.

Binding and elution of the EpiNE-7 and MA-ITI-D1 display phage were found to be as previously described. The total fraction of input phages was high (0.4%) for EpiNE-7 phage and low (0.001%) for MA-ITI-D1 phage. Further, the EpiNE-7 phage showed maximum phage elution in the pH 3.5 fraction while the MA-ITI-D1 phage showed only a monotonic decrease in phage yields with decreasing pH, as seen above. Thus, ITI-D1 has very little if any affinity for hNE.

The two strains of MA-ITI-D1E7 phage show increased levels of binding to hNE beads relative to MA-ITI-D1 phage. The total fraction of the input phage eluted from the beads is 10-fold greater for both MA-ITI-D1E7 phage strains than for MA-ITI-D1 phage (although still 40-fold lower that EpiNE-7 phage). Further, the pH elution profiles of the MA-ITI-D1E7 phage strains show maximum elutions in the pH 3.5 fractions, similar to EpiNE-7 phage.

To further define the binding properties of MA-ITI-D1E7 phage, the extended pH fractionation procedure described previously was performed using phage bound to hNE beads. These data are summarized in Table 215. The pH elution profile of EpiNE-7 display phage is as previously described. In this more resolved, pH elution profile, MA-ITI-D1E7 phage show a broad elution maximum centered around pH 5. Once again, the total fraction of MA-ITI-D1E7 phage obtained on pH elution from hNE beads was about 40-fold less than that obtained using EpiNE-7 display phage.

The pH elution behavior of MA-ITI-D1E7 phage bound to hNE beads is qualitatively similar to that seen using BPTI[K15L]-III-MA phage. BPTI with the K15L mutation has an affinity for hNE of .apprxeq.3 nM. Assuming all else remains the same, the pH elution profile for MA-ITI-D1E7 suggests that the affinity of the free ITI-D1E7 domain for hNE might be in the nM range. If this is the case, the substitution of the EpiNE-7 sequence in place of the ITI-D1 sequence around the P1 region has produced a 20- to 50-fold increase in affinity for hNE (assuming K.sub.i =60 to 150 nM for the unaltered ITI-D1).

If EpiNE-7 and ITI-D1E7 have the same solution structure, these proteins present the identical amino acid sequences to hNE over the interaction surface. Despite this similarity, EpiNE-7 exhibits a roughly 1000-fold greater affinity for hNE than does ITI-D1E7. Again assuming similar structure, this observation highlights the importance of non-contacting secondary residues in modulating interaction strengths.

Native ITI light chain is glycosylated at two positions, Ser.sub.10 and Asn.sub.45 (GEBH86). Removal of the glycosaminoglycan chains has been shown to decrease the affinity of the inhibitor for hNE about 5-fold (SELL87). Another potentially important difference between EpiNE-7 and ITI-D1E7 is that of net charge. The changes in BPTI that produce EpiNE-7 reduce the total charge on the molecule from +6 to +1. Sequence differences between EpiNE-7 and ITI-D1E7 further reduce the charge on the latter to -1. Furthermore, the change in net charge between these two molecules arises from sequence differences occurring in the central portions of the molecules. Position 26 is Lys in EpiNE-7 and is Thr in ITI-D1E7, while at position 31 these residues are Gln and Glu, respectively. These changes in sequence not only alter the net charge on the molecules but also position a negatively charged residue close to the interaction surface in ITI-D1E7. It may be that the occurrence of a negative charge at position 31 (which is not found in any other of the hNE inhibitors described here) destabilized the inhibitor-protease interaction.

EXAMPLE 5

Preparation of BITI-E7 Phage

Possible reasons for MA-ITI-D1E7 phage having lower affinity for hNE than do MA-EpiNE7 phage include: a) incorrect cleavage of the IIIsignal::ITI-D1E7::matureIII fusion protein, b) inappropriate negative charge on the ITI-D1E7 domain, c) conformational or dynamic changes in the Kunitz backbone caused by substitutions such as Phe.sub.4 to Ser.sub.4, and d) non-optimal amino acids in the ITI-D1E7:hNE interface, such as Q.sub.34 or A.sub.11.

To investigate the first three possibilities, we substituted the first four amino acids of EpiNE7 for the first four amino acids of ITI-D1E7. This substitution should provide a peptide that can be cleaved by signal peptidase-I in the same manner as is the IIIsignal::EpiNE7::matureIII fusion. Furthermore, Phe.sub.4 of BPTI is part of the hydrophobic core of the protein; replacement with serine may alter the stability or dynamic character of ITI-D1E7 unfavorably. ITI-D1E7 has a negatively charged Glu at position 2 while EpiNE7 has Pro.

We introduced the three changes at the amino terminus of the ITI-D1E7 protein (K1R, E2P, and S4F) by oligonucleotide-directed mutagenesis. We used ssDNA purified from MA-ITI-D1E7 display phage as the template for mutagenesis and performed the mutagenesis using the Amersham Oligonueleotide-directed in vitro Mutagenesis System (Version 2) according to the manufacturer's specifications.

We extracted RF DNA from Ap.sup.r transformants and screened the RF DNA for the presence of an unique AccIII site introduced as a portion of the desired DNA sequence. We confirmed the entire DNA sequence encoding the altered ITI-D1E7 protein by DNA sequencing. Phage isolates containing the ITI-D1E7-III fusion gene incorporating the changes in the putative amino terminus of the displayed protein are called MA-BITI-E7.

We used the same mutagenic oligonucleotide to introduce the identical changes at the putative amino terminus of the ITI-III fusion protein displayed by the phage MA-ITI-D1. These phage isolates are called MA-BITI.

We compared the properties of the ITI-III fusion proteins displayed by phage MA-ITI-D1 and MA-BITI using Western analysis as described previously and found no significant differences in apparent size or relative abundance of the fusion proteins produced by either display phage strain. Thus, there are no large differences in the processed forms of either fusion protein displayed on the phage. By extension, there are also no large differences in the processed forms of the gene III fusion proteins displayed by MA-ITI-D1E7 and MA-EpiNE7. Large changes in protein conformation due to greatly altered processing are therefore not likely to be responsible for the great differences in binding to hNE-beads shown by MA-ITI-D1E7 and MA-EpiNE7 display phage.

We characterized the binding properties to hNE-beads of MA-BITI and MA-BITI-E7 display phage using the extended pH fractionation procedure described in U.S. Pat. No. 5,223,409. The results are summarized in Table 216. The pH elution profile of MA-EpiNE7 display phage bound to hNE-beads is similar to that previously described. In contrast, the pH elution profiles for MA-BITI and MA-BITI-E7 show significant differences from the profiles exhibited by MA-ITI-D1 and MA-ITI-D1E7 (cf. Tables 212 and 215). In both cases, the alterations at the putative amino terminus of the displayed fusion protein produce a several-fold increase in the fraction of the input display phage eluted from the hNE-beads.

The binding capacity of hNE-beads for display phage varies among preparations of beads and with age for each individual preparation of beads. Thus, it is difficult to directly compare absolute yields of phage from elutions performed at different times. For example, the fraction of MA-EpiNE7 display phage recovered from hNE-beads varies two-fold among the experiments shown in Tables 212, 215, and 216. However, the shapes of the pH elution profiles are similar. It is possible to correct somewhat for variations in binding capacity of hNE-beads by normalizing display phage yields to the total yield of MA-EpiNE7 phage recovered from the beads in a concurrent elution. When the data shown in Tables 212, 215, and 216 are so normalized, the recoveries of display phage, relative to recovered MA-EpiNE7, are:

TABLE 10______________________________________Recovery of Display phage Normalized fraction ofDisplay Phage strain input______________________________________MA-ITI-D1 0.0067MA-BITI 0.018MA-ITI-D1E7 0.027MA-BITI-E7 0.13______________________________________ Thus, the alterations in the amino terminal sequence of the displayed fusion protein produce a three- to five-fold increase in the fraction of display phage eluted from hNE-beads.

In addition to increased binding, the sequence changes introduced into MA-BITI-E7 produce display phage that elute from hNE-beads at a lower pH than do the parental MA-ITI-D1E7 phage. While the parental display phage elute with a broad pH maximum centered around pH 5.0, the pH elution profile for MA-BITI-E7 display phage has a pH maximum at around pH 4.75 to pH 4.5.

The pH elution maximum of the MA-BITI-E7 display phage is located between the maxima exhibited by the BPTI(K15L) and BPTI(K15V, R17L) display phage (pH 4.75 and pH 4.5 to pH 4.0, respectively) described in U.S. Pat. No. 5,223,409. From the pH maximum exhibited by the display phage we predict that the BITI-E7 protein free in solution may have an affinity for hNE in the 100 pM range. This would represent an approximately ten-fold increase in affinity for hNE over that estimated above for ITI-D1E7.

As was described above, Western analysis of phage proteins show that there are no large changes in gene III fusion proteins upon alteration of the amino terminal sequence. Thus, it is unlikely that the changes in affinity of display phage for hNE-beads can be attributed to large-scale alterations in protein folding resulting from altered ("correct") processing of the fusion protein in the amino terminal mutants. The improvements in binding may in part be due to: 1) the decrease in the net negative charge (-1 to 0) on the protein arising from the Glu to Pro change at position 2, or 2) increased protein stability resulting from the Ser to Phe substitution at residue 4 in the hydrophobic core of the protein, or 3) the combined effects of both substitutions.

EXAMPLE 6

Production and properties of MA-BITI-E7-1222 and MA-BITI-E7-141

Within the presumed Kunitz:hNE interface, BITI-E7 and EpiNE7 differ at only two positions: 11 and 34. In EpiNE7 these residues are Thr and Val, respectively. In BITI-E7 they are Ala and Gln. In addition BITI-E7 has Glu at 31 while EpiNE7 has Gln. The presence of this negative charge may influence binding although the residue is not directly in the interface: We used oligonucleotide-directed mutagenesis to investigate the effects of substitutions at positions 11, 31 and 34 on the protease:inhibitor interaction.

We used two mutagenic bottom-strand oligonueleotides in separate mutageneses to alter the sequence of the BITI-E7 polypeptide at residues 11 or at residues 31 and 34. In the first oligonucleotide, the codon for Ala.sub.11 was altered to encode Thr. The second mutagenic oligonucleotide was used to produce a E31Q, Q34V double mutation. Mutagenesis was performed as described above except that MA-BITI-E7 ssDNA was used as the template.

RF DNA isolated from Ap.sup.r transformants was assayed for correct structure by restriction enzyme analysis. We confirmed the entire DNA sequence encoding the altered BITI-E7 polypeptides by DNA sequencing. A phage strain containing the biti-e7::iii fusion gene incorporating the A11T change is called MA-BITI-E7-1222. Likewise, a phage strain containing the Biti-e7::iii fusion gene incorporating the E31Q, Q34V double mutation is called MA-BITI-E7-141.

We determined the binding properties to hNE-beads of MA-BITI-E7-1222 and MA-BITI-E7-141 display phage using the extended pH fractionation protocol described previously. The results are summarized in Tables 217 (for MA-BITI-E7 and MA-BITI-E7-1222) and 218 (for MA-EpiNE7 and MA-BITI-E7-141).

The pH elution profiles for the MA-BITI-E7 and MA-BITI-E7-1222 phage are almost identical (Table 217). Both phage strains exhibit pH elution profiles with identical maxima (between pH 5.0 and pH 4.5) as well as the same total fraction of input phage eluted from the hNE-beads (0.03%). Thus, the T11A substitution in the displayed ITI-D1 derivatives has no appreciable effect on the binding of display phage to hNE-beads.

In contrast, the changes at positions 31 and 34 profoundly affect the hNE-binding properties of the display phage (Table 218). The elution profile pH maximum of MA-BITI-E7-141 phage is shifted to lower pH relative to the parental MA-BITI-E7 phage. Further, the position of the maximum (between pH 4.5 and pH 4.0) is identical to that exhibited by MA-EpiNE7 phage in this experiment. Finally, the MA-BITI-E7-141 phage show a ten-fold increase, relative to the parental MA-BITI-E7, in the total fraction of input phage eluted from hNE-beads (0.3% vs 0.03%). Indeed, the total fraction of MA-BITI-E7-141 phage eluted from the hNE-beads is nearly twice that of MA-EpiNE7 phage.

The results discussed above show that binding by MA-BITI-E7-141 display phage to hNE-beads is comparable to that of MA-EpiNE7 phage. If the two proteins (EpiNE7 and BITI-E7-141) free in solution also have similar affinities for hNE, then the affinity of the BITI-E7-141 protein for hNE is on the order of 1 pM. Such an affinity is approximately 100-fold greater than that estimated above for the parental protein (BITI-E7) and is 10.sup.5 to 10.sup.6 times as great as the affinity for hNE reported for the intact ITI protein.

EXAMPLE 7

Mutagenesis of BITI-E7-141

BITI-E7-141 differs from ITI-D1 at nine positions (1, 2, 4, 15, 16, 18, 19, 31, and 34). To obtain the protein having the fewest changes from ITI-D1 while retaining high specific affinity for hNE, we have investigated the effects of reversing the changes at positions 1, 2, 4, 16, 19, 31, and 34. The changes we have introduced into the BITI-E7-141 protein are given in Table 40.

ITI-D1 residues in Table 40 are shown in bold type and residues found in neither ITI-D1 nor in BITI-E7-141 are shown underlined. The changes shown in Table 40 were accomplished via oligonucleotide directed mutagenesis.

Two mutagenic oligonucleotides introduced changes in the primary inhibitory loop of BITI-E7-141. MUT1619 restores the ITI-D1 residues Ala.sub.16 and Ser.sub.19. The sequence designated "MUTP1" asserts the amino acids I.sub.15, G.sub.16, S.sub.19 in the context of BITI-E7-141. It is likely that M.sub.17 and F.sub.18 are optimal for high affinity hNE binding. G.sub.16 and S.sub.19 occurred frequently in the high affinity hNE-binding BPTI-variants obtained from fractionation of a library of BPTI-variants against hNE (ROBE92). Thus, it seems likely that the ITI-D1 sequence at these positions can be restored while maintaining high specific affinity for hNE.

Three changes at the putative amino terminus of the displayed ITI-D1 domain were introduced to produce the MA-BITI series of display phage. AMINO1 carries the sequence K.sub.1 -E.sub.2 while AMINO2 carries K.sub.1 -S.sub.4. Other amino acids in the amino-terminal region of these sequences are as in ITI-D1.

Two changes had been introduced into the sequence for BITI-E7 to produce BITI-E7-141: E31Q and Q34V. The MUTQE mutagenic oligonucleotide reverses the change at position 31 by asserting Glu.sub.31.

Finally, the mutagenic oligonueleotide MUTT26A is intended to remove a potential site of N-linked glycosylation. The BITI-E7-141 protein sequence N.sub.24 -G.sub.25 -T.sub.26 matches the general recognition sequence Asn-X-Thr/Ser for N-linked glycosylation in eukaryotic organisms. In the intact ITI molecule isolated from human serum, the light chain polypeptide is glycosylated at this site (N.sub.45, ODOM90). It is likely that N.sub.24 will be glycosylated if the BITI-E7-141 protein is produced via eukaryotic expression. Such glycosylation may render the protein immunogenic when used for long-term treatment. The MUTT26A oligonucleotide asserts the mutation T26A and removes the potential glycosylation site with minimal changes in the overall chemical properties of the residue at that position (Ser, Pro, or Cys, were considered undesirable). In addition, an Ala residue is frequently found in other BPTI homologues at position 26.

Mutagenesis of ssDNA isolated from MA-BITI-E7-141 display phage was performed as previously described. The DNA sequence of the entire BITI-E7-141-derived insert in the mutagenized phage was confirmed by DNA sequencing. Individual populations of phage displaying mutagenized BITI-E7-141 proteins fused to gene III protein were prepared from large-scale cultures of bacteria infected with phage isolated from single plaques.

EXAMPLE 8

hNE-binding properties of mutagenized MA-BITI-E7-141 display phage

The binding properties of the individual phage populations to hNE-beads were determined using the abbreviated and extended pH elution protocols described previously. The results of these studies are presented, in a common format, in Table 219.

Table 219 shows pH elution data for the various display phage eluted from hNE-beads. Total pfu applied to the beads are shown in the second column. The fractions of this input pfu recovered in each pH fraction of the abbreviated pH elution protocol (pH 7.0, pH 3.5, and pH 2.0) are listed in the next three columns. For data obtained using the extended pH elution protocol, the pH 3.5 listing represents the sum of the fractions of input recovered in the pH 6.0, pH 5.5, pH 5.0, pH 4.5, pH 4.0, and pH 3.5 elution samples. Likewise, the pH 2.0 listing is the sum of the fractions of input obtained from the pH 3.0, pH 2.5, and pH 2.0 elution samples. The total fraction of the input pfu obtained throughout the pH elution protocol is recorded in the sixth column of Table 219. The final column of the table lists the total fraction of input pfu recovered normalized to the value obtained for MA-BITI-E7-141 display phage.

Two factors must be considered when making comparisons among the data shown in Table 219. The first is that due to the kinetic nature of phage release from hNE-beads and the longer time involved in the extended pH elution protocol, the fraction of input pfu recovered in the pH 3.5 fraction will be enriched at the expense of the pH 2.0 fraction in the extended protocol relative to those values obtained in the abbreviated protocol. The magnitude of this effect can be seen by comparing the results obtained when MA-BITI-E7-141 display phage were eluted from hNE-beads using the two protocols. The second factor is that, for the range of input pfu listed in Table 219, the input pfu influences recovery. The greater the input pfu, the greater the total fraction of the input recovered in the elution. This effect is apparent when input pfu differ by more than a factor of about 3 to 4. The effect can lead to an overestimate of affinity of display phage for hNE-beads when data from phage applied at higher titers is compared with that from phage applied at lower titers.

With these caveats in mind, we can interpret the data in Table 219. The effects of the mutations introduced into MA-BITI-E7-141 display phage ("parental") on binding of display phage to hNE-beads can be grouped into three categories: those changes that have little or no measurable effects, those that have moderate (2- to 3-fold) effects, and those that have large (>5-fold) effects.

The MUTF26A and MUTQE changes appear to have little effect on the binding of display phage to hNE-beads. In terms of total pfu recovered, the display phage containing these alterations bind as well as the parental to hNE-beads. Indeed, the pH elution profiles obtained for the parental and the MUTT26A display phage from the extended pH elution protocol are indistinguishable. The binding of the MUTTQE display phage appears to be slightly reduced relative to the parental and, in light of the applied pfu, it is likely that this binding is somewhat overestimated.

The sequence alterations introduced via the MUTP1 and MUT1619 oligonucleotides appear to reduce display phage binding to hNE-beads about 2- to 3-fold. In light of the input titers and the distributions of pfu recovered among the various elution fractions, it is likely that 1) both of these display phage have lower affinities for hNE-beads than do MA-EpiNE7 display phage, and 2) the MUT1619 display phage have a greater affinity for hNE-beads than do the MUTP1 display phage.

The sequence alterations at the amino terminus of BITI-E7-14 appear to reduce binding by the display phage to hNE-beads at least ten fold. The AMINO2 changes are likely to reduce display phage binding to a substantially greater extent than do the AMINO1 changes.

On the basis of the above interpretations of the data in Table 219, we can conclude that:

1.) The substitution of ALA for THR at position 26 in ITI-D1 and its derivatives has no effect on the interaction of the inhibitor with hNE. Thus, the possibility of glycosylation at Ash.sub.24 of an inhibitor protein produced in eukaryotic cell culture can be avoided with no reduction in affinity for hNE. 2.) The increase in affinity of display phage for hNE-beads produced by the changes Glu to Gln at position 31 and Gln to Val at 34 results primarily from the Val substitution at 34. 3.) All three changes introduced at the amino terminal region of ITI-D1 (positions 1,2, and 4) influence display phage binding to hNE-beads to varying extents. The change at position 4 (Ser to Phe) appears to have about the same effect as does the change at position 2 (Glu to Pro). The change at position 1 appears to have only a small effect. 4.) The changes in the region around the P1 residue in BITI-E7-141 (position 15) influence display phage binding to hNE. The changes Ala to Gly at 16 and Pro to Ser at 19 appear to reduce the affinity of the inhibitor somewhat (perhaps 3-fold). The substitution of Ile for Val at position 15 further reduces binding.

BITI-E7-141 differs from ITI-D1 at nine positions. On the basis of the discussion above it appears likely that a high affinity hNE-inhibitor based on ITI-D1 could be constructed that would differ from the ITI-D1 sequence at only five or six positions. These differences would be: Pro at position 2, Phe at position 4, Val at position 15, Phe at position 18, Val at position 34, and Ala at position 26. If glycosylation of Asn.sub.24 is not a concern Thr could be retained at 26.

Summary: estimated affinities of isolated ITI-D1 derivatives for hNE

On the basis of display phage binding to and elution from hNE beads, it is possible to estimate affinities for hNE that various derivatives of ITI-D1 may display free in solution. These estimates are summarized in Table 55. Table 220 and Table 221 give the amino-acid sequences of the ITI-D1-derived proteins grouped by affinity for hNE. Each of these sequences may be used as the sequence of an entire protein having hNE-inhibitory activity. One may also incorporate any of the sequences of Table 220 into a larger protein where each is expected to confer hNE-inhibition on the fusion protein.

hNE Inhibitors Derived from ITI Domain 2

In addition to hNE inhibitors derived from ITI-D1, the present invention comprises hNE inhibitors derived from ITI-D2. These inhibitors have been produced in the yeast Pichia pastoris in good yield. Tests on these inhibitors show that EPI-HNE-4 inhibits human neutrophil elastase with a K.sub.D .apprxeq.5 pM.

PURIFICATION AND PROPERTIES OF EPI-HNE PROTEINS I. EPI-HNE Proteins.

EXAMPLE 9

Amino-acid sequences of EPI-HNE-3 and EPI-HNE-4

Table 601 provides the amino acid sequences of four human-neutrophil-elastase (hNE) inhibitor proteins: EPI-HNE-1, EPI-HNE-2, EPI-HNE-3, and EPI-HNE4. These proteins have been derived from the parental Kunitz-type domains shown. Each of the proteins is shown aligned to the parental domain using the six cysteine residues (shaded) characteristic of the Kunitz-type domain. Residue position numbers are based on BPTI so that the first cysteine in each protein is assigned position 5. Residues within the inhibitor proteins that differ from those in the parental protein are highlighted in bold text. Entire proteins having the sequence shown in Table 601 have been produced. Larger proteins that comprise one of the sequences in Table 601 are expected to have potent hNE-inhibitory activity. It is expected that proteins that comprise part of one of the sequences found in Table 601, particularly if the sequence starting at the first cysteine and continuing through the last cysteine is retained, will exhibit potent hNE-inhibitory activity.

The hNE-inhibitors EPI-HNE-1 and EPI-HNE-2 are derived from the bovine protein BPTI (aprotinin). Within the Kunitz-type domain, these two inhibitors both differ from the parental protein sequence at the same eight positions: K15I, R17F, I18F, I19P, R39M, A40G, K41N, and R42G. In addition, EPI-HNE-2 differs from both BPTI and EPI-HNE-1 in the presence of four additional residues (EAEA) present at the amino terminus of the molecule. These residues were added to facilitate secretion of the protein in Pichia pastoris.

EPI-HNE-3 is derived from the second Kunitz-type domain of the light chain of the human inter-.alpha. inhibitor protein (ITI-D2). The amino acid sequence of EH-HNE-3 differs from that of ITI-D2 at only four positions: R15I, I18F, Q19P and L20R. EPI-HNE-4 differs from EPI-HNE-3 by the substitution A3E (the amino-terminal residue) which both facilitates secretion of the protein in P. pastoris and improves the K.sub.D for hNE.

Table 602 presents some physical properties of the hNE inhibitor proteins. All four proteins are small, high-affinity (K.sub.i =2 to 6 pM), fast-acting (k.sub.on =4 to 11.times.10.sup.6 M.sup.-1 s.sup.-1) inhibitors of hNE.

II. Production of the hNE-inhibitors EPI-HNE-2, EPI-HNE-3, and EPI-HNE-4.

EXAMPLE 10

Pichia pastoris production system.

Transformed strains of Pichia pastoris were used to express the various EPI-HNE proteins derived from BPTI and ITI-D2. Protein expression cassettes are cloned into the plasmid pHIL-D2 using the BstBI and EcoRI sites shown in FIG. 1. The DNA sequence of pHIL-D2 is given in Table 250. The cloned gene is under transcriptional control of P. pastoris upstream (labeled "aox1 5'") aox1 gene promoter and regulatory sequences (dark shaded region) and downstream polyadenylation and transcription termination sequences (second cross-hatched region, labeled "aox1 3'"). P. pastoris GS115 is a mutant strain containing a non-functional histidinol dehydrogenase (his4) gene. The his4 gene contained on plasmid pHIL-D2 and its derivatives can be used to complement the histidine deficiency in the host strain. Linearization of plasmid pHIL-D2 at the indicated sacI site directs plasmid incorporation into the host genome at the aox1 locus by homologous recombination during transformation. Strains of P. pastoris containing integrated copies of the expression plasmid will express protein genes under control of the aox1 promoter when the promoter is activated by growth in the presence of methanol as the sole carbon source.

We have used this high density Pichia pastoris production system to produce proteins by secretion into the cell culture medium. Expression plasmids were constructed by ligating synthetic DNA sequences encoding the S. cerevisiae mating factor .alpha. prepro peptide fused directly to the amino terminus of the desired hNE inhibitor into the plasmid pHIL-D2 using the BstBI and the EcoRI sites shown. Table 251 gives the DNA sequence of pHIL-D2(MF.alpha.-PrePro::EPI-HNE-3). In these constructions, the fusion protein is placed under control of the upstream inducible P. pastoris aox1 gene promoter and the downstream aox1 gene transcription termination and polyadenylation sequences. Expression plasmids were linearized by SacI digestion and the linear DNA was incorporated by homologous recombination into the genome of the P. pastoris strain GS115 by spheroplast transformation. Regenerated spheroplasts were selected for growth in the absence of added histidine, replated, and individual isolates were screened for methanol utilization phenotype (mut.sup.+), secretion levels, and gene dose (estimated via Southern hybridization experiments). High level secretion stains were selected for production of hNE inhibitors: PEY-33 for production of EPI-HNE-2 and PEY43 for production of EPI-HNE-3. In both of these strains, we estimate that four copies of the expression plasmid are integrated as a tandem array into the aox1 gene locus.

To facilitate alteration of the Kunitz-domain encoding segment of pHIL-D2 derived plasmids, we removed two restriction sites shown in FIG. 1: the BstBI at about 7 o'clock and the AatII site at about 8 o'clock. Thus, the Kunitz-domain encoding segment is bounded by unique AatII and EcoRI sites. The new plasmids are called pD2pick("insert") where "insert" defines the domain encoded under control of the aox1 promoter. Table 253 gives the DNA sequence of pD2pick(MF.alpha.::EPI-HNE-3). Table 254 gives a list of restriction sites in pD2pick(MF.alpha.::EPI-HNE-3).

EPI-HNE-4 is encoded by pD2pick(MF.alpha.PrePro::EPI-HNE-4) which differs from pHIL-D2 in that: 1) the AatII/EcoRI segment of the sequence given in Table 251 is replaced by the segment shown in Table 252 and 2) the changes in the restriction sites discussed above have been made. Strain PEY-53 is P. pastoris GS115 transformed with pD2pick(MF.alpha.::EPI-HNE-4).

EXAMPLE 11

Protein Production

To produce the proteins, P. pastoris strains were grown in mixed-feed fermentations similar to the procedure described by Digan et al. (DIGA89). Although others have reported production of Kunitz domains in P. pastoris, it is well known that many secretion systems involve proteases. Thus, it is not automatic that an altered Kunitz domain having a high potency in inhibiting hNE could be secreted from P. pastoris because the new inhibitor might inhibit some key enzyme in the secretion pathway. Nevertheless, we have found that P. pastoris can secrete hNE inhibitors in high yield.

Briefly, cultures were first grown in batch mode with glycerol as the carbon source. Following exhaustion of glycerol, the culture was grown for about four hours in glycerol-limited feed mode to further increase cell mass and to derepress the aox1 promoter. In the final production phase, the culture was grown in methanol-limited feed mode. During this phase, the aox1 promoter is fully active and protein is secreted into the culture medium.

Table 607 and Table 608 give the kinetics of cell growth (estimated as A.sub.600) and protein secretion (mg/l) for cultures of PEY-33 and PEY-43 during the methanol-limited feed portions of the relevant fermentations. Concentrations of the inhibitor proteins in the fermentation cultures were determined from in vitro assays of hNE inhibition by diluted aliquots of cell-free culture media obtained at the times indicated. Despite similarities in gene dose, fermentation conditions, cell densities, and secretion kinetics, the final concentrations of inhibitor proteins secreted by the two strains differ by nearly an order of magnitude. The final concentration of EPI-HNE-2 in the PEY-33 fermentation culture medium was 720 mg/l. The final concentration of EPI-HNE-3 in the PEY-43 fermentation culture medium was 85 mg/l. The differences in final secreted protein concentrations may result from idiosyncratic differences in the efficiencies with which the yeast synthesis and processing systems interact with the different protein sequences.

Strain PEY-33 secreted EPI-HNE-2 protein into the culture medium as a single molecular species which amino acid composition and N-terminal sequencing reveled to be the correctly-processed Kunitz domain with the sequence shown in Table 601. The major molecular species produced by PEY-43 cultures was the properly-processed EPI-HNE-3 protein. However, this strain also secreted a small amount (about 15% to 20% of the total EPI-HNE-3) of incorrectly-processed material. This material proved to be a mixture of proteins with amino terminal extensions (primarily nine or seven residues in length) arising from incorrect cleavage of the MF .alpha. PrePro leader peptide from the mature Kunitz domain. The correctly processed protein was purified substantially free of these contaminants as described below.

III. Purification of the hNE-inhibitors EPI-HNE-2 and EPI-HNE-3.

The proteins can be readily purified from fermenter culture medium by standard biochemical techniques. The specific purification procedure varies with the specific properties of each protein as described below.

EXAMPLE 12

Purification of EPI-HNE-2.

Table 603 gives particulars of the purification of EPI-HNE-2, lot 1. The PEY-33 fermenter culture was harvested by centrifugation at 8000.times.g for 15 min and the cell pellet was discarded. The 3.3 liter supernatant fraction was microfiltered used a Minitan Ultrafiltration System (Millipore Corporation, Bedford, Mass.) equipped with four 0.2.mu. filter packets.

The filtrate obtained from the microfiltration step was used in two subsequent ultrafiltration steps. First, two 30K ultrafiltrations were performed on the 0.2.mu. microfiltrate using the Minitan apparatus equipped with eight 30,000 NMWL polysulfone filter plates (#PLTK0MP04, Millipore Corporation, Bedford, Mass.). The retentate solution from the first 30K ultrafiltration was diluted with 10 mM NaCitrate, pH=3.5, and subjected to a second 30K ultrafiltration. The two 30K ultrafiltrates were combined to give a final volume of 5 liters containing about 1.4 gram of EPI-HNE-2 protein (estimated from hNE-inhibition measurements).

The 30K ultrafiltrate was concentrated with change of buffer in the second ultrafiltration step using the Minitan apparatus equipped with eight 5,000 NMWL filter plates (#PLCC0MP04, Millipore Corporation, Bedford, Mass.). At two times during the 5K ultrafiltration, the retentate solution was diluted from about 300 ml to 1.5 liters with 10 mM NaCitrate, pH=3.5. The final 5K ultrafiltration retentate (Ca. 200 ml) was diluted to a final volume of 1000 ml with 10 mM NaCitrate, pH-3.5.

EPI-HNE-2 protein was obtained from the 5K ultrafiltration retentate solution by ammonium sulfate precipitation at room temperature. 100 ml of 0.25M ammonium acetate, pH=3.2, (1/10 volume) was added to the 5K ultrafiltration retentate, followed by one final volume (1.1 liter) of 3M ammonium sulfate. Following a 30 minute incubation at room temperature, precipitated material was pelleted by centrifugation at 10,000.times.g for 45 minutes. The supernatant solution was removed, the pellet was dissolved in water in a final volume of 400 ml, and the ammonium sulfate precipitation was repeated using the ratios described above. The pellet from the second ammonium sulfate precipitation was dissolved in 50 mM sodium acetate, pH=3.5 at a final volume of 300 ml.

Residual ammonium sulfate was removed from the EPI-HNE-2 preparation by ion exchange chromatography. The solution from the ammonium sulfate precipitation step was applied to a strong cation-exchange column (50 ml bed volume Macroprep 50S) (Bio-Rad Laboratories, Inc, Hercules, Calif.) previously equilibrated with 10 mM NaCitrate, pH=3.5. After loading, the column was washed with 300 ml of 10 mM NaCitrate, pH=3.5. EPI-HNE-2 was then batch-eluted from the column with 300 ml of 50 mM NH.sub.4 OAc, pH=6.2. Fractions containing EPI-HNE-2 activity were pooled and the resulting solution was lyophilized. The dried protein powder was dissolved in 50 ml dH.sub.2 O and the solution was passed through a 0.2.mu. filter (#4192, Gelman Sciences, Ann Arbor, Mich.). The concentration of the active inhibitor in the final stock solution was determined to be 2 mM (13.5 mg/ml). This stock solution (EPI-HNE-2, Lot 1) has been stored as 1 ml aliquots at both 4.degree. C. and -70.degree. C. for more than eleven months with no loss in activity.

Table 603 summarizes the yields and relative purity of EPI-HNE-2 at various steps in the purification procedure. The overall yield of the purification procedure was about 30%. The major source of loss was retention of material in the retentate fractions of the 0.2.mu. microfiltration and 30k ultrafiltration steps.

EXAMPLE 13

Purification of EPI-HNE-3.

Purification of EPI-HNE-3, lot 1, is set out in Table 604. The PEY-43 fermenter culture was harvested by centrifugation at 8,000.times.g for 15 min and the cell pellet was discarded. The superantant solution (3100 ml) was microfiltered through 0.2.mu. Minitan packets (4 packets). After the concentration, a diafiltration of the retentate was performed so that the final filtrate volume from the 0.2.mu. filtration was 3300 ml.

A 30K ultrafiltration was performed on the filtrate from the 0.2.mu. microfiltration step. When the retentate volume had been reduced to 250 ml, a diafiltration of the retentate was performed at a constant retentate volume (250 ml) for 30 min at a rate of 10 ml/min. The resulting final volume of filtrate was 3260 ml.

EPI-HNE-3 protein and other medium components were found to precipitate from solution when the fermenter culture medium was concentrated. For this reason, the 5k ultrafiltration step was not performed.

Properly processed EPI-HNE-3 was purified substantially free of mis-processed forms and other fermenter culture components by ion exchange chromatography. A 30 ml bed volume strong cation ion exchange column (Macroprep 50S) was equilibrated with 10 mM NaCitrate pH=3.5. The 30K ultrafiltration filtrate was applied to the column and binding of EPI-HNE-3 to the column was confirmed by demonstrating the complete loss of inhibitor activity in the column flow through. The column was then washed with 300 ml of 10 mM NaCitrate, pH=3.5.

EPI-HNE-3 was removed from the column over the course of a series of step elutions. The column was sequentially eluted with 300 ml volumes of the following solutions:

100 mM ammonium acetate, pH=3.5 50 mM ammonium acetate, pH=4.8 50 mM ammonium acetate, pH=6.0 50 mM ammonium acetate, pH=6.0, 0.1M NaCl 50 mM ammonium acetate, pH=6.0, 0.2M NaCl 50 mM ammonium acetate, pH=6.0, 0.3M NaCl 50 mM ammonium acetate, pH=6.0, 0.4M NaCl 50 mN Tris/Cl pH=8.0, 1.0 NaCl The majority of the EPI-HNE-3 eluted in two 50 mM ammonium acetate, pH=6.0 fractions. The 0.1M NaCl fraction contained about 19% of the input EPI-HNE-3 activity (28 mg of 159 mg input) and essentially all of the mis-processed forms of EPI-HNE-3. The 0.2M NaCl fraction contained about 72% (114 mg) of the input EPI-HNE-3 and was almost completely free of the higher molecular weight mis-processed forms and other UV-absorbing contaminants. The fractions from the 50 mM ammonium acetate, pt=6.0, 0.2M NaCl elution having the highest concentrations of EPI-HNE-3 were combined (95 mg).

An ammonium sulfate precipitation was performed on the 0.2M NaCl, pH=6.0 ion exchange column eluate. 800 ml of 3M ammonium sulfate was added to 160 ml of eluate solution (final ammonium sulfate concentration=2.5M) and the mixture was incubated at room temperature for 18 hours. The precipitated material was then pelleted by centrifugation at 10,000.times.g for 45 minutes. The supernatant fluid was discarded and the pelleted material was dissolved in 100 ml of water.

Residual ammonium sulfate was removed from the EPI-HNE-3 preparation by batch ion exchange chromatography. The pH of the protein solution was adjusted to 3.0 with diluted (1/10) HOAc and the solution was then applied to a 10 ml bed volume Macroprep 50S column that had been equilibrated with 10 mM NaCitrate, pH=3.5. Following sample loading, the column was washed with 100 ml of 10 mM NaCitrate, pH=3.5 followed by 100 ml of dH.sub.2 O. EPI-HNE-3 was eluted from the column with 100 ml of 50 mM NH.sub.4 CO.sub.3, pH-9.0. pH9 fractions having the highest concentrations of EPI-HNE-3 were combined (60 mg) and stored at 4.degree. C. for 7 days before lyophilization.

The lyophilized protein powder was dissolved in 26 ml dH.sub.2 O and the solution was passed through a 0.2.mu. filter (#4912, Gelman Sciences, Ann Arbor, Mich.). The concentration of active inhibitor in the final stock solution was found to be 250 .mu.M (1.5 mg/ml). This stock solution (EPI-HNE-3, Lot 1) has been stored as 1 ml aliquots at -70.degree. C. for more than six months with no loss of activity. EPI-HNE-3 stored in water solution (without any buffering) deteriorated when kept at 4.degree. C. After five months, about 70% of the material was active with a K.sub.i of about 12 pM.

Table 604 summarizes the yield and relative purity of EPI-HNE-3 at various steps in the purification procedure. A major purification step occurred at the first ion exchange chromatography procedure. The ammonium sulfate precipitation step provided only a small degree of further purification. Some loss of inhibitor activity occurred on incubation at pt=9 (See pH stability data).

Production and purification of EPI-HNE-1 and EPI-HNE-4 were analogous to the production and purification of EPI-HNE-2 and EPI-HNE-3.

EXAMPLE 14

Tricine-PAGE Analysis of EPI-HNE-2 and EPI-HNE-3.

The high resolution tricine gel system of Schagger and von Jagow (SCHA87) was used to analyze the purified proteins produced as described above. For good resolution of the low molecular weight EPI-HNE proteins we used a 16.5% resolving layer in conjunction with 10% separating and 4% stacking layers. Following silver staining, we inspected a gel having:

Lane 1: EPI-HNE-2 25 ng, Lane 2: EPI-HNE-2 50 ng, Lane 3: EPI-HNE-2 100 ng, Lane 4: EPI-HNE-2 200 ng, Lane 5: EPI-HNE-3 25 ng, Lane 6: EPI-HNE-3 50 ng, Lane 7: EPI-HNE-3 100 ng, Lane 8: EPI-HNE-3 200 ng, and Lane 9: Molecular-weight standards: RPN 755, (Amersham Corporation, Arlington Heights, Ill.). Stained proteins visible on the gel and their molecular weights in Daltons are: ovalbin (46,000), carbonic anhydrase (30,000), trypsin inhibitor (21,500), lysozyme (14,300), and aprotinin (6,500). The amount of protein loaded was determined from measurements of hNE-inhibition. We found the following features. EPI-HNE-2, Lot 1 shows a single staining band of the anticipated size (ca. 6,700 D) at all loadings. Similarly, EPI-HNE-3, Lot 1 protein shows a single staining band of the anticipated size (ca. 6,200 D). At the highest loading, traces of the higher molecular weight (ca. 7,100 D) incorrectly processed form can be detected. On the basis of silver-stained high-resolution PAGE analysis, the purity of both protein preparations is assessed to be significantly greater than 95%. IV. Properties of EPI-HNE-2 and EPI-HNE-3. A. Inhibition of hNE.

EXAMPLE 15

Measured K.sub.D s of EPI-HNE proteins for hNE

Inhibition constants for the proteins reacting with hNE (K.sub.i) were determined using room temperature measurements of hydrolysis of a fluorogenic substrate (N-methoxysuccinyl-Ala-Ala-Pro-Val-7-amino-4-methylcoumarin, Sigma M-9771) by hNE. For these measurements, aliquots of the appropriately diluted inhibitor stocks were added to 2 ml solutions of 0.847 nM hNE in reaction buffer (50 mM Tris-Cl, pH=8.0, 150 mM NaCl, 1 mM CaCl.sub.2, 0.25% Triton-X-100) in plastic fluorescence cuvettes. The reactions were incubated at room temperature for 30 minutes. At the end of the incubation period, the fluorogenic substrate was added at a concentration of 25 .mu.M and the time course for increase in fluorescence at 470 nm (excitation at 380 nm) due to enzymatic substrate cleavage was recorded using a spectrofluorimeter (Perkin-Elmer 650-15) and strip chart recorder. We did not correct for competition between substrate and inhibitor because (S.sub.0 /K.sub.m) is 0.07 (where S.sub.0 is the substrate concentration and K.sub.m is the binding constant of the substrate for hNE). K.sub.i is related to K.sub.apparent by ##EQU1## The correction is small compared to the possible errors in determining K.sub.apparent. Rates of enzymatic substrate cleavage were determined from the linear slopes of the recorded increases in fluorescence. The percent residual activity of hNE in the presence of the inhibitor was calculated as the percentage of the rate of fluorescence increase observed in the presence of the inhibitor to that observed when no added inhibitor was present.

We recorded data used to determine K.sub.i for EPI-HNE-2 and EPI-HNE-3 reacting with hNE. Data obtained as described above are recorded as percent residual activity plotted as a function of added inhibitor. Values for K.sub.i and for active inhibitor concentration in the stock are obtained from a least-squares fit program. From the data, K.sub.i values for EPI-HNE-2 and for EPI-HNE-3 reacting with hNE at room temperature were calculated to be 4.8 pM and 6.2 pM, respectively. Determinations of K.sub.i for EPI-HNE-2 and EPI-HNE-3 reacting with hNE are given in Table 610 and Table 611.

The kinetic on-rates for the inhibitors reacting with hNE (k.sub.on) were determined from measurements of progressive inhibition of substrate hydrolytic activity by hNE following addition of inhibitor. For these experiments, a known concentration of inhibitor was added to a solution of hNE (0.847 nM) and substrate (25 .mu.M) in 2 ml of reaction buffer in a plastic fluorescence cuvette. The change in fluorescence was recorded continuously following addition of the inhibitor. In these experiments, sample fluorescence did not increase linearly with time. Instead, the rate of fluorescence steadily decreased reflecting increasing inhibition of hNE by the added inhibitor. The enzymatic rate at selected times following addition of the inhibitor was determined from the slope of the tangent to the fluorescence time course at that time.

The kinetic constant k.sub.on for EPI-HNE-2 reacting with hNE was determined as follows. EPI-HNE-2 at 1.3 nM was added to buffer containing 0.867 nM hNE (I:E=1.5:1) at time 0. Measured percent residual activity was recorded as a function of time after addition of inhibitor. A least-squares fit program was used to obtain the value of k.sub.on =4.0.times.10.sup.6 M.sup.-1 s.sup.-1.

The kinetic off rate, k.sub.off, is calculated from the measured values of K.sub.i and k.sub.on as:

k.sub.off =K.sub.D .times.k.sub.on The values from such measurements are included in Table 602. The EPI-HNE proteins are small, high affinity, fast acting inhibitors of hNE. B. Specificity.

EXAMPLE 16

Specificity of EPI-HNE proteins

We attempted to determine inhibition constants for EPI-HNE proteins reacting with several serine proteases. The results are summarized in Table 605. In all cases except chymotrypsin, we were unable to observe any inhibition even when 10 to 100 .mu.M inhibitor was added to enzyme at concentrations in the nM range. In Table 605, our calculated values for K.sub.i (for the enzymes other than chymotrypsin) are based on the conservative assumption of less than 10% inhibition at the highest concentrations of inhibitor tested. For chymotrypsin, the K.sub.i is about 10 .mu.M and is probably not specific.

C. In Vitro Stability.

EXAMPLE 17

Resistance to Oxidative Inactivation.

Table 620 shows measurements of the susceptibility of EPI-HNE proteins to oxidative inactivation as compared with that of two other natural protein hNE inhibitors: .alpha. 1 Protease Inhibitor (API) and Secretory Leucocyte Protease Inhibitor (SLPI). API (10 .mu.M), SLPI (8.5 .mu.M), EPI-HNE-1 (5 .mu.M), EPI-HNE-2 (10 .mu.M), EPI-HNE-3 (10 .mu.M), and EPI-HNE-4 (10 .mu.M) were exposed to the potent oxidizing agent, Chloramine-T, at the indicated oxidant:inhibitor ratios in 50 mM phosphate buffer, pH=7.0 for 20 minutes at room temperature. At the end of the incubation period, the oxidation reactions were quenched by adding methionine to a final concentration of 4 mM. After a further 10 minute incubation, the quenched reactions were diluted and assayed for residual inhibitor activity in our standard hNE-inhibition assay.

Both API and SLPI are inactivated by low molar ratios of oxidant to inhibitor. The Chloramine-T:protein molar ratios required for 50% inhibition of API and SLPI are about 1:1 and 2:1, respectively. These ratios correspond well with the reported presence of two and four readily oxidized methionine residues in API and SLPI, respectively. In contrast, all four EPI-HNE proteins retain essentially complete hNE-inhibition activity following exposure to Chloramine-T at all molar ratios tested (up to 50:1, in the cases of EPI-HNE-3 and EPI-HNE-4). Neither EPI-HNE-3 nor EPI-HNE-4 contain any methionine residues. In contrast, EPI-HNE-1 and EPI-HNE-2 each contains two methionine residues (see Tables 401 and 601). The resistance of these proteins to oxidative inactivation indicates that the methionine residues are either inaccessible to the oxidant or are located in a region of the protein that does not interact with hNE.

EXAMPLE 18

pH Stability.

Table 612 shows the results of measurements of the pH stability of EPI-HNE proteins. The stability of the proteins to exposure to pH conditions in the range of pH 1 to pH 10 was assessed by maintaining the inhibitors in buffers of defined pH at 37.degree. C. for 18 hours and determining the residual hNE inhibitory activity in the standard hNE-inhibition assay. Proteins were incubated at a concentration of 1 .mu.M. The following buffers were formulated as described (STOL90) and used in the pH ranges indicated:

TABLE 14______________________________________Buffers used in stability studiesBuffer Lowest pH Highest pH______________________________________Glycine-HCl 1 2.99Citrate-Phosphate 3 7Phosphate 7 8Glycine-NaOH 8.5 10______________________________________

Both BPTI-derived inhibitors, EPI-HNE-1 and EPI-HNE-2, are stable at all pH values tested. EPI-HNE-3 and EPI-HNE-4, the inhibitors derived from the human protein Kunitz-type domain, were stable when incubated at low pH, but showed some loss of activity at high pH. When incubated at 37.degree. C. for 18 hours at pH=7.5, the EPI-HNE-3 preparation lost 10 to 15% of its hNE-inhibition activity. EPI-HNE-4 retains almost full activity to pH 8.5. Activity of the ITI-D2-derived inhibitor declined sharply at higher pH levels so that at pH 10 only 30% of the original activity remained. The sensitivity of EPI-HNE-3 to incubation at high pH probably explains the loss of activity of the protein in the final purification step noted previously.

EXAMPLE 19

Temperature Stability.

The stability of EPI-HNE proteins to exposure to temperatures in the range 0.degree. C. to 95.degree. C. was assessed by incubating the inhibitors for thirty minutes at various temperatures and determining residual inhibitory activity for hNE. In these experiments, protein concentrations were 1 .mu.M in phosphate buffer at pH=7. As is shown in Table 630, the four inhibitors are quite temperature stable.

EPI-HNE-1 and EPI-HNE-2 maintain full activity at all temperatures below about 90.degree. C. EPI-HNE-3 and EPI-HNE-4 maintain full inhibitory activity when incubated at temperatures below 65.degree. C. The activity of the protein declines somewhat at higher temperatures. However, all three proteins retain more than .apprxeq.50% activity even when incubated at 95.degree. C. for 30 minutes.

EXAMPLE 20

Relationship of various hNE-inhibiting Kunitz Domains:

Table 399 shows the number of amino-acid differences between 1) the consensus Kunitz domain, 2) BPTI, and 3) several hNE-inhibitory Kunitz domains. Of all the actual proteins listed, EPI-HNE-1 and EPI-HNE-2 are most like the consensus. Although EPI-HNE-3 and EPI-HNE-4 differ substantially from EPI-HNE-1 and EPI-HNE-2, all four proteins have remarkably similar abilities to inhibit HNE.

ROUTES to OTHER hNE-INHIBITORY SEQUENCES:

The present invention demonstrates that very high-affinity hNE inhibitors can be devised from Kunitz domains of human origin with very few amino-acid substitutions. It is believed that almost any Kunitz domain can be made into a potent and specific hNE inhibitor with eight or fewer substitutions. In particular, any one of the known human Kunitz domains could be remodeled to provide a highly stable, highly potent, and highly selective hNE inhibitor. There are at least three routes to hNE inhibitory Kunitz domains: 1) replacement of segments known to be involved in specifying hNE binding, 2) replacement of single residues thought to be important for hNE binding, and 3) use of libraries of Kunitz domains to select hNE inhibitors.

EXAMPLE 21

Substitution of Segments in Kunitz Domains

Table 700 shows the amino-acid sequences of 12 Kunitz domains. One of these is a consensus of seventy naturally-occurring Kunitz domains, one is bovine pancreatic trypsin inhibitor, and the rest are of human origin. The sequences have been broken into ten segments. Segments 1, 3, 5, 7, and 9 contain residues that show strong influence on the binding properties of Kunitz domains. Segment 1 is at the amino terminus and influences the binding by affecting the stability and dynamics of the protein. Segments 3, 5, 7, and 9 contain residues that contact serine proteases when a Kunitz domain binds in the active site. Other than segment 1, all the segments are the same length except for TFPI-2 Domain 2 which carries an extra residue in segment 2 and two extra residues in segment 10.

High-affinity hNE inhibition requires a molecule that is highly complementary to hNE. The sequences in segments 1, 3, 5, 7, and 9 must work together in the context supplied by the each other and the other segments. Nevertheless, we have demonstrated that very many sequences are capable of high-affinity hNE inhibition. It may be desirable to have an hNE inhibitor that is highly similar to a human protein to reduce the chance of immunogenicity. Candidate high-affinity hNE inhibitor protein sequences may be obtained by taking Segments 2, 4, 6, 8, and 10 for one protein in Table 700. The sequences for Segments 1, 3, 5, 7, and 9 are taken from Tables 701, 702, 703, 704, and 705 or may be taken from Table 700 for the parental protein. Segments of any other Kunitz domain could also be used.

EXAMPLE 22

Point substitutions in Kunitz Domains

Table 710 shows a collection of very potent hNB inhibitory Kunitz domains. At the bottom of Table 710 we have collected the amino-acid types at each residue that are compatible with high-affinity hNE binding. It is not believed that all the amino-acid positions are equally important. The two most important positions are 18 and 15. Any Kunitz domain is likely to become a very good hNE inhibitor if Val or Ile is at 15 and Phe is at 18. If a Kunitz domain has Phe at 18 and either Ile or Val at 15 and is not a good hNE inhibitor, there must be one or more residues in the interface preventing proper binding. Imposing the mutations X18F and either X15V or X15I on a Kunitz domain is the first step in making an hNE inhibitor.

The Kunitz domains having high affinity for hNE here disclosed have no charged groups at residues 10, 13, 16, 17, 21, and 32. At positions 11 and 19, only neutral and positively charged groups have been observed in high affinity hNE inhibitors. At position 31, only neutral and negatively charged groups have been observed in high-affinity hNE inhibitors. If a parental Kunitz domain has a charged group at any of those positions where only neutral groups are allowed, then each of the charged groups should be changed to an uncharged group picked from the possibilities in Table 790 as the next step in improving binding to hNE. Similarly, negatively charged groups at 11 and 19 and positively charged groups at 31 should be replaced by groups picked from Table 790.

Most Kunitz domains (82%) have either Gly or Ala at 16 and this may be quite important. If residue 16 is not Gly or Ala, change 16 to either Gly or Ala.

Position 17 in potent hNE inhibitors has one of Met, Phe, Ile, or Leu. preferred. Met should be used only if resistance to oxidation is not important.

It has been shown that high-affinity hNE inhibitors may have one of Pro, Ser, Gln, or Lys at position 19.

All of the high-affinity hNE inhibitors produced so far have Pro.sub.13, but it has not been shown that this is required. Many (62.5%) Kunitz domains have Pro.sub.13. If 13 is not Pro, then changing to Pro may improve the hNE affinity. Val may also be acceptable here.

It appears that many amino acid types may be placed at position 34 while retaining high affinity for hNE; large hydrophobic residues (Phe, Trp, Tyr) are unfavorable. Val, Gln, and Pro are most preferred at 34.

Position 39 seems to tolerate a variety of types. Met and Gln are known to work in very high-affinity inhibitors.

Position 32 may be outside the Kunitz-hNE interface, but unsuitable residues here could substantially reduce binding. Thr and Leu are known to work at 32.

Position 31 may be outside the Kunitz-hNE interface, but unsuitable residues here could substantially reduce binding. Gln, Glu, and Val are known to work here.

Position 12 is always Gly. At position 11, Thr, Ala, and Arg are known to be compatible with high-affinity hNE inhibition. At position 10, Tyr, Ser, and Val are known to be compatible with high-affinity hNE inhibition.

Either Ala or GIy are acceptable at position 40.

Finally, positions that are highly conserved in Kunitz domains may be converted to the conserved type if needed. For example, the mutations X36G, X37G, and X12G may be desirable in those cases that do not already have these amino acids at these positions.

The above mutations are summarized in Table 711. Table 711 contains, for example, mutations of the form X15I which means change the residue at position 15 (whatever it is) to Ile or leave it alone if it is already Ile. A Kunitz domain that contains the mutation X18F and either X15V or X15I will have strong affinity for hNE. As from one up to about eight of the mutations found in Table 711 are asserted, the affinity of the protein for hNE will increase so that the K.sub.i approaches the range 1-5 pM.

Table 706 shows some candidate hNE inhibitors. The sequence of CEPINE001 was constructed from the sequence of human LACI-D2 by the mutations R15V and I18F. The rest of the sequence of LACI-D2 appears to be compatible with hNE binding. CEPINE002 carries two further mutations that make it more like the hNE inhibitors here disclosed: Y17F and K34V. CEPINE003 has the additional mutation N25A that will prevent glycosylation when the protein is produced in a eukaryotic cell. Other substitutions that would prevent glycosylation include: N25K, T27A, T27E, N25S, and N25S. CEPINE004 moves further toward the ITI-D1, ITI-D2, and BPTI derivatives that are known to have affinity for hNE in the 1-5 pM range through the mutations I13P, R15V, Y17F, I18F, T19Q, N25A, K34V, and L39Q. In CEPINE005, the T19Q and N25A mutations have been reverted. Thus the protein would be glycosylated in yeast or other eukaryotic cells at N.sub.25.

CEPINE010 is derived from human LACI domain 3 by the mutations R15V and E18F. CEPINE011 carries the mutations R15V, N17F, E18F, and T46K. The T46K mutation should prevent glycosylation at N.sub.44. CEPINE012 carries more mutations so that it is much more similar to the known high-affinity hNE inhibitors. The mutations are D10V, L13P, R15V, N17F, E18F, K34V, 836G, and T46K.

EXAMPLE 23

Libraries of Kunitz Domains

Other Kunitz domains that can potently inhibit hNE may be derived from human Kunitz domains either by substituting hNE-inhibiting sequences into human domains or by using the methods of U.S. Pat. No. 5,223,409 and related patents. Table 720 shows a gene that will cause display of human LACI-D2 on M13 gIIIp; essentially the same gene could be used to achieve display on M13 gVIIIp or other anchor proteins (such as bacterial outer-surface proteins (OSPs)). Table 725 shows a gene to cause display of human LACI D1 while Table 750 shows a gene to cause display of LACI-D3.

Table 730, Table 735, and Table 760 give variegations of LACI-D1, LACI-D2, and LACI-D3 respectively. Each of these is divided into variegation of residues 10-21 in one segment and residues 31-42 in another. In each case, the appropriate vgDNA is introduced into a vector that displays the parental protein and the library of display phage are fractionated for binding to immobilized hNE.

Table 800 gives the sequences of naturally-occurring Kunitz domains. Table 810 gives the cumulative composition of each position over the sequences on Table 800 and shows which residues are found in five interaction surfaces defined in U.S. Pat. No. 5,223,409. ##TBL5## ##TBL6##

TABLE 35__________________________________________________________________________IIIsp::itiD1::matureIII fusion gene.DNA has SEQ ID NO. 006; amino-acid sequence has SEQ ID NO. 007. The DNAis a linear segmentand the amino-acid sequence is a protein that is processed in vivo andwhich contains disulfides.__________________________________________________________________________ ##STR1## ##STR2## ##STR3## ##STR4## ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16## ##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22## ##STR23## ##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29## ##STR30## ##STR31## ##STR32## ##STR33##__________________________________________________________________________ TABLE 40______________________________________Local sequences of Kunitz domains derived from BPTI or ITI-D1.ResidueProtein 1 2 3 4 11 15 16 17 18 19 26 31 34______________________________________EpiNE-7 R P D F T V A M F P K Q V SEQ ID NO. 001 ITI-D1 K E D S A M G M T S T E Q SEQ ID NO. 008 ITI-D1E7 K E D S A V A M F P T E Q SEQ ID NO. 009 BITI-E7 R P D F A V A M F P T E Q SEQ ID NO. 010 BITI-E7- R P D F A V A M F P T E Q 141 SEQ ID NO. 011 BITI-E7- R P D F T V A M F P T E Q 1222 SEQ ID NO. 012 MUT1619 R P D F A V G M F S T Q V SEQ ID NO. 013 MUTP1 R P D F A I G M F S T Q V SEQ ID NO. 014 AMINO1 K E D F A V A M F P T Q V SEQ ID NO. 015 AMINO2 K P D S A V A M F P T Q V SEQ ID NO. 016 MUTQE R P D F A V A M F P T E V SEQ ID NO. 017 MUTT R P D F A V A M F P A Q V 26A SEQ ID NO. 018______________________________________ TABLE 55__________________________________________________________________________Affinity Classes of ITI-D1-derived hNE inhibitorsAffinity Estimated Fraction of pH ElutionClass K.sub.D Input bound Maximum Protein__________________________________________________________________________WEAK K.sub.D > 10 nM <0.005% >6.0 ITI-D1MODERATE 1 to 10 nM 0.01% to 5.5 to 5.0 BITI 0.03% ITI-D1E7STRONG 10 to 1000 pM 0.03% to 5.0 to 4.5 BITI-E7 0.06% BITI-E7-1222 AMINO1 AMINO2 MUTP1VERY <10 pM >0.1% .ltoreq.4.0 BITI-E7-141STRONG MUTT26A MUTQE MUT1619__________________________________________________________________________ TABLE 100 - hNE-inhibiting Kunitz domains and their parental domains ##STR34## ##STR35## The lines show disulfides. The numbers in parentheses after Epine3, Epine7, and Epine1 show how many times these sequences were isolated. TABLE 208__________________________________________________________________________SEQUENCES OF THE EpiNE CLONES IN THE P1 REGIONProteins have the sequence of BPTI at other residues except that allcarry the changesR39M, A40G, K41N, and R42G. Residue 15Protein 13 14 P1 16 17 18 19 20 21__________________________________________________________________________EpiNE3 P C V G F F S R YSEQ ID NO. 022 CCT TGC GTC GGT TTC TTC TCA CGC TATEpiNE6 P C V G F F Q R YSEQ ID NO. 023 CCT TGC GTC GGT TTC TTC CAA CGC TATEpiNE7 P C V A M F P R YSEQ ID NO. 001 CCT TGC GTC GCT ATG TTC CCA CGC TATEpiNE4 P C V A I F P R YSEQ ID NO. 024 CCT TGC GTC GCT ATC TTC CCA CGC TATEpiNE8 P C V A I F K R SSEQ ID NO. 025 CCT TGC GTC GCT ATC TTC AAA CGC TCTEpiNE1 P C I A F F P R YSEQ ID NO. 026 CCT TGC ATC GCT TTC TTC CCA CGC TATEpiNE5 P C I A F F Q R YSEQ ID NO. 028 CCT TGC ATC GCT TTC TTC CAA CGC TATEpiNE2 P C I A L F K R YSEQ ID NO. 029 CCT TGC ATC GCT TTG TTC AAA CGC TAT__________________________________________________________________________ TABLE 209__________________________________________________________________________BPTI analogues selected for binding to Cathepsin GDNA sequences and predicted amino acid sequences around the P1 region ofBPTIanalogues selected for binding to Cathepsin G. Proteins have the sequenceof BPTI atother residues except that all carry the changes R39M, A40G, K41N, andR42G. Residue 15Protein 10 11 12 13 14 P1 16 17 18 19__________________________________________________________________________BPTI Y T G P C K A R I ISEQ ID NO. 021 TAC ACT GGG CCC TGC AAA GCG CGC ATC ATCEpiC 1 Y T G P C M G F S KSEQ ID NO. 031 TAC ACT GGG CCC TGC ATG GGT TTC TCC AAAEpiC 7 Y T G P C M A L F KSEQ ID NO. 032 TAC ACT GGG CCC TGC ATG GCT TTG TTC AAAEpiC 8 N T G P C F A I T PSEQ ID NO. 033 AAC ACT GGG CCC TGC TTC GCT ATC ACC CCAEpiC 10 Y T G P C M A L F QSEQ ID NO. 034 TAC ACT GGG CCC TGC ATG GCT TTG TTC CAAEpiC 20 Y T G P C M A I S PSEQ ID NO. 035 TAC ACT GGG CCC TGC ATG GCT ATC TCC CCA__________________________________________________________________________ TABLE 210__________________________________________________________________________Derivatives of EpiNE7 Obtained by Variegation at positions 34, 36, 39, 40and 41__________________________________________________________________________ ##STR36##RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFlYgGCkgkGNNFKSAEDCMRTCGGA EpiNE7.6036RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGCwakGNNFKSAEDCMRTCGGA EpiNE7.8, 7.9,& 7.31037RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFgYaGCrakGNNFKSAEDCMRTCGGA EpiNE7.11038RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGChaeGNNFKSAEDCMRTCGGA EpiNE7.7039RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFlYgGCwaqGNNFKSAEDCMRTCGGA EpiNE7.4 &7.1440RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFrYgGClaeGNNFKSAEDCMRTCGGA EpiNE7.5041RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFdYgGChadGNNFKSAEDCMRTCGGA EpiNE7.10 &7.20042RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGClahGNNFKSAEDCMRTCGGA EpiNE7.1043RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGCwanGNNFKSAEDCMRTCGGA EpiNE7.16044RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFnYgGCegkGNNFKSAEDCMRTCGGA EpiNE7.19045RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFqYgGCegyGNNFKSAEDCMRTCGGA EpiNE7.12046RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFqYgGClgeGNNFKSAEDCMRTCGGA EpiNE7.17047RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFhYgGCwgqGNNFKSAEDCMRTCGGA EpiNE7.21048RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFhYgGCwgeGNNFKSAEDCMRTCGGA EpiNE7.22049RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwgkGNNFKSAEDCMRTCGGA EpiNE7.23050RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGChgnGNNFKSAEDCMRTCGGA EpiNE7.24051RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFpYgGCwakGNNFKlAEDCMRTCGGA EpiNE7.25052RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwghGNNFKSAEDCMRTCGGA EpiNE7.26053RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFnYgGCwgkGNNFKSAEDCMRTCGGA EpiNE7.27054RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGClghGNNFKSAEDCMRTCGGA EpiNE7.28055RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGClgyGNNFKSAEDCMRTCGGA EpiNE7.29056RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwaeGNNFKSAEDCMRTCGGA EpiNE7.30,.34, & .35057RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFgYgGCwgeGNNFKSAEDCMRTCGGA EpiNE7.32058RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGCwanGNNFKSAEDCMRTCGGA EpiNE7.33059RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFvYgGChgdGNNFKSAEDCMRTCGGA EpiNE7.36060RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFmYgGCqgkGNNFKSAEDCMRTCGGA EpiNE7.37061RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFyYgGCwakGNNFKSAEDCMRTCGGA EpiNE7.38062RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFmYgGCwgdGNNFKSAEDCMRTCGGA EpiNE7.39063RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGChgnGNNFKSAEDCMRTCGGA__________________________________________________________________________EpiNE7.40064 Notes to Table 210: a) Lower case letters in EpiNE7.6 to 7.38 indicate changes from BPTI that were selected in the first round (residues 15-19) or positions where the PBD was variegated in the second round (residues 34, 36, 39, 40, and 41). b) All EpiNE7 derivatives have G.sub.42. TABLE 211______________________________________Effects of antisera on phage infectivityStrain(dilution of Incubation Relativestock) Conditions pfu/ml Titer______________________________________MA-ITI-D1 PBS 1.2 .multidot. 10.sup.11 1.00(0.10) NRS 6.8 .multidot. 10.sup.10 0.57 anti-ITI 1.1 .multidot. 10.sup.10 0.09MA-ITI-D1 PBS 7.7 .multidot. 10.sup.8 1.00(0.001) NRS 6.7 .multidot. 10.sup.8 0.87 anti-ITI 8.0 .multidot. 10.sup.6 0.01MA PBS 1.3 .multidot. 10.sup.12 1.00(0.10) NRS 1.4 .multidot. 10.sup.12 1.10 anti-ITI 1.6 .multidot. 10.sup.12 1.20MA PBS 1.3 .multidot. 10.sup.10 1.00(0.001) NRS 1.2 .multidot. 10.sup.10 0.92 anti-ITI 1.5 .multidot. 10.sup.10 1.20______________________________________ PBS is phosphate buffered saline NRS is Normal Rabbit serum antiITI is serum from rabbits immunized to human ITI. TABLE 212______________________________________Fractionation of EpiNE-7 and MA-ITI-D1 phage on hNE beads EpiNE-7 MA-ITI-D1 pfu pfu/INPUT pfu pfu/INPUT______________________________________INPUT 3.3 .multidot. 10.sup.9 1.00 3.4 .multidot. 10.sup.11 1.00Final 3.8 .multidot. 10.sup.5 1.2 .multidot. 10.sup.-4 1.8 .multidot. 10.sup.6 5.3 .multidot. 10.sup.-6TBS-TWEENWashpH7.0 6.2 .multidot. 10.sup.5 1.8 .multidot. 10.sup.-4 1.66 4.7 .multidot. 10.sup.-66.0 1.4 .multidot. 10.sup.6 4.1 .multidot. 10.sup.-4 1.0 .multidot. 10.sup.6 2.9 .multidot. 10.sup.-65.5 9.4 .multidot. 10.sup.5 2.8 .multidot. 10.sup.-4 1.6 .multidot. 10.sup.6 4.7 .multidot. 10.sup.-65.0 9.5 .multidot. 10.sup.5 2.9 .multidot. 10.sup.-4 3.1 .multidot. 10.sup.5 9.1 .multidot. 10.sup.-74.5 1.2 .multidot. 10.sup.6 3.5 .multidot. 10.sup.-4 1.2 .multidot. 10.sup.5 3.5 .multidot. 10.sup.-74.0 1.6 .multidot. 10.sup.6 4.8 .multidot. 10.sup.-4 7.2 .multidot. 10.sup.4 2.1 .multidot. 10.sup.-73.5 9.5 .multidot. 10.sup.5 2.9 .multidot. 10.sup.-4 4.9 .multidot. 10.sup.4 1.4 .multidot. 10.sup.-73.0 6.6 .multidot. 10.sup.5 2.0 .multidot. 10.sup.-4 2.9 .multidot. 10.sup.4 8.5 .multidot. 10.sup.-82.5 1.6 .multidot. 10.sup.5 4.8 .multidot. 10.sup.-5 1.4 .multidot. 10.sup.4 4.1 .multidot. 10.sup.-82.0 3.0 .multidot. 10.sup.5 9.1 .multidot. 10.sup.-5 1.7 .multidot. 10.sup.4 5.0 .multidot. 10.sup.-8SUM 6.4 .multidot. 10.sup.6 3 .multidot. 10.sup.-3 5.7 .multidot. 10.sup.6 2 .multidot. 10.sup.-5______________________________________ *SUM is the total pfu (or fraction of input) obtained from all pH elution fractions TABLE 213______________________________________Fractionation of EpiC-10 and MA-ITI-D1 phage on Cat-G beads EpiC-10 MA-ITI-D1 pfu pfu/INPUT pfu pfu/INPUT______________________________________INPUT 5.0 .multidot. 10.sup.11 1.00 4.6 .multidot. 10.sup.11 1.00Final 1.8 .multidot. 10.sup.7 3.6 .multidot. 10.sup.-5 7.1 .multidot. 10.sup.6 1.5 .multidot. 10.sup.-5TBS-TWEENWashpH7.0 1.5 .multidot. 10.sup.7 3.0 .multidot. 10.sup.-5 6.1 .multidot. 10.sup.6 1.3 .multidot. 10.sup.-56.0 2.3 .multidot. 10.sup.7 4.6 .multidot. 10.sup.-5 2.3 .multidot. 10.sup.6 5.0 .multidot. 10.sup.-65.5 2.5 .multidot. 10.sup.7 5.0 .multidot. 10.sup.-5 1.2 .multidot. 10.sup.6 2.6 .multidot. 10.sup.-65.0 2.1 .multidot. 10.sup.7 4.2 .multidot. 10.sup.-5 1.1 .multidot. 10.sup.6 2.4 .multidot. 10.sup.-64.5 1.1 .multidot. 10.sup.7 2.2 .multidot. 10.sup.-5 6.7 .multidot. 10.sup.5 1.5 .multidot. 10.sup.-64.0 1.9 .multidot. 10.sup.6 3.8 .multidot. 10.sup.-6 4.4 .multidot. 10.sup.5 9.6 .multidot. 10.sup.-73.5 1.1 .multidot. 10.sup.6 2.2 .multidot. 10.sup.-6 4.4 .multidot. 10.sup.5 9.6 .multidot. 10.sup.-73.0 4.8 .multidot. 10.sup.5 9.6 .multidot. 10.sup.-7 3.6 .multidot. 10.sup.5 7.8 .multidot. 10.sup.-72.5 2.0 .multidot. 10.sup.5 4.0 .multidot. 10.sup.-7 2.7 .multidot. 10.sup.5 5.9 .multidot. 10.sup.-72.0 2.4 .multidot. 10.sup.5 4.8 .multidot. 10.sup.-7 3.2 .multidot. 10.sup.5 7.0 .multidot. 10.sup.-7SUM 9.9 .multidot. 10.sup.7 2 .multidot. 10.sup.-4 1.4 .multidot. 10.sup.7 3 .multidot. 10.sup.-5______________________________________ SUM is the total pfu (or fraction of input) obtained from all pH elution fractions TABLE 214______________________________________Abbreviated fractionation of display phage on hNE beadsDisplay phage MA-ITI-D1E7 MA-ITI-D1E7EpiNE-7 MA-ITI-D1 2 1 2______________________________________INPUT 1.00 1.00 1.00 1.00(pfu) (1.8 .times. 10.sup.9) (1.2 .times. 10.sup.10 (3.3 .times. 10.sup.9) (1.1 .times. 10.sup.9)Wash 6 .multidot. 10.sup.-5 1 .multidot. 10.sup.-5 2 .multidot. 10.sup.-5 2 .multidot. 10.sup.-5pH 7.0 3 .multidot. 10.sup.-4 1 .multidot. 10.sup.-5 2 .multidot. 10.sup.-5 4 .multidot. 10.sup.-5pH 3.5 3 .multidot. 10.sup.-3 3 .multidot. 10.sup.-6 8 .multidot. 10.sup.-5 8 .multidot. 10.sup.-5pH 2.0 1 .multidot. 10.sup.-3 1 .multidot. 10.sup.-6 6 .multidot. 10.sup.-6 2 .multidot. 10.sup.-5SUM 4.3 .multidot. 10.sup.-3 1.4 .multidot. 10.sup.-5 1.1 .multidot. 10.sup.-4 1.4 .multidot. 10.sup.-4______________________________________ Each entry is the fraction of input obtained in that component. SUM is the total fraction of input pfu obtained from all pH elution fractions TABLE 215______________________________________Fractionation of EpiNE-7 and MA-ITI-D1E7 phage on hNE beadsEpiNE-7 MA-ITI-D1E7 Fraction of In- Fraction of In-Total pfu put Total pfu put______________________________________INPUT 1.8 .multidot. 10.sup.9 1.00 3.0 .multidot. 10.sup.9 1.00pH 7.0 5.2 .multidot. 10.sup.5 2.9 .multidot. 10.sup.-4 6.4 .multidot. 10.sup.4 2.1 .multidot. 10.sup.-5pH 6.0 6.4 .multidot. 10.sup.5 3.6 .multidot. 10.sup.-4 4.5 .multidot. 10.sup.4 1.5 .multidot. 10.sup.-5pH 5.5 7.8 .multidot. 10.sup.5 4.3 .multidot. 10.sup.-4 5.0 .multidot. 10.sup.4 1.7 .multidot. 10.sup.-5pH 5.0 8.4 .multidot. 10.sup.5 4.7 .multidot. 10.sup.-4 5.2 .multidot. 10.sup.4 1.7 .multidot. 10.sup.-5pH 4.5 1.1 .multidot. 10.sup.6 6.1 .multidot. 10.sup.-4 4.4 .multidot. 10.sup.4 1.5 .multidot. 10.sup.-5pH 4.0 1.7 .multidot. 10.sup.6 9.4 .multidot. 10.sup.-4 2.6 .multidot. 10.sup.4 8.7 .multidot. 10.sup.-6pH 3.5 1.1 .multidot. 10.sup.6 6.1 .multidot. 10.sup.-4 1.3 .multidot. 10.sup.4 4.3 .multidot. 10.sup.-6pH 3.0 3.8 .multidot. 10.sup.5 2.1 .multidot. 10.sup.-4 5.6 .multidot. 10.sup.3 1.9 .multidot. 10.sup.-6pH 2.5 2.8 .multidot. 10.sup.5 1.6 .multidot. 10.sup.-4 4.9 .multidot. 10.sup.3 1.6 .multidot. 10.sup.-6pH 2.0 2.9 .multidot. 10.sup.5 1.6 .multidot. 10.sup.-4 2.2 .multidot. 10.sup.3 7.3 .multidot. 10.sup.-7SUM 7.6 .multidot. 10.sup.6 4.1 .multidot. 10.sup.-3 3.1 .multidot. 10.sup.5 1.1 .multidot. 10.sup.-4______________________________________ SUM is the total pfu (or fraction of input) obtained from all pH elution fractions TABLE 216__________________________________________________________________________Fractionation of MA-EpiNE-7, MA-BITI and MA-BITI-E7 on hNE beadsMA-BITI MA-BITI-E7 MA-EpiNE7pfu pfu/Input pfu pfu/Input pfu pfu/Input__________________________________________________________________________INPUT 2.0 .multidot. 10.sup.10 1.2 .multidot. 10.sup.-5 6.0 .multidot. 10.sup.9 1.00 1.5 .multidot. 10.sup.9 1.00pH7.0 2.4 .multidot. 10.sup.5 1.2 .multidot. 10.sup.-5 2.8 .multidot. 10.sup.5 4.7 .multidot. 10.sup.-5 2.9 .multidot. 10.sup.5 1.9 .multidot. 10.sup.-46.0 2.5 .multidot. 10.sup.5 1.2 .multidot. 10.sup.-5 2.8 .multidot. 10.sup.5 4.7 .multidot. 10.sup.-5 3.7 .multidot. 10.sup.5 2.5 .multidot. 10.sup.-45.0 9.6 .multidot. 10.sup.4 4.8 .multidot. 10.sup.-6 3.7 .multidot. 10.sup.5 6.2 .multidot. 10.sup.-5 4.9 .multidot. 10.sup.5 3.3 .multidot. 10.sup.-44.5 4.4 .multidot. 10.sup.4 2.2 .multidot. 10.sup.-6 3.8 .multidot. 10.sup.5 6.3 .multidot. 10.sup.-5 6.0 .multidot. 10.sup.5 4.0 .multidot. 10.sup.-44.0 3.1 .multidot. 10.sup.4 1.6 .multidot. 10.sup.-6 2.4 .multidot. 10.sup.5 4.0 .multidot. 10.sup.-5 6.4 .multidot. 10.sup.5 4.3 .multidot. 10.sup.-43.5 8.6 .multidot. 10.sup.4 4.3 .multidot. 10.sup.-6 9.0 .multidot. 10.sup.4 1.5 .multidot. 10.sup.-5 5.0 .multidot. 10.sup.5 3.3 .multidot. 10.sup.-43.0 2.2 .multidot. 10.sup.4 1.1 .multidot. 10.sup.-6 8.9 .multidot. 10.sup.4 1.5 .multidot. 10.sup.-5 1.9 .multidot. 10.sup.5 1.3 .multidot. 10.sup.-42.5 2.2 .multidot. 10.sup.4 1.1 .multidot. 10.sup.-6 2.3 .multidot. 10.sup.4 3.8 .multidot. 10.sup.-6 7.7 .multidot. 10.sup.4 5.1 .multidot. 10.sup.-52.0 7.7 .multidot. 10.sup.3 3.8 .multidot. 10.sup.-7 8.7 .multidot. 10.sup.3 1.4 .multidot. 10.sup.-6 9.7 .multidot. 10.sup.4 6.5 .multidot. 10.sup.-5SUM 8.0 .multidot. 10.sup.5 3.9 .multidot. 10.sup.-5 1.8 .multidot. 10.sup.6 2.9 .multidot. 10.sup.-4 3.3 .multidot. 10.sup.6 2.2 .multidot. 10.sup.-3__________________________________________________________________________ *SUM is the total pfu (or fraction of input) obtained from all pH elution fractions TABLE 217______________________________________Fractionation of MA-BITI-E7 and MA-BITI-E7-1222 on hNE beadsMA-BITI-E7 MA-BITI-E7-1222pfu pfu/INPUT pfu pfu/INPUT______________________________________INPUT 1.3 .multidot. 10.sup.9 1.00 1.2 .multidot. 10.sup.9 1.00pH7.0 4.7 .multidot. 10.sup.4 3.6 .multidot. 10.sup.-5 4.0 .multidot. 10.sup.4 3.3 .multidot. 10.sup.-56.0 5.3 .multidot. 10.sup.4 4.1 .multidot. 10.sup.-5 5.5 .multidot. 10.sup.4 4.6 .multidot. 10.sup.-55.5 7.1 .multidot. 10.sup.4 5.5 .multidot. 10.sup.-5 5.4 .multidot. 10.sup.4 4.5 .multidot. 10.sup.-55.0 9.0 .multidot. 10.sup.4 6.9 .multidot. 10.sup.-5 6.7 .multidot. 10.sup.4 5.6 .multidot. 10.sup.-54.5 6.2 .multidot. 10.sup.4 4.8 .multidot. 10.sup.-5 6.7 .multidot. 10.sup.4 5.6 .multidot. 10.sup.-54.0 3.4 .multidot. 10.sup.4 2.6 .multidot. 10.sup.-5 2.7 .multidot. 10.sup.4 2.2 .multidot. 10.sup.-53.5 1.8 .multidot. 10.sup.4 1.4 .multidot. 10.sup.-5 2.3 .multidot. 10.sup.4 1.9 .multidot. 10.sup.-53.0 2.5 .multidot. 10.sup.3 1.9 .multidot. 10.sup.-6 6.3 .multidot. 10.sup.3 5.2 .multidot. 10.sup.-62.5 <1.3 .multidot. 10.sup.3 <1.0 .multidot. 10.sup.-6 <1.3 .multidot. 10.sup.3 <1.0 .multidot. 10.sup.-62.0 1.3 .multidot. 10.sup.3 1.0 .multidot. 10.sup.-6 1.3 .multidot. 10.sup.3 1.0 .multidot. 10.sup.-6SUM 3.8 .multidot. 10.sup.5 2.9 .multidot. 10.sup.-4 3.4 .multidot. 10.sup.5 2.8 .multidot. 10.sup.-4______________________________________ SUM is the total pfu (or fraction of input) obtained from all pH elution fractions TABLE 218______________________________________Fractionation of MA-EpiNE7 and MA-BITI-E7-141 on hNE beads MA-EpiNE7 MA-BITI-E7-141 pfu pfu/INPUT pfu pfu/INPUT______________________________________INPUT 6.1 .multidot. 10.sup.8 1.00 2.0 .multidot. 10.sup.9 1.00pH7.0 5.3 .multidot. 10.sup.4 8.7 .multidot. 10.sup.-5 4.5 .multidot. 10.sup.5 2.2 .multidot. 10.sup.-46.0 9.7 .multidot. 10.sup.4 1.6 .multidot. 10.sup.-4 4.4 .multidot. 10.sup.5 2.2 .multidot. 10.sup.-45.5 1.1 .multidot. 10.sup.5 1.8 .multidot. 10.sup.-4 4.4 .multidot. 10.sup.5 2.2 .multidot. 10.sup.-45.0 1.4 .multidot. 10.sup.5 2.3 .multidot. 10.sup.-4 7.2 .multidot. 10.sup.5 3.6 .multidot. 10.sup.-44.5 1.0 .multidot. 10.sup.5 1.6 .multidot. 10.sup.-4 1.3 .multidot. 10.sup.6 6.5 .multidot. 10.sup.-44.0 2.0 .multidot. 10.sup.5 3.3 .multidot. 10.sup.-4 1.1 .multidot. 10.sup.6 5.5 .multidot. 10.sup.-43.5 9.7 .multidot. 10.sup.4 1.6 .multidot. 10.sup.-4 5.9 .multidot. 10.sup.5 3.0 .multidot. 10.sup.-43.0 3.8 .multidot. 10.sup.4 6.2 .multidot. 10.sup.-5 2.3 .multidot. 10.sup.5 1.2 .multidot. 10.sup.-42.5 1.3 .multidot. 10.sup.4 2.1 .multidot. 10.sup.-5 1.2 .multidot. 10.sup.5 6.0 .multidot. 10.sup.-52.0 1.6 .multidot. 10.sup.4 2.6 .multidot. 10.sup.-5 1.0 .multidot. 10.sup.5 5.0 .multidot. 10.sup.-5SUM 8.6 .multidot. 10.sup.5 1.4 .multidot. 10.sup.-3 5.5 .multidot. 10.sup.6 2.8 .multidot. 10.sup.-3______________________________________ SUM is the total pfu (or fraction of input) obtained from all pH elution fractions. TABLE 219__________________________________________________________________________pH Elution Analysis of hNE Binding by BITI-E7-141 Varient Display Phage Input Fraction of Input recovered at pH Recovery PFU pH3.5 pH2.0 TotalDisplayed protein (.times. 10.sup.9) pH7.0 .times. 10.sup.-4 .times. 10.sup.-4 .times. 10.sup.-4 Relative__________________________________________________________________________AMINO1 (EE) 0.96 0.24 2.3 0.35 2.9 0.11AMINO2 (AE) 6.1 0.57 2.1 0.45 3.1 0.12BITI-E7-1222 (EE) 1.2 0.72 4.0 0.64 5.4 0.21EpiNE7 (EE) 0.72 0.44 6.4 2.2 9.0 0.35MUTP1 (AE) 3.9 1.8 9.2 1.2 12.0 0.46MUT1619 (EE) 0.78 0.82 9.9 0.84 12.0 0.46MUTQE (AE) 4.7 1.2 16. 5.3 22.0 0.85MUTT26A (EE) 0.51 2.5 19.0 3.3 25.0 0.96BITI-E7-141 (AE) 1.7 2.2 18.0 5.4 26.0 1.00BITI-E7-141 (EE) 0.75 2.1 21. 3.2 26.0 1.00__________________________________________________________________________Notes:EE Extended pH elution protocolAe Abbreviated pH elution protocolTotal Total fraction of input = Sum of fractions collected at pH 7.0, pH 3.5, and pH 2.0.Relative Total fraction of input recovered divided by total fraction of input recovered for BITI-E7-141 TABLE 220__________________________________________________________________________ITI-Dl-derived hNE Inhibitors__________________________________________________________________________WEAK (K.sub.D > 10.sup.-8 M) ##STR37##MODERATE (10.sup.-8 > RD 22 10.sup.-9)2. KEDSCQLGYSAGPCVAMFPRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA3. RPDFCQLGYSAGPCMGMTSRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGASTRONG (10.sup.-9 > KD > 10.sup.-11 D)4. RPDFCQLGYSAGPCVAMFPRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA5. RPDFCQLGYSTGPCVAMFPRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA6. KEDFCQLGYSAGPCVAMFPRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA7. KPDSCQLGYSAGPCVAMFPRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA8. RPDFCQLGYSAGPCIGMFSRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGAVERY STRONG (K.sub.D < 10.sup.-11 M)9. RPDFCQLGYSAGPCVAMFPRYFYNGTSMACQTFVYGGCMGNGNNFVTEKDCLQTCRGA10. RPDFCQLGYSAGPCVAMFPRYFYNGASMACQTFVYGGCMGNGNNFVTEKDCLQTCRGA11. RPDFCQLGYSAGPCVAMFPRYFYNGTSMACETFVYGGCMGNGNNFVTEKDCLQTCRGA12. RPDFCQLGYSAGPCVGMFSRYFYNGTSMACQTFVYGGCMGNGNNFVTEKDCLQTCRGA__________________________________________________________________________ Residues shown underlined and bold are changed from those presen in ITID1 Sequences Key:1. ITI-D1 SEQ ID NO. 0082. ITI-DlE7 SEQ ID NO. 0093. BITI SEQ ID NO. 0304. BITI-E7 SEQ ID NO. 0105. BITI-E7-1222 SEQ ID NO. 0126. AMINO1 SEQ ID NO. 0157. AMINO2 SEQ ID NO. 0168. MUTP1 SEQ ID NO. 0149. BITI-E7-141 SEQ ID NO. 01110. MUTT26A SEQ ID NO. 018 MUTQE SEQ ID NO. 017 MUT1619 SEQ ID NO. 013 TABLE 221__________________________________________________________________________Same sequences as in Table 220 showing only changes (and Cysteines foralignment).__________________________________________________________________________WEAK (K.sub.D > 10.sup.-8 M) ##STR38##MODERATE (10.sup.-8 > RD 22 10.sup.-9)---C--------CVA-FP----------C-------C------------C---C---3. RP--C--------C---------------C-------C------------C---C---STRONG (10.sup.-9 > KD > 10.sup.-11 D)4. RP--C--------CVA-FP----------C-------C------------C---C---5. RP--C-----T--CVA-FP----------C-------C------------C---C-----FC--------CVA-FP----------C-------C------------C---C---P--C--------CVA-FP----------C-------C------------C---C---8. RP-FC--------CI--FP----------C-------C------------C---C---VERY STRONG (K.sub.D < 10.sup.-11 M)9. RP-FC--------CVA-FP----------CQ--V---C------------C---C---10. RP-FC--------CVA-FP------A---CQ--V---C------------C---C---11. RP-FC--------CVA-FP----------C---V---C------------C---C---- F ----------CQ--V---C------------C---C---__________________________________________________________________________ Residues shown underlined and bold are changed from those present in ITID1. TABLE 250__________________________________________________________________________Plasmid pHIL-D2 SEQ ID NO. 0658157 base pairs. Only one strand is shown, but the DNA exists asdouble-stranded circular DNA in vivo.__________________________________________________________________________ 1 2 3 4 5 1234567890 1234567890 1234567890 1234567890 1234567890 1 AgATCgCggC CgCgATCTAA CATCCAAAgA CgAAAggTTg AATgAAACCT 51 TTTTgCCATC CgACATCCAC AggTCCATTC TCACACATAA gTgCCAAACg101 CAACAggAgg ggATACACTA gCAgCAgACC gTTgCAAACg CAggACCTCC151 ACTCCTCTTC TCCTCAACAC CCACTTTTgC CATCgAAAAA CCAgCCCAgT201 TATTgggCTT gATTggAgCT CgCTCATTCC AATTCCTTCT ATTAggCTAC251 TAACACCATg ACTTTATTAg CCTgTCTATC CTggCCCCCC TggCgAggTC301 ATgTTTgTTT ATTTCCgAAT gCAACAAgCT CCgCATTACA CCCgAACATC351 ACTCCAgATg AgggCTTTCT gAgTgTgggg TCAAATAgTT TCATgTTCCC401 AAATggCCCA AAACTgACAg TTTAAACgCT gTCTTggAAC CTAATATgAC451 AAAAgCgTgA TCTCATCCAA gATgAACTAA gTTTggTTCg TTgAAATgCT501 AACggCCAgT TggTCAAAAA gAAACTTCCA AAAgTCgCCA TACCgTTTgT551 CTTgTTTggT ATTgATTgAC gAATgCTCAA AAATAATCTC ATTAATgCTT601 AgCgCAgTCT CTCTATCgCT TCTgAACCCg gTggCACCTg TgCCgAAACg651 CAAATggggA AACAACCCgC TTTTTggATg ATTATgCATT gTCCTCCACA701 TTgTATgCTT CCAAgATTCT ggTgggAATA CTgCTgATAg CCTAACgTTC751 ATgATCAAAA TTTAACTgTT CTAACCCCTA CTTgACAggC AATATATAAA801 CAgAAggAAg CTgCCCTgTC TTAAACCTTT TTTTTTATCA TCATTATTAg851 CTTACTTTCA TAATTgCgAC TggTTCCAAT TgACAAgCTT TTgATTTTAA901 CgACTTTTAA CgACAACTTg AgAAgATCAA AAAACAACTA ATTATTCgAA BstBI951 ACgAggAATTCgCCTTAgAC ATgACTgTTC CTCAgTTCAA gTTgggCATTEcoRI1001 ACgAgAAgAC CggTCTTgCT AgATTCTAAT CAAgAggATg TCAgAATgCC1051 ATTTgCCTgA gAgATgCAgg CTTCATTTTT gATACTTTTT TATTTgTAAC1101 CTATATAgTA TAggATTTTT TTTgTCATTT TgTTTCTTCT CgTACgAgCT1151 TgCTCCTgAT CAgCCTATCT CgCAgCTgAT gAATATCTTg TggTAggggT1201 TTgggAAAAT CATTCgAgTT TgATgTTTTT CTTggTATTT CCCACTCCTC1251 TTCAgAgTAC AgAAgATTAA gTgAgAAgTT CgTTTgTgCA AgCTTATCgA1301 TAAgCTTTAA TgCggTAgTT TATCACAgTT AAATTgCTAA CgCAgTCAgg1351 CACCgTgTAT gAAATCTAAC AATgCgCTCA TCgTCATCCT CggCACCgTC1401 ACCCTggATg CTgTAggCAT AggCTTggTT ATgCCggTAC TgCCgggCCT1451 CTTgCgggAT ATCgTCCATT CCgACAgCAT CgCCAgTCAC TATggCgTgC1501 TgCTAgCgCT ATATgCgTTg ATgCAATTTC TATgCgCACC CgTTCTCggA1551 gCACTgTCCg ACCgCTTTgg CCgCCgCCCA gTCCTgCTCg CTTCgCTACT1601 TggAgCCACT ATCgACTACg CgATCATggC gACCACACCC gTCCTgTggA1651 TCTATCgAAT CTAAATgTAA gTTAAAATCT CTAAATAATT AAATAAgTCC1701 CAgTTTCTCC ATACgAACCT TAACAgCATT gCggTgAgCA TCTAgACCTT1751 CAACAgCAgC CAgATCCATC ACTgCTTggC CAATATgTTT CAgTCCCTCA1801 ggAgTTACgT CTTgTgAAgT gATgAACTTC TggAAggTTg CAgTgTTAAC1851 TCCgCTgTAT TgACgggCAT ATCCgTACgT TggCAAAgTg TggTTggTAC1901 CggAggAgTA ATCTCCACAA CTCTCTggAg AgTAggCACC AACAAACACA1951 gATCCAgCgT gTTgTACTTg ATCAACATAA gAAgAAgCAT TCTCgATTTg2001 CAggATCAAg TgTTCAggAg CgTACTgATT ggACATTTCC AAAgCCTgCT2051 CgTAggTTgC AACCgATAgg gTTgTAgAgT gTgCAATACA CTTgCgTACA2101 ATTTCAACCC TTggCAACTg CACAgCTTgg TTgTgAACAg CATCTTCAAT2151 TCTggCAAgC TCCTTgTCTg TCATATCgAC AgCCAACAgA ATCACCTggg2201 AATCAATACC ATgTTCAgCT TgAgCAgAAg gTCTgAggCA ACgAAATCTg2251 gATCAgCgTA TTTATCAgCA ATAACTAgAA CTTCAgAAgg CCCAgCAggC2301 ATgTCAATAC TACACAgggC TgATgTgTCA TTTTgAACCA TCATCTTggC2351 AgCAgTAACg AACTggTTTC CTggACCAAA TATTTTgTCA CACTTAggAA2401 CAgTTTCTgT TCCgTAAgCC ATAgCAgCTA CTgCCTgggC gCCTCCTgCT2451 AgCACgATAC ACTTAgCACC AACCTTgTgg gCAACgTAgA TgACTTCTgg2501 ggTAAgggTA CCATCCTTCT TAggTggAgA TgCAAAAACA ATTTCTTTgC2551 AACCAgCAAC TTTggCAggA ACACCCAgCA TCAgggAAgT ggAAggCAgA2601 ATTgCggTTC CACCAggAAT ATAgAggCCA ACTTTCTCAA TAggTCTTgC2651 AAAACgAgAg CAgACTACAC CAgggCAAgT CTCAACTTgC AACgTCTCCg2701 TTAgTTgAgC TTCATggAAT TTCCTgACgT TATCTATAgA gAgATCAATg2751 gCTCTCTTAA CgTTATCTgg CAATTgCATA AgTTCCTCTg ggAAAggAgC2801 TTCTAACACA ggTgTCTTCA AAgCgACTCC ATCAAACTTg gCAgTTAgTT2851 CTAAAAgggC TTTgTCACCA TTTTgACgAA CATTgTCgAC AATTggTTTg2901 ACTAATTCCA TAATCTgTTC CgTTTTCTgg ATAggACgAC gAAgggCATC2951 TTCAATTTCT TgTgAggAgg CCTTAgAAAC gTCAATTTTg CACAATTCAA3001 TACgACCTTC AgAAgggACT TCTTTAggTT TggATTCTTC TTTAggTTgT3051 TCCTTggTgT ATCCTggCTT ggCATCTCCT TTCCTTCTAg TgACCTTTAg3101 ggACTTCATA TCCAggTTTC TCTCCACCTC gTCCAACgTC ACACCgTACT3151 TggCACATCT AACTAATgCA AAATAAAATA AgTCAgCACA TTCCCAggCT3201 ATATCTTCCT TggATTTAgC TTCTgCAAgT TCATCAgCTT CCTCCCTAAT3251 TTTAgCgTTC AACAAAACTT CgTCgTCAAA TAACCgTTTg gTATAAgAAC3301 CTTCTggAgC ATTgCTCTTA CgATCCCACA AggTgCTTCC ATggCTCTAA3351 gACCCTTTgA TTggCCAAAA CAggAAgTgC gTTCCAAgTg ACAgAAACCA3401 ACACCTgTTT gTTCAACCAC AAATTTCAAg CAgTCTCCAT CACAATCCAA3451 TTCgATACCC AgCAACTTTT gAgTTCgTCC AgATgTAgCA CCTTTATACC3501 ACAAACCgTg ACgACgAgAT TggTAgACTC CAgTTTgTgT CCTTATAgCC3551 TCCggAATAg ACTTTTTggA CgAgTACACC AggCCCAACg AgTAATTAgA3601 AgAgTCAgCC ACCAAAgTAg TgAATAgACC ATCggggCgg TCAgTAgTCA3651 AAgACgCCAA CAAAATTTCA CTgACAgggA ACTTTTTgAC ATCTTCAgAA3701 AgTTCgTATT CAgTAgTCAA TTgCCgAgCA TCAATAATgg ggATTATACC3751 AgAAgCAACA gTggAAgTCA CATCTACCAA CTTTgCggTC TCAgAAAAAg3801 CATAAACAgT TCTACTACCg CCATTAgTgA AACTTTTCAA ATCgCCCAgT3851 ggAgAAgAAA AAggCACAgC gATACTAgCA TTAgCgggCA AggATgCAAC3901 TTTATCAACC AgggTCCTAT AgATAACCCT AgCgCCTggg ATCATCCTTT3951 ggACAACTCT TTCTgCCAAA TCTAggTCCA AAATCACTTC ATTgATACCA4001 TTATACggAT gACTCAACTT gCACATTAAC TTgAAgCTCA gTCgATTgAg4051 TgAACTTgAT CAggTTgTgC AgCTggTCAg CAgCATAggg AAACACggCT4101 TTTCCTACCA AACTCAAggA ATTATCAAAC TCTgCAACAC TTgCgTATgC4151 AggTAgCAAg ggAAATgTCA TACTTgAAgT CggACAgTgA gTgTAgTCTT4201 gAgAAATTCT gAAgCCgTAT TTTTATTATC AgTgAgTCAg TCATCAggAg4251 ATCCTCTACg CCggACgCAT CgTggCCggC ATCACCggCg CCACAggTgC4301 ggTTgCTggC gCCTATATCg CCgACATCAC CgATggggAA gATCgggCTC4351 gCCACTTCgg gCTCATgAgC gCTTgTTTCg gCgTgggTAT ggTggCAggC4401 CCCgTggCCg ggggACTgTT gggCgCCATC TCCTTgCATg CACCATTCCT4451 TgCggCggCg gTgCTCAACg gCCTCAACCT ACTACTgggC TgCTTCCTAA4501 TgCAggAgTC gCATAAgggA gAgCgTCgAg TATCTATgAT TggAAgTATg4551 ggAATggTgA TACCCgCATT CTTCAgTgTC TTgAggTCTC CTATCAgATT4601 ATgCCCAACT AAAgCAACCg gAggAggAgA TTTCATggTA AATTTCTCTg4651 ACTTTTggTC ATCAgTAgAC TCgAACTgTg AgACTATCTC ggTTATgACA4701 gCAgAAATgT CCTTCTTggA gACAgTAAAT gAAgTCCCAC CAATAAAgAA4751 ATCCTTgTTA TCAggAACAA ACTTCTTgTT TCgAACTTTT TCggTgCCTT4801 gAACTATAAA ATgTAgAgTg gATATgTCgg gTAggAATgg AgCgggCAAA4851 TgCTTACCTT CTggACCTTC AAgAggTATg TAgggTTTgT AgATACTgAT4901 gCCAACTTCA gTgACAACgT TgCTATTTCg TTCAAACCAT TCCgAATCCA4951 gAgAAATCAA AgTTgTTTgT CTACTATTgA TCCAAgCCAg TgCggTCTTg5001 AAACTgACAA TAgTgTgCTC gTgTTTTgAg gTCATCTTTg TATgAATAAA5051 TCTAgTCTTT gATCTAAATA ATCTTgACgA gCCAAggCgA TAAATACCCA5101 AATCTAAAAC TCTTTTAAAA CgTTAAAAgg ACAAgTATgT CTgCCTgTAT5151 TAAACCCCAA ATCAgCTCgT AgTCTgATCC TCATCAACTT gAggggCACT5201 ATCTTgTTTT AgAgAAATTT gCggAgATgC gATATCgAgA AAAAggTACg5251 CTgATTTTAA ACgTgAAATT TATCTCAAgA TCgCggCCgC gATCTCgAAT5301 AATAACTgTT ATTTTTCAgT gTTCCCgATC TgCgTCTATT TCACAATACC5351 AACATgAgTC AgCTTATCgA TgATAAgCTg TCAAACATgA gAATTAATTC5401 gATgATAAgC TgTCAAACAT gAgAAATCTT gAAgACgAAA gggCCTCgTg5451 ATACgCCTAT TTTTATAggT TAATgTCATg ATAATAATgg TTTCTTAgAC5501 gTCAggTggC ACTTTTCggg gAAATgTgCg CggAACCCCT ATTTgTTTAT5551 TTTTCTAAAT ACATTCAAAT ATgTATCCgC TCATgAgACA ATAACCCTgA5601 TAAATgCTTC AATAATATTg AAAAAggAAg AgTATgAgTA TTCAACATTT5651 CCgTgTCgCC CTTATTCCCT TTTTTgCggC ATTTTgCCTT CCTgTTTTTg5701 CTCACCCAgA AACgCTggTg AAAgTAAAAg ATgCTgAAgA TCAgTTgggT5751 gCACgAgTgg gTTACATCgA ACTggATCTC AACAgCggTA AgATCCTTgA5801 gAgTTTTCgC CCCgAAgAAC gTTTTCCAAT gATgAgCACT TTTAAAgTTC5851 TgCTATgTgg CgCggTATTA TCCCgTgTTg ACgCCgggCA AgAgCAACTC5901 ggTCgCCgCA TACACTATTC TCAgAATgAC TTggTTgAgT ACTCACCAgT5951 CACAgAAAAg CATCTTACgg ATggCATgAC AgTAAgAgAA TTATgCAgTg6001 CTgCCATAAC CATgAgTgAT AACACTgCgg CCAACTTACT TCTgACAACg6051 ATCggAggAC CgAAggAgCT AACCgCTTTT TTgCACAACA TgggggATCA6101 TgTAACTCgC CTTgATCgTT gggAACCggA gCTgAATgAA gCCATACCAA6151 ACgACgAgCg TgACACCACg ATgCCTgCAg CAATggCAAC AACgTTgCgC6201 AAACTATTAA CTggCgAACT ACTTACTCTA gCTTCCCggC AACAATTAAT6251 AgACTggATg gAggCggATA AAgTTgCAgg ACCACTTCTg CgCTCggCCC6301 TTCCggCTgg CTggTTTATT gCTgATAAAT CTggAgCCgg TgAgCgTggg6351 TCTCgCggTA TCATTgCAgC ACTggggCCA gATggTAAgC CCTCCCgTAT6401 CgTAgTTATC TACACgACgg ggAgTCAggC AACTATggAT gAACgAAATA6451 gACAgATCgC TgAgATAggT gCCTCACTgA TTAAgCATTg gTAACTgTCA6501 gACCAAgTTT ACTCATATAT ACTTTAgATT gATTTAAATT gTAAACgTTA6551 ATATTTTgTT AAAATTCgCg TTAAATTTTT gTTAAATCAg CTCATTTTTT6601 AACCAATAgg CCgAAATCgg CAAAATCCCT TATAAATCAA AAgAATAgAC6651 CgAgATAggg TTgAgTgTTg TTCCAgTTTg gAACAAgAgT CCACTATTAA6701 AgAACgTggA CTCCAACgTC AAAgggCgAA AAACCgTCTA TCAgggCgAT6751 ggCCCACTAC gTgAACCATC ACCCTAATCA AgTTTTTTgg ggTCgAggTg6801 CCgTAAAgCA CTAAATCggA ACCCTAAAgg gAgCCCCCgA TTTAgAgCTT6851 gACggggAAA gCCggCgAAC gTggCgAgAA AggAAgggAA gAAAgCgAAA6901 ggAgCgggCg CTAgggCgCT ggCAAgTgTA gCggTCACgC TgCgCgTAAC6951 CACCACACCC gCCgCgCTTA ATgCgCCgCT ACAgggCgCg TAAAAggATC7001 TAggTgAAgA TCCTTTTTgA TAATCTCATg ACCAAAATCC CTTAACgTgA7051 gTTTTCgTTC CACTgAgCgT CAgACCCCgT AgAAAAgATC AAAggATCTT7101 CTTgAgATCC TTTTTTTCTg CgCgTAATCT gCTgCTTgCA AACAAAAAAA7151 CCACCgCTAC CAgCggTggT TTgTTTgCCg gATCAAgAgC TACCAACTCT7201 TTTTCCgAAg gTAACTggCT TCAgCAgAgC gCAgATACCA AATACTgTCC7251 TTCTAgTgTA gCCgTAgTTA ggCCACCACT TCAAgAACTC TgTAgCACCg7301 CCTACATACC TCgCTCTgCT AATCCTgTTA CCAgTggCTg CTgCCAgTgg7351 CgATAAgTCg TgTCTTACCg ggTTggACTC AAgACgATAg TTACCggATA7401 AggCgCAgCg gTCgggCTgA ACggggggTT CgTgCACACA gCCCAgCTTg7451 gAgCgAACgA CCTACACCgA ACTgAgATAC CTACAgCgTg AgCATTgAgA7501 AAgCgCCACg CTTCCCgAAg ggAgAAAggC ggACAggTAT CCggTAAgCg7551 gCAgggTCgg AACAggAgAg CgCACgAggg AgCTTCCAgg gggAAACgCC7601 TggTATCTTT ATAgTCCTgT CgggTTTCgC CACCTCTgAC TTgAgCgTCg7651 ATTTTTgTgA TgCTCgTCAg gggggCggAg CCTATggAAA AACgCCAgCA7701 ACgCggCCTT TTTACggTTC CTggCCTTTT gCTggCCTTT TgCTCACATg7751 TTCTTTCCTg CgTTATCCCC TgATTCTgTg gATAACCgTA TTACCgCCTT7801 TgAgTgAgCT gATACCgCTC gCCgCAgCCg AACgACCgAg CgCAgCgAgT7851 CAgTgAgCgA ggAAgCggAA gAgCgCCTgA TgCggTATTT TCTCCTTACg7901 CATCTgTgCg gTATTTCACA CCgCATATgg TgCACTCTCA gTACAATCTg7951 CTCTgATgCC gCATAgTTAA gCCAgTATAC ACTCCgCTAT CgCTACgTgA8001 CTgggTCATg gCTgCgCCCC gACACCCgCC AACACCCgCT gACgCgCCCT8051 gACgggCTTg TCTgCTCCCg gCATCCgCTT ACAgACAAgC TgTgACCgTC8101 TCCgggAgCT gCATgTgTCA gAggTTTTCA CCgTCATCAC CgAAACgCgC8151 gAggCAg__________________________________________________________________________ TABLE 251__________________________________________________________________________pHIL-D2 (MF.alpha.PrePro::EPI-HNE-3) 8584 b.p.DNA has SEQ ID NO. 066; Encoded polypeptide has SEQ ID NO. 067DNA is circular and double stranded, only one strand is shown.Translation of the protein to be expressed is shown.__________________________________________________________________________ ##STR39## 1AgATCgCggCCgCgATCTAACATCCAAAgACgAAAggTTgAATgAAACCT 51TTTTgCCATCCgACATCCACAggTCCATTCTCACACATAAgTgCCAAACg 101CAACAggAggggATACACTAgCAgCAgACCgTTgCAAACgCAggACCTCC 151ACTCCTCTTCTCCTCAACACCCACTTTTgCCATCgAAAAACCAgCCCAgT 201TATTgggCTTgATTggAgCTCgCTCATTCCAATTCCTTCTATTAggCTAC 251TAACACCATgACTTTATTAgCCTgTCTATCCTggCCCCCCCTggCgAggTC 301ATgTTTgTTTATTTCCgAATgCAACAAgCTCCgCATTACACCCgAACATC 351ACTCCAgATgAgggCTTTCTgAgTgTggggTCAAATAgTTTCATgTTCCC 401AAATggCCCAAAACTgACAgTTTAAACgCTgTCTTggAACCTAATATgAC 451AAAAgCgTgATCTCATCCAAgATgAACTAAgTTTggTTCgTTgAAATgCT 501AACggCCAgTTggTCAAAAAgAAACTTCCAAAAgTCgCCATACCgTTTgT 551CTTgTTTggTATTgATTgACgAATgCTCAAAAATAATCTCATTAATgCTT 601AgCgCAgTCTCTCTATCgCTTCTgAACCCggTggCACCTgTgCCgAAACg 651CAAATggggAAACAACCCgCTTTTTggATgATTATgCATTgTCCTCCACA 701TTgTATgCTTCCAAgATTCTggTgggAATACTgCTgATAgCCTAACgTTC 751ATgATCAAAATTTAACTgTTCTAACCCCTACTTgACAggCAATATATAAA 801CAgAAggAAgCTgCCCTgTCTTAAACCTTTTTTTTTATCATCATTATTAg 851CTTACTTTCATAATTgCgACTggTTCCAATTgACAAgCTTTTgATTTTAA ##STR40## ##STR41## ##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48## ##STR49## ##STR50## ##STR51## ##STR52##1451TTCTAATCAAgAggATgTCAgAATgCCATTTgCCTgAgAgATgCAggCTT1501CATTTTTgATACTTTTTTATTTgTAACCTATATAgTATAggATTTTTTTT1551gTCATTTTgTTTCTTCTCgTACgAgCTTgCTCCTgATCAgCCTATCTCgC1601AgCTgATgAATATCTTgTggTAggggTTTgggAAAATCATTCgAgTTTgA1651TgTTTTTCTTggTATTTCCCACTCCTCTTCAgAgTACAgAAgATTAAgTg1701AgAAgTTCgTTTgTgCAAgCTTATCgATAAgCTTTAATgCggTAgTTTAT1751CACAgTTAAATTgCTAACgCAgTCAggCACCgTgTATgAAATCTAACAAT1801gCgCTCATCgTCATCCTCggCACCgTCACCCTggATgCTgTAggCATAgg1851CTTggTTATgCCggTACTgCCgggCCTCTTgCgggATATCgTCCATTCCg1901ACAgCATCgCCAgTCACTATggCgTgCTgCTAgCgCTATATgCgTTgATg1951CAATTTCTATgCgCACCCgTTCTCggAgCACTgTCCgACCgCTTTggCCg2001CCgCCCAgTCCTgCTCgCTTCgCTACTTggAgCCACTATCgACTACgCgA2051TCATggCgACCACACCCgTCCTgTggATCTATCgAATCTAAATgTAAgTT2101AAAATCTCTAAATAATTAAATAAgTCCCAgTTTCTCCATACgAACCTTAA2151CAgCATTgCggTgAgCATCTAgACCTTCAACAgCAgCCAgATCCATCACT2201gCTTggCCAATATgTTTCAgTCCCTCAggAgTTACgTCTTgTgAAgTgAT2251gAACTTCTggAAggTTgCAgTgTTAACTCCgCTgTATTgACgggCATATC2301CgTACgTTggCAAAgTgTggTTggTACCggAggAgTAATCTCCACAACTC2351TCTggAgAgTAggCACCAACAAACACAgATCCAgCgTgTTgTACTTgATC2401AACATAAgAAgAAgCATTCTCgATTTgCAggATCAAgTgTTCAggAgCgT2451ACTgATTggACATTTCCAAAgCCTgCTCgTAggTTgCAACCgATAgggTT2501gTAgAgTgTgCAATACACTTgCgTACAATTTCAACCCTTggCAACTgCAC2551AgCTTggTTgTgAACAgCATCTTCAATTCTggCAAgCTCCTTgTCTgTCA2601TATCgACAgCCAACAgAATCACCTgggAATCAATACCATgTTCAgCTTgA2651gCAgAAggTCTgAggCAACgAAATCTggATCAgCgTATTTATCAgCAATA2701ACTAgAACTTCAgAAggCCCAgCAggCATgTCAATACTACACAgggCTgA2751TgTgTCATTTTgAACCATCATCTTggCAgCAgTAACgAACTggTTTCCTg2801gACCAAATATTTTgTCACACTTAggAACAgTTTCTgTTCCgTAAgCCATA2851gCAgCTACTgCCTgggCgCCTCCTgCTAgCACgATACACTTAgCACCAAC2901CTTgTgggCAACgTAgATgACTTCTggggTAAgggTACCATCCTTCTTAg2951gTggAgATgCAAAAACAATTTCTTTgCAACCAgCAACTTTggCAggAACA3001CCCAgCATCAgggAAgTggAAggCAgAATTgCggTTCCACCAggAATATA3051gAggCCAACTTTCTCAATAggTCTTgCAAAACgAgAgCAgACTACACCAg3101ggCAAgTCTCAACTTgCAACgTCTCCgTTAgTTgAgCTTCATggAATTTC3151CTgACgTTATCTATAgAgAgATCAATggCTCTCTTAACgTTATCTggCAA3201TTgCATAAgTTCCTCTgggAAAggAgCTTCTAACACAggTgTCTTCAAAg3251CgACTCCATCAAACTTggCAgTTAgTTCTAAAAgggCTTTgTCACCATTT3301TgACgAACATTgTCgACAATTggTTTgACTAATTCCATAATCTgTTCCgT3351TTTCTggATAggACgACgAAgggCATCTTCAATTTCTTgTgAggAggCCT3401TAgAAACgTCAATTTTgCACAATTCAATACgACCTTCAgAAgggACTTCT3451TTAggTTTggATTCTTCTTTAggTTgTTCCTTggTgTATCCTggCTTggC3501ATCTCCTTTCCTTCTAgTgACCTTTAgggACTTCATATCCAggTTTCTCT3551CCACCTCgTCCAACgTCACACCgTACTTggCACATCTAACTAATgCAAAA3601TAAAATAAgTCAgCACATTCCCAggCTATATCTTCCTTggATTTAgCTTC3651TgCAAgTTCATCAgCTTCCTCCCTAATTTTAgCgTTCAACAAAACTTCgT3701CgTCAAATAACCgTTTggTATAAgAACCTTCTggAgCATTgCTCTTACgA3751TCCCACAAggTgCTTCCATggCTCTAAgACCCTTTgATTggCCAAAAACAg3801gAAgTgCgTTCCAAgTgACAgAAACCAACACCTgTTTgTTCAACCACAAA3851TTTCAAgCAgTCTCCATCACAATCCAATTCgATACCCAgCAACTTTTgAg3901TTCgTCCAgATgTAgCACCTTTATACCACAAACCgTgACgACgAgATTgg3951TAgACTCCAgTTTgTgTCCTTATAgCCTCCggAATAgACTTTTTggACgA4001gTACACCAggCCCAACgAgTAATTAgAAgAgTCAgCCACCAAAgTAgTgA4051ATAgACCATCggggCggTCAgTAgTCAAAgACgCCAACAAAATTTCACTg4101ACAgggAACTTTTTgACATCTTCAgAAAgTTCgTATTCAgTAgTCAATTg4151CCgAgCATCAATAATggggATTATACCAgAAgCAACAgTggAAgTCACAT4201CTACCAACTTTgCggTCTCAgAAAAAgCATAAACAgTTCTACTACCgCCA4251TTAgTgAAACTTTTCAAATCgCCCAgTggAgAAgAAAAAggCACAgCgAT4301ACTAgCATTAgCgggCAAggATgCAACTTTATCAACCAgggTCCTATAgA4351TAACCCTAgCgCCTgggATCATCCTTTggACAACTCTTTCTgCCAAATCT4401AggTCCAAAATCACTTCATTgATACCATTATACggATgACTCAACTTgCA4451CATTAACTTgAAgCTCAgTCgATTgAgTgAACTTgATCAggTTgTgCAgC4501TggTCAgCAgCATAgggAAACACggCTTTTCCTACCAAACTCAAggAATT4551ATCAAACTCTgCAACACTTgCgTATgCAggTAgCAAgggAAATgTCATAC4601TTgAAgTCggACAgTgAgTgTAgTCTTgAgAAATTCTgAAgCCgTATTTT4651TATTATCAgTgAgTCAgTCATCAggAgATCCTCTACgCCggACgCATCgT4701ggCCggCATCACCggCgCCACAggTgCggTTgCTggCgCCTATATCgCCg4751ACATCACCgATggggAAgATCgggCTCgCCACTTCgggCTCATgAgCgCT4801TgTTTCggCgTgggTATggTggCAggCCCCgTggCCgggggACTgTTggg4851CgCCATCTCCTTgCATgCACCATTCCTTgCggCggCggTgCTCAACggCC4901TCAACCTACTACTgggCTgCTTCCTAATgCAggAgTCgCATAAgggAgAg4951CgTCgAgTATCTATgATTggAAgTATgggAATggTgATACCCgCATTCTT5001CAgTgTCTTgAggTCTCCTATCAgATTATgCCCAACTAAAgCAACCggAg5051gAggAgATTTCATggTAAATTTCTCTgACTTTTggTCATCAgTAgACTCg5101AACTgTgAgACTATCTCggTTATgACAgCAgAAATgTCCTTCTTggAgAC5151AgTAAATgAAgTCCCACCAATAAAgAAATCCTTgTTATCAggAACAAACT ##STR53##5251ATgTCgggTAggAATggAgCgggCAAATgCTTACCTTCTggACCTTCAAg5301AggTATgTAgggTTTgTAgATACTgATgCCAACTTCAgTgACAACgTTgC5351TATTTCgTTCAAACCATTCCgAATCCAgAgAAATCAAAgTTgTTTgTCTA5401CTATTgATCCAAgCCAgTgCggTCTTgAAACTgACAATAgTgTgCTCgTg5451TTTTgAggTCATCTTTgTATgAATAAATCTAgTCTTTgATCTAAATAATC5501TTgACgAgCCAAggCgATAAATACCCAAATCTAAAACTCTTTTAAAACgT5551TAAAAggACAAgTATgTCTgCCTgTATTAAACCCCAAATCAgCTCgTAgT5601CTgATCCTCATCAACTTgAggggCACTATCTTgTTTTAgAgAAATTTgCg5651gAgATgCgATATCgAgAAAAAggTACgCTgATTTTAAACgTgAAATTTAT5701CTCAAgATCgCggCCgCgATCTCgAATAATAACTgTTATTTTTCAgTgTT5751CCCgATCTgCgTCTATTTCACAATACCAACATgAgTCAgCTTATCgATgA5801TAAgCTgTCAAACATgAgAATTAATTCgATgATAAgCTgTCAAACATgAg5851AAATCTTgAAgACgAAAgggCCTCgTgATACgCCTATTTTTATAggTTAA ##STR54##5951ATgTgCgCggAACCCCTATTTgTTTATTTTTCTAAATACATTCAAATATg6001TATCCgCTCATgAgACAATAACCCTgATAAATgCTTCAATAATATTgAAA6051AAggAAgAgTATgAgTATTCAACATTTCCgTgTCgCCCTTATTCCCTTTT6101TTgCggCATTTTgCCTTCCTgTTTTTgCTCACCCAgAAACgCTggTgAAA6151gTAAAAgATgCTgAAgATCAgTTgggTgCACgAgTgggTTACATCgAACT6201ggATCTCAACAgCggTAAgATCCTTgAgAgTTTTCgCCCCgAAgAACgTT6251TTCCAATgATgAgCACTTTTAAAgTTCTgCTATgTggCgCggTATTATCC6301CgTgTTgACgCCgggCAAgAgCAACTCggTCgCCgCATACACTATTCTCA6351gAATgACTTggTTgAgTACTCACCAgTCACAgAAAAgCATCTTACggATg6401gCATgACAgTAAgAgAATTATgCAgTgCTgCCATAACCATgAgTgATAAC6451ACTgCggCCAACTTACTTCTgACAACgATCggAggACCgAAggAgCTAAC6501CgCTTTTTTgCACAACATgggggATCATgTAACTCgCCTTgATCgTTggg6551AACCggAgCTgAATgAAgCCATACCAAACgACgAgCgTgACACCACgATg6601CCTgCAgCAATggCAACAACgTTgCgCAAACTATTAACTggCgAACTACT6651TACTCTAgCTTCCCggCAACAATTAATAgACTggATggAggCggATAAAg6701TTgCAggACCACTTCTgCgCTCggCCCTTCCggCTggCTggTTTATTgCT6751gATAAATCTggAgCCggTgAgCgTgggTCTCgCggTATCATTgCAgCACT6801ggggCCAgATggTAAgCCCTCCCgTATCgTAgTTATCTACACgACggggA6851gTCAggCAACTATggATgAACgAAATAgACAgATCgCTgAgATAggTgCC6901TCACTgATTAAgCATTggTAACTgTCAgACCAAgTTTACTCATATATACT6951TTAgATTgATTTAAATTgTAAACgTTAATATTTTgTTAAAATTCgCgTTA7001AATTTTTgTTAAATCAgCTCATTTTTTAACCAATAggCCgAAATCggCAA7051AATCCCTTATAAATCAAAAgAATAgACCgAgATAgggTTgAgTgTTgTTC7101CAgTTTggAACAAgAgTCCACTATTAAAgAACgTggACTCCAACgTCAAA7151gggCgAAAAACCgTCTATCAgggCgATggCCCACTACgTgAACCATCACC7201CTAATCAAgTTTTTTggggTCgAggTgCCgTAAAgCACTAAATCggAACC7251CTAAAgggAgCCCCCgATTTAgAgCTTgACggggAAAgCCggCgAACgTg7301gCgAgAAAggAAgggAAgAAAgCgAAAggAgCgggCgCTAgggCgCTggC7351AAgTgTAgCggTCACgCTgCgCgTAACCACCACACCCgCCgCgCTTAATg7401CgCCgCTACAgggCgCgTAAAAggATCTAggTgAAgATCCTTTTTgATAA7451TCTCATgACCAAAATCCCTTAACgTgAgTTTTCgTTCCACTgAgCgTCAg7501ACCCCgTAgAAAAgATCAAAggATCTTCTTgAgATCCTTTTTTTCTgCgC7551gTAATCTgCTgCTTgCAAACAAAAAAACCACCgCTACCAgCggTggTTTg7601TTTgCCggATCAAgAgCTACCAACTCTTTTTCCgAAggTAACTggCTTCA7651gCAgAgCgCAgATACCAAATACTgTCCTTCTAgTgTAgCCgTAgTTAggC7701CACCACTTCAAgAACTCTgTAgCACCgCCTACATACCTCgCTCTgCTAAT7751CCTgTTACCAgTggCTgCTgCCAgTggCgATAAgTCgTgTCTTACCgggT7801TggACTCAAgACgATAgTTACCggATAAggCgCAgCggTCgggCTgAACg7851gggggTTCgTgCACACAgCCCAgCTTggAgCgAACgACCTACACCgAACT7901gAgATACCTACAgCgTgAgCATTgAgAAAgCgCCACgCTTCCCgAAgggA7951gAAAggCggACAggTATCCggTAAgCggCAgggTCggAACAggAgAgCgC8001ACgAgggAgCTTCCAgggggAAACgCCTggTATCTTTATAgTCCTgTCgg8051gTTTCgCCACCTCTgACTTgAgCgTCgATTTTTgTgATgCTCgTCAgggg8101ggCggAgCCTATggAAAAACgCCAgCAACgCggCCTTTTTACggTTCCTg8151gCCTTTTgCTggCCTTTTgCTCACATgTTCTTTCCTgCgTTATCCCCTgA8201TTCTgTggATAACCgTATTACCgCCTTTgAgTgAgCTgATACCgCTCgCC8251gCAgCCgAACgACCgAgCgCAgCgAgTCAgTgAgCgAggAAgCggAAgAg8301CgCCTgATgCggTATTTTCTCCTTACgCATCTgTgCggTATTTCACACCg8351CATATggTgCACTCTCAgTACAATCTgCTCTgATgCCgCATAgTTAAgCC8401AgTATACACTCCgCTATCgCTACgTgACTgggTCATggCTgCgCCCCgAC8451ACCCgCCAACACCCgCTgACgCgCCCTgACgggCTTgTCTgCTCCCggCA8501TCCgCTTACAgACAAgCTgTgACCgTCTCCgggAgCTgCATgTgTCAgAg8551gTTTTCACCgTCATCACCgAAACgCgCgAggCAgRestriction map of pHIL-D2 (MF.alpha.PrePro::EPI-HNE-3)Non-cuttersAflIIApaIAscIAvaIAvrIIBamHIBglIIBssHIIBstEIIMluINruIPacIPmlIRsrIISacIISfiISnaBISpeIXhoIXmaICutters, 5 or fewer sitesAatII210985925AccI533123950509253968402AflIII18173AgeI11436AlwNI3282828527759ApaLI3617678598357AseI3 59158206672BanII4 216477247867258BbsI41032143232415858BclI4 752158423964484BglI3 28427176724BsaAI271858421BsaBI4 958144916055603BsgI225454494BsiWI215682301BsmI5 317571147124144993BspDI217235793BspEI13978BspHI5 7494790590360087453BspMI14576Bst1107I18402BstBI (AsuII)2 9455207BstXI3 71127652896Bsu36I12223DraI (AhaIII)5 4215541568362686960DraIII237547182DrdI510925557713680658478EagI3 757118591Eam1105I250776843EarI5 1551675402660548295Ecl136I1 216Eco47III219324795EcoNI3343349235293EcoRI11383EcoRV218855658Esp3I (BsaI)231208524EspI (Bpu1102I)1 597FspI219606623HincII41017227233126304HindIII3 88517171729HpaI210172272KasI42865471447354849KpnI223232934MscI222043789MunI4 877319833174145NcoI13766NdeI18351NgoMI247027288NheI219292875NotI3 657108590NsiI2 6841241PflMI2 1961302PmeI1 420PpuMI2 1424339PstI16602PvuI16476PvuII216004497SacI1 216SalI13312ScaI213606365SphI14863SspI3280660416977StuI13395Tth111I18426XbaI12168XcmI1 711XmnI528254256521058186244__________________________________________________________________________ TABLE 252__________________________________________________________________________BstBI-AatII-EcoRI cas8ette for expression of EPI-HNE-4 DNA has SEQ ID NO.068;amino-acid sequence has SEQ ID NO. 069__________________________________________________________________________ 5'-TTCgAA ACg! BstBI! M RFPS I F T A V L F A 13 ATg AgATTCCCATCT ATC TTC ACT gCT gTT TTg TTC gCT! .vertline.BsaBi.vertline.!!! A S S A L A A P VN T T T E 27 gCT TCC TCT gCT TTg gCT gCT CCA gTTAAC ACC ACT ACT gAA! BpmI HpaI BbsI!! D E T A Q I P A E A V I G Y 41 gAC gAg ACT gCT CAA ATT CCT gCT gAg gCT gTC ATC ggT TAC BbsI!! S D L E G D F DV A V L P F 55 TCT gAC TTg gAA ggT gAC TTC gACgTC gCT gTT TTg CCA TTC AatII!! S N S T N N G L L F I N T T 69 TCT AAC TCT ACT AAC AAC ggT TTg TTg TTC ATC AAC ACT ACC!! I A S I A A K E E G V S L D 83 ATC gCT TCT ATC gCT gCT AAg gAg gAA ggT gTT TCC TTg gAC!! K R E A C N L P AAg AgA gAg gCT TgT AAC TTg CCA 91!! I V R G PCI A F F P R W A 105 ATC gTC AgA ggT CCATgCATT gCT TTC TTC CCA AgA Tgg gCT! NsiI!! F D A V K G K C V L F P Y G 119 TTC gAC gCT gTT AAg ggT AAg TgC gTC TTg TTC CCA TAC ggT! .vertline. PflMI!! G C Q G N G N K F Y S E K E 133 ggT TgT CAA ggT AAC ggT AAC AAg TTC TAC TCT gAg AAg gAg! PflMI!! C R E Y C G V P . . 141 TgT AgA gAg TAC TgT ggT gTT CCA TAg TAA gAATTCgCCT! EcoRI__________________________________________________________________________ The DNA is a linear fragment that is double stranded in vivo, only one strand is shown. The amino acid sequence is that of a disulfidecontaining protein that is processed in vivo. TABLE 253__________________________________________________________________________pD2pick(MF.alpha.PrePro::EPI-HNE-3), 8590 bp, CIRCULARdsDNA, one strand shown. pD2pick(MF.alpha.PrePro::EPI-HNE-3) DNA hasSEQ ID NO. 070 Encoded protein has SEQ ID NO. 069__________________________________________________________________________ ##STR55##1 AgATCgCggCCgCgATCTAACATCCAAAgACgAAAggTTg AATgAAACCT51 TTTTgCCATCCgACATCCACAggTCCATTCTCACACATAAgTgCCAAACg101 CAACAggAggggATACACTA gCAgCAgACCgTTgCAAACg CAggACCTCC151 ACTCCTCTTC TCCTCAACAC CCACTTTTgC CATCgAAAAA CCAgCCCAgT ##STR56##251 TAACACCATgACTTTATTAgCCTgTCTATCCTggCCCCCCTggCgAggTC301 ATgTTTgTTTATTTCCgAATgCAACAAgCTCCgCATTACACCCgAACATC351 ACTCCAgATgAgggCTTTCTgAgTgTggggTCAAATAgTTTCATgTTCCC ##STR57##451 AAAAgCgTgATCTCATCCAAgATgAACTAAgTTTggTTCgTTgAAATgCT501 AACggCCAgTTggTCAAAAAgAAACTTCCAAAAgTCgCCATACCgTTTgT ##STR58##604 gCAgTCTCTCTATCgCTTCTgAACCCggTggCACCTgTgCCgAAACg651 CAAATggggAAACAACCCgCTTTTTggATgATTATgCATTgTCCTCCACA ##STR59##751 ATgATCAAAATTTAACTgTTCTAACCCCTACTTgACAggCAATATATAAA801 CAgAAggAAgCTgCCCTgTCTTAAACCTTTTTTTTTATCATCATTATTAg851 CTTACTTTCATAATTgCgACTggTTCCAATTgACAAgCTTTTgATTTTAA ##STR60##951 ACg ##STR61## ##STR62## ##STR63## ##STR64## ##STR65## ##STR66## ##STR67## ##STR68## ##STR69## ##STR70## ##STR71## ##STR72##1451 TTCTAATCAAgAggATgTCAgAATgCCATTTgCCTgAgAgATgCAggCTT1501 CATTTTTgATACTTTTTTATTTgTAACCTATATAgTATAggATTTTTTTT1551 gTCATTTTgTTTCTTCTCgTACgAgCTTgCTCCTgATCAgCCTATCTCgC1601 AgCTgATgAATATCTTgTggTAggggTTTgggAAAATCATTCgAgTTTgA1651 TgTTTTTCTTggTATTTCCCACTCCTCTTCAgAgTACAgAAgATTAAgTg1701 AgAAgTTCgTTTgTgCAAgCTTATCgATAAgCTTTAATgCggTAgTTTAT1751 CACAgTTAAATTgCTAACgCAgTCAggCACCgTgTATgAAATCTAACAAT1801 gCgCTCATCgTCATCCTCggCACCgTCACCCTggATgCTgTAggCATAgg1851 CTTggTTATgCCggTACTgCCgggCCTCTTgCgggATATCgTCCATTCCg1901 ACAgCATCgCCAgTCACTATggCgTgCTgCTAgCgCTATATgCgTTgATg1951 CAATTTCTATgCgCACCCgTTCTCggAgCACTgTCCgACCgCTTTggCCg2001 CCgCCCAgTCCTgCTCgCTTCgCTACTTggAgCCACTATCgACTACgCgA2051 TCATggCgACCACACCCgTCCTgTggATCTATCgAATCTAAATgTAAgTT2101 AAAATCTCTAAATAATTAAATAAgTCCCAgTTTCTCCATACgAACCTTAA ##STR73## ##STR74##2251 gAACTTCTggAAggTTgCAgTgTTAACTCCgCTgTATTgACgggCATATC2301 CgTACgTTggCAAAgTgTggTTggTACCggAggAgTAATCTCCACAACTC2351 TCTggAgAgTAggCACCAACAAACACAgATCCAgCgTgTTgTACTTgATC2401 AACATAAgAAgAAgCATTCTCgATTTgCAggATCAAgTgTTCAggAgCgT2451 ACTgATTggACATTTCCAAAgCCTgCTCgTAggTTgCAACCgATAgggTT2501 gTAgAgTgTgCAATACACTTgCgTACAATTTCAACCCTTggCAACTgCAC2551 AgCTTggTTgTgAACAgCATCTTCAATTCTggCAAgCTCCTTgTCTgTCA2601 TATCgACAgCCAACAgAATCACCTgggAATCAATACCATgTTCAgCTTgA2651 gCAgAAggTCTgAggCAACgAAATCTggATCAgCgTATTTATCAgCAATA2701 ACTAgAACTTCAgAAggCCCAgCAggCATgTCAATACTACACAgggCTgA2751 TgTgTCATTTTgAACCATCATCTTggCAgCAgTAACgAACTggTTTCCTg2801 gACCAAATATTTTgTCACACTTAggAACAgTTTCTgTTCCgTAAgCCATA2851 gCAgCTACTgCCTgggCgCCTCCTgCTAgCACgATACACTTAgCACCAAC2901 CTTgTgggCAACgTAgATgACTTCTggggTAAgggTACCATCCTTCTTAg2951 gTggAgATgCAAAAACAATTTCTTTgCAACCAgCAACTTTggCAggAACA3001 CCCAgCATCAgggAAgTggAAggCAgAATTgCggTTCCACCAggAATATA3051 gAggCCAACTTTCTCAATAggTCTTgCAAAACgAgAgCAgACTACACCAg3101 ggCAAgTCTCAACTTgCAACgTCTCCgTTAgTTgAgCTTCATggAATTTC3151 CTgACgTTATCTATAgAgAgATCAATggCTCTCTTAACgTTATCTggCAA3201 TTgCATAAgTTCCTCTgggAAAggAgCTTCTAACACAggTgTCTTCAAAg3251 CgACTCCATCAAACTTggCAgTTAgTTCTAAAAgggCTTTgTCACCATTT3301 TgACgAACATTgTCgACAATTggTTTgACTAATTCCATAATCTgTTCCgT ##STR75##3401 TAgAAACgTCAATTTTgCACAATTCAATACgACCTTCAgAAgggACTTCT3451 TTAggTTTggATTCTTCTTTAggTTgTTCCTTggTgTATCCTggCTTggC3501 ATCTCCTTTCCTTCTAgTgACCTTTAgggACTTCATATCCAggTTTCTCT3551 CCACCTCgTCCAACgTCACACCgTACTTggCACATCTAACTAATgCAAAA3601 TAAAATAAgTCAgCACATTCCCAggCTATATCTTCCTTggATTTAgCTTC3651 TgCAAgTTCATCAgCTTCCTCCCTAATTTTAgCgTTCAACAAAACTTCgT3701 CgTCAAATAACCgTTTggTATAAgAACCTTCTggAgCATTgCTCTTACgA ##STR76##3801 gAAgTgCgTTCCAAgTgACAgAAACCAACACCTgTTTgTTCAACCACAAA3851 TTTCAAgCAgTCTCCATCACAATCCAATTCgATACCCAgCAACTTTTgAg3901 TTCgTCCAgATgTAgCACCTTTATACCACAAACCgTgACgACgAgATTgg ##STR77##4001 gTACACCAggCCCAACgAgTAATTAgAAgAgTCAgCCACCAAAgTAgTgA4051 ATAgACCATCggggCggTCAgTAgTCAAAgACgCCAACAAAATTTCACTg4101 ACAgggAACTTTTTgACATCTTCAgAAAgTTCgTATTCAgTAgTCAATTg4151 CCgAgCATCAATAATggggATTATACCAgAAgCAACAgTggAAgTCACAT4201 CTACCAACTTTgCggTCTCAgAAAAAgCATAAACAgTTCTACTACCgCCA4251 TTAgTgAAACTTTTCAAATCgCCCAgTggAgAAgAAAAAggCACAgCgAT4301 ACTAgCATTAgCgggCAAggATgCAACTTTATCAACCAgggTCCTATAgA4351 TAACCCTAgCgCCTgggATCATCCTTTggACAACTCTTTCTgCCAAATCT4401 AggTCCAAAATCACTTCATTgATACCATTATACggATgACTCAACTTgCA4451 CATTAACTTgAAgCTCAgTCgATTgAgTgAACTTgATCAggTTgTgCAgC4501 TggTCAgCAgCATAgggAAACACggCTTTTCCTACCAAACTCAAggAATT4551 ATCAAACTCTgCAACACTTgCgTATgCAggTAgCAAgggAAATgTCATAC4601 TTgAAgTCggACAgTgAgTgTAgTCTTgAgAAATTCTgAAgCCgTATTTT4651 TATTATCAgTgAgTCAgTCATCAggAgATCCTCTACgCCggACgCATCgT4701 ggCCggCATCACCggCgCCACAggTgCggTTgCTggCgCCTATATCgCCg4751 ACATCACCgATggggAAgATCgggCTCgCCACTTCgggCTCATgAgCgCT4801 TgTTTCggCgTgggTATggTggCAggCCCCgTggCCgggggACTgTTggg4851 CgCCATCTCCTTgCATgCACCATTCCTTgCggCggCggTgCTCAACggCC4901 TCAACCTACTACTgggCTgCTTCCTAATgCAggAgTCgCATAAgggAgAg4951 CgTCgAgTATCTATgATTggAAgTATgggAATggTgATACCCgCATTCTT5001 CAgTgTCTTgAggTCTCCTATCAgATTATgCCCAACTAAAgCAACCggAg5051 gAggAgATTTCATggTAAATTTCTCTgACTTTTggTCATCAgTAgACTCg5101 AACTgTgAgACTATCTCggTTATgACAgCAgAAATgTCCTTCTTggAgAC ##STR78##5151 AgTAAATgAAgTCCCACCAATAAAgAAATCCTTgTTATCAggAACAAACT5201 TCTTgTTTCgCgAACTTTTTCggTgCCTTgAACTATAAAATgTAgAgTgg5251 ATATgTCgggTAggAATggAgCgggCAAATgCTTACCTTCTggACCTTCA5301 AgAggTATgTAgggTTTgTAgATACTgATgCCAACTTCAgTgACAACgTT5351 gCTATTTCgTTCAAACCATTCCgAATCCAgAgAAATCAAAgTTgTTTgTC5401 TACTATTgATCCAAgCCAgTgCggTCTTgAAACTgACAATAgTgTgCTCg5451 TgTTTTgAggTCATCTTTgTATgAATAAATCTAgTCTTTgATCTAAATAA5501 TCTTgACgAgCCAAggCgATAAATACCCAAATCTAAAACTCTTTTAAAAC5551 gTTAAAAggACAAgTATgTCTgCCTgTATTAAACCCCAAATCAgCTCgTA5601 gTCTgATCCTCATCAACTTgAggggCACTATCTTgTTTTAgAgAAATTTg5651 CggAgATgCgATATCgAgAAAAAggTACgCTgATTTTAAACgTgAAATTT5701 ATCTCAAgATCgCggCCgCgATCTCgAATAATAACTgTTATTTTTCAgTg5751 TTCCCgATCTgCgTCTATTTCACAATACCAACATgAgTCAgCTTATCgAT5801 gATAAgCTgTCAAACATgAgAATTAATTCgATgATAAgCTgTCAAACATg5851 AgAAATCTTgAAgACgAAAgggCCTCgTgATACgCCTATTTTTATAggTT5901 AATgTCATgATAATAATggTTTCTTAgACgTACgTCAggTggCACTTTTC5951 ggggAAATgTgCgCggAACCCCTATTTgTTTATTTTTCTAAATACATTCA6001 AATATgTATCCgCTCATgAgACAATAACCCTgATAAATgCTTCAATAATA6051 TTgAAAAAggAAgAgTATgAgTATTCAACATTTCCgTgTCgCCCTTATTC6101 CCTTTTTTgCggCATTTTgCCTTCCTgTTTTTgCTCACCCAgAAACgCTg6151 gTgAAAgTAAAAgATgCTgAAgATCAgTTgggTgCACgAgTgggTTACAT6201 CgAACTggATCTCAACAgCggTAAgATCCTTgAgAgTTTTCgCCCCgAAg6251 AACgTTTTCCAATgATgAgCACTTTTAAAgTTCTgCTATgTggCgCggTA6301 TTATCCCgTgTTgACgCCgggCAAgAgCAACTCggTCgCCgCATACACTA6351 TTCTCAgAATgACTTggTTgAgTACTCACCAgTCACAgAAAAgCATCTTA6401 CggATggCATgACAgTAAgAgAATTATgCAgTgCTgCCATAACCATgAgT6451 gATAACACTgCggCCAACTTACTTCTgACAACgATCggAggACCgAAggA6501 gCTAACCgCTTTTTTgCACAACATgggggATCATgTAACTCgCCTTgATC6551 gTTgggAACCggAgCTgAATgAAgCCATACCAAACgACgAgCgTgACACC6601 ACgATgCCTgCAgCAATggCAACAACgTTgCgCAAACTATTAACTggCgA6651 ACTACTTACTCTAgCTTCCCggCAACAATTAATAgACTggATggAggCgg6701 ATAAAgTTgCAggACCACTTCTgCgCTCggCCCTTCCggCTggCTggTTT6751 ATTgCTgATAAATCTggAgCCggTgAgCgTgggTCTCgCggTATCATTgC6801 AgCACTggggCCAgATggTAAgCCCTCCCgTATCgTAgTTATCTACACgA6851 CggggAgTCAggCAACTATggATgAACgAAATAgACAgATCgCTgAgATA6901 ggTgCCTCACTgATTAAgCATTggTAACTgTCAgACCAAgTTTACTCATA6951 TATACTTTAgATTgATTTAAATTgTAAACgTTAATATTTTgTTAAAATTC7001 gCgTTAAATTTTTgTTAAATCAgCTCATTTTTTAACCAATAggCCgAAAT7051 CggCAAAATCCCTTATAAATCAAAAgAATAgACCgAgATAgggTTgAgTg7101 TTgTTCCAgTTTggAACAAgAgTCCACTATTAAAgAACgTggACTCCAAC7151 gTCAAAgggCgAAAAACCgTCTATCAgggCgATggCCCACTACgTgAACC7201 ATCACCCTAATCAAgTTTTTTggggTCgAggTgCCgTAAAgCACTAAATC7251 ggAACCCTAAAgggAgCCCCCgATTTAgAgCTTgACggggAAAgCCggCg7301 AACgTggCgAgAAAggAAgggAAgAAAgCgAAAggAgCgggCgCTAgggC7351 gCTggCAAgTgTAgCggTCACgCTgCgCgTAACCACCACACCCgCCgCgC7401 TTAATgCgCCgCTACAgggCgCgTAAAAggATCTAggTgAAgATCCTTTT7451 TgATAATCTCATgACCAAAATCCCTTAACgTgAgTTTTCgTTCCACTgAg ##STR79##7551 CTgCgCgTAATCTgCTgCTTgCAAACAAAAAAACCACCgCTACCAgCggT7601 ggTTTgTTTgCCggATCAAgAgCTACCAACTCTTTTTCCgAAggTAACTg7651 gCTTCAgCAgAgCgCAgATACCAAATACTgTCCTTCTAgTgTAgCCgTAg7701 TTAggCCACCACTTCAAgAACTCTgTAgCACCgCCTACATTCgTgTCTTA7751 gCTAATCCTgTTACCAgTggCTgCTgCCAgTggCgATAAgTCgTgTCTTA7801 CCgggTTggACTCAAgACgATAgTTACCggATAAggCgCAgCggTCgggC7851 TgAACggggggTTCgTgCACACAgCCCAgCTTggAgCgAACgAACTACAC7901 CgAACTgAgATACCTACAgCgTgAgCATTgAgAAAgCgCCACgCTTCCCg7951 AAgggAgAAAggCggACAggTATCCggTAAgCggCAgggTCggAACAggA8001 gAgCgCACgAgggAgCTTCCAgggggAAACgCCTggTATCTTTATAgTCC8051 TgTCgggTTTCgCCACCTCTgACTTgAgCgTCgATTTTTgTgATgCTCgT8101 CAggggggCggAgCCTATggAAAAACgCCAgCAACgCggCCTTTTTACgg8151 TTCCTggCCTTTTgCTggCCTTTTgCTCACATgTTCTTTCCTgCgTTATC8201 CCCTgATTCTgTggATAACCgTATTACCgCCTTTgAgTgAgCTgATACCg8251 CTCgCCgCAgCCgAACgACCgAgCgCAgCgAgTCAgTgAgCgAggAggCg8301 gAAgAgCgCCTgATgCggTATTTTCTCCTTACgCATCTgTgCggTATTTC8351 ACACCgCATATggTgCACTCTCAgTACAATCTgCTCTgATgCCgCATAgT8401 TAAgCCAgTATACACTCCgCTATCgCTACgTgACTgggTCATggCTgCgC8451 CCCgACACCCgCCAACACCCgCTgACgCgCCCTgACgggCTTgTCTgCTC8501 CCggCATCCgCTTACAgACAAgCTgTgACCgTCTCCgggAgCTgCATgTg8551 TCAgAggTTTTCACCgTCATCACCgAAACgCgCgAggCAg__________________________________________________________________________ TABLE 254______________________________________restriction map of pD2pick (MF.alpha.PrePro::EPI-HNE-3)______________________________________Non-cuttersAflII ApaI AscI AvaI AvrIIBamHI BglII BssHII BstEII MluIPacI PmlI RsrII SacII SfiISnaBI SpeI XhoI XmaICutters, 5 or fewer sitesAatII 1 1098AccI 5 3312 3950 5092 5398 8408AflIII 1 8179AgeI 1 1436AlwNI 3 2828 2852 7765ApaLI 3 6182 7865 8363AseI 3 591 5822 6678BanII 4 216 4772 4786 7264BbsI 4 1032 1432 3241 5860BclI 4 752 1584 2396 4484BglI 3 284 2717 6730BsaAI 2 7191 8427BsaBI 4 958 1449 1605 5605BsgI 2 2545 4494BsiWI 3 1568 2301 5929BsmI 5 317 571 1471 2414 4993BspDI 2 1723 5795BspEI 1 3978BspHI 5 749 4790 5905 6014 7459BspMI 1 4576Bst1107I 1 8408BstBI (AsuII) 1 945BstXI 3 711 2765 2896Bsu36I 1 2223DraI (AhaIII) 5 421 5543 5685 6274 6966DraIII 2 3754 7188DrdI 5 1092 5559 7142 8071 8484EagI 3 7 5713 8597Eam1105I 2 5077 6849EarI 5 155 1675 4026 6060 8301Ecl136I 1 216Eco47III 2 1932 4795EcoNI 3 3433 4923 5295EcoRI 1 1383EcoRV 2 1885 5660Esp3I (BsaI) 2 3120 8530EspI (Bpu1102I) 1 597FspI 2 1960 6629HincII 4 1017 2272 3312 6310HindIII 3 885 1717 1729HpaI 2 1017 2272KasI 4 2865 4714 4735 4849KpnI 2 2323 2934MscI 2 2204 3789MunI 4 877 3198 3317 4145NcoI 1 3766NdeI 1 8357NgoMI 2 4702 7294NheI 2 1929 2875NotI 3 6 5712 8596NruI 1 5208NsiI 2 684 1241PflMI 2 196 1302PmeI 1 420PpuMI 2 142 4339PstI 1 6608PvuI 1 6482PvuII 2 1600 4497SacI 1 216SalI 1 3312ScaI 2 1360 6371SphI 1 4863SspI 3 2806 6047 6983StuI 1 3395Tth111I 1 8432XbaI 1 2168XcmI 1 711XmnI 5 2825 4256 5212 5820 6250______________________________________ TABLE 399__________________________________________________________________________Number of amino-acid differences between some Kunitz domainsDifferences counted for resideues 3 through 57 where residue 5 is thefirst cysteine of each domain. Consensus BPTI ITI-D1 ITI-D2 EPI-HNE-1 EPI-HNE-2 EPI-HNE-3 EPI-HNE-4__________________________________________________________________________Consensus -- 21 26 27 19 19 27 27BPTI 21 -- 32 34 8 8 34 34ITI-D1 26 32 -- 34 28 28 33 33ITI-D2 27 34 34 -- 31 31 4 5EPI-HNE-1 19 8 28 31 -- -- 27 27EPI-HNE-2 19 8 28 31 -- -- 27 27EPI-HNE-3 27 34 33 4 27 27 -- 1EPI-HNE-4 27 34 33 5 27 27 1 --__________________________________________________________________________ TABLE 400__________________________________________________________________________Amino-acid Sequence of ITI light chain (SEQ ID NO. 072)__________________________________________________________________________111111111122123456789012345678901 avlpqeeegsgggqlvtevtk22222222333333333344444444445555555555666666666677777772345678901234567890123456789012345678901234567890123456 ##STR80##7778878901rtvaa111111111111111111111111111111111111888888889999999999000000000011111111112222222222333333234567890123456789012345678901234567890123456789012345 ##STR81##ITI-D1 comprises residues 22-76 and optionally one of residue 77,residues 77 and 78, or residues 77-79.ITI-D2 comprises residues 80-135 and optionally one of residue 79 orresidues 78-79.The lines under the sequences represent disulfides.__________________________________________________________________________ TABLE 401 - Kunitz-domain hNE inhibitors producible in Pichia pastoris ##STR82## ##STR83## ##STR84## Each of the proteins has the same disulfide-bonding patern shown for EPI-HNE-4. TABLE 601 - Sequences of purified hNE inhibitors derived from Kunitz domains ##STR85## ##STR86## ##STR87## ##STR88## ##STR89## - means that the named protein has the same amino acid as the parental domain. TABLE 602__________________________________________________________________________Physical properties of hNE inhibitors derived from Kunitz domains k.sub.on k.sub.offProtein Parent # Residues Mol Wt Pre-dicted pI K.sub.D (pM) (10.sup.6 /M/s) (10.sup.-6 /s)__________________________________________________________________________EPI-HNE-1 BPTI 58 6359 9.10 2.0 3.7 7.4EPI-HNE-2 BPTI 62 6759 4.89 4.9 4.0 20.EPI-HNE-3 ITI-D2 56 6179 10.04 6.2 8.0 50.EPI-HNE-4 ITI-D2 56 6237 9.73 4.6 10.6 49.__________________________________________________________________________ The constants K.sub.D and k.sub.on above were measured with [hNE] = 8.47 .times. 10.sup.-10 molar; k.sub.off was calculated from k.sub.off = K.sub.D .times. k.sub.on. TABLE 603______________________________________SUMMARY OF PURIFICATION OF EPI-HNE-2 Volume Concentration Total ActivitySTAGE (ml) (mg/ml) (mg) (mg/A.sub.280)______________________________________HARVEST 3,300 0.70 2.31 <0.0130K ULTRA- 5,000 0.27 1.40 <0.01FILTRATIONFILTRATE5K ULTRA- 1,000 1.20 1.20 0.63FILTRATIONFILTRATEAMMONIUM 300 2.42 0.73 1.05SULFATEPRECIPITATEIEX pH6.2 98 6.88 0.67 1.03ELUATEEPI-HNE-3, 50 13.5 0.68 1.04LOT 1______________________________________ TABLE 604______________________________________SUMMARY OF PURIFICATION OF EPI-HNE-3 CONCENTRA- VOLUME TION TOTAL ACTIVITYSTAGE (ml) (mg/ml) (mg) (mg/A.sub.280)______________________________________HARVEST 3,100 0.085 263 ND30K ULTRA- 3,260 0.055 179 0.007FILTRATIONFILTRATEFIRST IEX: 180 0.52 94 0.59pH6.2ELUATEAMMONIUM 100 0.75 75 0.59SULFATEPRECIPITATEIEX pH9 60 1.01 60 0.59ELUATEEPI-HNE-3, 26 1.54 40 0.45LOT 1______________________________________ TABLE 605__________________________________________________________________________K.sub.I VALUES OF EPI-HNE PROTEINSFOR VARIOUS HUMAN SERUM SERINE PROTEASES Inhibitor:Enzyme EPI-HNE-1 EPI-HNE-2 EPI-HNE-3 EPI-HNE-4__________________________________________________________________________Human Neutrophil Elastase 2 pM 5 pM 6 pM 5 pMHuman Serum Plasmin >6 .mu.M >100 .mu.M >100 .mu.M >90 .mu.MHuman Serum Kallikrein >10 .mu.M >100 .mu.M >100 .mu.M >90 .mu.MHuman Serum Thrombin >90 .mu.M >100 .mu.M >100 .mu.M >90 .mu.MHuman Urine Urokinase >90 .mu.M >100 .mu.M >100 .mu.M >90 .mu.MHuman Plasma Factor X.sub.a >90 .mu.M >100 .mu.M >100 .mu.M >90 .mu.MHuman Pancreatic Chymotrypsin .about.10 .mu.M .about.10 .mu.M .about.30 .mu.M .about.10 .mu.M__________________________________________________________________________ TABLE 607______________________________________PEY-33 which Produces EPI-HNE-2Elapse Fermenter Time Cell Density Activity in supernatentHours:minutes (A.sub.600) (mg/l)______________________________________41:09 89 2843:08 89 5751:54 95 9257:05 120 14062:43 140 24574:45 160 36087:56 170 47398:13 190 656102:25 200 678109:58 230 710______________________________________ Fermenter culture growth and EPIHNE protein secretion by P. pastoris strains PEY33. Time course is shown for fermenter cultures following initiation of methanollimited feed growth phase. Increase in cell mass is estimated by A.sub.600. Concentration of inhibitor protein in the fermenter culture medium was determined from measurements of hNE inhibition by diluted aliquots of cellfree culture medium obtained at the times indicated and stored at -20.degree. C. until assay. TABLE 608______________________________________PEY-43 Which produces EPI-HNE-3Elapse Fermenter Time Cell Density Activity in supernatentHours:minutes (A.sub.600) (mg/l)______________________________________44:30 107 0.6350:24 70 9.452:00 117 14.62:00 131 28.76:00 147 39.86:34 200 56.100:27 185 70.113:06 207 85.______________________________________ Fermenter culture growth and EPIHNE protein secretion by P. pastoris strains PEY43. Time course is shown for fermenter cultures following initiation of methanollimited feed growth phase. Increase in cell mass is estimated by A.sub.600. Concentration of inhibitor protein in the fermenter culture medium was determined from measurements of hNE inhibition by diluted aliquots of cellfree culture medium obtained at the times indicated and stored at -20.degree. C. until assay. TABLE 610______________________________________Inhibitory properties of EPI-BNE-2.mu.l of EPI-HNE-2 solution Percent residual hNEadded activity______________________________________0. 101.10. 100.00. 100.00. 100.00. 100.00. 98.910. 82.920. 71.830. 59.540. 46.250. 39.255. 32.260. 22.565. 23.570. 15.075. 10.480. 8.685. 4.890. 1.495. 2.0100. 2.5120. 0.2150. 0.2200. 0.04______________________________________ TABLE 611______________________________________hNE inhibitory properties of EPI-BNE-3.mu.l of EPI-HNE-3 solution Percent residual hNEadded activity______________________________________0. 101.20. 100.00. 100.00. 100.00. 100.00. 98.810. 81.620. 66.930. 53.440. 38.050. 27.655. 21.560. 13.065. 11.070. 7.975. 3.880. 3.385. 2.190. 1.8100. 1.6110. 0.8120. 0.7160. 0.6200. 0.2______________________________________ TABLE 612______________________________________pH stability of Kunitz-domain hNE inhibitors Percent Residual hNE Inhibitory ActivityIncubation pH EPI-HNE-1 EPI-HNE-2 EPI-HNE-3 EPI-HNE-4______________________________________1.0 102 98 97 982.0 100 97 97 1002.6 1013.0 100 101 100 964.0 98 101 102 945.0 1005.5 99 99 1096.0 100 103 996.5 99 1007.0 93 103 103 937.5 87 1098.0 96 84 838.5 104 68 869.4 100 44 4010.0 98 102 27 34______________________________________ Proteins were incubated at 37.degree. C. for 18 hours in buffers of defined pH (see text). In all cases protein concentrations were 1 .mu.M. At the end of the incubation period, aliquots of the reactions were diluted and residual hNEinhibition activity determined. TABLE 620__________________________________________________________________________Stability of hNE inhibitory proteins to oxidation by Chloramine-TMolar Ratio Percent Residual hNE-Inhibitory ActivityCHL-T: .alpha.1 antiInhibitor EPI-HNE-1 EPI-HNE-2 EPI-HNE-3 EPI-HNE-4 trypsin SLPI__________________________________________________________________________0 100 100 100 100 100 1000.25 940.29 930.30 97.48 102.50 102 97 100 85.59 82.88 73.95 1001.0 102 97 100 411.2 651.4 981.5 951.9 1022.0 1022.1 72.4 483.0 97 1003.8 944.0 955.0 94 1005.2 75.9 189.5 9510. 98 97 10410.4 >512. 1519. 9230. 100 10050. 94 100__________________________________________________________________________ Inhibitors were incubated in the presence of ChloramineT at the molar ratios indicated for 20 minutes at room temperature. Oxidation reactions were quenched by adding methionine to a final concentration of 4 mM. Residual hNEinhibition activity remaining in the quenched reactions is shown as a percentage of the activity observed with no added oxidant. Proteins and concentrations in the oxidation reactions are: EPIHNE-1, (5 .mu.M); EPIHNE-2, (10 .mu.M); EPIHNE-3, (10 .mu.M); EPIHNE-4, (10 .mu.M); API, (10 .mu.M); and SLPI, (8.5 .mu.M). TABLE 630______________________________________Temperature stability of EPI-HNE proteinsTemperature Residual hNE Inhibitory Activity(.degree.C.) EPI-HNE-1 EPI-HNE-2 EPI-HNE-3 EPI-HNE-4______________________________________0 97 101 96 10023 100 103 105 10337 100 97 99 9845 10352 101 10055 99 9865 94 95 8769 8275 10080 101 7985 106 6393 88 5795 64 48______________________________________ Proteins were incubated at the stated temperature for 18 hours in buffer at pH 7.0. In all cases protein concentrations were 1 .mu.M. At the end o the incubation period, aliquots of the reactions were diluted and residua hNEinhibition activity determined. TABLE 700__________________________________________________________________________Kunitz domains in segments. Segment # 1 2 3 4 5 6 7 8 9 10 N-4 5-9 10-13 14 15-21 22-30 31-35 36-38 39-42 43-58__________________________________________________________________________Consensus RPDF CLLPA ETGP C RAMIPRF YYNAKSGKC EPFIY GGC GGNA NNFKTEEECRRTCGGAKunitz domainSEQ ID NO. 071HUMAN VREV CSEQA ETGP C RAMISRW YFDVTEGKC APFFY GGC GGNR NNFDTEEYCMAVCGSAPROTEASENEXIN-IIP05067SEQ ID NO. 073Human RNREV CSEQA ETGP C RAMISRW YFDVTEGKC APFFY GGC GGNR NNFDTEEYCMAVCGSAAlzheimer's.beta. proteaseinhibitorSEQ ID NO. 074BPTI SEQ ID RPDF CLEPP YTGP C KARIIRY FYNAKAGLC QTFVY GGC RAKR NNFKSAEDCMRTCGGANO. 021Human LACI-D3 GPSW CLTPA DRGL C RANENRF YYNSVIGKC RPFKY SGC GGNE NNFTSKQECLRACKKGp10646SEQ ID NO. 075Human ITI-D1 KEDS CQLGY SAGP C MGMTSRY FYNGTSMAC ETFQY GGC MGNG NNFVTEKECLQTCRTVP02760(HI-8e)SEQ ID NO. 002Human ITI-D2 TVAA CNLPI VRGP C RAFIQLW AFDAVKGKC VLFPY GGC QGNG NKFYSEKECREYCGVPP02760(HI-8t)SEQ ID NO. 003Human KPDF CFLEE DPGI C RGYITRY FYNNQTKQC ERFKY GGC LGNM NNFETLEECKNICEDGLACI-D2P10646SEQ ID NO 076Human LACI-D1 MHSF CAFKA DDGP C KAIMKRF FFNIFTRQC EEFIY GGC EGNQ NRFESLEECKKMCTRDP10646SEQ ID NO. 077Human HKI B9 LPNV CAFPM EKGP C QTYMTRW FFNFETGEC ELFAY GGC GGNS NNFLRKEKCEKFCKFTDomainSEQ ID NO. 078Human ETDI CKLPK DEGT C RDFILKW YYDPNTKSC ARFWY GGC GGNE NKFGSQKECEKVCAPVcollagen .alpha.3domainSEQ ID NO. 079TFPI-2 D1 NAEI CLLPL DYGP C RALLLRY YYDRYTQSC RQFLY GGC EGNA NNFYTWEACDDACWRIPNAS 91:3353-3357 ('94)SEQ ID NO. 080TFPI-2 D2 VPKV CRLQVS VDDQ C EGSTEKY FFNLSSMTC EKFFS GGC HRNR IENRFPDEATCMGFCAPKPNAS 91:3353-3357 ('94)SEQ ID NO. 081TFPI-2 D3 IPSF CYSPK DEGL C SANVTRY YFNPRYRTC DAFTY TGC GGND NNFVSREDCKRACAKAPNAS 91:3353-3357 ('94)SEQ ID NO. 082__________________________________________________________________________ TABLE 701______________________________________Substitutions for Segment 1 (amino terminus to residue 4)that are likely to give Kunitz Domains that could have very-highaffinity for hNE.Sequence: SEQ IDNH.sub.3 -Residue 4 Source and reason NO.______________________________________RPDF BPTI, consensus KuDom, EpiNE1-8, 163EAEARPDF EPI-HNE-2 164KEDS ITI-D1, ITI-D1E7 165KEDf AMINO1 166KPDS AMINO2 167TVAA ITI-D2 168AA EPI-HNE-3 169EA EPI-HNE-4 170DF Truncation of EpiNE1 171______________________________________ TABLE 702______________________________________Substitutions for Segment 3 (residues 10-13) that arelikely to give Kunitz Domains that could have very-high affinityfor hNE. SEQ IDSequence: 10-13 Source and reason NO.______________________________________YTGP BPTI, EpiNE1-EpiNE8, EPI-HNE-2 172SAGP ITI-D1 and derivatives 173STGP BITI-E7-1222 174VRGP ITI-D2, EPI-HNE-3, EPI-HNE-4 175______________________________________ TABLE 703______________________________________Substitutions for Segment 5 (residues 15-21) that arelikely to give Kunitz Domains that could have very-high affinityfor hNE. SEQ IDSequence: 15-21 Source and reason NO.______________________________________vAmfpRY EpiNE7, ITI-D1E7 176vgffsRY EpiNE3 177vgffqRY EpiNE6 178vAifpRY EpiNE4 179vAffkRS EpiNE8 180iAffpRY EpiNE1, EPI-HNE-2 181iAffqRY EpiNE5 182iAlfkRY EpiNE2 183iGMfSRY MUTP1 184iAFfprW EPI-HNE-3, EPI-HNE-4 185VAFFPRW Analogy to EPI-HNE-3 with 186 P1.dbd.ValVAIFPRW Combine EPI-HNE-3 and EpiNE4 187VAFFPRW Combine EPI-HNE-3 and EpiNE1 188vgffsRW Combine EPI-HNE-3 and EpiNE3 189vAmfpRW Combine EPI-HNE-3 and EpiNE7 190VAFFPRF SEQ 188 with F21 191vgffsRF SEQ 189 with F21 192vAmfpRF SEQ 190 with F21 193______________________________________ TABLE 704______________________________________Substitutions for Segment 7 (residues 31-35) that arelikely to give Kunitz Domains that could have very-high affinityfor hNE.Sequence: SEQ IDResidues 31-35 Source and reason NO.______________________________________QTFVY BPTI, EpiNE1-8, EpiNE7.36 194VLFPY EPI-HNE-3, EPI-HNE-4 195ETFQY ITI-DL and derivatives 196qTFvY BITI-E7-141, MUTT26A, MUT1619 197ETFvY MUTQE 198VLFPY ITI-D2 and Derivatives 199QTFlY EpiNE7.6, 7.4 & 7.14 200QTFeY EpiNE7.8, 7.7, 7.33 201QTFgY EpiNE7.11, 7.32 202QTFrY EpiNE7.5 203QTFdy EpiNE7.10 & 7.20 204QTFkY EpiNE7.1, 7.23, 7.24, 7.26, 7.30, .34, 205 & .35QTFtY EpiNE7.16, 7.28, 7.29 206QTFnY EpiNE7.19, 7.27 207QTFqY EpiNE7.12, 7.17 208QTFHY EpiNE7.21, 7.22 209QTFpY EpiNE7.25 210______________________________________ TABLE 705______________________________________Substitutions for Segment 9 (residues 39-42) that arelikely to give Kunitz Domains that could have very-high affinityfor hNE.Sequence: SEQ IDResidues 39-42 Source and reason NO.______________________________________mgng EpiNE1-8, ITI-D1 and derivatives 211QGNG ITI-D2 and derivatives 212kgkG EpiNE7.6 213wakg EpiNE7.8, 7.9, 7.31, 7.25 214rakG EpiNE7.13, 215haeG EpiNE7.7 216waqG EpiNE7.4 & 7.14 217laeG EpiNE7.5 218hadg EpiNE7.10 & 7.20 219lahG EpiNE7.1 220wanG EpiNE7.16, 7.33 221egkG EpiNE7.19 222egyG EpiNE7.12 223lgeg EpiNE7.17 224wgqG EpiNE7.21 225wgeG EpiNE7.22, 7.32 226wgkG EpiNE7.23, 7.27 227hgnG EpiNE7.24 228wghg EpiNE7.26 229lghG EpiNE7.28 230lgyG EpiNE7.29 231waeG EpiNE7.30, .34, & .35 232hgdG EpiNE7.36 233______________________________________ TABLE 706__________________________________________________________________________Sample Candidate hNE inhibitor proteins11223344555 SEQ505050505058 ID NO.__________________________________________________________________________hLACI-D2 KPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG 076CEPINE001 KPDFCFLEEDPGICvGYfTRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDG 083V--F----------------------------------------CEPINE002 KPDFCFLEEDPGICvGffTRYFYNNQTKQCERFvYGGCLGNMNNFETLEECKNICEDG 084V-FF---------------V------------------------CEPINE003 KPDFCFLEEDPGICvGffTRYFYNaQTKQCERFvYGGCLGNMNNFETLEECKNICEDG 085V-FF-------A-------V------------------------CEPINE004 KPDFCFLEEDPGpCvGffqRYFYNaQTKQCERFvYGGCqGNMNNFETLEECKNICEDG 086P-V-FFQ------A-------V----Q-------------------CEPINE005 DFCFLEEDPGpCvGffTRYFYNNQTKQCERFvYGGCqGNMNNFETLEECKNICEDG 087P-V-FF---------------V----Q-------------------hLACI-D3 GPSWCLTPADRGLCRANENRFYYNSVIGKCRPFKYSGCGGNENNFTSKQECLRACKKG 075CEPINE010 GPSWCLTPADRGLCvANfNRFYYNSVIGKCRPFKYSGCGGNENNFTSKQECLRACKKG 088V--F----------------------------------------CEPINE011 GPSWCLTPADRGLCvAffNRFYYNSVIGKCRPFKYSGCGGNENNFkSKQECLRACKKG 089V-FF---------------------------K------------CEPINE012 GPSWCLTPAvRGpCvAffNRFYYNSVIGKCRPFvYgGCGGNENNFkSKQECLRACKKG 090V--P-V-FF---------------V-G---------K------------__________________________________________________________________________ TABLE 710__________________________________________________________________________Cumulative collection of allowed amino acids.__________________________________________________________________________RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE7 (SEQ ID NO: 1)RPDFCLEPPYTGPCvgffsRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE3 (SEQ ID NO: 22)RPDFCLEPPYTGPCvgffqRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE6 (SEQ ID NO: 23)RPDFCLEPPYTGPCvAifpRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE4 (SEQ ID NO: 24)RPDFCLEPPYTGPCvAffkRsFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE8 (SEQ ID NO: 25)RPDFCLEPPYTGPCiAffpRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE1 (SEQ ID NO: 26)RPDFCLEPPYTGPCiAffqRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE5 (SEQ ID NO: 28)RPDFCLEPPYTGPCiAlfkRYFYNAKAGLCQTFVYGGCmgngNNFKSAEDCMRTCGGA EpiNE2 (SEQ ID NO: 29)rpDfCQLGYSAGPCvaMfpRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA BITI-E7 (SEQ ID NO: 10)rpDfCQLGYStGPCvaMfpRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA BITI-E7-1222 (SEQ ID NO: 12)KEDfCQLGYSAGPCvaMfpRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA AMINO1 (SEQ ID NO: 15)KpDSCQLGYSAGPCvaMfpRYFYNGTSMACETFQYGGCMGNGNNFVTEKDCLQTCRGA AMINO2 (SEQ ID NO: 16)AACNLPIVRGPCiAFfprWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVP EPI-hNE-3 (SEQ ID NO: 19)EACNLPIVRGPCiAFfprWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVP EPI-hNE-4 (SEQ ID NO: 20)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFlYgGCkgkGNNFKSAEDCMRTCGGA EpiNE7.6 (SEQ ID NO: 36)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGCwakGNNFKSAEDCMRTCGGA EpiNE7.8 (SEQ ID NO: 37)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFgYaGCrakGNNFKSAEDCMRTCGGA EpiNE7.11 (SEQ ID NO: 38)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGChaeGNNFKSAEDCMRTCGGA EpiNE7.7 (SEQ ID NO: 39)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFlYgGCwaqGNNFKSAEDCMRTCGGA EpiNE7.4 (SEQ ID NO: 40)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFrYgGClaeGNNFKSAEDCMRTCGGA EpiNE7.5 (SEQ ID NO: 41)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFdYgGChadGNNFKSAEDCMRTCGGA EpiNE7.10 (SEQ ID NO: 42)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGClahGNNFKSAEDCMRTCGGA EpiNE7.1 (SEQ ID NO: 43)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGCwanGNNFKSAEDCMRTCGGA EpiNE7.16 (SEQ ID NO: 44)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFnYgGCegkGNNFKSAEDCMRTCGGA EpiNE7.19 (SEQ ID NO: 45)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFqYgGCegyGNNFKSAEDCMRTCGGA EpiNE7.12 (SEQ ID NO: 46)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFhYgGCwgqGNNFKSAEDCMRTCGGA EpiNE7.21 (SEQ ID NO: 48)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFhYgGCwgeGNNFKSAEDCMRTCGGA EpiNE7.22 (SEQ ID NO: 49)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwgkGNNFKSAEDCMRTCGGA EpiNE7.23 (SEQ ID NO: 50)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGChgnGNNFKSAEDCMRTCGGA EpiNE7.24 (SEQ ID NO: 51)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFpYgGCwakGNNFKlAEDCMRTCGGA EpiNE7.25 (SEQ ID NO: 52)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwghGNNFKSAEDCMRTCGGA EpiNE7.26 (SEQ ID NO: 53)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFnYgGCwgkGNNFKSAEDCMRTCGGA EpiNE7.27 (SEQ ID NO: 54)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGClghGNNFKSAEDCMRTCGGA EpiNE7.28 (SEQ ID NO: 55)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGClgyGNNFKSAEDCMRTCGGA EpiNE7.29 (SEQ ID NO: 56)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFkYgGCwaeGNNFKSAEDCMRTCGGA EpiNE7.30 (SEQ ID NO: 57)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFgYgGCwgeGNNFKSAEDCMRTCGGA EpiNE7.32 (SEQ ID NO: 58)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFeYgGCwanGNNFKSAEDCMRTCGGA EpiNE7.33 (SEQ ID NO: 59)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFvYgGChgdGNNFKSAEDCMRTCGGA EpiNE7.36 (SEQ ID NO: 60)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFmYgGCqgkGNNFKSAEDCMRTCGGA EpiNE7.37 (SEQ ID NO: 61)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFyYgGCwakGNNFKSAEDCMRTCGGA EpiNE7 38 (SEQ ID NO: 62)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFmYgGCwgdGNNFKSAEDCMRTCGGA EpiNE7.39 (SEQ ID NO: 63)RPDFCLEPPYTGPCvAmfpRYFYNAKAGLCQTFtYgGChgnGNNFKSAEDCMRTCGGA EpiNE7.40 (SEQ ID NO: 64) ##STR90## Cumulative (SEQ ID NO. 134) ##STR91## (SEQ ID NO.__________________________________________________________________________ 134) TABLE 711______________________________________Mutations that are likely to improve the affinity of aKunitz domain for hNE______________________________________X18F; Required[X15V, X15I];[X16A, X16G]; Important[X17F, X17L, X17I, X17L];[X19P, X190, X19K, X19S];X13P; Desirable and perhaps important[X34V, X34P, X34Q];[X39Q, X39M];[X32T, X32L];[X31Q, X31E, X31V];[X11T, X11A, X11R];[X10Y, X10S, X10V];[X40G, X40A];X36G;X37G;X12G.______________________________________ TABLE 720______________________________________M13.sub.-- III.sub.-- signal::Human.sub.-- LACI-D2::mature.sub.--M13.sub.-- IIIDNA has SEQ ID NO. 135, amino-acid sequence has SEQ ID NO. 136DNA is linear and in vivo it is double stranded.Amino-acid sequence is of a protein that is processed in vivo bycleavage after Ala.sub.-1 ; the entire gene encodes an amino-acidsequence that continues to give a functional M13 III protein.______________________________________ ##STR92## ##STR93## ##STR94## ##STR95## ##STR96## ##STR97## ##STR98## ##STR99##Ala.sub.101 is the first residue of mature M13 III.______________________________________ TABLE 725______________________________________Synthetic laci-d1 with sites for cloning into display vectorDNA has SEQ ID NO. 137, amino-acid sequence has SEQ ID NO.______________________________________138 ##STR100## ##STR101## ##STR102## ##STR103## ##STR104## ##STR105##Ala.sub.101 is the first residue of mature M13 III.______________________________________ TABLE 730______________________________________LACI-D1 hNE LibraryDNA has SEQ ID NO. 139, amino-acid sequence has SEQ ID NO.______________________________________140 ##STR106## ##STR107## ##STR108## ##STR109## ##STR110## ##STR111##Variegation at 10, 11, 13, 15, 16, 17, 19, and20 gives rise to 253,400 amino-acid sequences and589,824 DNA sequences.Variegation at 31, 32, 34, 39, 40, and42 gives 23,328 amino-acid and DNA sequences.There are about 5.9 .times. 10.sup.9 protein sequences and 1.4 .times.10.sup.10DNA sequences. Ala.sub.101 would be the first residue of mature M13______________________________________III. TABLE 735______________________________________LACI-D2 hNE LibraryDNA has SEQ ID NO. 141; amino-acid sequence has SEQ ID NO.______________________________________142 ##STR112## ##STR113## ##STR114## ##STR115## ##STR116## ##STR117##6.37 .times. 10.sup.10 amino acid sequences; 1.238 .times. 10.sup.11 DNAsequences______________________________________ TABLE 750______________________________________M13.sub.-- III.sub.-- signal::Human.sub.-- LACI-D3::mature.sub.--M13.sub.-- IIIDNA has SEQ ID NO. 143; amino-acid sequence has SEQ ID NO.______________________________________144. ##STR118## ##STR119## ##STR120## ##STR121## ##STR122## ##STR123## ##STR124##V26S to allow an XhoI site between the two loops to be varied.T46E to avoid glycosylation site.______________________________________ TABLE 760______________________________________Variegation of LACI-D3DNA has SEQ ID NO. 145; amino-acid sequence has SEQ ID NO.______________________________________146. ##STR125## ##STR126## ##STR127## ##STR128## ##STR129##______________________________________ TABLE 790______________________________________Amino acids allowed inhNE-inhibiting Kunitz domainsPosition Allowed amino acids______________________________________ 5 C10 YSVN11 TARQP12 G13 PAV14 C15 IV16 AG17 FILVM18 F19 PSQKR20 R21 YWF30 C31 QEV32 TLP33 F34 VQP35 Y36 G37 G38 C39 MQ40 GA41 N42 G43 N45 F51 C55 C______________________________________ TABLE 800__________________________________________________________________________Amino-acid sequnces of Kunitz domains__________________________________________________________________________1 rpdfClLPa-etGPCrAmIpRfYYNaksgkCepFiYGGCgGNa--NNFkTeeECrrtCgga (SEQ ID NO. 071) Consensus KuDom 93.09.28 (Upper case indicates majority of 72 naturally occurring Kunitz domains have this amino-acid type at this position).QDHPKFCYLPA-DPGRCKAHIPRFYYDSASNKCNKFIYGGCPGNA--NNFKTWDECRQTCGASA (SEQ ID NO. 091) P00991 Vipera ammodytes ammodytes (western sand viper) CTI toxin3RDRPKFCYLPA-DPGRCLAYMPRFYYNPASNKCEKFIYGGCRGNA--NNFKTWDECRHTCVASGIQPR (SEQ ID NO. 092) IVB3.sub.-- VIPAA, A#P00992 Vipera ammodytes ammodytes (western sand viper)4FCYLPD-DPGVCKAHIPRFYYNPASNKCKNFIYGGCGGNA--NNFETRAECRHTCVASGKGGPR (SEQ ID NO. 093) SP:IVBT.sub.-- ERIMA, A#P24541 Eristocophis macmahoni (leaf-nosed viper)5RPDFCELPA-ETGLCKAYIRSFHYNLAAQQCLQFIYGGCGGNA--NRFKTIDECRRTCVG------- (SEQ ID NO. 094) SP:IVB2.sub.-- HEMHA, A#P00985 Hemachatus haemachatus HHV II6HDRPTFCNLPP-ESGRCRGHIRRIYYNLESNKCKVFFYGGCGGNA--NNFETRDECRETCGGK------ (SEQ ID NO. 095) Vipera russelli (Russel's viper) RVV II (TAKA74)7KNRPTFCNLLP-ETGRCNALIPAFYYNSHLHKCQKFNYGGCGGNA--NNFKTIDECQRTCAAKYGRSS (SEQ ID NO. 096) P25660 Bungarus fasciatus VIII B toxin (banded krait)8INGDCELPK- VVGPCRARFPRYYYNSSSKRCEKFIYGGCGGNA--NNFHTLEECEKVCGVRSVGR-- (SEQ ID NO. 097) P10280 Anemonia sulcata (snake-locks sea anemone) 5 II9EVCSEQA-ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNR--NNFDTEEYCMAVCGSVMSQSLR (SEQ ID NO. 098) P29216 Macaca mulatta (rhesus macaque)10RPRFCELPA-ETGLCKARIRSFHYNRAAQQCLEFIYGGCGGNA--NRFKTIDECHRTCVG------- (SEQ ID NO. 099) P00986 Naja nivea (cape cobra) NNV II11 SVEEVVREVCSEQA-ETGPCRAMISRWYFDVTEGKCVPFFYGGCGGNR--NNFDTEEYCMAVCGSVSTQSL L (SEQ ID NO. 100) P12023 A4 protein homolog precursor12VVREVCSEQA-ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNR--NNFDTEEYCMAVCGSVMSQSLR (SEQ ID NO. 101) M58726 Macaca fascicularis myloid b-protein precursor KuDom13 SVEEVVREVCSEQA-ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNR--NNFDTEEYCMAVCGSA--- (SEQ ID NO. 073) P05067 PROTEASE NEXIN-II (PN-II) (APPI)14RNREVCSEQA-ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNR--NNFDTEEYCMAVCGSAI- (SEQ ID NO. 074) Schweitz et al. PNAS (1994) 91: 878-882., Shina &al ('90)15AAKYCKLPL-RIGPCKRKIPSFYYKWKAKQCLPFDYSGCGGNA--NRFKTIEECRRTCVG (SEQ ID NO. 102) P00981 Dendroaspis polylepis polylepis (black mamba) Kvenom16AAKYCKLPV-RYGPCKKKFPSFYYNWKAKQCLPFNYSGCGGNA--NRFKTIEECRRTCVG------- (SEQ ID NO. 103) Dendroaspis angusticeps (Eastern green mamba) C13 S1 C3 tox (DUFT85)17AAKYCKLPV-RYGPCKKKIPSFYYKWKAKQCLPFDYSGCGGNA--NRFKTIEECRRTCVG (SEQ ID NO. 104) P00982 Dendroaspis angusticeps (eastern green mamba) K toxin18RPDFCLEPP-YTGPCKARIIRYFYNAKAGLCQPFVYGGCRAKR--NNFKSSEDCMRTCGGA--- (SEQ ID NO. 105) Isoaprotinin 2 SIEK8819LQHRTFCKLPA-EPGPCKASIPAFYYNWAAKKCQLFHYGGCKGNA--NRFSTIEKCRHACVG (SEQ ID NO. 106) P00984 Dendroaspis polylepis polylepis (black mamba) E toxin20 SVEEVVREVCSEQA ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNR--NNFDTEEYCMAVCGSVSSQSL L (SEQ ID NO. 107) P08592 Amyloid A4 PROTEIN HOMOLOG PRECURSOR A4.sub.-- RAT21RPGFCELPA-AKGLCKAHKPAFYYNKDSHRCQKFIYGGCGGNA--NRFRTIDECNRTCVG------- (SEQ ID NO. 108) P20229 Naja naja (indian cobra)22HDRPTFCNLAP-ESGRCRGHLRRIYYNLESNKCKVFFYGGCGGNA--NNFETRDECRETCGGK (SEQ ID NO. 109) P00990 Vipera russelli siamensis (siamese Russell's viper)23RPDFCLEPP-YTGPCKARMIRYFYNAKAGLCQPFVYGGCRAKR--NNFKSAEDCMRTCGGA------ (SEQ ID NO. 110) Isoaprotinin G-2: SIEK88.24ZRPDFCLEPP-YTGPCKARMIRYFYNAKAGLCQPFVYGGCRAKS--NNFKSAEDCMRTCGGA------ (SEQ ID NO. 111) Isoaprotinin G-1 SIEK8825TERPDFCLEPP-YTGPCKAAMIRYFYNAKAGFCETFVYGGCRAKS--NNFKSAEDCMRTCGGA------ (SEQ ID NO. 112) P00975 bovine serum basic protease inhibitor26QGDKRDICRLPP-EQGPCKGRIPRYFYNPASRMCESFIYGGCKGNK--NNFKTKAECVRACRPPERPGV- (SEQ ID NO. 113) P00993 chelonianin, red sea turtle egg white protease inhib.27 QAKAQRPDFCLEPP-YTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKR--NNFKSAEDCMRTCGGAIGPWE N (SEQ ID NO. 114) P00974 BPTI28RPDFCLEPP-YTGPCKARIIRYFYNAKAGLCQTFVYGGCRAKR--NNFKSAEDCMRTCGGA------ (SEQ ID NO. 021) BPTI29 LFEFHGPSWCLTPA-DRGLCRANENRFYYNSVIGKCRPFKYSGCGGNE--NNFTSKQECLRACKKGFIQRI S (SEQ ID NO. 075) P10646 Human LACI Domain 3. gim.vertline.14667: 217..26730 QAKAQRPDFCLEPP-YTGPCKAKMIRYFYNAKAGFCETFVYGGCKAKS--NNFRSAEDCMRTCGGAIGPRE N (SEQ ID NO. 115) P04815 bovine spleen trypsin inhibitors, TI II (FIOR85)31QGRPSFCNLPA-ETGPCKASFRQYYYNSKSGGCQQFIYGGCRGNQ--NRFDTTQQCQGVCV------ (SEQ ID NO. 116) P00994 Helix pomatia (roman snail)32RPYACELIV-AAGPCMFFISAFYYSKGANKCYPFTYSGCRGNA--NRFKTIEECRRTCVV---- (SEQ ID NO. 117) P00983 Dendroaspis polylepis polylepis (black mamba) B toxin33QPRRKLCILHR-NPGRCYDKIPAFYYNQKKKQCERFDWSGCGGNS--NRFKTIEECRRTCIG------- (SEQ ID NO. 118) P00980 Dendroaspis angusticeps (eastern green mamba) C13 S2 C3 tox34QPRRKLCILHR-NPGRCYDKIPAFYYNQKKKQCEGFTWSGCGGNS--NRFKTIEECRRTCIG------- (SEQ ID NO. 119) Green Mamba I venom CREI87.35EVVREVCSEQA ETGPCRAMISRWYYDVTESKCAQFIYGGCGGNR--NNFESDDYCMAVCGSVIPAT-- (SEQ ID NO. 120) bbs122117 APP747=b-amyloid prec. prot. APP751 homolog [Xenopus,tadpoles] 281ff36QPLRKLCILHR-NPGRCYQKIPAFYYNQKKKQCZGFTWSGCGGNS--NRFKTIEECRRTCIRK-- (SEQ ID NO. 121) P00979 Dendroaspis polylepis polylepis (black mamba) venom I37wqppwyckepv-rigsckkqfssfyfkwtakkclpflfsgcggna--nrfqtigecrkkclgk-- (SEQ ID NO. 122) Calcicludine from D. angusticeps SCHW94.38FQTPPDLCQLPQ-ARGPCKAALLRYFYNSTSNACEPFTYGGCQGNN--NNFETTEMCLRICEPPQQTDKS (SEQ ID NO. 123) P00976 bovine colostrum trypsin inhib39 TEVTKKEDSCQLGY-SAGPCMGMTSRYFYNGTSMACETFQYGGCMGNG--NNFVTEKECLQTCRTVAA--- - (SEQ ID NO. 002) SP:HC.sub.-- HUMAN, A#P02760 ITI-K1 222-286 (HI-8e)40 TFQKGKPDFCFLEE-DPGICRGYITRYFYNNQSKQCERFKYGGCLGNL--NNFESLEECKNTCENPTSDFQ V (SEQ ID NO. 124) P19761 Oryctolagus cuniculus (rabbit) LACI Domain 2: 121..17141 RWAFHGPSWCLPPA-DRGLCQANEIRFFYNAIIGKCRPFKYSGCGGNE--NNFTSKKACITACKKGFIPKS I (SEQ ID NO. 125) P19761 Oryctolagus cuniculus (rabbit) LACI D3: 213..26342RTVAACNLPI-VRGPCRAFIQLWAFDAVKGKCVLFPYGGCQGNG--NKFYSEKECREYCGVPGDGDEE (SEQ ID NO. 003) SP:HC.sub.-- HUMAN, A#P02760 ITI-K2 (HI-8t) 282-34643VDKSACLQPK-EVGPCRKSDFVFFYNADTKACEEFLYGGCRGND--NRFNTKEECEKLCL (SEQ ID NO. 126) P26228 Sarcophaga bullata (flesh fly)44RTVQACNLPI-VRGPCRAGIELWAFDAVKGKCVRFIYGGCNGNG--NQFYSQKECKEYCGIPGEADEE (SEQ ID NO. 127) SP:IATR.sub.-- SHEEP, A#P13371 sheep ITI-K245KEDSCQLGY-SQGPCLGMFKRYFYNGTSMACETFYYGGCMGNG--NNFPSEKECLQTCRTVQA---- (SEQ ID NO. 128) SP:IATR.sub.-- SHEEP, A#P13371 sheep ITI-K146KEDSCQLGY-SQGPCLGMIKRYFYNGSSMACETFHYGGCMGNG--NNFVSQKECLQTCRTVSA---- (SEQ ID NO. 129) SP:IATR.sub.-- PIG, A#P04366 Pig ITI-K147 TLQQEKPDFCFLEE-DPGICRGYITRYFYNNQTKQCERFKYGGCLGNM--NNFETLEECKNICEDGPNGFQ V (SEQ ID NO.076) SP:LACI.sub.-- HUMAN, A#P10646 Domain 2. gim.vertline.l4667: 125..17548KEDSCELGY-SQGPCLGMIKRYFYNGSSMACETFHYGGCMGNG--NNFVSQKECLQTCR-------- (SEQ ID NO. 130) Porcine ITI domain 1, in CREI8749 PLQKPTHSFCAMKV-DDGPCRAYIKRFFFNILTHQCEEFIYGGCEGNE--NRFESLEECKEKCARDYPKMT T (SEQ ID NO. 131) P19761 Oryctolagus cuniculus (rabbit) LACI Domain 1: 50..10050KEDSCQLDH-AQGPCLGMISRYFYNGTSMACETFQYGGCLGNG--NNFASQKECLQTCRTVAA---- (SEQ ID NO. 132) P04365 Horse ITI-K1 (CREI87)51RTVAACNLPI-VQGPCRAFIRLWAFDAAQGKCVLFTYGGCRGNG--NKFYSQKECKEYCGIPGDGDEE (SEQ ID NO. 133) P04365 Horse ITI-K2 (CREI87)52IAACNLPI-VQGPCRAGAELLAFDAAQGKCIQFIYGGCKGNN--NKFYSEPKCKWYCGVPGDGY-- (SEQ ID NO. 147) Trypstatin [KITO88]53IAACNLPI-VQGPCRAFAELLAFDAAQGKCIQFIYGGCKGNN--NKFYSEPKCKWYCGVPGDGY-- (SEQ ID NO. 148) P19603 Rattus norvegicus [rat]54RTVSACSLPI-VQGPCRAFIRLWAFDAAQGKCVLFNYGGCQGNG--NKFYSQKECKEYCGVPGEEDEE (SEQ ID NO. 149) SP:IATR PIG, A#P04366 Pig ITI-K2 [CREI87]55TERGFLDCTSPP-VTGPCRAGFKRYNYNTRTKQCEPFKYGGCKGNG--NRYKSEQDCLDACSGF------ (SEQ ID NO. 150) P16044 Tachypleus tridentatus [Japanese horseshoe crab, NAKA87]56 PPLKLMHSFCAFKA-DDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQ--NRFESLEECKKMCTRDNANRI I (SEQ ID NO. 077) SP:LACI.sub.-- HUMAN, A#P10646 Domain 1. gim.vertline.14667: 54..10457GSICLEPK- VVGPCTAYFPRFYFDSETGKCTPFIYGGCEGNS--YVDEKLHACRAICRA--- (SEQ ID NO. 151) P16344 Radianthus macrodactylus [sea anemone]58RTVEACNLPI-VQGPCRAFIQLWAFDAVKGKCVRFSYGGCKGNG--NKFYSQKECKEYCGIPGEADER (SEQ ID NO. 152) P00978 bovine [BI-8t]ITI-K259KADSCQLDY-SQGPCLGLFKRYFYNGTSMACETFLYGGCMGNL--NNFLSQKECLQTCRTVEA---- (SEQ ID NO. 153) P00978 bovine ITI-K1 [BI-8e]60DKPTTKPICEQAFGNSGPCFAYIKLYSYNQKTKKCEEFIYGGCKGND--NRFDTLAECEQKCIK--- (SEQ ID NO. 154) P10832 Bombyx mori chymotrypsin inhibitor sci-ii.61DKPTTKPICEQAFGNSGPCFAYIKLYSYNQKTKKCEEFIYGGCQGND--NRFITLAECEQKCIK------- (SEQ ID NO. 155) P10831 Bombyx mori (silk moth)62RPRFCELAP-SAGSCFGFVSSYYYNRYSNTCHSFTYSGCGKNA--NRFRTIDECNRTCVV---- (SEQ ID NO. 156) P19859 Naja naja (indian cobra)63DLLPNVCAFPM-EKGPCQTYMTRWFFNFETGECELFAYGGCGGNS--NNFLRKEKCEKFCKFT-- (SEQ ID NO. 078) Novo Nordisk HKI B9 domain64 EGPENVMDICLLQK-EEGTCRDFVLKWHYDLKTKSCARFWYGGCGGNE--NRFNTQKECEKACSPGNISPG V (SEQ ID NO. 157) P15989 Chicken C-term Kunitz domain of Collagen VI65ETDICKLPK-DEGTCRDFILKWYYDPNTKSCARFWYGGCGGNE--NKFGSQKECEKVCAPV------ (SEQ ID NO. 079) Human collagen a3 Kunitz domain66RQRHRDCDKPP-DKGNC-GPVRAFYYDTRLKTCKAFQYRGCDGDH--GNFKTETLCRCECLVYP----- (SEQ ID NO. 158) P00987 Bungarus multicinctus [many-banded krait]bungaro toxin B167 DEPTTDLPICEQAFGDAGLCFGYMKLYSYNQETKNCEEFIYGGCQGND--NRFSTLAECEQKCIN--- (SEQ ID NO. 159) P07481 Bombyx mori chymotrypsin inhibitor SCI-III. [SASA84]68RKRHPDCDKPP-DTKIC-QTVRAFYYKPSAKRCVQFRYGGCDGDH--GNFKSDHLCRCECELYR-- (SEQ ID NO. 160) P00989 Bungarus multicinctus [many-banded krait]69RQRHRDCDKPP-DKGNC-GPVRAFYYDTRLKTCKAFQYRGCDGDH--GNFKSDHLCRCECELY------ (SEQ ID NO. 161) P00988 Bungarus multicinctus (many-banded krait) bungaro toxin B270 KNPECGEPHSLDGSPNGISCRGYFPSWSYNPDAQQCVSFVYGGCGGNN--NRFGSQNECEERCI------- - (SEQ ID NO. 162) Drosophila funebris male accessory gland protease inhib P1142471 EPTGNNAEICLLPL-DYGPCRALLLRYYYDRYTQSCRQFLYGGCEGNA--NNFYTWEACDDACWRIEKV-- - (SEQ ID NO. 080) TFPI-2 DOMAIN 1, Specher et al, PNAS 91:3353-3357 (1994)72EKVPKVCRLQVSVDDQCEGSTEKYFFNLSSMTCEKFFSGGCHRNRIENRFPDEATCMGFCAPKKI- (SEQ ID NO. 081) tfpi-2 DOMAIN 2, Specher et al, PNAS 91:3353-3357 (1994)73PKKIPSFCYSPK-DEGLCSANVTRYYFNPRYRTCDAFTYTGCGGND--NNFVSREDCKRACAKALKKKKK (SEQ ID NO. 082) TFPI-2 DOMAIN 3, SPECHER ET AL. PNAS 91:3353-3357 (1994)Non-naturally-occurring Kunitz domains:RPDFCLEPP-YTGPCIAFFPRYFYNAKAGLCQTFVYGGCMGNG--NNFKSAEDCMRTCGGA (SEQ ID NO. 026)EPI-hNE-1EAEARPDFCLEPP-YTGPCIAFFPRYFYNAKAGLCQTFVYGGCMGNG--NNFKSAEDCMRTCGGA (SEQ ID NO. 027)EPI-hNE-2AACNLPIVRGPCIAFFPRWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVP (SEQ ID NO. 019)EPI-hNE-3EACNLPIVRGPCIAFFPRWAFDAVKGKCVLFPYGGCQGNGNKFYSEKECREYCGVP (SEQ ID NO. 020)EPI-hNE-4__________________________________________________________________________ TABLE 810__________________________________________________________________________Frequency of amino-acid types at the positions in BPTI-homologous Kunitzdomains and identification of residues in five surface groupsRes. DifferentId. AAs Contents 1 2 3 4 5__________________________________________________________________________1 15 R23 K9 T8 V7 -5 G4 A3 N2 P2 H2 I2 D2 L2 E M 52 15 P28 R11 E6 A5 H5 V5 K3 I2 -2 N G F T L M s 53 15 D21 E9 K9 S9 P5 R4 A4 T4 G2 N L Q W Y - 4 s4 10 F25 A9 V9 I8 S6 D5 L4 Y4 W2 H s 55 2 C72 S x x6 13 L15 E10 N10 S8 Q6 K6 Y4 D3 A3 I3 F2 R2 T 47 10 L42 E16 Q4 K3 F2 S2 P D M T s 48 10 P43 Q9 A5 G5 H3 K2 D2 E2 I L 3 49 15 A18 P16 I7 K6 V6 Y5 F3 R3 E2 L2 Q D S M H s 3 49a 4 -68 G3 S P s s 3 410 8 E19 D16 V11 Y7 N6 S6 R4 A4 s s 411 13 T21 Q11 P9 R5 A4 S4 K4 D3 E3 V3 Y3 I2 G 1 s 3 412 4 G70 D I K x x x13 9 P46 R8 L7 I3 S3 N2 T2 Q V 1 s 4 s14 1 C73 1 s s 515 12 R28 K21 L6 F4 Y3 -3 Q2 M2 S T E N A s 3 4 s16 8 A43 G17 D4 K4 Q2 F R T 1 s s s 517 15 M13 Y11 F9 R8 K7 H5 S4 L3 G3 N3 P2 A2 Q T I 1 2 3 s18 10 I39 F9 M8 V6 L3 E2 T2 A2 D K 1 s s 519 11 P17 S12 R10 K10 I8 L4 E4 T4 Q2 N F 1 2 3 s20 7 R40 L10 A10 S8 K3 Q V s s s 521 5 Y27 F26 W16 I2 L2 2 s s s22 6 Y35 F23 A7 S4 H3 N s 3 423 2 Y53 F20 s s24 4 N47 D21 K4 S s 325 14 A17 P7 S7 V7 G6 Q6 L5 W5 R3 T3 I2 N2 K2 F s s26 16 K18 T13 A11 S5 E5 R4 V4 D3 Q2 Y2 G H I F L N s 3 427 9 S20 A17 T13 E7 K6 Q4 L3 I2 Y 2 3 428 8 G26 K21 N8 M7 Q4 H3 R3 S 2 s s29 12 K29 Q14 A8 L5 T5 S3 R3 F2 E G M N 2 330 1 C73 x x x31 14 E26 Q9 A8 V8 L6 K5 R3 I2 H D T N Y Z 2 3 432 12 P20 T10 Q7 R7 E7 K6 L5 S3 A3 G2 V2 N 2 3 s33 1 F73 x x x x34 16 I20 F9 V8 T7 K5 L4 Q4 H3 D3 N3 W2 S P A R Y 1 2 3 x35 4 Y68 W3 F S s s s 536 4 G59 S11 R2 T 137 1 G73 x x38 1 C73 x x x39 11 G31 R11 K8 Q5 M5 E4 L3 D3 P H N 1 4 s40 4 G64 A7 K R s s 541 3 N63 K7 D3 4 s42 12 A19 R12 G11 S8 E5 D5 N4 H3 L2 Q2 K M s 542a 2 -72 I 542b 2 -72 E 543 3 N69 G3 Y s44 5 N40 R24 K7 Q V s45 3 F71 D Y s46 16 K24 E10 D8 Y8 V4 R3 P2 G2 S2 T2 L2 N2 I A Q H 547 5 T39 S31 R D K s 548 11 E15 I14 Q11 L9 A6 K5 R4 D3 W3 T2 S 2 s s49 10 E32 K14 D10 A6 H3 Q3 P2 G N T 2 s50 9 E44 D9 Y7 K4 L3 A3 Q T M s 551 1 C73 x x52 11 R21 M15 K11 E9 L9 Q2 N2 D H I V 2 s53 12 R24 Q10 E9 A8 K7 H3 C3 N2 D2 G2 W2 T s 554 11 T32 V10 A8 Y7 K5 E3 I3 F2 L M R 555 1 C73 x56 11 G26 V12 R8 I7 A5 E5 K3 L3 S2 T W57 14 G21 V8 S7 P5 A5 T5 K5 R4 -4 I3 L2 N2 F D58 13 -20 V1 A10 P10 K6 G4 Y3 S3 D2 T I R F__________________________________________________________________________ s indicates secondary set x indicates in or close to surface but buried and/or highly conserved.

CITATIONS

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Kueppers, "Alpha-1 Antitrypsin Production by in vivo Stimulated Blood Monocytes" __________________________________________________________________________SEQUENCE LISTING(1) GENERAL INFORMATION:(iii) NUMBER OF SEQUENCES: 234(2) INFORMATION FOR SEQ ID NO:1:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:2:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:LysGluAspSerCysGlnLeuGlyTyrSerAlaGlyProCysMetGly151015MetThrSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgThrVal5055(2) INFORMATION FOR SEQ ID NO:3:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:ThrValAlaAlaCysAsnLeuProIleValArgGlyProCysArgAla151015PheIleGlnLeuTrpAlaPheAspAlaValLysGlyLysCysValLeu202530PheProTyrGlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSerGlu354045LysGluCysArgGluTyrCysGlyValPro5055(2) INFORMATION FOR SEQ ID NO:4:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:1449 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:GTGAAAAAATTATTATTCGCAATTCCTTTAGTTGTTCCTTTCTATTCTGG50CGCCCGTCCGGATTTCTGTCTCGAGCCACCATACACTGGGCCCTGCAAAG100CGCGCATCATCCGCTATTTCTACAATGCTAAAGCAGGCCTGTGCCAGACC150TTTGTATACGGTGGTTGCCGTGCTAAGCGTAACAACTTTAAATCGGCCGA200AGATTGCATGCGTACCTGCGGTGGCGCCGCTGAAACTGTTGAAAGTTGTT250TAGCAAAACCCCATACAGAAAATTCATTTACTAACGTCTGGAAAGACGAC300AAAACTTTAGATCGTTACGCTAACTATGAGGGTTGTCTGTGGAATGCTAC350AGGCGTTGTAGTTTGTACTGGTGACGAAACTCAGTGTTACGGTACATGGG400TTCCTATTGGGCTTGCTATCCCTGAAAATGAGGGTGGTGGCTCTGAGGGT450GGCGGTTCTGAGGGTGGCGGTTCTGAGGGTGGCGGTACTAAACCTCCTGA500GTACGGTGATACACCTATTCCGGGCTATACTTATATCAACCCTCTCGACG550GCACTTATCCGCCTGGTACTGAGCAAAACCCCGCTAATCCTAATCCTTCT600CTTGAGGAGTCTCAGCCTCTTAATACTTTCATGTTTCAGAATAATAGGTT650CCGAAATAGGCAGGGGGCATTAACTGTTTATACGGGCACTGTTACTCAAG700GCACTGACCCCGTTAAAACTTATTACCAGTACACTCCTGTATCATCAAAA750GCCATGTATGACGCTTACTGGAACGGTAAATTCAGAGACTGCGCTTTCCA800TTCTGGCTTTAATGAGGATCCATTCGTTTGTGAATATCAAGGCCAATCGT850CTGACCTGCCTCAACCTCCTGTCAATGCTGGCGGCGGCTCTGGTGGTGGT900TCTGGTGGCGGCTCTGAGGGTGGTGGCTCTGAGGGTGGCGGTTCTGAGGG950TGGCGGCTCTGAGGGAGGCGGTTCCGGTGGTGGCTCTGGTTCCGGTGATT1000TTGATTATGAAAAGATGGCAAACGCTAATAAGGGGGCTATGACCGAAAAT1050GCCGATGAAAACGCGCTACAGTCTGACGCTAAAGGCAAACTTGATTCTGT1100CGCTACTGATTACGGTGCTGCTATCGATGGTTTCATTGGTGACGTTTCCG1150GCCTTGCTAATGGTAATGGTGCTACTGGTGATTTTGCTGGCTCTAATTCC1200CAAATGGCTCAAGTCGGTGACGGTGATAATTCACCTTTAATGAATAATTT1250CCGTCAATATTTACCTTCCCTCCCTCAATCGGTTGAATGTCGCCCTTTTG1300TCTTTAGCGCTGGTAAACCATATGAATTTTCTATTGATTGTGACAAAATA1350AACTTATTCCGTGGTGTCTTTGCGTTTCTTTTATATGTTGCCACCTTTAT1400GTATGTATTTTCTACGTTTGCTAACATACTGCGTAATAAGGAGTCTTAA1449(2) INFORMATION FOR SEQ ID NO:5:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:482 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:MetLysLysLeuLeuPheAlaIleProLeuValValProPheTyrSer151015GlyAlaArgProAspPheCysLeuGluProProTyrThrGlyProCys202530LysAlaArgIleIleArgTyrPheTyrAsnAlaLysAlaGlyLeuCys354045GlnThrPheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLys505560SerAlaGluAspCysMetArgThrCysGlyGlyAlaAlaGluThrVal65707580GluSerCysLeuAlaLysProHisThrGluAsnSerPheThrAsnVal859095TrpLysAspAspLysThrLeuAspArgTyrAlaAsnTyrGluGlyCys100105110LeuTrpAsnAlaThrGlyValValValCysThrGlyAspGluThrGln115120125CysTyrGlyThrTrpValProIleGlyLeuAlaIleProGluAsnGlu130135140GlyGlyGlySerGluGlyGlyGlySerGluGlyGlyGlySerGluGly145150155160GlyGlyThrLysProProGluTyrGlyAspThrProIleProGlyTyr165170175ThrTyrIleAsnProLeuAspGlyThrTyrProProGlyThrGluGln180185190AsnProAlaAsnProAsnProSerLeuGluGluSerGlnProLeuAsn195200205ThrPheMetPheGlnAsnAsnArgPheArgAsnArgGlnGlyAlaLeu210215220ThrValTyrThrGlyThrValThrGlnGlyThrAspProValLysThr225230235240TyrTyrGlnTyrThrProValSerSerLysAlaMetTyrAspAlaTyr245250255TrpAsnGlyLysPheArgAspCysAlaPheHisSerGlyPheAsnGlu260265270AspProPheValCysGluTyrGlnGlyGlnSerSerAspLeuProGln275280285ProProValAsnAlaGlyGlyGlySerGlyGlyGlySerGlyGlyGly290295300SerGluGlyGlyGlySerGluGlyGlyGlySerGluGlyGlyGlySer305310315320GluGlyGlyGlySerGlyGlyGlySerGlySerGlyAspPheAspTyr325330335GluLysMetAlaAsnAlaAsnLysGlyAlaMetThrGluAsnAlaAsp340345350GluAsnAlaLeuGlnSerAspAlaLysGlyLysLeuAspSerValAla355360365ThrAspTyrGlyAlaAlaIleAspGlyPheIleGlyAspValSerGly370375380LeuAlaAsnGlyAsnGlyAlaThrGlyAspPheAlaGlySerAsnSer385390395400GlnMetAlaGlnValGlyAspGlyAspAsnSerProLeuMetAsnAsn405410415PheArgGlnTyrLeuProSerLeuProGlnSerValGluCysArgPro420425430PheValPheSerAlaGlyLysProTyrGluPheSerIleAspCysAsp435440445LysIleAsnLeuPheArgGlyValPheAlaPheLeuLeuTyrValAla450455460ThrPheMetTyrValPheSerThrPheAlaAsnIleLeuArgAsnLys465470475480GluSer(2) INFORMATION FOR SEQ ID NO:6:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:1455 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:GTGAAAAAATTATTATTCGCAATTCCTTTAGTTGTTCCTTTCTATTCTGG50CGCCAAAGAAGACTCTTGCCAGCTGGGCTACTCGGCCGGTCCCTGCATGG100GAATGACCAGCAGGTATTTCTATAATGGTACATCCATGGCCTGTGAGACT150TTCCAGTACGGCGGCTGCATGGGCAACGGTAACAACTTCGTCACAGAAAA200GGAGTGTCTGCAGACCTGCCGAACTGTGGGCGCCGCTGAAACTGTTGAAA250GTTGTTTAGCAAAACCCCATACAGAAAATTCATTTACTAACGTCTGGAAA300GACGACAAAACTTTAGATCGTTACGCTAACTATGAGGGTTGTCTGTGGAA350TGCTACAGGCGTTGTAGTTTGTACTGGTGACGAAACTCAGTGTTACGGTA400CATGGGTTCCTATTGGGCTTGCTATCCCTGAAAATGAGGGTGGTGGCTCT450GAGGGTGGCGGTTCTGAGGGTGGCGGTTCTGAGGGTGGCGGTACTAAACC500TCCTGAGTACGGTGATACACCTATTCCGGGCTATACTTATATCAACCCTC550TCGACGGCACTTATCCGCCTGGTACTGAGCAAAACCCCGCTAATCCTAAT600CCTTCTCTTGAGGAGTCTCAGCCTCTTAATACTTTCATGTTTCAGAATAA650TAGGTTCCGAAATAGGCAGGGGGCATTAACTGTTTATACGGGCACTGTTA700CTCAAGGCACTGACCCCGTTAAAACTTATTACCAGTACACTCCTGTATCA750TCAAAAGCCATGTATGACGCTTACTGGAACGGTAAATTCAGAGACTGCGC800TTTCCATTCTGGCTTTAATGAGGATCCATTCGTTTGTGAATATCAAGGCC850AATCGTCTGACCTGCCTCAACCTCCTGTCAATGCTGGCGGCGGCTCTGGT900GGTGGTTCTGGTGGCGGCTCTGAGGGTGGTGGCTCTGAGGGTGGCGGTTC950TGAGGGTGGCGGCTCTGAGGGAGGCGGTTCCGGTGGTGGCTCTGGTTCCG1000GTGATTTTGATTATGAAAAGATGGCAAACGCTAATAAGGGGGCTATGACC1050GAAAATGCCGATGAAAACGCGCTACAGTCTGACGCTAAAGGCAAACTTGA1100TTCTGTCGCTACTGATTACGGTGCTGCTATCGATGGTTTCATTGGTGACG1150TTTCCGGCCTTGCTAATGGTAATGGTGCTACTGGTGATTTTGCTGGCTCT1200AATTCCCAAATGGCTCAAGTCGGTGACGGTGATAATTCACCTTTAATGAA1250TAATTTCCGTCAATATTTACCTTCCCTCCCTCAATCGGTTGAATGTCGCC1300CTTTTGTCTTTAGCGCTGGTAAACCATATGAATTTTCTATTGATTGTGAC1350AAAATAAACTTATTCCGTGGTGTCTTTGCGTTTCTTTTATATGTTGCCAC1400CTTTATGTATGTATTTTCTACGTTTGCTAACATACTGCGTAATAAGGAGT1450CTTAA1455(2) INFORMATION FOR SEQ ID NO:7:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:484 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:MetLysLysLeuLeuPheAlaIleProLeuValValProPheTyrSer151015GlyAlaLysGluAspSerCysGlnLeuGlyTyrSerAlaGlyProCys202530MetGlyMetThrSerArgTyrPheTyrAsnGlyThrSerMetAlaCys354045GluThrPheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheVal505560ThrGluLysGluCysLeuGlnThrCysArgThrValGlyAlaAlaGlu65707580ThrValGluSerCysLeuAlaLysProHisThrGluAsnSerPheThr859095AsnValTrpLysAspAspLysThrLeuAspArgTyrAlaAsnTyrGlu100105110GlyCysLeuTrpAsnAlaThrGlyValValValCysThrGlyAspGlu115120125ThrGlnCysTyrGlyThrTrpValProIleGlyLeuAlaIleProGlu130135140AsnGluGlyGlyGlySerGluGlyGlyGlySerGluGlyGlyGlySer145150155160GluGlyGlyGlyThrLysProProGluTyrGlyAspThrProIlePro165170175GlyTyrThrTyrIleAsnProLeuAspGlyThrTyrProProGlyThr180185190GluGlnAsnProAlaAsnProAsnProSerLeuGluGluSerGlnPro195200205LeuAsnThrPheMetPheGlnAsnAsnArgPheArgAsnArgGlnGly210215220AlaLeuThrValTyrThrGlyThrValThrGlnGlyThrAspProVal225230235240LysThrTyrTyrGlnTyrThrProValSerSerLysAlaMetTyrAsp245250255AlaTyrTrpAsnGlyLysPheArgAspCysAlaPheHisSerGlyPhe260265270AsnGluAspProPheValCysGluTyrGlnGlyGlnSerSerAspLeu275280285ProGlnProProValAsnAlaGlyGlyGlySerGlyGlyGlySerGly290295300GlyGlySerGluGlyGlyGlySerGluGlyGlyGlySerGluGlyGly305310315320GlySerGluGlyGlyGlySerGlyGlyGlySerGlySerGlyAspPhe325330335AspTyrGluLysMetAlaAsnAlaAsnLysGlyAlaMetThrGluAsn340345350AlaAspGluAsnAlaLeuGlnSerAspAlaLysGlyLysLeuAspSer355360365ValAlaThrAspTyrGlyAlaAlaIleAspGlyPheIleGlyAspVal370375380SerGlyLeuAlaAsnGlyAsnGlyAlaThrGlyAspPheAlaGlySer385390395400AsnSerGlnMetAlaGlnValGlyAspGlyAspAsnSerProLeuMet405410415AsnAsnPheArgGlnTyrLeuProSerLeuProGlnSerValGluCys420425430ArgProPheValPheSerAlaGlyLysProTyrGluPheSerIleAsp435440445CysAspLysIleAsnLeuPheArgGlyValPheAlaPheLeuLeuTyr450455460ValAlaThrPheMetTyrValPheSerThrPheAlaAsnIleLeuArg465470475480AsnLysGluSer(2) INFORMATION FOR SEQ ID NO:8:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:LysGluAspSerCysGlnLeuGlyTyrSerAlaGlyProCysMetGly151015MetThrSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:9:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:LysGluAspSerCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:10:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:11:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:12:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:ArgProAspPheCysGlnLeuGlyTyrSerThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:13:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValGly151015MetPheSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:14:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysIleGly151015MetPheSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:15:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:LysGluAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:16:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:LysProAspSerCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:17:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:18:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysValAla151015MetPheProArgTyrPheTyrAsnGlyAlaSerMetAlaCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:19:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:56 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:AlaAlaCysAsnLeuProIleValArgGlyProCysIleAlaPhePhe151015ProArgTrpAlaPheAspAlaValLysGlyLysCysValLeuPhePro202530TyrGlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSerGluLysGlu354045CysArgGluTyrCysGlyValPro5055(2) INFORMATION FOR SEQ ID NO:20:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:56 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:GluAlaCysAsnLeuProIleValArgGlyProCysIleAlaPhePhe151015ProArgTrpAlaPheAspAlaValLysGlyLysCysValLeuPhePro202530TyrGlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSerGluLysGlu354045CysArgGluTyrCysGlyValPro5055(2) INFORMATION FOR SEQ ID NO:21:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:ArgProAspPheCysLeuGluProProTyrThrGlyProCysLysAla151015ArgIleIleArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:22:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValGly151015PhePheSerArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:23:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValGly151015PhePheGlnArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:24:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015IlePheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:25:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015PhePheLysArgSerPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:26:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:ArgProAspPheCysLeuGluProProTyrThrGlyProCysIleAla151015PhePheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:27:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:GluAlaGluAlaArgProAspPheCysLeuGluProProTyrThrGly151015ProCysIleAlaPhePheProArgTyrPheTyrAsnAlaLysAlaGly202530LeuCysGlnThrPheValTyrGlyGlyCysMetGlyAsnGlyAsnAsn354045PheLysSerAlaGluAspCysMetArgThrCysGlyGlyAla505560(2) INFORMATION FOR SEQ ID NO:28:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:ArgProAspPheCysLeuGluProProTyrThrGlyProCysIleAla151015PhePheGlnArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:29:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:ArgProAspPheCysLeuGluProProTyrThrGlyProCysIleAla151015LeuPheLysArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:30:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:ArgProAspPheCysGlnLeuGlyTyrSerAlaGlyProCysMetGly151015MetThrSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValThrGlu354045LysAspCysLeuGlnThrCysArgGlyAla5055(2) INFORMATION FOR SEQ ID NO:31:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:ArgProAspPheCysLeuGluProProTyrThrGlyProCysMetGly151015PheSerLysArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:32:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:ArgProAspPheCysLeuGluProProTyrThrGlyProCysMetAla151015LeuPheLysArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:33:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:ArgProAspPheCysLeuGluProProAsnThrGlyProCysPheAla151015IleThrProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:34:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:ArgProAspPheCysLeuGluProProTyrThrGlyProCysMetAla151015LeuPheGlnArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:35:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:ArgProAspPheCysLeuGluProProTyrThrGlyProCysMetAla151015IleSerProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:36:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLeuTyrGlyGlyCysLysGlyLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:37:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGluTyrGlyGlyCysTrpAlaLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:38:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGlyTyrAlaGlyCysArgAlaLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:39:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGluTyrGlyGlyCysHisAlaGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:40:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLeuTyrGlyGlyCysTrpAlaGlnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:41:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheArgTyrGlyGlyCysLeuAlaGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:42:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheAspTyrGlyGlyCysHisAlaAspGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:43:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLysTyrGlyGlyCysLeuAlaHisGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:44:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheThrTyrGlyGlyCysTrpAlaAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:45:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheAsnTyrGlyGlyCysGluGlyLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:46:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGlnTyrGlyGlyCysGluGlyTyrGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:47:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGlnTyrGlyGlyCysLeuGlyGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:48:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheHisTyrGlyGlyCysTrpGlyGlnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:49:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheHisTyrGlyGlyCysTrpGlyGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:50:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLysTyrGlyGlyCysTrpGlyLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:51:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLysTyrGlyGlyCysHisGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:52:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheProTyrGlyGlyCysTrpAlaLysGlyAsnAsnPheLysLeuAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:53:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLysTyrGlyGlyCysTrpGlyHisGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:54:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheAsnTyrGlyGlyCysTrpGlyLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:55:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheThrTyrGlyGlyCysLeuGlyHisGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:56:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheThrTyrGlyGlyCysLeuGlyTyrGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:57:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheLysTyrGlyGlyCysTrpAlaGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:58:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGlyTyrGlyGlyCysTrpGlyGluGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:59:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheGluTyrGlyGlyCysTrpAlaAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:60:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheValTyrGlyGlyCysHisGlyAspGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:61:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheMetTyrGlyGlyCysGlnGlyLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:62:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheTyrTyrGlyGlyCysTrpAlaLysGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:63:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheMetTyrGlyGlyCysTrpGlyAspGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:64:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:ArgProAspPheCysLeuGluProProTyrThrGlyProCysValAla151015MetPheProArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnThr202530PheThrTyrGlyGlyCysHisGlyAsnGlyAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:65:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:8157 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: CIRCULAR(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION: DNA plasmid(xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:AGATCGCGGCCGCGATCTAACATCCAAAGACGAAAGGTTGAATGAAACCT50TTTTGCCATCCGACATCCACAGGTCCATTCTCACACATAAGTGCCAAACG100CAACAGGAGGGGATACACTAGCAGCAGACCGTTGCAAACGCAGGACCTCC150ACTCCTCTTCTCCTCAACACCCACTTTTGCCATCGAAAAACCAGCCCAGT200TATTGGGCTTGATTGGAGCTCGCTCATTCCAATTCCTTCTATTAGGCTAC250TAACACCATGACTTTATTAGCCTGTCTATCCTGGCCCCCCTGGCGAGGTC300ATGTTTGTTTATTTCCGAATGCAACAAGCTCCGCATTACACCCGAACATC350ACTCCAGATGAGGGCTTTCTGAGTGTGGGGTCAAATAGTTTCATGTTCCC400AAATGGCCCAAAACTGACAGTTTAAACGCTGTCTTGGAACCTAATATGAC450AAAAGCGTGATCTCATCCAAGATGAACTAAGTTTGGTTCGTTGAAATGCT500AACGGCCAGTTGGTCAAAAAGAAACTTCCAAAAGTCGCCATACCGTTTGT550CTTGTTTGGTATTGATTGACGAATGCTCAAAAATAATCTCATTAATGCTT600AGCGCAGTCTCTCTATCGCTTCTGAACCCGGTGGCACCTGTGCCGAAACG650CAAATGGGGAAACAACCCGCTTTTTGGATGATTATGCATTGTCCTCCACA700TTGTATGCTTCCAAGATTCTGGTGGGAATACTGCTGATAGCCTAACGTTC750ATGATCAAAATTTAACTGTTCTAACCCCTACTTGACAGGCAATATATAAA800CAGAAGGAAGCTGCCCTGTCTTAAACCTTTTTTTTTATCATCATTATTAG850CTTACTTTCATAATTGCGACTGGTTCCAATTGACAAGCTTTTGATTTTAA900CGACTTTTAACGACAACTTGAGAAGATCAAAAAACAACTAATTATTCGAA950ACGAGGAATTCGCCTTAGACATGACTGTTCCTCAGTTCAAGTTGGGCATT1000ACGAGAAGACCGGTCTTGCTAGATTCTAATCAAGAGGATGTCAGAATGCC1050ATTTGCCTGAGAGATGCAGGCTTCATTTTTGATACTTTTTTATTTGTAAC1100CTATATAGTATAGGATTTTTTTTGTCATTTTGTTTCTTCTCGTACGAGCT1150TGCTCCTGATCAGCCTATCTCGCAGCTGATGAATATCTTGTGGTAGGGGT1200TTGGGAAAATCATTCGAGTTTGATGTTTTTCTTGGTATTTCCCACTCCTC1250TTCAGAGTACAGAAGATTAAGTGAGAAGTTCGTTTGTGCAAGCTTATCGA1300TAAGCTTTAATGCGGTAGTTTATCACAGTTAAATTGCTAACGCAGTCAGG1350CACCGTGTATGAAATCTAACAATGCGCTCATCGTCATCCTCGGCACCGTC1400ACCCTGGATGCTGTAGGCATAGGCTTGGTTATGCCGGTACTGCCGGGCCT1450CTTGCGGGATATCGTCCATTCCGACAGCATCGCCAGTCACTATGGCGTGC1500TGCTAGCGCTATATGCGTTGATGCAATTTCTATGCGCACCCGTTCTCGGA1550GCACTGTCCGACCGCTTTGGCCGCCGCCCAGTCCTGCTCGCTTCGCTACT1600TGGAGCCACTATCGACTACGCGATCATGGCGACCACACCCGTCCTGTGGA1650TCTATCGAATCTAAATGTAAGTTAAAATCTCTAAATAATTAAATAAGTCC1700CAGTTTCTCCATACGAACCTTAACAGCATTGCGGTGAGCATCTAGACCTT1750CAACAGCAGCCAGATCCATCACTGCTTGGCCAATATGTTTCAGTCCCTCA1800GGAGTTACGTCTTGTGAAGTGATGAACTTCTGGAAGGTTGCAGTGTTAAC1850TCCGCTGTATTGACGGGCATATCCGTACGTTGGCAAAGTGTGGTTGGTAC1900CGGAGGAGTAATCTCCACAACTCTCTGGAGAGTAGGCACCAACAAACACA1950GATCCAGCGTGTTGTACTTGATCAACATAAGAAGAAGCATTCTCGATTTG2000CAGGATCAAGTGTTCAGGAGCGTACTGATTGGACATTTCCAAAGCCTGCT2050CGTAGGTTGCAACCGATAGGGTTGTAGAGTGTGCAATACACTTGCGTACA2100ATTTCAACCCTTGGCAACTGCACAGCTTGGTTGTGAACAGCATCTTCAAT2150TCTGGCAAGCTCCTTGTCTGTCATATCGACAGCCAACAGAATCACCTGGG2200AATCAATACCATGTTCAGCTTGAGCAGAAGGTCTGAGGCAACGAAATCTG2250GATCAGCGTATTTATCAGCAATAACTAGAACTTCAGAAGGCCCAGCAGGC2300ATGTCAATACTACACAGGGCTGATGTGTCATTTTGAACCATCATCTTGGC2350AGCAGTAACGAACTGGTTTCCTGGACCAAATATTTTGTCACACTTAGGAA2400CAGTTTCTGTTCCGTAAGCCATAGCAGCTACTGCCTGGGCGCCTCCTGCT2450AGCACGATACACTTAGCACCAACCTTGTGGGCAACGTAGATGACTTCTGG2500GGTAAGGGTACCATCCTTCTTAGGTGGAGATGCAAAAACAATTTCTTTGC2550AACCAGCAACTTTGGCAGGAACACCCAGCATCAGGGAAGTGGAAGGCAGA2600ATTGCGGTTCCACCAGGAATATAGAGGCCAACTTTCTCAATAGGTCTTGC2650AAAACGAGAGCAGACTACACCAGGGCAAGTCTCAACTTGCAACGTCTCCG2700TTAGTTGAGCTTCATGGAATTTCCTGACGTTATCTATAGAGAGATCAATG2750GCTCTCTTAACGTTATCTGGCAATTGCATAAGTTCCTCTGGGAAAGGAGC2800TTCTAACACAGGTGTCTTCAAAGCGACTCCATCAAACTTGGCAGTTAGTT2850CTAAAAGGGCTTTGTCACCATTTTGACGAACATTGTCGACAATTGGTTTG2900ACTAATTCCATAATCTGTTCCGTTTTCTGGATAGGACGACGAAGGGCATC2950TTCAATTTCTTGTGAGGAGGCCTTAGAAACGTCAATTTTGCACAATTCAA3000TACGACCTTCAGAAGGGACTTCTTTAGGTTTGGATTCTTCTTTAGGTTGT3050TCCTTGGTGTATCCTGGCTTGGCATCTCCTTTCCTTCTAGTGACCTTTAG3100GGACTTCATATCCAGGTTTCTCTCCACCTCGTCCAACGTCACACCGTACT3150TGGCACATCTAACTAATGCAAAATAAAATAAGTCAGCACATTCCCAGGCT3200ATATCTTCCTTGGATTTAGCTTCTGCAAGTTCATCAGCTTCCTCCCTAAT3250TTTAGCGTTCAACAAAACTTCGTCGTCAAATAACCGTTTGGTATAAGAAC3300CTTCTGGAGCATTGCTCTTACGATCCCACAAGGTGCTTCCATGGCTCTAA3350GACCCTTTGATTGGCCAAAACAGGAAGTGCGTTCCAAGTGACAGAAACCA3400ACACCTGTTTGTTCAACCACAAATTTCAAGCAGTCTCCATCACAATCCAA3450TTCGATACCCAGCAACTTTTGAGTTCGTCCAGATGTAGCACCTTTATACC3500ACAAACCGTGACGACGAGATTGGTAGACTCCAGTTTGTGTCCTTATAGCC3550TCCGGAATAGACTTTTTGGACGAGTACACCAGGCCCAACGAGTAATTAGA3600AGAGTCAGCCACCAAAGTAGTGAATAGACCATCGGGGCGGTCAGTAGTCA3650AAGACGCCAACAAAATTTCACTGACAGGGAACTTTTTGACATCTTCAGAA3700AGTTCGTATTCAGTAGTCAATTGCCGAGCATCAATAATGGGGATTATACC3750AGAAGCAACAGTGGAAGTCACATCTACCAACTTTGCGGTCTCAGAAAAAG3800CATAAACAGTTCTACTACCGCCATTAGTGAAACTTTTCAAATCGCCCAGT3850GGAGAAGAAAAAGGCACAGCGATACTAGCATTAGCGGGCAAGGATGCAAC3900TTTATCAACCAGGGTCCTATAGATAACCCTAGCGCCTGGGATCATCCTTT3950GGACAACTCTTTCTGCCAAATCTAGGTCCAAAATCACTTCATTGATACCA4000TTATACGGATGACTCAACTTGCACATTAACTTGAAGCTCAGTCGATTGAG4050TGAACTTGATCAGGTTGTGCAGCTGGTCAGCAGCATAGGGAAACACGGCT4100TTTCCTACCAAACTCAAGGAATTATCAAACTCTGCAACACTTGCGTATGC4150AGGTAGCAAGGGAAATGTCATACTTGAAGTCGGACAGTGAGTGTAGTCTT4200GAGAAATTCTGAAGCCGTATTTTTATTATCAGTGAGTCAGTCATCAGGAG4250ATCCTCTACGCCGGACGCATCGTGGCCGGCATCACCGGCGCCACAGGTGC4300GGTTGCTGGCGCCTATATCGCCGACATCACCGATGGGGAAGATCGGGCTC4350GCCACTTCGGGCTCATGAGCGCTTGTTTCGGCGTGGGTATGGTGGCAGGC4400CCCGTGGCCGGGGGACTGTTGGGCGCCATCTCCTTGCATGCACCATTCCT4450TGCGGCGGCGGTGCTCAACGGCCTCAACCTACTACTGGGCTGCTTCCTAA4500TGCAGGAGTCGCATAAGGGAGAGCGTCGAGTATCTATGATTGGAAGTATG4550GGAATGGTGATACCCGCATTCTTCAGTGTCTTGAGGTCTCCTATCAGATT4600ATGCCCAACTAAAGCAACCGGAGGAGGAGATTTCATGGTAAATTTCTCTG4650ACTTTTGGTCATCAGTAGACTCGAACTGTGAGACTATCTCGGTTATGACA4700GCAGAAATGTCCTTCTTGGAGACAGTAAATGAAGTCCCACCAATAAAGAA4750ATCCTTGTTATCAGGAACAAACTTCTTGTTTCGAACTTTTTCGGTGCCTT4800GAACTATAAAATGTAGAGTGGATATGTCGGGTAGGAATGGAGCGGGCAAA4850TGCTTACCTTCTGGACCTTCAAGAGGTATGTAGGGTTTGTAGATACTGAT4900GCCAACTTCAGTGACAACGTTGCTATTTCGTTCAAACCATTCCGAATCCA4950GAGAAATCAAAGTTGTTTGTCTACTATTGATCCAAGCCAGTGCGGTCTTG5000AAACTGACAATAGTGTGCTCGTGTTTTGAGGTCATCTTTGTATGAATAAA5050TCTAGTCTTTGATCTAAATAATCTTGACGAGCCAAGGCGATAAATACCCA5100AATCTAAAACTCTTTTAAAACGTTAAAAGGACAAGTATGTCTGCCTGTAT5150TAAACCCCAAATCAGCTCGTAGTCTGATCCTCATCAACTTGAGGGGCACT5200ATCTTGTTTTAGAGAAATTTGCGGAGATGCGATATCGAGAAAAAGGTACG5250CTGATTTTAAACGTGAAATTTATCTCAAGATCGCGGCCGCGATCTCGAAT5300AATAACTGTTATTTTTCAGTGTTCCCGATCTGCGTCTATTTCACAATACC5350AACATGAGTCAGCTTATCGATGATAAGCTGTCAAACATGAGAATTAATTC5400GATGATAAGCTGTCAAACATGAGAAATCTTGAAGACGAAAGGGCCTCGTG5450ATACGCCTATTTTTATAGGTTAATGTCATGATAATAATGGTTTCTTAGAC5500GTCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTAT5550TTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGA5600TAAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAGTATTCAACATTT5650CCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTG5700CTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGT5750GCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGA5800GAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGTTC5850TGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGAGCAACTC5900GGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCACCAGT5950CACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTG6000CTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACG6050ATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCA6100TGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAA6150ACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCGC6200AAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAAT6250AGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCC6300TTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGG6350TCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTAT6400CGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATA6450GACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCA6500GACCAAGTTTACTCATATATACTTTAGATTGATTTAAATTGTAAACGTTA6550ATATTTTGTTAAAATTCGCGTTAAATTTTTGTTAAATCAGCTCATTTTTT6600AACCAATAGGCCGAAATCGGCAAAATCCCTTATAAATCAAAAGAATAGAC6650CGAGATAGGGTTGAGTGTTGTTCCAGTTTGGAACAAGAGTCCACTATTAA6700AGAACGTGGACTCCAACGTCAAAGGGCGAAAAACCGTCTATCAGGGCGAT6750GGCCCACTACGTGAACCATCACCCTAATCAAGTTTTTTGGGGTCGAGGTG6800CCGTAAAGCACTAAATCGGAACCCTAAAGGGAGCCCCCGATTTAGAGCTT6850GACGGGGAAAGCCGGCGAACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAA6900GGAGCGGGCGCTAGGGCGCTGGCAAGTGTAGCGGTCACGCTGCGCGTAAC6950CACCACACCCGCCGCGCTTAATGCGCCGCTACAGGGCGCGTAAAAGGATC7000TAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGA7050GTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTT7100CTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAA7150CCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCT7200TTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCC7250TTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCG7300CCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGG7350CGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATA7400AGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTG7450GAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCATTGAGA7500AAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCG7550GCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCC7600TGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCG7650ATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCA7700ACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATG7750TTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTT7800TGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGT7850CAGTGAGCGAGGAAGCGGAAGAGCGCCTGATGCGGTATTTTCTCCTTACG7900CATCTGTGCGGTATTTCACACCGCATATGGTGCACTCTCAGTACAATCTG7950CTCTGATGCCGCATAGTTAAGCCAGTATACACTCCGCTATCGCTACGTGA8000CTGGGTCATGGCTGCGCCCCGACACCCGCCAACACCCGCTGACGCGCCCT8050GACGGGCTTGTCTGCTCCCGGCATCCGCTTACAGACAAGCTGTGACCGTC8100TCCGGGAGCTGCATGTGTCAGAGGTTTTCACCGTCATCACCGAAACGCGC8150GAGGCAG8157(2) INFORMATION FOR SEQ ID NO:66:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:8584 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: circular(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION: DNA plasmid(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:AGATCGCGGCCGCGATCTAACATCCAAAGACGAAAGGTTGAATGAAACCT50TTTTGCCATCCGACATCCACAGGTCCATTCTCACACATAAGTGCCAAACG100CAACAGGAGGGGATACACTAGCAGCAGACCGTTGCAAACGCAGGACCTCC150ACTCCTCTTCTCCTCAACACCCACTTTTGCCATCGAAAAACCAGCCCAGT200TATTGGGCTTGATTGGAGCTCGCTCATTCCAATTCCTTCTATTAGGCTAC250TAACACCATGACTTTATTAGCCTGTCTATCCTGGCCCCCCTGGCGAGGTC300ATGTTTGTTTATTTCCGAATGCAACAAGCTCCGCATTACACCCGAACATC350ACTCCAGATGAGGGCTTTCTGAGTGTGGGGTCAAATAGTTTCATGTTCCC400AAATGGCCCAAAACTGACAGTTTAAACGCTGTCTTGGAACCTAATATGAC450AAAAGCGTGATCTCATCCAAGATGAACTAAGTTTGGTTCGTTGAAATGCT500AACGGCCAGTTGGTCAAAAAGAAACTTCCAAAAGTCGCCATACCGTTTGT550CTTGTTTGGTATTGATTGACGAATGCTCAAAAATAATCTCATTAATGCTT600AGCGCAGTCTCTCTATCGCTTCTGAACCCGGTGGCACCTGTGCCGAAACG650CAAATGGGGAAACAACCCGCTTTTTGGATGATTATGCATTGTCCTCCACA700TTGTATGCTTCCAAGATTCTGGTGGGAATACTGCTGATAGCCTAACGTTC750ATGATCAAAATTTAACTGTTCTAACCCCTACTTGACAGGCAATATATAAA800CAGAAGGAAGCTGCCCTGTCTTAAACCTTTTTTTTTATCATCATTATTAG850CTTACTTTCATAATTGCGACTGGTTCCAATTGACAAGCTTTTGATTTTAA900CGACTTTTAACGACAACTTGAGAAGATCAAAAAACAACTAATTATTCGAA950ACGATGAGATTCCCATCTATCTTCACTGCTGTTTTGTTCGCTGCTTCCTC1000TGCTTTGGCTGCTCCAGTTAACACCACTACTGAAGACGAGACTGCTCAAA1050TTCCTGCTGAGGCTGTCATCGGTTACTCTGACTTGGAAGGTGACTTCGAC1100GTCGCTGTTTTGCCATTCTCTAACTCTACTAACAACGGTTTGTTGTTCAT1150CAACACTACCATCGCTTCTATCGCTGCTAAGGAGGAAGGTGTTTCCTTGG1200ACAAGAGAGCTGCTTGTAACTTGCCAATCGTCAGAGGTCCATGCATTGCT1250TTCTTCCCAAGATGGGCTTTCGACGCTGTTAAGGGTAAGTGCGTCTTGTT1300CCCATACGGTGGTTGTCAAGGTAACGGTAACAAGTTCTACTCTGAGAAGG1350AGTGTAGAGAGTACTGTGGTGTTCCATAGTAAGAATTCGCCTTAGACATG1400ACTGTTCCTCAGTTCAAGTTGGGCATTACGAGAAGACCGGTCTTGCTAGA1450TTCTAATCAAGAGGATGTCAGAATGCCATTTGCCTGAGAGATGCAGGCTT1500CATTTTTGATACTTTTTTATTTGTAACCTATATAGTATAGGATTTTTTTT1550GTCATTTTGTTTCTTCTCGTACGAGCTTGCTCCTGATCAGCCTATCTCGC1600AGCTGATGAATATCTTGTGGTAGGGGTTTGGGAAAATCATTCGAGTTTGA1650TGTTTTTCTTGGTATTTCCCACTCCTCTTCAGAGTACAGAAGATTAAGTG1700AGAAGTTCGTTTGTGCAAGCTTATCGATAAGCTTTAATGCGGTAGTTTAT1750CACAGTTAAATTGCTAACGCAGTCAGGCACCGTGTATGAAATCTAACAAT1800GCGCTCATCGTCATCCTCGGCACCGTCACCCTGGATGCTGTAGGCATAGG1850CTTGGTTATGCCGGTACTGCCGGGCCTCTTGCGGGATATCGTCCATTCCG1900ACAGCATCGCCAGTCACTATGGCGTGCTGCTAGCGCTATATGCGTTGATG1950CAATTTCTATGCGCACCCGTTCTCGGAGCACTGTCCGACCGCTTTGGCCG2000CCGCCCAGTCCTGCTCGCTTCGCTACTTGGAGCCACTATCGACTACGCGA2050TCATGGCGACCACACCCGTCCTGTGGATCTATCGAATCTAAATGTAAGTT2100AAAATCTCTAAATAATTAAATAAGTCCCAGTTTCTCCATACGAACCTTAA2150CAGCATTGCGGTGAGCATCTAGACCTTCAACAGCAGCCAGATCCATCACT2200GCTTGGCCAATATGTTTCAGTCCCTCAGGAGTTACGTCTTGTGAAGTGAT2250GAACTTCTGGAAGGTTGCAGTGTTAACTCCGCTGTATTGACGGGCATATC2300CGTACGTTGGCAAAGTGTGGTTGGTACCGGAGGAGTAATCTCCACAACTC2350TCTGGAGAGTAGGCACCAACAAACACAGATCCAGCGTGTTGTACTTGATC2400AACATAAGAAGAAGCATTCTCGATTTGCAGGATCAAGTGTTCAGGAGCGT2450ACTGATTGGACATTTCCAAAGCCTGCTCGTAGGTTGCAACCGATAGGGTT2500GTAGAGTGTGCAATACACTTGCGTACAATTTCAACCCTTGGCAACTGCAC2550AGCTTGGTTGTGAACAGCATCTTCAATTCTGGCAAGCTCCTTGTCTGTCA2600TATCGACAGCCAACAGAATCACCTGGGAATCAATACCATGTTCAGCTTGA2650GCAGAAGGTCTGAGGCAACGAAATCTGGATCAGCGTATTTATCAGCAATA2700ACTAGAACTTCAGAAGGCCCAGCAGGCATGTCAATACTACACAGGGCTGA2750TGTGTCATTTTGAACCATCATCTTGGCAGCAGTAACGAACTGGTTTCCTG2800GACCAAATATTTTGTCACACTTAGGAACAGTTTCTGTTCCGTAAGCCATA2850GCAGCTACTGCCTGGGCGCCTCCTGCTAGCACGATACACTTAGCACCAAC2900CTTGTGGGCAACGTAGATGACTTCTGGGGTAAGGGTACCATCCTTCTTAG2950GTGGAGATGCAAAAACAATTTCTTTGCAACCAGCAACTTTGGCAGGAACA3000CCCAGCATCAGGGAAGTGGAAGGCAGAATTGCGGTTCCACCAGGAATATA3050GAGGCCAACTTTCTCAATAGGTCTTGCAAAACGAGAGCAGACTACACCAG3100GGCAAGTCTCAACTTGCAACGTCTCCGTTAGTTGAGCTTCATGGAATTTC3150CTGACGTTATCTATAGAGAGATCAATGGCTCTCTTAACGTTATCTGGCAA3200TTGCATAAGTTCCTCTGGGAAAGGAGCTTCTAACACAGGTGTCTTCAAAG3250CGACTCCATCAAACTTGGCAGTTAGTTCTAAAAGGGCTTTGTCACCATTT3300TGACGAACATTGTCGACAATTGGTTTGACTAATTCCATAATCTGTTCCGT3350TTTCTGGATAGGACGACGAAGGGCATCTTCAATTTCTTGTGAGGAGGCCT3400TAGAAACGTCAATTTTGCACAATTCAATACGACCTTCAGAAGGGACTTCT3450TTAGGTTTGGATTCTTCTTTAGGTTGTTCCTTGGTGTATCCTGGCTTGGC3500ATCTCCTTTCCTTCTAGTGACCTTTAGGGACTTCATATCCAGGTTTCTCT3550CCACCTCGTCCAACGTCACACCGTACTTGGCACATCTAACTAATGCAAAA3600TAAAATAAGTCAGCACATTCCCAGGCTATATCTTCCTTGGATTTAGCTTC3650TGCAAGTTCATCAGCTTCCTCCCTAATTTTAGCGTTCAACAAAACTTCGT3700CGTCAAATAACCGTTTGGTATAAGAACCTTCTGGAGCATTGCTCTTACGA3750TCCCACAAGGTGCTTCCATGGCTCTAAGACCCTTTGATTGGCCAAAACAG3800GAAGTGCGTTCCAAGTGACAGAAACCAACACCTGTTTGTTCAACCACAAA3850TTTCAAGCAGTCTCCATCACAATCCAATTCGATACCCAGCAACTTTTGAG3900TTCGTCCAGATGTAGCACCTTTATACCACAAACCGTGACGACGAGATTGG3950TAGACTCCAGTTTGTGTCCTTATAGCCTCCGGAATAGACTTTTTGGACGA4000GTACACCAGGCCCAACGAGTAATTAGAAGAGTCAGCCACCAAAGTAGTGA4050ATAGACCATCGGGGCGGTCAGTAGTCAAAGACGCCAACAAAATTTCACTG4100ACAGGGAACTTTTTGACATCTTCAGAAAGTTCGTATTCAGTAGTCAATTG4150CCGAGCATCAATAATGGGGATTATACCAGAAGCAACAGTGGAAGTCACAT4200CTACCAACTTTGCGGTCTCAGAAAAAGCATAAACAGTTCTACTACCGCCA4250TTAGTGAAACTTTTCAAATCGCCCAGTGGAGAAGAAAAAGGCACAGCGAT4300ACTAGCATTAGCGGGCAAGGATGCAACTTTATCAACCAGGGTCCTATAGA4350TAACCCTAGCGCCTGGGATCATCCTTTGGACAACTCTTTCTGCCAAATCT4400AGGTCCAAAATCACTTCATTGATACCATTATACGGATGACTCAACTTGCA4450CATTAACTTGAAGCTCAGTCGATTGAGTGAACTTGATCAGGTTGTGCAGC4500TGGTCAGCAGCATAGGGAAACACGGCTTTTCCTACCAAACTCAAGGAATT4550ATCAAACTCTGCAACACTTGCGTATGCAGGTAGCAAGGGAAATGTCATAC4600TTGAAGTCGGACAGTGAGTGTAGTCTTGAGAAATTCTGAAGCCGTATTTT4650TATTATCAGTGAGTCAGTCATCAGGAGATCCTCTACGCCGGACGCATCGT4700GGCCGGCATCACCGGCGCCACAGGTGCGGTTGCTGGCGCCTATATCGCCG4750ACATCACCGATGGGGAAGATCGGGCTCGCCACTTCGGGCTCATGAGCGCT4800TGTTTCGGCGTGGGTATGGTGGCAGGCCCCGTGGCCGGGGGACTGTTGGG4850CGCCATCTCCTTGCATGCACCATTCCTTGCGGCGGCGGTGCTCAACGGCC4900TCAACCTACTACTGGGCTGCTTCCTAATGCAGGAGTCGCATAAGGGAGAG4950CGTCGAGTATCTATGATTGGAAGTATGGGAATGGTGATACCCGCATTCTT5000CAGTGTCTTGAGGTCTCCTATCAGATTATGCCCAACTAAAGCAACCGGAG5050GAGGAGATTTCATGGTAAATTTCTCTGACTTTTGGTCATCAGTAGACTCG5100AACTGTGAGACTATCTCGGTTATGACAGCAGAAATGTCCTTCTTGGAGAC5150AGTAAATGAAGTCCCACCAATAAAGAAATCCTTGTTATCAGGAACAAACT5200TCTTGTTTCGAACTTTTTCGGTGCCTTGAACTATAAAATGTAGAGTGGAT5250ATGTCGGGTAGGAATGGAGCGGGCAAATGCTTACCTTCTGGACCTTCAAG5300AGGTATGTAGGGTTTGTAGATACTGATGCCAACTTCAGTGACAACGTTGC5350TATTTCGTTCAAACCATTCCGAATCCAGAGAAATCAAAGTTGTTTGTCTA5400CTATTGATCCAAGCCAGTGCGGTCTTGAAACTGACAATAGTGTGCTCGTG5450TTTTGAGGTCATCTTTGTATGAATAAATCTAGTCTTTGATCTAAATAATC5500TTGACGAGCCAAGGCGATAAATACCCAAATCTAAAACTCTTTTAAAACGT5550TAAAAGGACAAGTATGTCTGCCTGTATTAAACCCCAAATCAGCTCGTAGT5600CTGATCCTCATCAACTTGAGGGGCACTATCTTGTTTTAGAGAAATTTGCG5650GAGATGCGATATCGAGAAAAAGGTACGCTGATTTTAAACGTGAAATTTAT5700CTCAAGATCGCGGCCGCGATCTCGAATAATAACTGTTATTTTTCAGTGTT5750CCCGATCTGCGTCTATTTCACAATACCAACATGAGTCAGCTTATCGATGA5800TAAGCTGTCAAACATGAGAATTAATTCGATGATAAGCTGTCAAACATGAG5850AAATCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAA5900TGTCATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAA5950ATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATG6000TATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAA6050AAGGAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTT6100TTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAA6150GTAAAAGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGAACT6200GGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTT6250TTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCC6300CGTGTTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCA6350GAATGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCTTACGGATG6400GCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAAC6450ACTGCGGCCAACTTACTTCTGACAACGATCGGAGGACCGAAGGAGCTAAC6500CGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGG6550AACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATG6600CCTGCAGCAATGGCAACAACGTTGCGCAAACTATTAACTGGCGAACTACT6650TACTCTAGCTTCCCGGCAACAATTAATAGACTGGATGGAGGCGGATAAAG6700TTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCT6750GATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACT6800GGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGA6850GTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCC6900TCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATATATACT6950TTAGATTGATTTAAATTGTAAACGTTAATATTTTGTTAAAATTCGCGTTA7000AATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAATCGGCAA7050AATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTGTTGTTC7100CAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAACGTCAAA7150GGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACCATCACC7200CTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATCGGAACC7250CTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCGAACGTG7300GCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGCGCTGGC7350AAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGCTTAATG7400CGCCGCTACAGGGCGCGTAAAAGGATCTAGGTGAAGATCCTTTTTGATAA7450TCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAG7500ACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGC7550GTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTG7600TTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCA7650GCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTAGTTAGGC7700CACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAAT7750CCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGT7800TGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACG7850GGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACT7900GAGATACCTACAGCGTGAGCATTGAGAAAGCGCCACGCTTCCCGAAGGGA7950GAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGC8000ACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGG8050GTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGG8100GGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTG8150GCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGA8200TTCTGTGGATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCC8250GCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAGAG8300CGCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCG8350CATATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCC8400AGTATACACTCCGCTATCGCTACGTGACTGGGTCATGGCTGCGCCCCGAC8450ACCCGCCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCGGCA8500TCCGCTTACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCAGAG8550GTTTTCACCGTCATCACCGAAACGCGCGAGGCAG8584(2) INFORMATION FOR SEQ ID NO:67:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:141 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:MetArgPheProSerIlePheThrAlaValLeuPheAlaAlaSerSer151015AlaLeuAlaAlaProValAsnThrThrThrGluAspGluThrAlaGln202530IleProAlaGluAlaValIleGlyTyrSerAspLeuGluGlyAspPhe354045AspValAlaValLeuProPheSerAsnSerThrAsnAsnGlyLeuLeu505560PheIleAsnThrThrIleAlaSerIleAlaAlaLysGluGluGlyVal65707580SerLeuAspLysArgAlaAlaCysAsnLeuProIleValArgGlyPro859095CysIleAlaPhePheProArgTrpAlaPheAspAlaValLysGlyLys100105110CysValLeuPheProTyrGlyGlyCysGlnGlyAsnGlyAsnLysPhe115120125TyrSerGluLysGluCysArgGluTyrCysGlyValPro130135140(2) INFORMATION FOR SEQ ID NO:68:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:448 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:TTCGAAACGATGAGATTCCCATCTATCTTCACTGCTGTTTTGTTCGCTGC50TTCCTCTGCTTTGGCTGCTCCAGTTAACACCACTACTGAAGACGAGACTG100CTCAAATTCCTGCTGAGGCTGTCATCGGTTACTCTGACTTGGAAGGTGAC150TTCGACGTCGCTGTTTTGCCATTCTCTAACTCTACTAACAACGGTTTGTT200GTTCATCAACACTACCATCGCTTCTATCGCTGCTAAGGAGGAAGGTGTTT250CCTTGGACAAGAGAGAGGCTTGTAACTTGCCAATCGTCAGAGGTCCATGC300ATTGCTTTCTTCCCAAGATGGGCTTTCGACGCTGTTAAGGGTAAGTGCGT350CTTGTTCCCATACGGTGGTTGTCAAGGTAACGGTAACAAGTTCTACTCTG400AGAAGGAGTGTAGAGAGTACTGTGGTGTTCCATAGTAAGAATTCGCCT448(2) INFORMATION FOR SEQ ID NO:69:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:141 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:MetArgPheProSerIlePheThrAlaValLeuPheAlaAlaSerSer151015AlaLeuAlaAlaProValAsnThrThrThrGluAspGluThrAlaGln202530IleProAlaGluAlaValIleGlyTyrSerAspLeuGluGlyAspPhe354045AspValAlaValLeuProPheSerAsnSerThrAsnAsnGlyLeuLeu505560PheIleAsnThrThrIleAlaSerIleAlaAlaLysGluGluGlyVal65707580SerLeuAspLysArgGluAlaCysAsnLeuProIleValArgGlyPro859095CysIleAlaPhePheProArgTrpAlaPheAspAlaValLysGlyLys100105110CysValLeuPheProTyrGlyGlyCysGlnGlyAsnGlyAsnLysPhe115120125TyrSerGluLysGluCysArgGluTyrCysGlyValPro130135140(2) INFORMATION FOR SEQ ID NO:70:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:8590 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: circular(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION: DNA plasmid(xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:AGATCGCGGCCGCGATCTAACATCCAAAGACGAAAGGTTGAATGAAACCT50TTTTGCCATCCGACATCCACAGGTCCATTCTCACACATAAGTGCCAAACG100CAACAGGAGGGGATACACTAGCAGCAGACCGTTGCAAACGCAGGACCTCC150ACTCCTCTTCTCCTCAACACCCACTTTTGCCATCGAAAAACCAGCCCAGT200TATTGGGCTTGATTGGAGCTCGCTCATTCCAATTCCTTCTATTAGGCTAC250TAACACCATGACTTTATTAGCCTGTCTATCCTGGCCCCCCTGGCGAGGTC300ATGTTTGTTTATTTCCGAATGCAACAAGCTCCGCATTACACCCGAACATC350ACTCCAGATGAGGGCTTTCTGAGTGTGGGGTCAAATAGTTTCATGTTCCC400AAATGGCCCAAAACTGACAGTTTAAACGCTGTCTTGGAACCTAATATGAC450AAAAGCGTGATCTCATCCAAGATGAACTAAGTTTGGTTCGTTGAAATGCT500AACGGCCAGTTGGTCAAAAAGAAACTTCCAAAAGTCGCCATACCGTTTGT550CTTGTTTGGTATTGATTGACGAATGCTCAAAAATAATCTCATTAATGCTT600AGCGCAGTCTCTCTATCGCTTCTGAACCCGGTGGCACCTGTGCCGAAACG650CAAATGGGGAAACAACCCGCTTTTTGGATGATTATGCATTGTCCTCCACA700TTGTATGCTTCCAAGATTCTGGTGGGAATACTGCTGATAGCCTAACGTTC750ATGATCAAAATTTAACTGTTCTAACCCCTACTTGACAGGCAATATATAAA800CAGAAGGAAGCTGCCCTGTCTTAAACCTTTTTTTTTATCATCATTATTAG850CTTACTTTCATAATTGCGACTGGTTCCAATTGACAAGCTTTTGATTTTAA900CGACTTTTAACGACAACTTGAGAAGATCAAAAAACAACTAATTATTCGAA950ACGATGAGATTCCCATCTATCTTCACTGCTGTTTTGTTCGCTGCTTCCTC1000TGCTTTGGCTGCTCCAGTTAACACCACTACTGAAGACGAGACTGCTCAAA1050TTCCTGCTGAGGCTGTCATCGGTTACTCTGACTTGGAAGGTGACTTCGAC1100GTCGCTGTTTTGCCATTCTCTAACTCTACTAACAACGGTTTGTTGTTCAT1150CAACACTACCATCGCTTCTATCGCTGCTAAGGAGGAAGGTGTTTCCTTGG1200ACAAGAGAGCTGCTTGTAACTTGCCAATCGTCAGAGGTCCATGCATTGCT1250TTCTTCCCAAGATGGGCTTTCGACGCTGTTAAGGGTAAGTGCGTCTTGTT1300CCCATACGGTGGTTGTCAAGGTAACGGTAACAAGTTCTACTCTGAGAAGG1350AGTGTAGAGAGTACTGTGGTGTTCCATAGTAAGAATTCGCCTTAGACATG1400ACTGTTCCTCAGTTCAAGTTGGGCATTACGAGAAGACCGGTCTTGCTAGA1450TTCTAATCAAGAGGATGTCAGAATGCCATTTGCCTGAGAGATGCAGGCTT1500CATTTTTGATACTTTTTTATTTGTAACCTATATAGTATAGGATTTTTTTT1550GTCATTTTGTTTCTTCTCGTACGAGCTTGCTCCTGATCAGCCTATCTCGC1600AGCTGATGAATATCTTGTGGTAGGGGTTTGGGAAAATCATTCGAGTTTGA1650TGTTTTTCTTGGTATTTCCCACTCCTCTTCAGAGTACAGAAGATTAAGTG1700AGAAGTTCGTTTGTGCAAGCTTATCGATAAGCTTTAATGCGGTAGTTTAT1750CACAGTTAAATTGCTAACGCAGTCAGGCACCGTGTATGAAATCTAACAAT1800GCGCTCATCGTCATCCTCGGCACCGTCACCCTGGATGCTGTAGGCATAGG1850CTTGGTTATGCCGGTACTGCCGGGCCTCTTGCGGGATATCGTCCATTCCG1900ACAGCATCGCCAGTCACTATGGCGTGCTGCTAGCGCTATATGCGTTGATG1950CAATTTCTATGCGCACCCGTTCTCGGAGCACTGTCCGACCGCTTTGGCCG2000CCGCCCAGTCCTGCTCGCTTCGCTACTTGGAGCCACTATCGACTACGCGA2050TCATGGCGACCACACCCGTCCTGTGGATCTATCGAATCTAAATGTAAGTT2100AAAATCTCTAAATAATTAAATAAGTCCCAGTTTCTCCATACGAACCTTAA2150CAGCATTGCGGTGAGCATCTAGACCTTCAACAGCAGCCAGATCCATCACT2200GCTTGGCCAATATGTTTCAGTCCCTCAGGAGTTACGTCTTGTGAAGTGAT2250GAACTTCTGGAAGGTTGCAGTGTTAACTCCGCTGTATTGACGGGCATATC2300CGTACGTTGGCAAAGTGTGGTTGGTACCGGAGGAGTAATCTCCACAACTC2350TCTGGAGAGTAGGCACCAACAAACACAGATCCAGCGTGTTGTACTTGATC2400AACATAAGAAGAAGCATTCTCGATTTGCAGGATCAAGTGTTCAGGAGCGT2450ACTGATTGGACATTTCCAAAGCCTGCTCGTAGGTTGCAACCGATAGGGTT2500GTAGAGTGTGCAATACACTTGCGTACAATTTCAACCCTTGGCAACTGCAC2550AGCTTGGTTGTGAACAGCATCTTCAATTCTGGCAAGCTCCTTGTCTGTCA2600TATCGACAGCCAACAGAATCACCTGGGAATCAATACCATGTTCAGCTTGA2650GCAGAAGGTCTGAGGCAACGAAATCTGGATCAGCGTATTTATCAGCAATA2700ACTAGAACTTCAGAAGGCCCAGCAGGCATGTCAATACTACACAGGGCTGA2750TGTGTCATTTTGAACCATCATCTTGGCAGCAGTAACGAACTGGTTTCCTG2800GACCAAATATTTTGTCACACTTAGGAACAGTTTCTGTTCCGTAAGCCATA2850GCAGCTACTGCCTGGGCGCCTCCTGCTAGCACGATACACTTAGCACCAAC2900CTTGTGGGCAACGTAGATGACTTCTGGGGTAAGGGTACCATCCTTCTTAG2950GTGGAGATGCAAAAACAATTTCTTTGCAACCAGCAACTTTGGCAGGAACA3000CCCAGCATCAGGGAAGTGGAAGGCAGAATTGCGGTTCCACCAGGAATATA3050GAGGCCAACTTTCTCAATAGGTCTTGCAAAACGAGAGCAGACTACACCAG3100GGCAAGTCTCAACTTGCAACGTCTCCGTTAGTTGAGCTTCATGGAATTTC3150CTGACGTTATCTATAGAGAGATCAATGGCTCTCTTAACGTTATCTGGCAA3200TTGCATAAGTTCCTCTGGGAAAGGAGCTTCTAACACAGGTGTCTTCAAAG3250CGACTCCATCAAACTTGGCAGTTAGTTCTAAAAGGGCTTTGTCACCATTT3300TGACGAACATTGTCGACAATTGGTTTGACTAATTCCATAATCTGTTCCGT3350TTTCTGGATAGGACGACGAAGGGCATCTTCAATTTCTTGTGAGGAGGCCT3400TAGAAACGTCAATTTTGCACAATTCAATACGACCTTCAGAAGGGACTTCT3450TTAGGTTTGGATTCTTCTTTAGGTTGTTCCTTGGTGTATCCTGGCTTGGC3500ATCTCCTTTCCTTCTAGTGACCTTTAGGGACTTCATATCCAGGTTTCTCT3550CCACCTCGTCCAACGTCACACCGTACTTGGCACATCTAACTAATGCAAAA3600TAAAATAAGTCAGCACATTCCCAGGCTATATCTTCCTTGGATTTAGCTTC3650TGCAAGTTCATCAGCTTCCTCCCTAATTTTAGCGTTCAACAAAACTTCGT3700CGTCAAATAACCGTTTGGTATAAGAACCTTCTGGAGCATTGCTCTTACGA3750TCCCACAAGGTGCTTCCATGGCTCTAAGACCCTTTGATTGGCCAAAACAG3800GAAGTGCGTTCCAAGTGACAGAAACCAACACCTGTTTGTTCAACCACAAA3850TTTCAAGCAGTCTCCATCACAATCCAATTCGATACCCAGCAACTTTTGAG3900TTCGTCCAGATGTAGCACCTTTATACCACAAACCGTGACGACGAGATTGG3950TAGACTCCAGTTTGTGTCCTTATAGCCTCCGGAATAGACTTTTTGGACGA4000GTACACCAGGCCCAACGAGTAATTAGAAGAGTCAGCCACCAAAGTAGTGA4050ATAGACCATCGGGGCGGTCAGTAGTCAAAGACGCCAACAAAATTTCACTG4100ACAGGGAACTTTTTGACATCTTCAGAAAGTTCGTATTCAGTAGTCAATTG4150CCGAGCATCAATAATGGGGATTATACCAGAAGCAACAGTGGAAGTCACAT4200CTACCAACTTTGCGGTCTCAGAAAAAGCATAAACAGTTCTACTACCGCCA4250TTAGTGAAACTTTTCAAATCGCCCAGTGGAGAAGAAAAAGGCACAGCGAT4300ACTAGCATTAGCGGGCAAGGATGCAACTTTATCAACCAGGGTCCTATAGA4350TAACCCTAGCGCCTGGGATCATCCTTTGGACAACTCTTTCTGCCAAATCT4400AGGTCCAAAATCACTTCATTGATACCATTATACGGATGACTCAACTTGCA4450CATTAACTTGAAGCTCAGTCGATTGAGTGAACTTGATCAGGTTGTGCAGC4500TGGTCAGCAGCATAGGGAAACACGGCTTTTCCTACCAAACTCAAGGAATT4550ATCAAACTCTGCAACACTTGCGTATGCAGGTAGCAAGGGAAATGTCATAC4600TTGAAGTCGGACAGTGAGTGTAGTCTTGAGAAATTCTGAAGCCGTATTTT4650TATTATCAGTGAGTCAGTCATCAGGAGATCCTCTACGCCGGACGCATCGT4700GGCCGGCATCACCGGCGCCACAGGTGCGGTTGCTGGCGCCTATATCGCCG4750ACATCACCGATGGGGAAGATCGGGCTCGCCACTTCGGGCTCATGAGCGCT4800TGTTTCGGCGTGGGTATGGTGGCAGGCCCCGTGGCCGGGGGACTGTTGGG4850CGCCATCTCCTTGCATGCACCATTCCTTGCGGCGGCGGTGCTCAACGGCC4900TCAACCTACTACTGGGCTGCTTCCTAATGCAGGAGTCGCATAAGGGAGAG4950CGTCGAGTATCTATGATTGGAAGTATGGGAATGGTGATACCCGCATTCTT5000CAGTGTCTTGAGGTCTCCTATCAGATTATGCCCAACTAAAGCAACCGGAG5050GAGGAGATTTCATGGTAAATTTCTCTGACTTTTGGTCATCAGTAGACTCG5100AACTGTGAGACTATCTCGGTTATGACAGCAGAAATGTCCTTCTTGGAGAC5150AGTAAATGAAGTCCCACCAATAAAGAAATCCTTGTTATCAGGAACAAACT5200TCTTGTTTCGCGAACTTTTTCGGTGCCTTGAACTATAAAATGTAGAGTGG5250ATATGTCGGGTAGGAATGGAGCGGGCAAATGCTTACCTTCTGGACCTTCA5300AGAGGTATGTAGGGTTTGTAGATACTGATGCCAACTTCAGTGACAACGTT5350GCTATTTCGTTCAAACCATTCCGAATCCAGAGAAATCAAAGTTGTTTGTC5400TACTATTGATCCAAGCCAGTGCGGTCTTGAAACTGACAATAGTGTGCTCG5450TGTTTTGAGGTCATCTTTGTATGAATAAATCTAGTCTTTGATCTAAATAA5500TCTTGACGAGCCAAGGCGATAAATACCCAAATCTAAAACTCTTTTAAAAC5550GTTAAAAGGACAAGTATGTCTGCCTGTATTAAACCCCAAATCAGCTCGTA5600GTCTGATCCTCATCAACTTGAGGGGCACTATCTTGTTTTAGAGAAATTTG5650CGGAGATGCGATATCGAGAAAAAGGTACGCTGATTTTAAACGTGAAATTT5700ATCTCAAGATCGCGGCCGCGATCTCGAATAATAACTGTTATTTTTCAGTG5750TTCCCGATCTGCGTCTATTTCACAATACCAACATGAGTCAGCTTATCGAT5800GATAAGCTGTCAAACATGAGAATTAATTCGATGATAAGCTGTCAAACATG5850AGAAATCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTT5900AATGTCATGATAATAATGGTTTCTTAGACGTACGTCAGGTGGCACTTTTC5950GGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCA6000AATATGTATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATA6050TTGAAAAAGGAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTC6100CCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTG6150GTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACAT6200CGAACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAG6250AACGTTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTA6300TTATCCCGTGTTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTA6350TTCTCAGAATGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCTTA6400CGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGT6450GATAACACTGCGGCCAACTTACTTCTGACAACGATCGGAGGACCGAAGGA6500GCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATC6550GTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACC6600ACGATGCCTGCAGCAATGGCAACAACGTTGCGCAAACTATTAACTGGCGA6650ACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGGATGGAGGCGG6700ATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTT6750ATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGC6800AGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGA6850CGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATA6900GGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATA6950TATACTTTAGATTGATTTAAATTGTAAACGTTAATATTTTGTTAAAATTC7000GCGTTAAATTTTTGTTAAATCAGCTCATTTTTTAACCAATAGGCCGAAAT7050CGGCAAAATCCCTTATAAATCAAAAGAATAGACCGAGATAGGGTTGAGTG7100TTGTTCCAGTTTGGAACAAGAGTCCACTATTAAAGAACGTGGACTCCAAC7150GTCAAAGGGCGAAAAACCGTCTATCAGGGCGATGGCCCACTACGTGAACC7200ATCACCCTAATCAAGTTTTTTGGGGTCGAGGTGCCGTAAAGCACTAAATC7250GGAACCCTAAAGGGAGCCCCCGATTTAGAGCTTGACGGGGAAAGCCGGCG7300AACGTGGCGAGAAAGGAAGGGAAGAAAGCGAAAGGAGCGGGCGCTAGGGC7350GCTGGCAAGTGTAGCGGTCACGCTGCGCGTAACCACCACACCCGCCGCGC7400TTAATGCGCCGCTACAGGGCGCGTAAAAGGATCTAGGTGAAGATCCTTTT7450TGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAG7500CGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTT7550CTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGT7600GGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTG7650GCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTAG7700TTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCT7750GCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTA7800CCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGC7850TGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACAC7900CGAACTGAGATACCTACAGCGTGAGCATTGAGAAAGCGCCACGCTTCCCG7950AAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGA8000GAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCC8050TGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGT8100CAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGG8150TTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATC8200CCCTGATTCTGTGGATAACCGTATTACCGCCTTTGAGTGAGCTGATACCG8250CTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCG8300GAAGAGCGCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTC8350ACACCGCATATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGT8400TAAGCCAGTATACACTCCGCTATCGCTACGTGACTGGGTCATGGCTGCGC8450CCCGACACCCGCCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTC8500CCGGCATCCGCTTACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTG8550TCAGAGGTTTTCACCGTCATCACCGAAACGCGCGAGGCAG8590(2) INFORMATION FOR SEQ ID NO:71:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:ArgProAspPheCysLeuLeuProAlaGluThrGlyProCysArgAla151015MetIleProArgPheTyrTyrAsnAlaLysSerGlyLysCysGluPro202530PheIleTyrGlyGlyCysGlyGlyAsnAlaAsnAsnPheLysThrGlu354045GluGluCysArgArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:72:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:147 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:AlaValLeuProGlnGluGluGluGlySerGlyGlyGlyGlnLeuVal151015ThrGluValThrLysLysGluAspSerCysGlnLeuGlyTyrSerAla202530GlyProCysMetGlyMetThrSerArgTyrPheTyrAsnGlyThrSer354045MetAlaCysGluThrPheGlnTyrGlyGlyCysMetGlyAsnGlyAsn505560AsnPheValThrGluLysGluCysLeuGlnThrCysArgThrValAla65707580AlaCysAsnLeuProIleValArgGlyProCysArgAlaPheIleGln859095LeuTrpAlaPheAspAlaValLysGlyLysCysValLeuPheProTyr100105110GlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSerGluLysGluCys115120125ArgGluTyrCysGlyValProGlyAspGlyAspGluGluLeuLeuArg130135140PheSerAsn145(2) INFORMATION FOR SEQ ID NO:73:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:ValArgGluValCysSerGluGlnAlaGluThrGlyProCysArgAla151015MetIleSerArgTrpTyrPheAspValThrGluGlyLysCysAlaPro202530PhePheTyrGlyGlyCysGlyGlyAsnArgAsnAsnPheAspThrGlu354045GluTyrCysMetAlaValCysGlySerAla5055(2) INFORMATION FOR SEQ ID NO:74:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:ArgAsnArgGluValCysSerGluGlnAlaGluThrGlyProCysArg151015AlaMetIleSerArgTrpTyrPheAspValThrGluGlyLysCysAla202530ProPhePheTyrGlyGlyCysGlyGlyAsnArgAsnAsnPheAspThr354045GluGluTyrCysMetAlaValCysGlySerAla5055(2) INFORMATION FOR SEQ ID NO:75:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:ThrValAlaAlaCysAsnLeuProIleValArgGlyProCysArgAla151015PheIleGlnLeuTrpAlaPheAspAlaValLysGlyLysCysValLeu202530PheProTyrGlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSerGlu354045LysGluCysArgGluTyrCysGlyValPro5055(2) INFORMATION FOR SEQ ID NO:76:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:LysProAspPheCysPheLeuGluGluAspProGlyIleCysArgGly151015TyrIleThrArgTyrPheTyrAsnAsnGlnThrLysGlnCysGluArg202530PheLysTyrGlyGlyCysLeuGlyAsnMetAsnAsnPheGluThrLeu354045GluGluCysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:77:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:MetHisSerPheCysAlaPheLysAlaAspAspGlyProCysLysAla151015IleMetLysArgPhePhePheAsnIlePheThrArgGlnCysGluGlu202530PheIleTyrGlyGlyCysGluGlyAsnGlnAsnArgPheGluSerLeu354045GluGluCysLysLysMetCysThrArgAsp5055(2) INFORMATION FOR SEQ ID NO:78:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:LeuProAsnValCysAlaPheProMetGluLysGlyProCysGlnThr151015TyrMetThrArgTrpPhePheAsnPheGluThrGlyGluCysGluLeu202530PheAlaTyrGlyGlyCysGlyGlyAsnSerAsnAsnPheLeuArgLys354045GluLysCysGluLysPheCysLysPheThr5055(2) INFORMATION FOR SEQ ID NO:79:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:GluThrAspIleCysLysLeuProLysAspGluGlyThrCysArgAsp151015PheIleLeuLysTrpTyrTyrAspProAsnThrLysSerCysAlaArg202530PheTrpTyrGlyGlyCysGlyGlyAsnGluAsnLysPheGlySerGln354045LysGluCysGluLysValCysAlaProVal5055(2) INFORMATION FOR SEQ ID NO:80:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:AsnAlaGluIleCysLeuLeuProLeuAspTyrGlyProCysArgAla151015LeuLeuLeuArgTyrTyrTyrAspArgTyrThrGlnSerCysArgGln202530PheLeuTyrGlyGlyCysGluGlyAsnAlaAsnAsnPheTyrThrTrp354045GluAlaCysAspAspAlaCysTrpArgIle5055(2) INFORMATION FOR SEQ ID NO:81:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:ValProLysValCysArgLeuGlnValSerValAspAspGlnCysGlu151015GlySerThrGluLysTyrPhePheAsnLeuSerSerMetThrCysGlu202530LysPhePheSerGlyGlyCysHisArgAsnArgIleGluAsnArgPhe354045ProAspGluAlaThrCysMetGlyPheCysAlaProLys505560(2) INFORMATION FOR SEQ ID NO:82:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:IleProSerPheCysTyrSerProLysAspGluGlyLeuCysSerAla151015AsnValThrArgTyrTyrPheAsnProArgTyrArgThrCysAspAla202530PheThrTyrThrGlyCysGlyGlyAsnAspAsnAsnPheValSerArg354045GluAspCysLysArgAlaCysAlaLysAla5055(2) INFORMATION FOR SEQ ID NO:83:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:LysProAspPheCysPheLeuGluGluAspProGlyIleCysValGly151015TyrPheThrArgTyrPheTyrAsnAsnGlnThrLysGlnCysGluArg202530PheLysTyrGlyGlyCysLeuGlyAsnMetAsnAsnPheGluThrLeu354045GluGluCysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:84:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:LysProAspPheCysPheLeuGluGluAspProGlyIleCysValGly151015PhePheThrArgTyrPheTyrAsnAsnGlnThrLysGlnCysGluArg202530PheValTyrGlyGlyCysLeuGlyAsnMetAsnAsnPheGluThrLeu354045GluGluCysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:85:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:LysProAspPheCysPheLeuGluGluAspProGlyIleCysValGly151015PhePheThrArgTyrPheTyrAsnAlaGlnThrLysGlnCysGluArg202530PheValTyrGlyGlyCysLeuGlyAsnMetAsnAsnPheGluThrLeu354045GluGluCysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:86:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:LysProAspPheCysPheLeuGluGluAspProGlyProCysValGly151015PhePheGlnArgTyrPheTyrAsnAlaGlnThrLysGlnCysGluArg202530PheValTyrGlyGlyCysGlnGlyAsnMetAsnAsnPheGluThrLeu354045GluGluCysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:87:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:56 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:AspPheCysPheLeuGluGluAspProGlyProCysValGlyPhePhe151015ThrArgTyrPheTyrAsnAsnGlnThrLysGlnCysGluArgPheVal202530TyrGlyGlyCysGlnGlyAsnMetAsnAsnPheGluThrLeuGluGlu354045CysLysAsnIleCysGluAspGly5055(2) INFORMATION FOR SEQ ID NO:88:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:GlyProSerTrpCysLeuThrProAlaAspArgGlyLeuCysValAla151015AsnPheAsnArgPheTyrTyrAsnSerValIleGlyLysCysArgPro202530PheLysTyrSerGlyCysGlyGlyAsnGluAsnAsnPheThrSerLys354045GlnGluCysLeuArgAlaCysLysLysGly5055(2) INFORMATION FOR SEQ ID NO:89:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:GlyProSerTrpCysLeuThrProAlaAspArgGlyLeuCysValAla151015PhePheAsnArgPheTyrTyrAsnSerValIleGlyLysCysArgPro202530PheLysTyrSerGlyCysGlyGlyAsnGluAsnAsnPheLysSerLys354045GlnGluCysLeuArgAlaCysLysLysGly5055(2) INFORMATION FOR SEQ ID NO:90:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:GlyProSerTrpCysLeuThrProAlaValArgGlyProCysValAla151015PhePheAsnArgPheTyrTyrAsnSerValIleGlyLysCysArgPro202530PheValTyrGlyGlyCysGlyGlyAsnGluAsnAsnPheLysSerLys354045GlnGluCysLeuArgAlaCysLysLysGly5055(2) INFORMATION FOR SEQ ID NO:91:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:GlnAspHisProLysPheCysTyrLeuProAlaAspProGlyArgCys151015LysAlaHisIleProArgPheTyrTyrAspSerAlaSerAsnLysCys202530AsnLysPheIleTyrGlyGlyCysProGlyAsnAlaAsnAsnPheLys354045ThrTrpAspGluCysArgGlnThrCysGlyAlaSerAla505560(2) INFORMATION FOR SEQ ID NO:92:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:ArgAspArgProLysPheCysTyrLeuProAlaAspProGlyArgCys151015LeuAlaTyrMetProArgPheTyrTyrAsnProAlaSerAsnLysCys202530GluLysPheIleTyrGlyGlyCysArgGlyAsnAlaAsnAsnPheLys354045ThrTrpAspGluCysArgHisThrCysValAlaSerGlyIleGlnPro505560Arg65(2) INFORMATION FOR SEQ ID NO:93:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:PheCysTyrLeuProAspAspProGlyValCysLysAlaHisIlePro151015ArgPheTyrTyrAsnProAlaSerAsnLysCysLysAsnPheIleTyr202530GlyGlyCysGlyGlyAsnAlaAsnAsnPheGluThrArgAlaGluCys354045ArgHisThrCysValAlaSerGlyLysGlyGlyProArg505560(2) INFORMATION FOR SEQ ID NO:94:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:ArgProAspPheCysGluLeuProAlaGluThrGlyLeuCysLysAla151015TyrIleArgSerPheHisTyrAsnLeuAlaAlaGlnGlnCysLeuGln202530PheIleTyrGlyGlyCysGlyGlyAsnAlaAsnArgPheLysThrIle354045AspGluCysArgArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:95:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:HisAspArgProThrPheCysAsnLeuProProGluSerGlyArgCys151015ArgGlyHisIleArgArgIleTyrTyrAsnLeuGluSerAsnLysCys202530LysValPhePheTyrGlyGlyCysGlyGlyAsnAlaAsnAsnPheGlu354045ThrArgAspGluCysArgGluThrCysGlyGlyLys505560(2) INFORMATION FOR SEQ ID NO:96:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:LysAsnArgProThrPheCysAsnLeuLeuProGluThrGlyArgCys151015AsnAlaLeuIleProAlaPheTyrTyrAsnSerHisLeuHisLysCys202530GlnLysPheAsnTyrGlyGlyCysGlyGlyAsnAlaAsnAsnPheLys354045ThrIleAspGluCysGlnArgThrCysAlaAlaLysTyrGlyArgSer505560Ser65(2) INFORMATION FOR SEQ ID NO:97:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:IleAsnGlyAspCysGluLeuProLysValValGlyProCysArgAla151015ArgPheProArgTyrTyrTyrAsnSerSerSerLysArgCysGluLys202530PheIleTyrGlyGlyCysGlyGlyAsnAlaAsnAsnPheHisThrLeu354045GluGluCysGluLysValCysGlyValArgSerValGlyArg505560(2) INFORMATION FOR SEQ ID NO:98:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:GluValCysSerGluGlnAlaGluThrGlyProCysArgAlaMetIle151015SerArgTrpTyrPheAspValThrGluGlyLysCysAlaProPhePhe202530TyrGlyGlyCysGlyGlyAsnArgAsnAsnPheAspThrGluGluTyr354045CysMetAlaValCysGlySerValMetSerGlnSerLeuArg505560(2) INFORMATION FOR SEQ ID NO:99:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:ArgProArgPheCysGluLeuProAlaGluThrGlyLeuCysLysAla151015ArgIleArgSerPheHisTyrAsnArgAlaAlaGlnGlnCysLeuGlu202530PheIleTyrGlyGlyCysGlyGlyAsnAlaAsnArgPheLysThrIle354045AspGluCysHisArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:100:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:SerValGluGluValValArgGluValCysSerGluGlnAlaGluThr151015GlyProCysArgAlaMetIleSerArgTrpTyrPheAspValThrGlu202530GlyLysCysValProPhePheTyrGlyGlyCysGlyGlyAsnArgAsn354045AsnPheAspThrGluGluTyrCysMetAlaValCysGlySerValSer505560ThrGlnSerLeuLeu65(2) INFORMATION FOR SEQ ID NO:101:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:ValValArgGluValCysSerGluGlnAlaGluThrGlyProCysArg151015AlaMetIleSerArgTrpTyrPheAspValThrGluGlyLysCysAla202530ProPhePheTyrGlyGlyCysGlyGlyAsnArgAsnAsnPheAspThr354045GluGluTyrCysMetAlaValCysGlySerValMetSerGlnSerLeu505560Arg65(2) INFORMATION FOR SEQ ID NO:102:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:AlaAlaLysTyrCysLysLeuProLeuArgIleGlyProCysLysArg151015LysIleProSerPheTyrTyrLysTrpLysAlaLysGlnCysLeuPro202530PheAspTyrSerGlyCysGlyGlyAsnAlaAsnArgPheLysThrIle354045GluGluCysArgArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:103:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:AlaAlaLysTyrCysLysLeuProValArgTyrGlyProCysLysLys151015LysPheProSerPheTyrTyrAsnTrpLysAlaLysGlnCysLeuPro202530PheAsnTyrSerGlyCysGlyGlyAsnAlaAsnArgPheLysThrIle354045GluGluCysArgArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:104:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:AlaAlaLysTyrCysLysLeuProValArgTyrGlyProCysLysLys151015LysIleProSerPheTyrTyrLysTrpLysAlaLysGlnCysLeuPro202530PheAspTyrSerGlyCysGlyGlyAsnAlaAsnArgPheLysThrIle354045GluGluCysArgArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:105:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:ArgProAspPheCysLeuGluProProTyrThrGlyProCysLysAla151015ArgIleIleArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnPro202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerSer354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:106:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:LeuGlnHisArgThrPheCysLysLeuProAlaGluProGlyProCys151015LysAlaSerIleProAlaPheTyrTyrAsnTrpAlaAlaLysLysCys202530GlnLeuPheHisTyrGlyGlyCysLysGlyAsnAlaAsnArgPheSer354045ThrIleGluLysCysArgHisAlaCysValGly5055(2) INFORMATION FOR SEQ ID NO:107:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:SerValGluGluValValArgGluValCysSerGluGlnAlaGluThr151015GlyProCysArgAlaMetIleSerArgTrpTyrPheAspValThrGlu202530GlyLysCysAlaProPhePheTyrGlyGlyCysGlyGlyAsnArgAsn354045AsnPheAspThrGluGluTyrCysMetAlaValCysGlySerValSer505560SerGlnSerLeuLeu65(2) INFORMATION FOR SEQ ID NO:108:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:ArgProGlyPheCysGluLeuProAlaAlaLysGlyLeuCysLysAla151015HisLysProAlaPheTyrTyrAsnLysAspSerHisArgCysGlnLys202530PheIleTyrGlyGlyCysGlyGlyAsnAlaAsnArgPheArgThrIle354045AspGluCysAsnArgThrCysValGly5055(2) INFORMATION FOR SEQ ID NO:109:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:HisAspArgProThrPheCysAsnLeuAlaProGluSerGlyArgCys151015ArgGlyHisLeuArgArgIleTyrTyrAsnLeuGluSerAsnLysCys202530LysValPhePheTyrGlyGlyCysGlyGlyAsnAlaAsnAsnPheGlu354045ThrArgAspGluCysArgGluThrCysGlyGlyLys505560(2) INFORMATION FOR SEQ ID NO:110:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:ArgProAspPheCysLeuGluProProTyrThrGlyProCysLysAla151015ArgMetIleArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGlnPro202530PheValTyrGlyGlyCysArgAlaLysArgAsnAsnPheLysSerAla354045GluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:111:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:GlxArgProAspPheCysLeuGluProProTyrThrGlyProCysLys151015AlaArgMetIleArgTyrPheTyrAsnAlaLysAlaGlyLeuCysGln202530ProPheValTyrGlyGlyCysArgAlaLysSerAsnAsnPheLysSer354045AlaGluAspCysMetArgThrCysGlyGlyAla5055(2) INFORMATION FOR SEQ ID NO:112:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:ThrGluArgProAspPheCysLeuGluProProTyrThrGlyProCys151015LysAlaAlaMetIleArgTyrPheTyrAsnAlaLysAlaGlyPheCys202530GluThrPheValTyrGlyGlyCysArgAlaLysSerAsnAsnPheLys354045SerAlaGluAspCysMetArgThrCysGlyGlyAla505560(2) INFORMATION FOR SEQ ID NO:113:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:66 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:GlnGlyAspLysArgAspIleCysArgLeuProProGluGlnGlyPro151015CysLysGlyArgIleProArgTyrPheTyrAsnProAlaSerArgMet202530CysGluSerPheIleTyrGlyGlyCysLysGlyAsnLysAsnAsnPhe354045LysThrLysAlaGluCysValArgAlaCysArgProProGluArgPro505560GlyVal65(2) INFORMATION FOR SEQ ID NO:114:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:GlnAlaLysAlaGlnArgProAspPheCysLeuGluProProTyrThr151015GlyProCysLysAlaArgIleIleArgTyrPheTyrAsnAlaLysAla202530GlyLeuCysGlnThrPheValTyrGlyGlyCysArgAlaLysArgAsn354045AsnPheLysSerAlaGluAspCysMetArgThrCysGlyGlyAlaIle505560GlyProTrpGluAsn65(2) INFORMATION FOR SEQ ID NO:115:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:GlnAlaLysAlaGlnArgProAspPheCysLeuGluProProTyrThr151015GlyProCysLysAlaLysMetIleArgTyrPheTyrAsnAlaLysAla202530GlyPheCysGluThrPheValTyrGlyGlyCysLysAlaLysSerAsn354045AsnPheArgSerAlaGluAspCysMetArgThrCysGlyGlyAlaIle505560GlyProArgGluAsn65(2) INFORMATION FOR SEQ ID NO:116:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:GlnGlyArgProSerPheCysAsnLeuProAlaGluThrGlyProCys151015LysAlaSerPheArgGlnTyrTyrTyrAsnSerLysSerGlyGlyCys202530GlnGlnPheIleTyrGlyGlyCysArgGlyAsnGlnAsnArgPheAsp354045ThrThrGlnGlnCysGlnGlyValCysVal5055(2) INFORMATION FOR SEQ ID NO:117:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:ArgProTyrAlaCysGluLeuIleValAlaAlaGlyProCysMetPhe151015PheIleSerAlaPheTyrTyrSerLysGlyAlaAsnLysCysTyrPro202530PheThrTyrSerGlyCysArgGlyAsnAlaAsnArgPheLysThrIle354045GluGluCysArgArgThrCysValVal5055(2) INFORMATION FOR SEQ ID NO:118:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:GlnProArgArgLysLeuCysIleLeuHisArgAsnProGlyArgCys151015TyrAspLysIleProAlaPheTyrTyrAsnGlnLysLysLysGlnCys202530GluArgPheAspTrpSerGlyCysGlyGlyAsnSerAsnArgPheLys354045ThrIleGluGluCysArgArgThrCysIleGly5055(2) INFORMATION FOR SEQ ID NO:119:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:GlnProArgArgLysLeuCysIleLeuHisArgAsnProGlyArgCys151015TyrAspLysIleProAlaPheTyrTyrAsnGlnLysLysLysGlnCys202530GluGlyPheThrTrpSerGlyCysGlyGlyAsnSerAsnArgPheLys354045ThrIleGluGluCysArgArgThrCysIleGly5055(2) INFORMATION FOR SEQ ID NO:120:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:64 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:GluValValArgGluValCysSerGluGlnAlaGluThrGlyProCys151015ArgAlaMetIleSerArgTrpTyrTyrAspValThrGluSerLysCys202530AlaGlnPheIleTyrGlyGlyCysGlyGlyAsnArgAsnAsnPheGlu354045SerAspAspTyrCysMetAlaValCysGlySerValIleProAlaThr505560(2) INFORMATION FOR SEQ ID NO:121:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:GlnProLeuArgLysLeuCysIleLeuHisArgAsnProGlyArgCys151015TyrGlnLysIleProAlaPheTyrTyrAsnGlnLysLysLysGlnCys202530GlxGlyPheThrTrpSerGlyCysGlyGlyAsnSerAsnArgPheLys354045ThrIleGluGluCysArgArgThrCysIleArgLys505560(2) INFORMATION FOR SEQ ID NO:122:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:TrpGlnProProTrpTyrCysLysGluProValArgIleGlySerCys151015LysLysGlnPheSerSerPheTyrPheLysTrpThrAlaLysLysCys202530LeuProPheLeuPheSerGlyCysGlyGlyAsnAlaAsnArgPheGln354045ThrIleGlyGluCysArgLysLysCysLeuGlyLys505560(2) INFORMATION FOR SEQ ID NO:123:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:67 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:PheGlnThrProProAspLeuCysGlnLeuProGlnAlaArgGlyPro151015CysLysAlaAlaLeuLeuArgTyrPheTyrAsnSerThrSerAsnAla202530CysGluProPheThrTyrGlyGlyCysGlnGlyAsnAsnAsnAsnPhe354045GluThrThrGluMetCysLeuArgIleCysGluProProGlnGlnThr505560AspLysSer65(2) INFORMATION FOR SEQ ID NO:124:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:ThrPheGlnLysGlyLysProAspPheCysPheLeuGluGluAspPro151015GlyIleCysArgGlyTyrIleThrArgTyrPheTyrAsnAsnGlnSer202530LysGlnCysGluArgPheLysTyrGlyGlyCysLeuGlyAsnLeuAsn354045AsnPheGluSerLeuGluGluCysLysAsnThrCysGluAsnProThr505560SerAspPheGlnVal65(2) INFORMATION FOR SEQ ID NO:125:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:ArgTrpAlaPheHisGlyProSerTrpCysLeuProProAlaAspArg151015GlyLeuCysGlnAlaAsnGluIleArgPhePheTyrAsnAlaIleIle202530GlyLysCysArgProPheLysTyrSerGlyCysGlyGlyAsnGluAsn354045AsnPheThrSerLysLysAlaCysIleThrAlaCysLysLysGlyPhe505560IleProLysSerIle65(2) INFORMATION FOR SEQ ID NO:126:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:ValAspLysSerAlaCysLeuGlnProLysGluValGlyProCysArg151015LysSerAspPheValPhePheTyrAsnAlaAspThrLysAlaCysGlu202530GluPheLeuTyrGlyGlyCysArgGlyAsnAspAsnArgPheAsnThr354045LysGluGluCysGluLysLeuCysLeu5055(2) INFORMATION FOR SEQ ID NO:127:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:ArgThrValGlnAlaCysAsnLeuProIleValArgGlyProCysArg151015AlaGlyIleGluLeuTrpAlaPheAspAlaValLysGlyLysCysVal202530ArgPheIleTyrGlyGlyCysAsnGlyAsnGlyAsnGlnPheTyrSer354045GlnLysGluCysLysGluTyrCysGlyIleProGlyGluAlaAspGlu505560Glu65(2) INFORMATION FOR SEQ ID NO:128:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:LysGluAspSerCysGlnLeuGlyTyrSerGlnGlyProCysLeuGly151015MetPheLysArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheTyrTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheProSerGlu354045LysGluCysLeuGlnThrCysArgThrValGlnAla505560(2) INFORMATION FOR SEQ ID NO:129:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:LysGluAspSerCysGlnLeuGlyTyrSerGlnGlyProCysLeuGly151015MetIleLysArgTyrPheTyrAsnGlySerSerMetAlaCysGluThr202530PheHisTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValSerGln354045LysGluCysLeuGlnThrCysArgThrValSerAla505560(2) INFORMATION FOR SEQ ID NO:130:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:56 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:LysGluAspSerCysGluLeuGlyTyrSerGlnGlyProCysLeuGly151015MetIleLysArgTyrPheTyrAsnGlySerSerMetAlaCysGluThr202530PheHisTyrGlyGlyCysMetGlyAsnGlyAsnAsnPheValSerGln354045LysGluCysLeuGlnThrCysArg5055(2) INFORMATION FOR SEQ ID NO:131:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:ProLeuGlnLysProThrHisSerPheCysAlaMetLysValAspAsp151015GlyProCysArgAlaTyrIleLysArgPhePhePheAsnIleLeuThr202530HisGlnCysGluGluPheIleTyrGlyGlyCysGluGlyAsnGluAsn354045ArgPheGluSerLeuGluGluCysLysGluLysCysAlaArgAspTyr505560ProLysMetThrThr65(2) INFORMATION FOR SEQ ID NO:132:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:LysGluAspSerCysGlnLeuAspHisAlaGlnGlyProCysLeuGly151015MetIleSerArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheGlnTyrGlyGlyCysLeuGlyAsnGlyAsnAsnPheAlaSerGln354045LysGluCysLeuGlnThrCysArgThrValAlaAla505560(2) INFORMATION FOR SEQ ID NO:133:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:ArgThrValAlaAlaCysAsnLeuProIleValGlnGlyProCysArg151015AlaPheIleArgLeuTrpAlaPheAspAlaAlaGlnGlyLysCysVal202530LeuPheThrTyrGlyGlyCysArgGlyAsnGlyAsnLysPheTyrSer354045GlnLysGluCysLysGluTyrCysGlyIleProGlyAspGlyAspGlu505560Glu65(2) INFORMATION FOR SEQ ID NO:134:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:58 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:XaaXaaXaaXaaCysXaaXaaXaaXaaXaaXaaGlyProCysXaaXaa151015XaaPheXaaArgXaaXaaXaaXaaXaaXaaXaaXaaXaaCysXaaXaa202530PheXaaTyrGlyGlyCysXaaXaaXaaGlyAsnXaaPheXaaXaaXaa354045XaaXaaCysXaaXaaXaaCysXaaXaaXaa5055(2) INFORMATION FOR SEQ ID NO:135:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:249 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:ATGAAGAAGCTTCTCTTCGCCATTCCTCTGGTGGTACCTTTCTATTCCGG50CGCCAAGCCTGACTTCTGCTTCCTCGAGGAGGATCCCGGGATTTGCCGCG100GTTATATTACGCGTTATTTCTATAATAACCAGACTAAGCAATGTGAGCGG150TTCAAGTATGGTGGTTGCCTAGGTAATATGAACAACTTCGAGACTCTAGA200AGAGTGTAAGAACATATGTGAGGATGGTGGTGCTGAGACTGTTGAGTCT249(2) INFORMATION FOR SEQ ID NO:136:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:83 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:MetLysLysLeuLeuPheAlaIleProLeuValValProPheTyrSer151015GlyAlaLysProAspPheCysPheLeuGluGluAspProGlyIleCys202530ArgGlyTyrIleThrArgTyrPheTyrAsnAsnGlnThrLysGlnCys354045GluArgPheLysTyrGlyGlyCysLeuGlyAsnMetAsnAsnPheGlu505560ThrLeuGluGluCysLysAsnIleCysGluAspGlyGlyAlaGluThr65707580ValGluSer(2) INFORMATION FOR SEQ ID NO:137:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:189 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:GCGGCCGAGATGCATTCCTTCTGCGCTTTCAAAGCTGATGACGGTCCGTG50TAAAGCTATCATGAAACGTTTCTTCTTCAACATTTTCACGCGTCAGTGCG100AGGAATTCATTTACGGTGGTTGTGAAGGTAACCAGAACCGGTTCGAATCT150CTAGAGGAATGTAAGAAGATGTGCACTCGTGACGGCGCC189(2) INFORMATION FOR SEQ ID NO:138:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:63 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:AlaAlaGluMetHisSerPheCysAlaPheLysAlaAspAspGlyPro151015CysLysAlaIleMetLysArgPhePhePheAsnIlePheThrArgGln202530CysGluGluPheIleTyrGlyGlyCysGluGlyAsnGlnAsnArgPhe354045GluSerLeuGluGluCysLysLysMetCysThrArgAspGlyAla505560(2) INFORMATION FOR SEQ ID NO:139:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:189 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:GCGGCCGAGATGCATTCCTTCTGCGCTTTCAAAGCTNRTRVSGGTCNTTG50TRTTGSTNTCTTCMNSCGTTDSTTCTTCAACATTTTCACGCGTCAGTGCS100WGVHATTCVHATACGGTGGTTGTVHGGSTAACSRGAACCGGTTCGAATCT150CTAGAGGAATGTAAGAAGATGTGCACTCGTGACGGCGCC189(2) INFORMATION FOR SEQ ID NO:140:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:63 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:AlaAlaGluMetHisSerPheCysAlaPheLysAlaXaaXaaGlyXaa151015CysXaaXaaXaaPheXaaArgXaaPhePheAsnIlePheThrArgGln202530CysXaaXaaPheXaaTyrGlyGlyCysXaaXaaAsnXaaAsnArgPhe354045GluSerLeuGluGluCysLysLysMetCysThrArgAspGlyAla505560(2) INFORMATION FOR SEQ ID NO:141:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:201 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:GGCGCCAAGCCTGACTTCTGCTTCCTCGAGGAGNRTVVSGGGMNTTGCRT50TGSTNWTTTTMNSCGTTDSTTCTATAATAACCAGGCTAAGCAATGTSWGV100NATTCVHATATGGTGGTTGCVHGGSTAATVBGAACAACTTCGAGACTCTA150GAAGAGTGTAAGAACATATGTGAGGATGGTGGTGCTGAGACTGTTGAGTC200T201(2) INFORMATION FOR SEQ ID NO:142:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:67 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:GlyAlaLysProAspPheCysPheLeuGluGluXaaXaaGlyXaaCys151015XaaXaaXaaPheXaaArgXaaPheTyrAsnAsnGlnAlaLysGlnCys202530XaaArgPheXaaTyrGlyGlyCysXaaXaaAsnXaaAsnAsnPheGlu354045ThrLeuGluGluCysLysAsnIleCysGluAspGlyGlyAlaGluThr505560ValGluSer65(2) INFORMATION FOR SEQ ID NO:143:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:234 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:ATGAAGAAGCTTCTCTTCGCCATTCCTCTGGTGGTACCTTTCTATTCCGG50TGCTGGGCCCTCTTGGTGCCTTACGCCGGCNGACCGCGGTCTCTGCAGAG100CTAATGAGAATCGTTTCTACTACAACTCGAGTATTGGTAAGTGCAGACCT150TTTAAATATTCTGGTTGTGGTGGCAATGAGAATAATTTCGAATCTAAGCA200AGAGTGCCTGCGCGCATGCAAGAAGGGTGGCGCC234(2) INFORMATION FOR SEQ ID NO:144:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:78 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:MetLysLysLeuLeuPheAlaIleProLeuValValProPheTyrSer151015GlyAlaGlyProSerTrpCysLeuThrProAlaAspArgGlyLeuCys202530ArgAlaAsnGluAsnArgPheTyrTyrAsnSerSerIleGlyLysCys354045ArgProPheLysTyrSerGlyCysGlyGlyAsnGluAsnAsnPheGlu505560SerLysGlnGluCysLeuArgAlaCysLysLysGlyGlyAla657075(2) INFORMATION FOR SEQ ID NO:145:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:180 bases(B) TYPE: nucleic acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE:other nucleic acid(A) DESCRIPTION:synthetic DNA fragment(xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:GGGCCCTCTTGGTGCCTTACGCCGGCNNRTVVSGGTMNTTGCRTTGSTNW50TTTTMNSCGTTDSTACTACAACTCGAGTATTGGTAAGTGCSDGVNATTTV100HATATRGTGGTTGTVNGGSTAATVBGAATAATTTCGAATCTAAGCAAGAG150TGCCTGCGCGCATGCAAGAAGGGTGGCGCC180(2) INFORMATION FOR SEQ ID NO:146:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:GlyProSerTrpCysLeuThrProAlaXaaXaaGlyXaaCysXaaXaa151015XaaPheXaaArgXaaTyrTyrAsnSerSerIleGlyLysCysXaaXaa202530PheXaaTyrXaaGlyCysXaaXaaAsnXaaAsnAsnPheGluSerLys354045GlnGluCysLeuArgAlaCysLysLysGlyGlyAla505560(2) INFORMATION FOR SEQ ID NO:147:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:IleAlaAlaCysAsnLeuProIleValGlnGlyProCysArgAlaGly151015AlaGluLeuLeuAlaPheAspAlaAlaGlnGlyLysCysIleGlnPhe202530IleTyrGlyGlyCysLysGlyAsnAsnAsnLysPheTyrSerGluPro354045LysCysLysTrpTyrCysGlyValProGlyAspGlyTyr505560(2) INFORMATION FOR SEQ ID NO:148:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:IleAlaAlaCysAsnLeuProIleValGlnGlyProCysArgAlaPhe151015AlaGluLeuLeuAlaPheAspAlaAlaGlnGlyLysCysIleGlnPhe202530IleTyrGlyGlyCysLysGlyAsnAsnAsnLysPheTyrSerGluPro354045LysCysLysTrpTyrCysGlyValProGlyAspGlyTyr505560(2) INFORMATION FOR SEQ ID NO:149:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:ArgThrValSerAlaCysSerLeuProIleValGlnGlyProCysArg151015AlaPheIleArgLeuTrpAlaPheAspAlaAlaGlnGlyLysCysVal202530LeuPheAsnTyrGlyGlyCysGlnGlyAsnGlyAsnLysPheTyrSer354045GlnLysGluCysLysGluTyrCysGlyValProGlyGluGluAspGlu505560Glu65(2) INFORMATION FOR SEQ ID NO:150:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:61 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:ThrGluArgGlyPheLeuAspCysThrSerProProValThrGlyPro151015CysArgAlaGlyPheLysArgTyrAsnTyrAsnThrArgThrLysGln202530CysGluProPheLysTyrGlyGlyCysLysGlyAsnGlyAsnArgTyr354045LysSerGluGlnAspCysLeuAspAlaCysSerGlyPhe505560(2) INFORMATION FOR SEQ ID NO:151:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:56 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:GlySerIleCysLeuGluProLysValValGlyProCysThrAlaTyr151015PheProArgPheTyrPheAspSerGluThrGlyLysCysThrProPhe202530IleTyrGlyGlyCysGluGlyAsnSerTyrValAspGluLysLeuHis354045AlaCysArgAlaIleCysArgAla5055(2) INFORMATION FOR SEQ ID NO:152:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:65 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:ArgThrValGluAlaCysAsnLeuProIleValGlnGlyProCysArg151015AlaPheIleGlnLeuTrpAlaPheAspAlaValLysGlyLysCysVal202530ArgPheSerTyrGlyGlyCysLysGlyAsnGlyAsnLysPheTyrSer354045GlnLysGluCysLysGluTyrCysGlyIleProGlyGluAlaAspGlu505560Arg65(2) INFORMATION FOR SEQ ID NO:153:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:LysAlaAspSerCysGlnLeuAspTyrSerGlnGlyProCysLeuGly151015LeuPheLysArgTyrPheTyrAsnGlyThrSerMetAlaCysGluThr202530PheLeuTyrGlyGlyCysMetGlyAsnLeuAsnAsnPheLeuSerGln354045LysGluCysLeuGlnThrCysArgThrValGluAla505560(2) INFORMATION FOR SEQ ID NO:154:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:AspLysProThrThrLysProIleCysGluGlnAlaPheGlyAsnSer151015GlyProCysPheAlaTyrIleLysLeuTyrSerTyrAsnGlnLysThr202530LysLysCysGluGluPheIleTyrGlyGlyCysLysGlyAsnAspAsn354045ArgPheAspThrLeuAlaGluCysGluGlnLysCysIleLys505560(2) INFORMATION FOR SEQ ID NO:155:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:AspLysProThrThrLysProIleCysGluGlnAlaPheGlyAsnSer151015GlyProCysPheAlaTyrIleLysLeuTyrSerTyrAsnGlnLysThr202530LysLysCysGluGluPheIleTyrGlyGlyCysGlnGlyAsnAspAsn354045ArgPheIleThrLeuAlaGluCysGluGlnLysCysIleLys505560(2) INFORMATION FOR SEQ ID NO:156:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:57 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:ArgProArgPheCysGluLeuAlaProSerAlaGlySerCysPheGly151015PheValSerSerTyrTyrTyrAsnArgTyrSerAsnThrCysHisSer202530PheThrTyrSerGlyCysGlyLysAsnAlaAsnArgPheArgThrIle354045AspGluCysAsnArgThrCysValVal5055(2) INFORMATION FOR SEQ ID NO:157:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:69 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:GluGlyProGluAsnValMetAspIleCysLeuLeuGlnLysGluGlu151015GlyThrCysArgAspPheValLeuLysTrpHisTyrAspLeuLysThr202530LysSerCysAlaArgPheTrpTyrGlyGlyCysGlyGlyAsnGluAsn354045ArgPheAsnThrGlnLysGluCysGluLysAlaCysSerProGlyAsn505560IleSerProGlyVal65(2) INFORMATION FOR SEQ ID NO:158:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:ArgGlnArgHisArgAspCysAspLysProProAspLysGlyAsnCys151015GlyProValArgAlaPheTyrTyrAspThrArgLeuLysThrCysLys202530AlaPheGlnTyrArgGlyCysAspGlyAspHisGlyAsnPheLysThr354045GluThrLeuCysArgCysGluCysLeuValTyrPro505560(2) INFORMATION FOR SEQ ID NO:159:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:63 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:AspGluProThrThrAspLeuProIleCysGluGlnAlaPheGlyAsp151015AlaGlyLeuCysPheGlyTyrMetLysLeuTyrSerTyrAsnGlnGlu202530ThrLysAsnCysGluGluPheIleTyrGlyGlyCysGlnGlyAsnAsp354045AsnArgPheSerThrLeuAlaGluCysGluGlnLysCysIleAsn505560(2) INFORMATION FOR SEQ ID NO:160:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:60 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:ArgLysArgHisProAspCysAspLysProProAspThrLysIleCys151015GlnThrValArgAlaPheTyrTyrLysProSerAlaLysArgCysVal202530GlnPheArgTyrGlyGlyCysAspGlyAspHisGlyAsnPheLysSer354045AspHisLeuCysArgCysGluCysGluLeuTyrArg505560(2) INFORMATION FOR SEQ ID NO:161:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:59 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:ArgGlnArgHisArgAspCysAspLysProProAspLysGlyAsnCys151015GlyProValArgAlaPheTyrTyrAspThrArgLeuLysThrCysLys202530AlaPheGlnTyrArgGlyCysAspGlyAspHisGlyAsnPheLysSer354045AspHisLeuCysArgCysGluCysGluLeuTyr5055(2) INFORMATION FOR SEQ ID NO:162:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:62 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:LysAsnProGluCysGlyGluProHisSerLeuAspGlySerProAsn151015GlyIleSerCysArgGlyTyrPheProSerTrpSerTyrAsnProAsp202530AlaGlnGlnCysValSerPheValTyrGlyGlyCysGlyGlyAsnAsn354045AsnArgPheGlySerGlnAsnGluCysGluGluArgCysIle505560(2) INFORMATION FOR SEQ ID NO:163:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:ArgProAspPhe(2) INFORMATION FOR SEQ ID NO:164:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:8 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:GluAlaGluAlaArgProAspPhe15(2) INFORMATION FOR SEQ ID NO:165:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:LysGluAspSer1(2) INFORMATION FOR SEQ ID NO:166:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:LysGluAspPhe1(2) INFORMATION FOR SEQ ID NO:167:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:LysProAspSer1(2) INFORMATION FOR SEQ ID NO:168:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:ThrValAlaAla1(2) INFORMATION FOR SEQ ID NO:169:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:2 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:AlaAla1(2) INFORMATION FOR SEQ ID NO:170:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:2 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:GluAla1(2) INFORMATION FOR SEQ ID NO:171:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:2 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:AspPhe1(2) INFORMATION FOR SEQ ID NO:172:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:TyrThrGlyPro1(2) INFORMATION FOR SEQ ID NO:173:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:SerAlaGlyPro1(2) INFORMATION FOR SEQ ID NO:174:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:SerThrGlyPro1(2) INFORMATION FOR SEQ ID NO:175:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:ValArgGlyPro1(2) INFORMATION FOR SEQ ID NO:176:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:ValAlaMetPheProArgTyr15(2) INFORMATION FOR SEQ ID NO:177:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:ValGlyPhePheSerArgTyr15(2) INFORMATION FOR SEQ ID NO:178:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:ValGlyPhePheGlnArgTyr15(2) INFORMATION FOR SEQ ID NO:179:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:ValAlaIlePheProArgTyr15(2) INFORMATION FOR SEQ ID NO:180:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:ValAlaPhePheLysArgSer15(2) INFORMATION FOR SEQ ID NO:181:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:IleAlaPhePheProArgTyr15(2) INFORMATION FOR SEQ ID NO:182:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:IleAlaPhePheGlnArgTyr15(2) INFORMATION FOR SEQ ID NO:183:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:IleAlaLeuPheLysArgTyr15(2) INFORMATION FOR SEQ ID NO:184:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:IleGlyMetPheSerArgTyr15(2) INFORMATION FOR SEQ ID NO:185:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:IleAlaPhePheProArgTrp15(2) INFORMATION FOR SEQ ID NO:186:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:ValAlaPhePheProArgTrp15(2) INFORMATION FOR SEQ ID NO:187:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:ValAlaIlePheProArgTrp15(2) INFORMATION FOR SEQ ID NO:188:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:ValAlaPhePheProArgTrp15(2) INFORMATION FOR SEQ ID NO:189:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:ValGlyPhePheSerArgTrp15(2) INFORMATION FOR SEQ ID NO:190:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:ValAlaMetPheProArgTrp15(2) INFORMATION FOR SEQ ID NO:191:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:ValAlaPhePheProArgPhe15(2) INFORMATION FOR SEQ ID NO:192:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:ValGlyPhePheSerArgPhe15(2) INFORMATION FOR SEQ ID NO:193:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:7 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:ValAlaMetPheProArgPhe15(2) INFORMATION FOR SEQ ID NO:194:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:GlnThrPheValTyr15(2) INFORMATION FOR SEQ ID NO:195:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:195:ValLeuPheProTyr15(2) INFORMATION FOR SEQ ID NO:196:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:196:GluThrPheGlnTyr15(2) INFORMATION FOR SEQ ID NO:197:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:197:GlnThrPheValTyr15(2) INFORMATION FOR SEQ ID NO:198:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:198:GluThrPheValTyr15(2) INFORMATION FOR SEQ ID NO:199:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:199:ValLeuPheProTyr15(2) INFORMATION FOR SEQ ID NO:200:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:200:GlnThrPheLeuTyr15(2) INFORMATION FOR SEQ ID NO:201:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:201:GlnThrPheGluTyr15(2) INFORMATION FOR SEQ ID NO:202:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:202:GlnThrPheGlyTyr15(2) INFORMATION FOR SEQ ID NO:203:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:203:GlnThrPheArgTyr15(2) INFORMATION FOR SEQ ID NO:204:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:204:GlnThrPheAspTyr15(2) INFORMATION FOR SEQ ID NO:205:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:205:GlnThrPheLysTyr15(2) INFORMATION FOR SEQ ID NO:206:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:206:GlnThrPheThrTyr15(2) INFORMATION FOR SEQ ID NO:207:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:207:GlnThrPheAsnTyr15(2) INFORMATION FOR SEQ ID NO:208:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:208:GlnThrPheGlnTyr15(2) INFORMATION FOR SEQ ID NO:209:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:209:GlnThrPheHisTyr15(2) INFORMATION FOR SEQ ID NO:210:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:5 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:210:GlnThrPheProTyr15(2) INFORMATION FOR SEQ ID NO:211:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:211:MetGlyAsnGly1(2) INFORMATION FOR SEQ ID NO:212:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:212:GlnGlyAsnGly1(2) INFORMATION FOR SEQ ID NO:213:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:213:LysGlyLysGly1(2) INFORMATION FOR SEQ ID NO:214:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:214:TrpAlaLysGly1(2) INFORMATION FOR SEQ ID NO:215:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:215:ArgAlaLysGly1(2) INFORMATION FOR SEQ ID NO:216:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:216:HisAlaGluGly1(2) INFORMATION FOR SEQ ID NO:217:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:217:TrpAlaGlnGly1(2) INFORMATION FOR SEQ ID NO:218:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:218:LeuAlaGluGly1(2) INFORMATION FOR SEQ ID NO:219:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:219:HisAlaAspGly1(2) INFORMATION FOR SEQ ID NO:220:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:220:LeuAlaHisGly1(2) INFORMATION FOR SEQ ID NO:221:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:221:TrpAlaAsnGly1(2) INFORMATION FOR SEQ ID NO:222:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:222:GluGlyLysGly1(2) INFORMATION FOR SEQ ID NO:223:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:223:GluGlyTyrGly1(2) INFORMATION FOR SEQ ID NO:224:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:224:LeuGlyGluGly1(2) INFORMATION FOR SEQ ID NO:225:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:225:TrpGlyGlnGly1(2) INFORMATION FOR SEQ ID NO:226:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:226:TrpGlyGluGly1(2) INFORMATION FOR SEQ ID NO:227:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:227:TrpGlyLysGly1(2) INFORMATION FOR SEQ ID NO:228:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:228:HisGlyAsnGly1(2) INFORMATION FOR SEQ ID NO:229:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:229:TrpGlyHisGly1(2) INFORMATION FOR SEQ ID NO:230:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:230:LeuGlyHisGly1(2) INFORMATION FOR SEQ ID NO:231:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:231:LeuGlyTyrGly1(2) INFORMATION FOR SEQ ID NO:232:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:232:TrpAlaGluGly1(2) INFORMATION FOR SEQ ID NO:233:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:4 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:233:HisGlyAspGly1(2) INFORMATION FOR SEQ ID NO:234:(i) SEQUENCE CHARACTERISTICS:(A) LENGTH:51 amino acids(B) TYPE: amino acid(C) STRANDEDNESS: single(D) TOPOLOGY: linear(ii) MOLECULE TYPE: protein(xi) SEQUENCE DESCRIPTION: SEQ ID NO:234:CysXaaXaaXaaXaaXaaXaaGlyXaaCysXaaXaaXaaXaaXaaXaa151015XaaXaaTyrXaaXaaXaaXaaXaaXaaCysXaaXaaPheXaaTyrXaa202530GlyCysXaaXaaXaaXaaAsnXaaPheXaaXaaXaaXaaXaaCysXaa354045XaaXaaCys50__________________________________________________________________________

Claims

1. A protein that binds and inhibits human neutrophil elastase with a K.sub.i less than about 10 picomolar comprising an amino acid sequence picked from the set of sequences EpiNE1, EpiNE2, EpiNE3, EpiNE4, EpiNE5, EpiNE6, EpiNE7, EpiNE8, EPI-HNE-2, EPI-HNE-3, EPI-HNE-4, BITI-E7, BITI-E7-141, BITI-E7-1222, MUT1619, MUTP1, AMINO1, AMINO2, MUTQE, MUTT26A, EpiNE7.6, EpiNE7.8, EpiNE7.9, EpiNE7.31, EpiNE 7.11, EpiNE7.7, EpiNE7.4, EpiNE7.14, EpiNE7.5, EpiNE7.10, EpiNE7.20, EpiNE7.1, EpiNE7.16, EpiNE7.19, EpiNE7.12, EpiNE7.17, EpiNE7.21, EpiNE7.22, EpiNE7.23, EpiNE7.24, EpiNE7.25, EpiNE7.26, EpiNE7.27, EpiNE7.28, EpiNE7.29, EpiNE7.30, EpiNE7.32, EpiNE7.33, EpiNE7.36, EpiNE7.37, EpiNE7.38, EpiNE7.39, and EpiNE7.40.

2. A protein that binds and inhibits human neutrophil elastase with a K.sub.i less than about 10 picomolar that comprises an amino-acid sequence of at least about 51 amino acids that differs from an amino-acid sequence found in a protein of human origin by no more than about eight amino acids.

3. A protein that binds and inhibits hNE with an K.sub.i less than about 10 picomolar that comprises an amino-acid sequence derived from a parental Kunitz domain, said parental Kunitz domain having a K.sub.i for hNE greater than about 1.0 nanomolar and said derived Kunitz domain carrying at least the mutations X18F and a mutation picked from the set comprising X15V and X15I.

4. A protein as in claim 3 in which the derived Kunitz domain contains at least one mutation from the set comprising: X13P; X36G; X37G; and X12G.

5. A protein as in claim 4 that is secreted from the yeast Pichia pastoris.

6. A protein that binds and inhibits human neutrophil elastase with a K.sub.i less than 10 picomolar comprising an amino acid sequence that is substantially homologous to a sequence picked from the set of sequences consisting of EpiNE1, EpiNE2, EpiNE3, EpiNE4, EpiNE5, EpiNE6, EpiNE7, EpiNE8, EPI-HNE-2, EPI-HNE-3, EPI-HNE-4, BITI-E7, BITI-E7-141, BITI-E7-1222, MUT1619, MUTP1, AMINO1, AMINO2, MUTQE, MUTT26A, EpiNE7.6, EpiNE7.8, EpiNE7.9, EpiNE7.31, EpiNE 7.11, EpiNE7.7, EpiNE7.4, EpiNE7.14, EpiNE7.5, EpiNE7.10, EpiNE7.20, EpiNE7.1, EpiNE7.16, EpiNE7.19, EpiNE7.12, EpiNE7.17, EpiNE7.21, EpiNE7.22, EpiNE7.23, EpiNE7.24, EpiNE7.25, EpiNE7.26, EpiNE7.27, EpiNE7.28, EpiNE7.29, EpiNE7.30, EpiNE7.32, EpiNE7.33, EpiNE7.36, EpiNE7.37, EpiNE7.38, EpiNE7.39, and EpiNE7.40.

7. A protein as in claim 1 that is secreted from the yeast Pichia pastoris.

8. A protein as in claim 6 wherein the region of homology extends from at least the first cysteine to the last cysteine.

9. A protein as in claim 2 in which the number of differences is four or less.