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Document Page 138 action on the binding of antagonist peptides. In addition, it has been shown that bradykinin can be covalently crosslinked to the B2 receptor while antagonists cannot. These observations have fostered the belief that the agonist and antagonist binding sites of the receptor are not the same. At best, they may be partially overlapping, although there is no direct evidence for this. The ultimate identification of the amino acid residues that make up the antagonist site would be another important step toward the goal of structure-<strong>based</strong> design of novel nonpeptide antagonists. As described in a previous section of this chapter, characterizations of the bradykinin B2 receptors from rat and human using NPC 17410 (Figure 3) revealed different pharmacologies. Specifically, it showed a higher affinity for the human B2 receptor than it did for the rat B2 (human IC 50 = 0.95 nM, rat IC 50 = 48.0). This ligand “tool” provided a means for evaluating a series of bradykinin rat/human B2 receptor chimeras [51–53]. Several different chimeras were prepared in a systematic fashion and the affinity of NPC 17410 was determined for each. The chimeras are depicted schematically in Figure 6 together with the IC 50 values determined for NPC 17410. Chimeras I through III sample the N-and C-terminal sections of the receptor for any contributions to an antagonist binding site. The remaining chimeras sample the core transmembrane domains of the receptor. Each chimera was shown to induce a membrane depolarization similar to wild type receptor in response to bradykinin when expressed in Xenopus oocytes. For each NPC 17410 assay, [ 3H]-NPC 17731 was used as the radioligand. From this systematic approach, specific groups of contiguous residues within the receptor were identified as possible contributors to an antagonist binding site. The NPC 17410 binding to chimeras III, IV, and VIII showed rat-like pharmacology (low NPC 17410 affinity). The NPC 17410 binding to chimeras I, II, VI, and VII showed human-like NPC 17410 pharmacology (high receptor affinity). Binding to chimeras V and VIII, however, was similar to rat-like NPC 17410 pharmacology, but the affinity of the compound was slightly shifted back toward human-like results. Comparisons of rat and human receptor sequences in the regions sampled <strong>by</strong> the chimeras reveals that only two clusters of residues differ between rat and human B2 receptors. Specifically, TM2 has the same sequence in rat and human receptors so it is unlikely that the differential pharmacology associated with NPC 17410 binding can be attributed to residues there. However, TM3 has a cluster of 3 residues that differ (rat rarrow.gif human: Thr110 rarrow.gif Ala108, Met111 rarrow.gif Ile109, Tyr113 rarrow.gif Ser111) and TM6 has a cluster of 5 residues that differ (rat rarrow.gif human: Phe259 rarrow.gif Leu257, Leu256 rarrow.gif Ile254, Val255 rarrow.gif Ile253, Gly252 rarrow.gif Leu 250, Ala 249 rarrow.gif Val 247) in rat and human receptors. These differences represent important targets for follow-up point (and cluster) mutation experiments. Our current thinking is that the largest effects on NPC 17410 pharmacology, if any, might be derived from the TM3 mutants since http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_138.html [4/5/2004 4:59:54 PM]
Document Figure 6 Rat and human B2 receptor chimera constructs and affinity data for binding NPC 17410. Also shown is the affinity NPC 17410 to rat and human wild type receptors. Page 139 between rat and human, these are quite diverse. However, it is also possible that the cluster of residues identified in TM6, while not radically dissimilar, may as a group create different hydrophobic environments between these species homologues. The most significant individual difference within the TM6 zone is the Phe 259 (rat) rarrow.gif Leu 257 (human) swap and might therefore be most significant http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_139.html (1 of 2) [4/5/2004 5:00:00 PM]
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Document 60. Condra JH, Schleif WA,
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Document dine (3TC), and 2',3'-dide
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Document Analysis of various HIV-1
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Document Page 54 Table 2) [12,54].
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Document Page 56 It is also attract
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Document Table 3 HIV-1 RT Amino Aci
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Document ever, once an NNRTI is bou
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Document Page 61 now clear that the
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Document Page 63 most of the amino
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Document Page 65 cal properties of
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Document Page 67 Biochemical data s
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Document Page 69 determining the me
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Document Chris Tantillo. The work i
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Document Page 72 16. Goldman ME, Nu
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Document 30. Coffin JM. HIV populat
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Document 45. Majumadar C, Abbotts J
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Document 75. Ring CS, Sun E, McKerr
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Document 89. Hughes SH, Arnold E, H
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Document 106. Cirino NM, Cameron CE
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Document 122. Marshall WS, Beaton G
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Document dine) and didanosine (dide
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Document 149. Craig JC, Duncan IB,
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Document 163. Lacey SF, Larder BA.
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Document Figure 1 Retroviral lifecy
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Document Figure 2 In vivo reactions
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Document Page 88 transfer (Figure 3
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Page 117 and 118: Document Page 92 The role of the N-
Page 119 and 120: Document Figure 6 Molscript stereo
Page 121 and 122: Document Page 96 region in the HIV-
Page 123 and 124: Document day junction resolving enz
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Page 127 and 128: Document Page 101 crystallized unde
Page 129 and 130: Document Figure 8 Molscript stereo
Page 131 and 132: Document proposed mechanisms. For e
Page 133 and 134: Document Page 106 on the same ring
Page 135 and 136: Document Page 108 mulate during tre
Page 137 and 138: Document when metals are bound. Fin
Page 139 and 140: Document cubation of phosphotyrosin
Page 141 and 142: Document 4. Vink C, Plasterk RHA. T
Page 143 and 144: Document Page 115 21. Kulkosky J, J
Page 145 and 146: Document 44. Cushman M, Sherman P.
Page 147 and 148: Document 65. Gallay P, Swingler S,
Page 149 and 150: Document 4 Bradykinin Receptor Anta
Page 151 and 152: Document Page 121 Nearly all cells
Page 153 and 154: Document Page 123 were poorly satis
Page 155 and 156: Document Page 125 binding site on t
Page 157 and 158: Document Page 127 The des-Arg 9 for
Page 159 and 160: Document Page 129 tolerated by the
Page 161 and 162: Document receptor, it has not yet b
Page 163 and 164: Document Page 133 This initial stag
Page 165 and 166: Document Page 135 might be jointly
Page 167: Document Page 137 observed for the
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Page 175 and 176: Document Figure 9 Composition of te
Page 179 and 180: Document 16. Martorana PA, Kettenba
Page 181 and 182: Document 39. Mavunkel BJ, Lu Z, Kyl
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Page 187 and 188: Document We determined the structur
Page 189 and 190: Document Figure 3 Previously known
Page 195 and 196: Document large solvent channels and
Page 197 and 198: Document IV. Drug Design Progressio
Page 199 and 200: Document position eight from formin
Page 201 and 202: Document Table 1 Inhibition Data fo
Page 203 and 204: Document Page 166 As predicated, th
Page 205 and 206: Document References 1. Parks RE Jr.
Page 207 and 208: Document 17. Ealick SE, Rule SA, Ca
Page 209 and 210: Document 6 Structural Implications
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Page 215 and 216: Document Page 176 0.43 Å) as the c
Page 217 and 218: Document Page 178 studies show that
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Document Figure 5 (a) A cut away vi
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Document Page 182 (SAR) model. The
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Document IX. S2' Interactions Page
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Document 7 Structure—Function Rel
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Document Figure 2 Structure of lico
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Document Important for the validity
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Document Figure 4 Amino acids impor
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Document III. Results and Discussio
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Document Page 202 269, and valine-2
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Document Figure 6 Structure of α h
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Document Page 205 enzyme and of phe
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Document Page 207 sure and the acti
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Document 29. Baker ME. Genealogy of
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Document Page 214 viruses. Specific
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Document Figure 5 (a) Staurosporine
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Document protein kinase core is ess
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Document 24. Madhusudan Xuong N-H,
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Document 9 Structural Studies of Al
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Document Figure 4 Surface represent
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Document balance its pro- and antic
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Document Table 2 Naturally Occurrin
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Document Lys in the P1 position is
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Document Page 276 In both cases the
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Document 12 Polypeptide Modulators
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Document Page 323 been suggested th
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Document Page 327 this analog inter
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Document IV. Rational Drug Design F
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Document 17. Szelke M. Chemistry of
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Document Page 359 easily reach the
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Document Table 1 Trypanosomal Targe
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Document 65. João HC, Williams RJP
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Document 84. Verlinde CLMJ, Hol WGJ
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Document 16 Progress in the Design
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Document Table 1 Known Three-Dimens
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Document Page 398 with growth hormo
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Document All effects of the IL-1 fa
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Document Figure 2 Structural alignm
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Document Page 405 strands constitut
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Document Figure 4 (a) Stereo diagra
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Document Figure 6 (a) Stereo diagra
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Document Figure 7 (a) Superposition
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Document Page 412 ture is unlike ot
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Document Page 416 positions of the
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Document Figure 11 Functional resid
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Document Figure 13 The identified p
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Document B. Interleukin-1 Receptor
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Document Page 423 American Home Pro
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Document Page 425 Antinflammatory D
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Document Page 427 These aromatic di
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Document 5. Dinarello CA. On the Bi
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Document 21. Seckinger P, Lowenthal
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Document 39. Saurat JH, Schfferli J
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Document receptor antagonist into a
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Document 74. Bender PE, Lee JC., ed
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Document 102. Machin PJ, Osbond JM,
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document Page 441 sequence of the m
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Document Page 443 that allowed for
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Document Figure 4 Stereo view of IF
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Document Figure 5 Velcro-key model
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Document Figure 6 Proposed receptor
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Document Page 451 with the cytoplas
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Document for directed subcellular t
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Document 13. Stewart HJ, McCann SHE
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Document 33. Szente BE, Johnson HM.
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Document Figure 1 A schematic diagr
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Document Page 462 strains of influe
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Document Page 464 could not again b
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Document Figure 3 (a) A MOLSCRIPT [
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Document B. Protein Structure Page
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Document Page 471 molecules in the
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Document hydroxy, and 6 Neu5Ac2en -
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Document Figure 8 Stereo image of t
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Document Page 476 nM, respectively.
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Document Page 478 lished—was asso
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Document VI. Conclusion Page 480 It
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Document 21. Both GW, Sleigh MJ, Co
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Document 40. Drzenick R, Frank H, R
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Document 45. Varghese JN, Laver WG,
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Document 64. Ward CW, Elleman TC, A
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Document 80. Suzuki Y, Sato K, Kiso
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Document Page 486 95. Ryan DM, Tice
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Document Page 488 against most of t
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Document A. The Canyon Page 491 The
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Document Subsequent studies have sh
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Document Page 495 of the RNA and pr
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Document Figure 4 A ribbon diagram
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Document Figure 5 Some compounds wh
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Document Figure 7 HRV14 VP1 hydroph
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Document C. Structure-Activity Rela
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Document Page 514 sis. Large number
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Document conformational transition
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Document Figure 8 Minimized structu
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Document Page 555 N-acylpyrrolidine
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Document 10. Bobbyer DNA, Goodford
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Document 30. O'Shea EK, Rutkowski R
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Document Acknowledgments Page 620 I
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Document Med Biol 1991; 306:9-21; (
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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