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Document Figure 6 Stereo diagram of the NMR solution structure of the tick anticoagulant peptide. The crucial N-terminus Arg 3 is indicated along with the pattern of cysteine bonds. Page 273 mined by 2D-NMR studies [57,58] (Figure 6). With the exception of the region neighboring the Cys 15—Cys 39 bond in TAP, these studies support the originally proposed idea that there are significant structural similarities between TAP and Kunitz proteinase inhibitors [10]. Nevertheless, it is clear that TAP inhibitors FXa by a fundamentally different, and as yet, not fully understood mechanism. D. AcAP's In addition to ticks and leeches, other hematophagous organisms such as hook- worms have also evolved potent and selective Factor Xa inhibitors as anticoagulant strategies. Two such proteins, AcAP5 and AcAP6, have been isolated from the Ancylostoma caninum hookworm [19]. The AcAP5 protein is a 77amino-acid polypeptide with 10 cysteine residues. It inhibits the amidolytic activity of Factor Xa with a K i of 43 ± 5 pM. Incubation of rAcAP5 with its target enzyme Factor Xa results in partial cleavage of the Arg 40–Gly 41 peptide bond suggesting the sequence around this cleavage site can adopt the restricted conformational requirements of substrates [47]. The AcAP6 protein is a 75-amino-acid polypeptide, also with cysteines, with a K i for Factor Xa inhibition of 996 ± 65 pM. Alignment of the sequences of AcAP5 and AcAP6 suggest the P1 residue in AcAP6 is Phe 38 and not the basic residue usually associated with Factor Xa specificity [19]. Substitution of Phe 38 in AcAP6 with Arg resulted in a mutant that inhibited Factor Xa with a potency similar to rAcAP5. Both AcAP6 and ecotin suggest that an Arg or http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_273.html (1 of 2) [4/5/2004 5:13:03 PM]
Document Lys in the P1 position is not an absolute requirement for potent and selective activity. E. Ecotin Page 274 Ecotin, a protein isolated from Escherichia coli, is a promiscuous protease inhibitor that potently inhibits kallikrein, urokinase, Factor XIIa, granzyme B, trypsin, chymotrypsin, and elastase (reviewed in Reference 46). As with most protein inhibitors (hirudin [59] and TAP [10] being the exceptions) ecotin presents a ‘baitlike’ substrate sequence to the target protease resulting in a reversible cleavage of the P1–P1' peptide bond. However, unlike other Factor Xa inhibitors that require basic residues such as Arg or Lys in the P1 position, ecotin is cleaved between two hydrophobic amino acids, Met 84 and Met 85 [44]. Three preliminary crystal structures of ecotin with the serine proteases chymotrypsin, trypsin, and fiddler crab collagenase have been described [46]. The conformation of the sequence around the reactive site is similar to the bovine pancreatic trypsin inhibitor (BPTI) but differs in that the Cys at P' (not P2 as in BPTI) provides the rigidifying function for the reactive-loop sequence. Interestingly, antistasin has cysteines at both the P2 and P3' positions. The Pro at P4' is commonly found in FXa inhibitors including antistasin. In its complexes with the serine proteases for which structures are available [46] there is a sub van der Waals contact between Met 84-C and the enzyme Ser 195-O. The Met 84-O faces the oxyanion hole and forms hydrogen bonds with Ser 195 and Gly 193. In the trypsin structure the Met 84 side chain extends into the S1 site in a manner similar to Lys 15 in the BPTI-trypsin complex. Ecotin also forms both beta sheet hydrogen bonds to the enzyme Gly 216, Ser 82-N and O to Gly 216 O and N. VI. Small Molecule Inhibitors of Factor Xa While the x-ray structure of native Factor Xa has been reported [4] the nature of its crystal packing, specifically the fact that the active site of one Factor Xa molecule is blocked by the N-terminus of a second resulting in a “continuous polymeric structure,” apparently has precluded diffusing inhibitors into the preformed crystals to obtain complexes. Complexes with inhibitors cocrystallized with Factor Xa also have not been reported [81]. Thus, efforts to do structure-based design with this enzyme have relied on molecular modeling. Since, to date, it has not been possible to directly obtain x-ray structures of inhibitor complexes with Factor Xa, the substantial information available with respect to how serine proteases, particularly thrombin, bind inhibitors can http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_274.html [4/5/2004 5:13:05 PM]
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Structure-based Drug Design 14 Stru
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Document 74. Reddy RM, Varney MD, K
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Document 2 Structural Studies of HI
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Document dine (3TC), and 2',3'-dide
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Document monophosphate analogs whic
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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 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 reverse transcriptase inhi
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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 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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Document Page 92 The role of the N-
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Document Figure 6 Molscript stereo
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Document day junction resolving enz
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Document Page 106 on the same ring
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Document Page 108 mulate during tre
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Document when metals are bound. Fin
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Document cubation of phosphotyrosin
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Document 4 Bradykinin Receptor Anta
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Document Page 121 Nearly all cells
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Document Page 125 binding site on t
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Document Page 127 The des-Arg 9 for
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Document receptor, it has not yet b
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Document Page 133 This initial stag
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Document Page 137 observed for the
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Document Figure 6 Rat and human B2
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Document Figure 9 Composition of te
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Document 39. Mavunkel BJ, Lu Z, Kyl
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Document B. Pharmacology Figure 1 T
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Document We determined the structur
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Document Figure 3 Previously known
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Document large solvent channels and
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Document IV. Drug Design Progressio
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Document position eight from formin
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Document Table 1 Inhibition Data fo
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Document Page 166 As predicated, th
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Document 6 Structural Implications
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Document Page 176 0.43 Å) as the c
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Document Page 178 studies show that
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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 Page 205 enzyme and of phe
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Page 311 and 312: Document Cyclotheonamide A (CtA), a
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Page 363 and 364: Document 12 Polypeptide Modulators
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Document 17. Szelke M. Chemistry of
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Document 16 Progress in the Design
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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 13 The identified p
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Document 39. Saurat JH, Schfferli J
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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 Page 462 strains of influe
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Document B. Protein Structure Page
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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 VI. Conclusion Page 480 It
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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 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 Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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