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Document The conserved active-site residues (Asp25, Thr26, and Gly27 from both monomers) form a symmetrical and highly hydrogen-bonded arrangement virtually identical to that described for pepsin [17]. The two aspartates are nearly coplanar with the “inner” carboxylate oxygens hydrogen bonded to the amide hydrogens of Gly27/27'. This designation (e.g. Gly 27/27') will be used throughout this text to indicate equivalent residues of the dimer. The two threonines are inaccessible to solvent and are hydrogenbonded to the main-chain amide groups of the other monomer, forming a rigid network called a “fireman's grip” [17]. As in the case of the structures of eukaryotic pepsins, there is electron density for a water molecule bound between the two carboxylates of the active-site aspartates. Page 5 In the structure of the apo-form of HIV PR, the flaps from both monomers are related by crystallographic two-fold symmetry and can be considered as being in an open conformation. In the structures of related proteases from Rous Sarcoma Virus and HIV-2, the flaps are either crystallographically disordered or in a partly closed conformation [18]. This suggests that, in solution, in the absence of ligands, the flaps are rather flexible and that the stable conformation of the flaps observed in the crystal structure of the apo-enzyme of HIV PR could be considered to result from kinetic trapping during the crystallization process. In the apo-form of HIV PR, the active site residues are located at the bottom of a rather shallow groove. Upon binding an inhibitor, the protease undergoes significant structural changes, particularly apparent in the flap region. As a result, a tunnel-like site is formed, which runs diagonally across the dimer interface. The tunnel has a volume of approximately 1140 Å 3 and is 23 Å long. Because of the dimeric nature of HIV PR, the active site has approximate two-fold symmetry with the dyad axis intersecting the plane of the catalytic aspartates. Along the active site tunnel, starting from the central aspartates, there are distinct subsites S1, S2, S3, and S4, and corresponding symmetry related subsites S1', S2' S3', and S4' (Figure 2). It should be noted that in this chapter, the convention of Schechter and Burger [19] will be used to describe enzyme specificity subsites (S1, S1', etc.) and the corresponding side chains of inhibitors (P1, P1', etc.). The boundaries of the subsites are formed by residues from both monomers of HIV PR. All subsites, with the exception of S4/S4', which are exposed to solvent, are bounded by mostly aliphatic side chains and have hydrophobic character. The borders of the S1/S1' subsites are formed by the side chains of Ile23/23', Ile50/50', Ile84/84', Pro81/81', the γ carbon of Thr80/80', carboxylates of the active site Asp25/25', and the carbonyl oxygens of Gly27/27'. The S2/S2' subsites are bounded by Val32/32', Ile50/50', Ile47/47', Leu76/76', Ala28/28', and the carboxylates of Asp30/30'. The S3/S3', subsites are partly exposed to solvent and are bordered by the side chains of Leu23/23', Val82/82', Pro81/81', and the guanidinium groups of Arg8/8', which form a salt bridge with the carboxylates of Asp29/29'. Most of http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_5.html [2/29/2004 2:15:26 AM]
Document Figure 2 Schematic representation of the specificity subsites of the HIV PR active site with bound peptidic inhibitor JG-365. Amino acids forming the boundaries of the particular subsites are shown. the hydrogen bond donor and acceptor functional groups of the active site are located in an approximate plane that lies along the long axis of the tunnel and is somewhat perpendicular to the plane of the subsites. The hydrogen-bonding functionalities include the carboxylates of the catalytic aspartates, the carbonyl oxygens of Gly27 and Gly48, the amide nitrogens of Asp29' and Gly48, the carboxylate of Asp29', and the dimer symmetry-related groups on the other side of the active site. Additional groups capable of forming hydrogen bonds with ligands are located in the outer part of the S2/S2' subsite and include the amide nitrogens and the carboxylates of Asp30/30'. There are five conserved water molecules in the active site of HIV PR. Four of the waters are symmetrically distributed in the S3/S3' subsites and one, hereafter called Wat301, is located near the two-fold axis of the dimer and, in the presence of most inhibitors, is approximately tetrahedrally coordinated by the hydrogen bonds formed between carbonyl oxygens of the ligand(s) and the amide nitrogens of Ile50/50' of the flaps. In the ligand-bound form of HIV PR, Wat301 is completely inaccessible to solvent, and it has been speculated that its functional substitution could be energetically favorable [18] or at least may lead to discovery of novel nonpeptidic inhibitors [20]. Thus, there are 18 hydrogen bond donors or acceptors in http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_6.html [2/29/2004 2:15:34 AM] Page 6
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Page 19 and 20: Document Page 15 Thiazoles are less
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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 61 now clear that the
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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 reverse transcriptase inhi
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Document 75. Ring CS, Sun E, McKerr
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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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Document Page 92 The role of the N-
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Document Figure 6 Molscript stereo
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Document Page 96 region in the HIV-
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Document day junction resolving enz
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Document -62° for HIV-1 integrase,
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Document Page 101 crystallized unde
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Document Figure 8 Molscript stereo
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Document proposed mechanisms. For e
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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 receptor, it has not yet b
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Document Page 133 This initial stag
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Document Page 135 might be jointly
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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 Page 141 receptor with int
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Document Figure 9 Composition of te
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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 Figure 1 A ribbon model of
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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 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 Figure 6 (a) The pocket of
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Document 20. Murphy G, Docherty AJP
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Document Page 189 36. Bode W, Reine
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Document 7 Structure—Function Rel
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Document Figure 1 Reactions catalyz
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Document Figure 2 Structure of lico
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Document Figure 3 (Continued) Page
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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 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 13. Wilson RC, Krozowski Z
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Document 29. Baker ME. Genealogy of
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Document Figure 3 (a) Ternary compl
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Document Figure 5 (a) Staurosporine
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Document protein kinase core is ess
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Document 10. Knighton DR, Zheng J-H
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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 diverse ARIs have been sho
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Document Figure 3 C α trace of the
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Document Figure 4 Surface represent
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Document Figure 5 Schematic represe
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Document Figure 7 Stereo of zopolre
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Document B. Structures Figure 8 Seq
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Document This method was used to sc
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Document 10 Structure-Based Design
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Document Cyclotheonamide A (CtA), a
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Document Page 256 The discovery pro
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Document et al. [21]). Among these
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Document balance its pro- and antic
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Document Page 263 15. Tabernero L,
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Document 31. Kettner C, Shaw E. D-P
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Document Figure 1 The coagulation c
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Document Figure 2 Factor Xa structu
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Document Table 2 Naturally Occurrin
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Document Table 3 Active Site Sequen
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Document Figure 5 Predicted seconda
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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 Page 278 The n=3 chain len
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Document Figure 10 Proposed model o
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Document Figure 11 dArg-ATS 32-38 m
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Document Figure 12 Modeled fit of S
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Document Page 285 number of x-ray s
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Document Page 288 Additionally, the
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Document 12 Polypeptide Modulators
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Document Page 297 whereas, calcium
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Document Figure 2 Amino acid sequen
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Document A. Chemical Modification P
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Document Page 309 site 3 on the sod
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Document Page 314 anemone toxins an
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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 plasma. This may arise fro
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Document C. Specificity Figure 4 Th
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Document Figure 5 The S 3 specifici
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Document IV. Rational Drug Design F
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Document 2. Blundell TL, Cooper J,
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Document 17. Szelke M. Chemistry of
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Document Figure 8 The catalytic mac
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Document Page 359 easily reach the
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Document Figure 1 Available drugs f
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Document Table 1 Trypanosomal Targe
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Document Table 2 Three-Dimensional
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Document Because there are tens of
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Document Figure 12 Predicted bindin
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Document Page 388 nosine proved to
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Document 65. João HC, Williams RJP
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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 has a single membrane-span
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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 Figure 10 Schematic diagra
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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 425 Antinflammatory D
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Document Page 427 These aromatic di
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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 5 Velcro-key model
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Document Figure 6 Proposed receptor
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Document Acknowledgments Page 620 I
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Document D ddI, 152 tumour necrosis
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Document overview, 103-104, 108-109
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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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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