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Document Another is the loss from the ends of the viral DNA of the original two base pairs that preceded the conserved 3'-CA. B. In Vitro Assays to Monitor Integrase Activity Page 87 In contrast to the in vivo reaction, concerted integration in vitro of two HIV DNA ends into a target DNA molecule separated by a 5 base-pair stagger occurs very inefficiently. However, in vitro systems have been developed [6,7] using recombinant HIV integrase that have allowed the chemistry of the single-ended integration event to be studied in fine detail. It is possible and routine to use short, doublestranded synthetic oligonucleotides that mimic the viral ends to monitor the removal of two nucleotides from 3' ends (denoted 3' processing or cutting) and the subsequent insertion of one 3' processed DNA molecule into another (known as strand transfer or joining). Typical reactions are depicted in Figure 3. The stereochemical mechanism of 3' processing and strand transfer has been investigated using DNA substrates that incorporate phosphorothioate link-ages [8]. For both reactions, the introduced chiral centers are inverted in the products, implying that the reactions occur via a one-step in-line displacement mechanism rather than via a covalent intermediate. A third assay of integrase activity, termed disintegration, has more recently been developed [9] that monitors the apparent reversal of strand- Figure 3 Reactions carried out by integrase in vitro, using short oligonucleotide substrates. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_87.html [4/5/2004 4:54:38 PM]
Document Page 88 transfer (Figure 3). While disintegration probably has no physiological significance, it has been useful in defining aspects of integrase biochemistry. The three in vitro activities of integrase require divalent metal ions as cofactors. The only two metals that support these activities are Mn 2+ and Mg 2+. Since quite high metal concentrations must be added to assays (1–10 mM for optimal activity), it has been presumed that Mg 2+ is the ion used in vivo. C. Evidence for a Multimer as the Active Unit of Integrase Several lines of evidence demonstrate that the active unit of integrase is a multimer. It is clear, as an isolated protein in solution, that integrase forms dimers [6,10–12], and it has been shown by sedimentation equilibrium studies that Rous sarcoma virus (RSV) integrase exists in reversible equilibrium between monomeric, dimeric, and tetrameric forms [13]. Protein-protein cross-linking studies of HIV-1 [14] and RSV [15] integrases confirm the existence of protein dimers and tetramers in solution, and in vivo, the yeast GAL4 two-hybrid system has demonstrated that HIV-1 integrase can interact with itself [16]. Complementation studies using mutant proteins in vitro provide compelling evidence that the active form of integrase must be at least a dimer [14, 17]. This can be inferred from the result that when certain inactive forms of integrase—generated either by truncation or point mutation—are mixed, robust activity can be reconstituted. This indicates that different monomers in a multimer are capable of providing different essential functions in the context of an active complex. Collectively, these studies suggest that integrase acts as a multimer. This would also seem the most straight-forward model to explain the observation that viral integration requires two coordinated cutting and joining reactions on the target DNA during strand transfer. However, physical studies have not yet addressed what form of integrase actually binds to DNA and carries out the chemical reactions of integration. III. Properties of HIV-1 Integrase A. Domain Structure of Retroviral Integrases A consistent view of the domain structure of retroviral integrases has emerged by combining the results from biochemical studies using deletion and site-specific mutants, limited proteolysis experiments, and sequence comparisons among the family of retroviral integrases. The organization of the domains of integrase is shown schematically in Figure 4. The central domain of HIV-1 integrase, consisting approximately of residues 50 to 200, is largely conserved among retroviral integrases, and forms http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_88.html [4/5/2004 4:54:40 PM]
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Structure-based Drug Design 14 Stru
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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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Page 63 and 64: Document monophosphate analogs whic
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Page 67 and 68: Document Page 54 Table 2) [12,54].
Page 69 and 70: Document Page 56 It is also attract
Page 71 and 72: Document Table 3 HIV-1 RT Amino Aci
Page 73 and 74: Document ever, once an NNRTI is bou
Page 75 and 76: Document Page 61 now clear that the
Page 77 and 78: Document Page 63 most of the amino
Page 79 and 80: Document Page 65 cal properties of
Page 81 and 82: Document Page 67 Biochemical data s
Page 83 and 84: Document Page 69 determining the me
Page 85 and 86: Document Chris Tantillo. The work i
Page 87 and 88: Document Page 72 16. Goldman ME, Nu
Page 89 and 90: Document 30. Coffin JM. HIV populat
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Page 93 and 94: Document reverse transcriptase inhi
Page 95 and 96: Document 75. Ring CS, Sun E, McKerr
Page 97 and 98: Document 89. Hughes SH, Arnold E, H
Page 99 and 100: Document 106. Cirino NM, Cameron CE
Page 101 and 102: Document 122. Marshall WS, Beaton G
Page 103 and 104: Document dine) and didanosine (dide
Page 105 and 106: Document 149. Craig JC, Duncan IB,
Page 107 and 108: Document 163. Lacey SF, Larder BA.
Page 109 and 110: Document Figure 1 Retroviral lifecy
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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-
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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
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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 39. Mavunkel BJ, Lu Z, Kyl
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Document Figure 3 Previously known
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Document large solvent channels and
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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 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 1 Reactions catalyz
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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 protein kinase core is ess
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Document Cyclotheonamide A (CtA), a
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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 12 Polypeptide Modulators
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Document A. Chemical Modification P
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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 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 5-Methoxytryptamine 19.0 9
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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 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 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 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 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 Figure 5 (a) Stereo image
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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 64. Ward CW, Elleman TC, A
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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 C. Structure-Activity Rela
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Document Hydrophobicity Requirement
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Document Figure 9 A solvent-accessi
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Document accommodate a variety of d
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Document Figure 10 Possible hydroge
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Document Page 514 sis. Large number
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Document conformational transition
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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 Kininogen, 119 high molecu
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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