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Document Page 50 crystals, which were produced by soaking out a weakly bound NNRTI (HEPT) from pregrown crystals. When the crystals were grown in the presence of HEPT, the p66 thumb was presumably in an upright position similar to that seen in all of the known NNRTI-bound HIV-1 RT structures. As the weakly bound HEPT diffused out, the molecular packing arrangement may have constrained the position of the p66 thumb subdomain. As a consequence, this unliganded HIV-1 RT structure may represent an intermediate between the other unliganded structures and the structure of HIV-1 RT with a bound NNRTI. It is evident that the p66 thumb subdomain has considerable flexibility and can adopt substantially different conformations during the binding of template-primer or inhibitors and, presumably during DNA polymerization as well. III. Polymerase Active Site of HIV-1 RT and the NRTIs Polymerization of DNA by HIV-1 RT involves a sequential stepwise binding of the template-primer and deoxynucleoside triphosphate (dNTP) substrates at the polymerase active site [45,46]. The incoming dNTP is covalently linked via the α-phosphorus to the 3'-oxygen of the primer strand, accompanied by the release of pyrophosphate. An essential requirement for the polymerization reaction is the presence of a 3'-OH group at the end of the primer strand. Nucleoside analogs contain a modified sugar moiety in which the 3'-OH group is replaced by another group (e.g., hydrogen, halogen, or azido) (Figure la). To exert their antiviral activity at the level of RT, the NRTIs must be phosphorylated successively to the 5'monophosphate, 5'-diphosphate, and 5'-triphosphate forms by a series of kinases. Once the NRTI is converted to the triphosphate form and interacts with RT, it can inhibit polymerization in two possible ways. One possibility is that the NRTI binds preferentially to the dNTP-binding site and competitively inhibits the binding of natural dNTPs. Another possibility, which seems to be the predominant mode of inhibition, is that the NRTI is incorporated into the growing chain and acts as a terminator of chain elongation. Once an NRTI is incorporated, no additional nucleotides can be added to the DNA chain since the primer terminal 3'-OH group (the site of phosphodiester bond formation) is absent. Phosphorylation is a crucial step in the intracellular metabolism of the NRTI and often is a limiting factor for the antiviral activity of the NRTI [47]. In an attempt to bypass the first phosphorylation step, several acyclic nucleoside phosphonates have been developed in which the sugar moiety of normal NRTIs is replaced with an acyclic phosphonate group, such as 9-(2-phosphonylmethoxyethyl)adenine (PMEA), (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), and (S)-9-(3-fluoro-2phosphonylmethoxyethyl) adenine (FPMPA) (Figure la) (see reviews [5,11]). These acyclic nucleoside phosphonates are dideoxynucleoside http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_50.html [4/5/2004 4:49:13 PM]
Document monophosphate analogs which can easily be converted to the active triphosphate form by adding two additional phosphates [48,49], and can inhibit HIV replication [50,52]. Page 51 Analysis of the structure of the HIV-1 RT/DNA/Fab complex showed that the dNTP-binding site is composed of both protein and nucleic acid. In addition to the 5'-terminus of the template nucleotide and three carboxylate residues (Asp110, Asp185, and Asp186), the amino acid residues Asp113, Tyr115, Phe116, Gln151, Phe160, and possibly Met184 and Lys219 form part of the putative dNTP-binding site [12,53] (Figure 4 and Table 2). It is important to realize that the precise composition, position, and conformation of the template-primer can influence the recognition and incorporation of incoming nucleotides at the polymerase catalytic site. In the wild-type HIV-1 RT, the dNTP-binding Figure 4 Stereoview of the polymerase active site of HIV-1 RT [38]. The amino acid residues that compose the putative dNTP-binding site, including the three catalytically essential aspartic acids, are shown with side chains. The double-stranded nucleic acid is shown with the atomic model in the HIV-1 RT/DNA/Fab complex. The dNTP-binding site consists of structural elements from both protein and nucleic acid. The precise composition, position, and conformation of the template-primer can affect the recognition of incoming dNTPs at the polymerase active site. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_51.html (1 of 2) [4/5/2004 4:49:23 PM]
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Structure-based Drug Design 14 Stru
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Document Figure 2 Schematic represe
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
Page 47 and 48: Document 60. Condra JH, Schleif WA,
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Page 51 and 52: Document 2 Structural Studies of HI
Page 53 and 54: Document Figure 1 (a) Chemical stru
Page 55 and 56: Document dine (3TC), and 2',3'-dide
Page 57 and 58: Document Figure Continued Page 45 r
Page 59 and 60: Document Figure 2 Ribbon diagrams o
Page 61: Document Figure 3 Overall structure
Page 65 and 66: Document Analysis of various HIV-1
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
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Page 101 and 102: Document 122. Marshall WS, Beaton G
Page 103 and 104: Document dine) and didanosine (dide
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Page 107 and 108: Document 163. Lacey SF, Larder BA.
Page 109 and 110: Document Figure 1 Retroviral lifecy
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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 Page 96 region in the HIV-
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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 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 Page 176 0.43 Å) as the c
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Document Page 182 (SAR) model. The
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Document 7 Structure—Function Rel
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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 Cyclotheonamide A (CtA), a
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Document 12 Polypeptide Modulators
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Document IV. Rational Drug Design F
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Document Table 1 Trypanosomal Targe
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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 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 Page 425 Antinflammatory D
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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 462 strains of influe
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Document Page 464 could not again b
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Document B. Protein Structure Page
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Document Page 471 molecules in the
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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 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 antagonistic activity, 416
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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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