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Document Most of the amino acid residues that form the binding pocket are hydrophobic and five of them are aromatic residues. The hydrophobic interactions of the side chains of these residues, especially Tyr181, Tyr188, and Trp229, with the hydrophobic moieties of the NNRTIs appear to be important for inhibitor binding [32–34,59]. Since most of the NNRTIs also contain polar group(s), they have the potential to form hydrogen bonds with surrounding amino acid residues either directly or via water bridges [33–36]. In the structures of both liganded HIV-1 RT and the HIV-1 RT/DNA/Fab complex, there are two small surface depressions at the base of the NNIBP that are the putative entrances to the pocket [34,43]. One surface depression is located at the p66/p51 heterodimer interface and is composed of amino acid residues Leu100, Lys101, Lys103, Val179, Tyr181, and Tyr188 of p66, and Glu138 of p51 [34]. This putative entrance is narrow compared to the size of the NNRTIs. Another surface depression has been found at the location near the base of the p66 thumb subdomain between two adjacent structural elements: the β5–β6 connecting loop (Lys101 and Lys103) and the β13–β14 hairpin (Pro236 and Leu238) [43]. Since this site is also exposed to solvent, an NNRTI could approach the NNIBP from it. How- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_58.html (2 of 2) [4/5/2004 4:50:15 PM]
Document ever, once an NNRTI is bound to RT, only the first putative entrance remains accessible; the second disappears due to the conformational change and repositioning of the β12-β13-β14 sheet [43]. Page 59 It is evident, from comparison of the various HIV-1 RT structures that the NNIBP has a highly flexible structure that apparently allows the enzyme to accommodate various types of NNRTIs with different shapes and sizes. Despite apparent differences in the structures of the bound inhibitors, comparison of structures of several HIV-1 RT/NNRTI complexes revealed remarkable similarity in the geometry of both the bound inhibitors and the NNIBP [33,35]. All these chemically diverse NNRTIs assume a strikingly similar butterfly-like shape (Figure 6). The binding of NNRTIs in the NNIBP can be likened to a butterfly sitting on the β6-β10-β9 sheet and facing toward the putative entrance to the pocket. The angle between the two wings of the “butterfly” is approximately 112–115° in the TIBO, α-APA, and nevirapine complexes [35]. This angle might be critical in inhibitor binding and could be a crucial parameter in the design of new NNRTIs. There are many other NNRTIs that are significantly larger or smaller in size than α-APA, TIBO, or nevirapine. It is very likely that the NNIBP can adopt other conformations. For example, BHAP appears to be too large to fit into the NNIBP in any of the reported HIV-1 RT/NNRTI complexes. The NNIBP in the HIV-1 RT/BHAP complex would need to be significantly larger than that observed in the structures of the known HIV-1 RT/NNRTI complexes. It is possible that the BHAP inhibitor may not conform to a butterfly-like shape. This underscores the importance of solving crystal structures for as many HIV-1 RT/NNRTI complexes as possible. Additional structural and biochemical data for other HIV-1 RT/NNRTI complexes should provide the insight needed to define the limits of the flexibility of HIV-1 RT in the NNIBP region. VII. Process of NNRTI Binding In crystal structures of unliganded HIV-1 RT [40,41,43] and of HIV-1 RT/DNA/Fab complex [38], the NNIBP does not exist (although a small cavity is found in the region of the NNIBP proximal to the polymerase active site in the unliganded HIV-1 RT structure described <strong>by</strong> Esnouf et al. [42]). In these structures, the side chains of Tyr181 and Tyr188 in p66 point away from the polymerase active site and toward the hydrophobic core. However, in the HIV-1 RT/NNRTI complex structures, the side chains of Tyr181 and Tyr188 point toward the polymerase active site, and the side chain of Tyr181 is in a position that prevents Trp229 from occupying the position it has in the unliganded or DNA bound HIV-1 RT structures. Binding an NNRTI also moves the β12-β13-β14 sheet away from the hydrophobic core [34,35,37]. These conformational http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_59.html [4/5/2004 4:50:16 PM]
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Structure-based Drug Design 14 Stru
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
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Page 51 and 52: Document 2 Structural Studies of HI
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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: Document Table 3 HIV-1 RT Amino Aci
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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
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Page 99 and 100: Document 106. Cirino NM, Cameron CE
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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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Page 113 and 114: Document Page 88 transfer (Figure 3
Page 117 and 118: Document Page 92 The role of the N-
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Document day junction resolving enz
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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 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 Figure 9 Composition of te
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Document We determined the structur
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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 IX. S2' Interactions 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 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 A. Chemical Modification P
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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 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 Page 462 strains of influe
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Document B. Protein Structure Page
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Document Page 476 nM, respectively.
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Document Subsequent studies have sh
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Document Figure 5 Some compounds wh
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Document Acknowledgments Page 620 I
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document [Human immunodeficiency vi
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Document [Protease targets] serinyl
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