title: Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases.
abstract: The selection of drug resistant viruses is a major problem in efforts to combat HIV and AIDS, hence, new compounds are required. We report crystal structures of wild-type and mutant HIV-1 RT with bound non-nucleoside (NNRTI) GW420867X, aimed at investigating the basis for its high potency and improved drug resistance profile compared to the first-generation drug nevirapine. GW420867X occupies a smaller volume than many NNRTIs, yet accesses key regions of the binding pocket. GW420867X has few contacts with Tyr188, hence, explaining the small effect of mutating this residue on inhibitor-binding potency. In a mutated NNRTI pocket, GW420867X either remains in a similar position compared to wild-type (RT(Leu100Ile) and RT(Tyr188Cys)) or rearranges within the pocket (RT(Lys101Glu)). For RT(Leu100Ile), GW420867X does not shift position, in spite of forming different side-chain contacts. The small bulk of GW420867X allows adaptation to a mutated NNRTI binding site by repositioning or readjustment of side-chain contacts with only small reductions in binding affinity.
authors: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
authors: Jingshan
authors: J
authors: Ren
authors: Charles E
authors: CE
authors: Nichols
authors: Philip P
authors: PP
authors: Chamberlain
authors: Kurt L
authors: KL
authors: Weaver
authors: Steven A
authors: SA
authors: Short
authors: Joseph H
authors: JH
authors: Chan
authors: Jörg-Peter
authors: JP
authors: Kleim
authors: David K
authors: DK
authors: Stammers
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; C402066:GW420867X; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase