title: Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase.
abstract: A major problem in the development of antiviral therapies for AIDS has been the emergence of drug resistance. We report an analysis of the structure of a Val 82 to Ala mutant of HIV-1 proteinase complexed to A-77003, a C2 symmetry-based inhibitor. Modelling studies predicted that the V82A mutation would result in decreased van der Waals' interactions with the phenyl rings of A-77003 in both S1 and S1' subsites. Unexpected rearrangements of the protein backbone, however, resulted in favourable re-packing of inhibitor and enzyme atoms in the S1 but not the S1' subsite. This analysis reveals the importance of enzyme flexibility in accommodating alternate packing arrangements, and can be applied to the re-design of inhibitors targeted to drug resistant variants which emerge in the clinic.
authors.affiliation: Frederick Biomedical Supercomputing Center, PRI/DynCorp, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Baldwin
authors.forename: T N
authors.initials: TN
authors.lastname: Bhat
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004352:Drug Resistance, Microbial / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008782:Methylurea Compounds; D008958:Models, Molecular; D015394:Molecular Structure; D017354:Point Mutation; D011487:Protein Conformation; D011725:Pyridines; D013816:Thermodynamics; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D011725:Pyridines; C079555:Abbott 77003; D016333:HIV Protease; D014633:Valine