Document 0545
 DOCN  M9590545
 TI    Structural basis of drug resistance for the V82A mutant of HIV-1
       proteinase.
 DT    9509
 AU    Baldwin ET; Bhat TN; Liu B; Pattabiraman N; Erickson JW; Frederick
       Biomedical Supercomputing Center, PRI/DynCorp, National; Cancer
       Institute-Frederick Cancer Research and Development; Center, Maryland
       21702-1201, USA.
 SO    Nat Struct Biol. 1995 Mar;2(3):244-9. Unique Identifier : AIDSLINE
       MED/95292110
 AB    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.
 DE    Antiviral Agents/CHEMISTRY/PHARMACOLOGY  Drug Design  Drug Resistance,
       Microbial/GENETICS  Human  HIV Protease/*CHEMISTRY/*GENETICS  HIV
       Protease Inhibitors/CHEMISTRY/PHARMACOLOGY  HIV-1/DRUG
       EFFECTS/*ENZYMOLOGY/GENETICS  Models, Molecular  Molecular Structure
       Point Mutation  Protein Conformation  Thermodynamics  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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