Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site

Bhuvaneshwari Mahalingam, Yuan Fang Wang, Peter I. Boross, Jozsef Tozser, John M. Louis, Robert W. Harrison, Irene T. Weber

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PRV82A and PRL90M, have been determined in complex with the antiviral drug, indinavir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (K i) of PRV82A and PRL90M was 3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only a modest decrease, of 10-15%, in their kcat/Km values relative to PR. The crystal structures were refined to resolutions of 1.25-1.4 Å to reveal critical features associated with inhibitor resistance. PRV82A showed local changes in residues 81-82 at the site of the mutation, while PR L90M showed local changes near. Met90 and an additional interaction with indinavir. These structural differences concur with the kinetic data.

Original languageEnglish
Pages (from-to)1516-1524
Number of pages9
JournalEuropean Journal of Biochemistry
Volume271
Issue number8
DOIs
Publication statusPublished - Apr 1 2004

Keywords

  • Aspartic protease
  • Crystal structure
  • Drug resistance
  • HIV-1

ASJC Scopus subject areas

  • Biochemistry

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