Nine crystal structures determine the substrate envelope of the MDR HIV-1 protease

Zhigang Liu, Yong Wang, Joseph Brunzelle, Iulia A. Kovari, Ladislau C. Kovari

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Under drug selection pressure, emerging mutations render HIV-1 protease drug resistant, leading to the therapy failure in anti-HIV treatment. It is known that nine substrate cleavage site peptides bind to wild type (WT) HIV-1 protease in a conserved pattern. However, how the multidrug-resistant (MDR) HIV-1 protease binds to the substrate cleavage site peptides is yet to be determined. MDR769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) was selected for present study to understand the binding to its natural substrates. MDR769 HIV-1 protease was co-crystallized with nine substrate cleavage site hepta-peptides. Crystallographic studies show that MDR769 HIV-1 protease has an expanded substrate envelope with wide open flaps. Furthermore, ligand binding energy calculations indicate weaker binding in MDR769 HIV-1 protease-substrate complexes. These results help in designing the next generation of HIV-1 protease inhibitors by targeting the MDR HIV-1 protease.

Original languageEnglish (US)
Pages (from-to)173-183
Number of pages11
JournalProtein Journal
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • Crystallography
  • Drug design
  • HIV-1 protease
  • Multi-drug resistant
  • Substrate envelope

ASJC Scopus subject areas

  • Analytical Chemistry
  • Bioengineering
  • Biochemistry
  • Organic Chemistry

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