Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors

Yunfeng Tie, Yuan Fang Wang, Peter I. Boross, Ting Yi Chiu, Arun K. Ghosh, Jozsef Tozser, John M. Louis, Robert W. Harrison, Irene T. Weber

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Clinical inhibitor amprenavir (APV) is less effective on HIV-2 protease (PR 2) than on HIV-1 protease (PR 1). We solved the crystal structure of PR 2 with APV at 1.5 Å resolution to identify structural changes associated with the lowered inhibition. Furthermore, we analyzed the PR 1 mutant (PR 1M) with substitutions V32I, I47V, and V82I that mimic the inhibitor binding site of PR 2. PR 1M more closely resembled PR 2 than PR 1 in catalytic efficiency on four substrate peptides and inhibition by APV, whereas few differences were seen for two other substrates and inhibition by saquinavir (SQV) and darunavir (DRV). High resolution crystal structures of PR 1M with APV, DRV, and SQV were compared with available PR 1 and PR 2 complexes. Val/Ile32 and Ile/Val47 showed compensating interactions with SQV in PR 1M and PR 1, however, Ile82 interacted with a second SQV bound in an extension of the active site cavity of PR 1M. Residues 32 and 82 maintained similar interactions with DRV and APV in all the enzymes, whereas Val47 and Ile47 had opposing effects in the two subunits. Significantly diminished interactions were seen for the aniline of APV bound in PR 1M and PR 2 relative to the strong hydrogen bonds observed in PR 1, consistent with 15- and 19-fold weaker inhibition, respectively. Overall, PR 1M partially replicates the specificity of PR 2 and gives insight into drug resistant mutations at residues 32, 47, and 82. Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2. Published by Wiley-Blackwell.

Original languageEnglish
Pages (from-to)339-350
Number of pages12
JournalProtein Science
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 1 2012

Keywords

  • Antiviral inhibitors
  • Aspartic protease
  • Drug resistance
  • HIV/AIDS
  • Molecular recognition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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  • Cite this

    Tie, Y., Wang, Y. F., Boross, P. I., Chiu, T. Y., Ghosh, A. K., Tozser, J., Louis, J. M., Harrison, R. W., & Weber, I. T. (2012). Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors. Protein Science, 21(3), 339-350. https://doi.org/10.1002/pro.2019