Format

Send to

Choose Destination
See comment in PubMed Commons below
J Mol Biol. 2011 Jul 22;410(4):756-60. doi: 10.1016/j.jmb.2011.03.038.

Accessory mutations maintain stability in drug-resistant HIV-1 protease.

Author information

1
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

Abstract

The underlying mechanisms driving the evolution of drug resistance in human immunodeficiency virus (HIV) are only partially understood. We investigated the evolutionary cost of the major resistance mutations in HIV-1 protease in terms of protein stability. The accumulation of resistance mutations destabilizes the protease, limiting further adaptation. From an analysis of clinical isolates, we identified specific accessory mutations that were able to restore the stability of the protease or even increase it beyond the wild-type baseline. Resistance mutations were also found to decrease the activity of HIV protease near neutral pH values, while incorporating stabilizing mutations improved the enzyme's pH tolerance. These findings help us to explain the prevalence of mutations located far from the active site and underscore the importance of protein stability during the evolution of drug resistance in HIV.

PMID:
21762813
PMCID:
PMC3139113
DOI:
10.1016/j.jmb.2011.03.038
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center