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Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling.
- Source :
-
FEBS letters [FEBS Lett] 2014 Aug 25; Vol. 588 (17), pp. 3123-8. Date of Electronic Publication: 2014 Jun 28. - Publication Year :
- 2014
-
Abstract
- Conformational sampling of pre- and post-therapy subtype B HIV-1 protease sequences derived from a pediatric subject infected via maternal transmission with HIV-1 were characterized by double electron-electron resonance spectroscopy. The conformational ensemble of the PRE construct resembles native-like inhibitor bound states. In contrast, the POST construct, which contains accumulated drug-pressure selected mutations, has a predominantly semi-open conformational ensemble, with increased populations of open-like states. The single point mutant L63P, which is contained in PRE and POST, has decreased dynamics, particularly in the flap region, and also displays a closed-like conformation of inhibitor-bound states. These findings support our hypothesis that secondary mutations accumulate in HIV-1 protease to shift conformational sampling to stabilize open-like conformations, while maintaining the predominant semi-open conformation for activity.<br /> (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1873-3468
- Volume :
- 588
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- FEBS letters
- Publication Type :
- Academic Journal
- Accession number :
- 24983495
- Full Text :
- https://doi.org/10.1016/j.febslet.2014.06.051