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Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling.

Authors :
Carter JD
Gonzales EG
Huang X
Smith AN
de Vera IM
D'Amore PW
Rocca JR
Goodenow MM
Dunn BM
Fanucci GE
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