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

Autor:	Carter JD; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., Gonzales EG; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., Huang X; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., Smith AN; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., de Vera IM; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., D'Amore PW; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA., Rocca JR; Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA., Goodenow MM; Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-3633, USA., Dunn BM; Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL 32610-0245, USA., Fanucci GE; Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA. Electronic address: fanucci@chem.ufl.edu.
Jazyk:	angličtina
Zdroj:	FEBS letters [FEBS Lett] 2014 Aug 25; Vol. 588 (17), pp. 3123-8. Date of Electronic Publication: 2014 Jun 28.
DOI:	10.1016/j.febslet.2014.06.051
Abstrakt:	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. (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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