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

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.

SUBMITTER: Carter JD

PROVIDER: S-EPMC4335667 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Carter Jeffrey D JD Gonzales Estrella G EG Huang Xi X Smith Adam N AN de Vera Ian Mitchelle S IM D'Amore Peter W PW Rocca James R JR Goodenow Maureen M MM Dunn Ben M BM Fanucci Gail E GE

FEBS letters 20140628 17

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 populat ...[more]

PMID: 24983495

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Dataset Information

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

Publications

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

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