Conformational variation of an extreme drug resistant mutant of HIV protease
Abstract
Molecular mechanisms leading to high level drug resistance have been analyzed for the clinical variant of HIV-1 protease bearing 20 mutations (PR20); which has several orders of magnitude worse affinity for tested drugs. Two crystal structures of ligand-free PR20 with the D25N mutation of the catalytic aspartate (PR20D25N) revealed three dimers with different flap conformations. The diverse conformations of PR20D25N included a dimer with one flap in a unique “tucked” conformation; directed into the active site. Analysis of molecular dynamics (MD) simulations of the ligand-free PR20 and wild-type enzymes showed that the mutations in PR20 alter the correlated interactions between two monomers in the dimer. The two flaps tend to fluctuate more independently in PR20 than in the wild type enzyme. Combining the results of structural analysis by X-ray crystallography and MD simulations; unusual flap conformations and weakly correlated inter-subunit motions may lead to the high level resistance of PR20.
- Authors:
-
- Georgia State Univ., Atlanta, GA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1222023
- Alternate Identifier(s):
- OSTI ID: 1250921
- Grant/Contract Number:
- W-31-109-Eng-38
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Molecular Graphics and Modelling
- Additional Journal Information:
- Journal Volume: 62; Journal Issue: C; Journal ID: ISSN 1093-3263
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Shen, Chen-Hsiang, Chang, Yu-Chung, Agniswamy, Johnson, Harrison, Robert W., and Weber, Irene T. Conformational variation of an extreme drug resistant mutant of HIV protease. United States: N. p., 2015.
Web. doi:10.1016/j.jmgm.2015.09.006.
Shen, Chen-Hsiang, Chang, Yu-Chung, Agniswamy, Johnson, Harrison, Robert W., & Weber, Irene T. Conformational variation of an extreme drug resistant mutant of HIV protease. United States. https://doi.org/10.1016/j.jmgm.2015.09.006
Shen, Chen-Hsiang, Chang, Yu-Chung, Agniswamy, Johnson, Harrison, Robert W., and Weber, Irene T. Tue .
"Conformational variation of an extreme drug resistant mutant of HIV protease". United States. https://doi.org/10.1016/j.jmgm.2015.09.006. https://www.osti.gov/servlets/purl/1222023.
@article{osti_1222023,
title = {Conformational variation of an extreme drug resistant mutant of HIV protease},
author = {Shen, Chen-Hsiang and Chang, Yu-Chung and Agniswamy, Johnson and Harrison, Robert W. and Weber, Irene T.},
abstractNote = {Molecular mechanisms leading to high level drug resistance have been analyzed for the clinical variant of HIV-1 protease bearing 20 mutations (PR20); which has several orders of magnitude worse affinity for tested drugs. Two crystal structures of ligand-free PR20 with the D25N mutation of the catalytic aspartate (PR20D25N) revealed three dimers with different flap conformations. The diverse conformations of PR20D25N included a dimer with one flap in a unique “tucked” conformation; directed into the active site. Analysis of molecular dynamics (MD) simulations of the ligand-free PR20 and wild-type enzymes showed that the mutations in PR20 alter the correlated interactions between two monomers in the dimer. The two flaps tend to fluctuate more independently in PR20 than in the wild type enzyme. Combining the results of structural analysis by X-ray crystallography and MD simulations; unusual flap conformations and weakly correlated inter-subunit motions may lead to the high level resistance of PR20.},
doi = {10.1016/j.jmgm.2015.09.006},
journal = {Journal of Molecular Graphics and Modelling},
number = C,
volume = 62,
place = {United States},
year = {Tue Sep 08 00:00:00 EDT 2015},
month = {Tue Sep 08 00:00:00 EDT 2015}
}
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