Title
Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2014-11-11
Document Type
Article
Disciplines
Biochemistry | Biochemistry, Biophysics, and Structural Biology | Biological and Chemical Physics | Molecular Biology | Pharmacology | Structural Biology
Abstract
Drug resistance mutations in response to HIV-1 protease inhibitors are selected not only in the drug target but elsewhere in the viral genome, especially at the protease cleavage sites in the precursor protein Gag. To understand the molecular basis of this protease-substrate coevolution, we solved the crystal structures of drug resistant I50V/A71V HIV-1 protease with p1-p6 substrates bearing coevolved mutations. Analyses of the protease-substrate interactions reveal that compensatory coevolved mutations in the substrate do not restore interactions lost due to protease mutations, but instead establish other interactions that are not restricted to the site of mutation. Mutation of a substrate residue has distal effects on other residues' interactions as well, including through the induction of a conformational change in the protease. Additionally, molecular dynamics simulations suggest that restoration of active site dynamics is an additional constraint in the selection of coevolved mutations. Hence, protease-substrate coevolution permits mutational, structural, and dynamic changes via molecular mechanisms that involve distal effects contributing to drug resistance.
DOI of Published Version
10.1073/pnas.1414063111
Source
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15993-8. doi: 10.1073/pnas.1414063111. Epub 2014 Oct 29. Link to article on publisher's site
Journal/Book/Conference Title
Proceedings of the National Academy of Sciences of the United States of America
Related Resources
PubMed ID
25355911
Repository Citation
Ozen, Aysegul; Lin, Kuan-Hung; Yilmaz, Nese Kurt; and Schiffer, Celia A., "Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease" (2014). Biochemistry and Molecular Pharmacology Publications and Presentations. 202.
https://escholarship.umassmed.edu/bmp_pp/202
Comments
First author Aysegul Ozen is a doctoral student in the Biochemistry and Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.