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


Document Type



Biochemistry | Biochemistry, Biophysics, and Structural Biology | Biological and Chemical Physics | Molecular Biology | Pharmacology | Structural Biology


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



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


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.

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