Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.

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

SUBMITTER: Ozen A 

PROVIDER: S-EPMC4234576 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature