4QJ2: Crystal Structure Of Inactive Hiv-1 Protease Variant (i50v/a71v) In Complex With Wt P1-p6 Substrate

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.
PDB ID: 4QJ2Download
MMDB ID: 124348
PDB Deposition Date: 2014/6/3
Updated in MMDB: 2014/12
Experimental Method:
x-ray diffraction
Resolution: 2.13  Å
Source Organism:
Similar Structures:
Biological Unit for 4QJ2: trimeric; determined by author and by software (PISA)
Molecular Components in 4QJ2
Label Count Molecule
Proteins (3 molecules)
Molecule annotation
P1-p6 Peptide
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB