4qj2

Crystal structure of inactive HIV-1 protease variant (I50V/A71V) in complex with WT p1-p6 substrate

spinqualitylabelsall models 4qj2, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qj2 is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, PO4, SO4 Related: 4qj6, 4qj7, 4qj8, 4qj9, 4qja Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.,Ozen A, Lin KH, Kurt Yilmaz N, Schiffer CA Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15993-8. doi:, 10.1073/pnas.1414063111. Epub 2014 Oct 29. PMID:25355911 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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