4QJ6

Crystal structure of inactive HIV-1 protease variant (I50V/A71V) in complex with p1-p6 substrate variant (L449F)

Summary for 4QJ6

• Entry DOI: 10.2210/pdb4qj6/pdb
• Related: 4QJ6 4QJ7 4QJ8 4QJ9 4QJA
• Descriptor: Protease, p1-p6 peptide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: co-evolution, protease, hydrolase
• Biological source: Human immunodeficiency virus type 1 (ARV2/SF2 ISOLATE) (HIV-1); More
• Cellular location: Matrix protein p17: Virion . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• Total number of polymer chains: 6
• Total formula weight: 45922.13

Authors

Lin, K.H.,Schiffer, C.A. (deposition date: 2014-06-03, release date: 2014-10-29, Last modification date: 2024-02-28)

Primary citation

Ozen, A.,Lin, K.H.,Kurt Yilmaz, N.,Schiffer, C.A.
Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease.
Proc.Natl.Acad.Sci.USA, 111:15993-15998, 2014

PubMed 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.

PubMed: 25355911
DOI: 10.1073/pnas.1414063111

Experimental method

X-RAY DIFFRACTION (1.5 Å)