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4QJA

Crystal structure of inactive HIV-1 protease in complex with p1-p6 substrate variant (P453L)

Summary for 4QJA
Entry DOI10.2210/pdb4qja/pdb
Related4QJ2 4QJ6 4QJ7 4QJ8 4QJ9
DescriptorProtease, p1-p6 peptide, SULFATE ION, ... (4 entities in total)
Functional Keywordsco-evolution, protease, hydrolase
Biological sourceHuman immunodeficiency virus type 1 (ARV2/SF2 ISOLATE) (HIV-1)
More
Cellular locationMatrix protein p17: Virion . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
Total number of polymer chains3
Total formula weight23163.27
Authors
Lin, K.H.,Schiffer, C.A. (deposition date: 2014-06-03, release date: 2014-10-29, Last modification date: 2024-02-28)
Primary citationOzen, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.54 Å)
Structure validation

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