4QJ7

Crystal structure of inactive HIV-1 protease variant (I50V/A71V) in complex with p1-p6 substrate variant (R452S)

4QJ7 の概要

• エントリーDOI: 10.2210/pdb4qj7/pdb
• 関連するPDBエントリー: 4QJ2 4QJ6 4QJ8 4QJ9 4QJA
• 分子名称: Protease, p1-p6 peptide, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: co-evolution, protease, hydrolase
• 由来する生物種: Human immunodeficiency virus type 1 (ARV2/SF2 ISOLATE) (HIV-1); 詳細
• 細胞内の位置: Matrix protein p17: Virion . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 45808.84

構造登録者

Lin, K.H.,Schiffer, C.A. (登録日: 2014-06-03, 公開日: 2014-10-29, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.67 Å)