4OBJ

Crystal Structure of Inactive HIV-1 Protease in Complex with the p1-p6 substrate variant (S451N)

4OBJ の概要

• エントリーDOI: 10.2210/pdb4obj/pdb
• 関連するPDBエントリー: 4OBD 4OBF 4OBG 4OBH 4OBK
• 分子名称: HIV-1 Protease, p1-p6 peptide, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: co-evolution, resistance, hydrolase
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1); 詳細
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369; Gag polyprotein: Host cell membrane ; Lipid-anchor . Matrix protein p17: Virion membrane ; Lipid-anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion : P03349
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 23655.78

構造登録者

Kolli, M. (登録日: 2014-01-07, 公開日: 2014-11-26, 最終更新日: 2023-09-20)

主引用文献

Kolli, M.,Ozen, A.,Kurt-Yilmaz, N.,Schiffer, C.A.
HIV-1 protease-substrate coevolution in nelfinavir resistance.
J.Virol., 88:7145-7154, 2014

PubMed Abstract: Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue 30's interaction with the substrate are compensated by the coevolving L449F and S451N cleavage site mutations. This interdependency in the PR-p1-p6 interactions enhances intermolecular contacts and reinforces the overall fit of the substrate within the substrate envelope, likely enabling coevolution to sustain substrate recognition and cleavage in the presence of PR resistance mutations.

PubMed: 24719428
DOI: 10.1128/JVI.00266-14

実験手法

X-RAY DIFFRACTION (1.75 Å)