3D1X

Crystal structure of HIV-1 mutant I54M and inhibitor saquinavir

3D1X の概要

• エントリーDOI: 10.2210/pdb3d1x/pdb
• 関連するPDBエントリー: 3CYW 3CYX 3D1Y 3D1Z 3D20
• 関連するBIRD辞書のPRD_ID: PRD_000454
• 分子名称: HIV-1 Protease, CHLORIDE ION, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide, ... (5 entities in total)
• 機能のキーワード: drug resistance, hiv-1, i54m, flap mutant, aids, aspartyl protease, capsid maturation, capsid protein, hydrolase-hydrolase inhibitor complex, viral nucleoprotein, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P04587
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22386.72

構造登録者

Liu, F.,Weber, I.T. (登録日: 2008-05-06, 公開日: 2008-06-03, 最終更新日: 2023-08-30)

主引用文献

Liu, F.,Kovalevsky, A.Y.,Tie, Y.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir.
J.Mol.Biol., 381:102-115, 2008

PubMed Abstract: HIV-1 (human immunodeficiency virus type 1) protease (PR) and its mutants are important antiviral drug targets. The PR flap region is critical for binding substrates or inhibitors and catalytic activity. Hence, mutations of flap residues frequently contribute to reduced susceptibility to PR inhibitors in drug-resistant HIV. Structural and kinetic analyses were used to investigate the role of flap residues Gly48, Ile50, and Ile54 in the development of drug resistance. The crystal structures of flap mutants PR(I50V) (PR with I50V mutation), PR(I54V) (PR with I54V mutation), and PR(I54M) (PR with I54M mutation) complexed with saquinavir (SQV) as well as PR(G48V) (PR with G48V mutation), PR(I54V), and PR(I54M) complexed with darunavir (DRV) were determined at resolutions of 1.05-1.40 A. The PR mutants showed changes in flap conformation, interactions with adjacent residues, inhibitor binding, and the conformation of the 80s loop relative to the wild-type PR. The PR contacts with DRV were closer in PR(G48V)-DRV than in the wild-type PR-DRV, whereas they were longer in PR(I54M)-DRV. The relative inhibition of PR(I54V) and that of PR(I54M) were similar for SQV and DRV. PR(G48V) was about twofold less susceptible to SQV than to DRV, whereas the opposite was observed for PR(I50V). The observed inhibition was in agreement with the association of G48V and I50V with clinical resistance to SQV and DRV, respectively. This analysis of structural and kinetic effects of the mutants will assist in the development of more effective inhibitors for drug-resistant HIV.

PubMed: 18597780
DOI: 10.1016/j.jmb.2008.05.062

実験手法

X-RAY DIFFRACTION (1.05 Å)