1MT7

Viability of a drug-resistant HIV-1 protease mutant: structural insights for better antiviral therapy

1MT7 の概要

• エントリーDOI: 10.2210/pdb1mt7/pdb
• 関連するPDBエントリー: 1KJ4 1MT8 1MT9 1MTB 1MTR
• 分子名称: PROTEASE RETROPEPSIN, Substrate analogue, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: matrix, capsid, gag cleavage, drug resistance, substrate recognition, hydrolase-hydrolase substrate complex, hydrolase/hydrolase substrate
• 由来する生物種: Human immunodeficiency virus 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
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 23060.98

構造登録者

Prabu-Jeyabalan, M.,Nalivaika, E.A.,King, N.M.,Schiffer, C.A. (登録日: 2002-09-20, 公開日: 2003-01-07, 最終更新日: 2024-02-14)

主引用文献

Prabu-Jeyabalan, M.,Nalivaika, E.A.,King, N.M.,Schiffer, C.A.
Viability of drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy
J.Virol., 77:1305-1315, 2003

PubMed Abstract: Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

PubMed: 12502847
DOI: 10.1128/JVI.77.2.1306-1315.2003

実験手法

X-RAY DIFFRACTION (1.9 Å)