2G69

Structure of Unliganded HIV-1 Protease F53L Mutant

2G69 の概要

• エントリーDOI: 10.2210/pdb2g69/pdb
• 分子名称: protease (2 entities in total)
• 機能のキーワード: aspartic protease, catalysis, unliganded, flap mutant, non-active site mutant, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10706.66

構造登録者

Kovalevsky, A.Y.,Liu, F. (登録日: 2006-02-24, 公開日: 2006-05-09, 最終更新日: 2024-02-14)

主引用文献

Liu, F.,Kovalevsky, A.Y.,Louis, J.M.,Boross, P.I.,Wang, Y.F.,Harrison, R.W.,Weber, I.T.
Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation.
J.Mol.Biol., 358:1191-1199, 2006

PubMed Abstract: Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PR(F53L) showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PR(F53L) was determined in the unliganded form at 1.35 Angstrom resolution in space group P4(1)2(1)2. The tips of the flaps in PR(F53L) had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50'. The changes in interactions between the flaps agreed with the reduced stability of PR(F53L) relative to wild-type PR. The altered flap interactions in the unliganded form of PR(F53L) suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.

PubMed: 16569415
DOI: 10.1016/j.jmb.2006.02.076

実験手法

X-RAY DIFFRACTION (1.35 Å)