4YE3

Crystal Structure of Multidrug Resistant HIV-1 Protease Clinical Isolate PR20 with Inhibitor GRL-4410A

4YE3 の概要

• エントリーDOI: 10.2210/pdb4ye3/pdb
• 分子名称: Protease, YTTRIUM ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: hiv-1 protease, drug resistance, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (HIV-1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22842.86

構造登録者

Agniswamy, J.,Weber, I.T. (登録日: 2015-02-23, 公開日: 2015-06-10, 最終更新日: 2023-09-27)

主引用文献

Agniswamy, J.,Louis, J.M.,Shen, C.H.,Yashchuk, S.,Ghosh, A.K.,Weber, I.T.
Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20.
J.Med.Chem., 58:5088-5095, 2015

PubMed Abstract: An extremely drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with two potent antiviral investigational inhibitors. GRL-5010A and GRL-4410A were designed to introduce hydrogen bond interactions with the flexible flaps of the PR by incorporating gem-difluorines and alkoxy, respectively, at the C4 position of the bis-THF of darunavir. PR20 provides an excellent model for high level resistance, since clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme. GRL-5010A and GRL-4410A show inhibition constants of 4.3 ± 7.0 and 1.7 ± 1.8 nM, respectively, for PR20, compared to the binding affinity of 41 ± 1 nM measured for darunavir. Crystal structures of PR20 in complexes with the two inhibitors confirmed the new hydrogen bond interactions with Gly 48 in the flap of the enzyme. The two new compounds are more effective than darunavir in inhibiting mature PR20 and show promise for further development of antiviral agents targeting highly resistant PR mutants.

PubMed: 26010498
DOI: 10.1021/acs.jmedchem.5b00474

実験手法

X-RAY DIFFRACTION (1.35 Å)