3H5B

Crystal structure of wild type HIV-1 protease with novel P1'-ligand GRL-02031

3H5B の概要

• エントリーDOI: 10.2210/pdb3h5b/pdb
• 関連するPDBエントリー: 2HB3 2IEN 2Z4O 3DJK 3DK1
• 分子名称: HIV-1 protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: hiv-1, wild type protease, protease inhibitor, p1'-ligand, aids, hydrolase
• 由来する生物種: Human immunodeficiency virus type 1 (BRU ISOLATE) (HIV-1)
• 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 : P03367
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22269.06

構造登録者

Tie, Y.,Wang, Y.F.,Weber, I.T. (登録日: 2009-04-21, 公開日: 2009-06-16, 最終更新日: 2023-09-06)

主引用文献

Ghosh, A.K.,Leshchenko-Yashchuk, S.,Anderson, D.D.,Baldridge, A.,Noetzel, M.,Miller, H.B.,Tie, Y.,Wang, Y.F.,Koh, Y.,Weber, I.T.,Mitsuya, H.
Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies.
J.Med.Chem., 52:3902-3914, 2009

PubMed Abstract: Structure-based design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1'-ligands. These ligands are designed to interact with Gly-27' carbonyl and Arg-8 side chain in the S1'-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1'-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1' and S2 subsites of HIV-1 protease.

PubMed: 19473017
DOI: 10.1021/jm900303m

実験手法

X-RAY DIFFRACTION (1.29 Å)