4I4H

Crystal structure of CYP3A4 ligated to pyridine-substituted desoxyritonavir

4I4H の概要

• エントリーDOI: 10.2210/pdb4i4h/pdb
• 関連するPDBエントリー: 3NXU 4I4G
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, pyridin-3-ylmethyl [(2R,5S)-5-{[N-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-D-valyl]amino}-1,6-diphenylhexan-2-yl]carbamate (3 entities in total)
• 機能のキーワード: monooxygenase, cytochrome p450 reductase, cytochrome b5, endoplasmic reticulum, cytochrome p450, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Single-pass membrane protein: P08684
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57073.22

構造登録者

Sevrioukova, I.F.,Poulos, T.L. (登録日: 2012-11-27, 公開日: 2013-04-24, 最終更新日: 2023-09-20)

主引用文献

Sevrioukova, I.F.,Poulos, T.L.
Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir.
J.Med.Chem., 56:3733-3741, 2013

PubMed Abstract: Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.

PubMed: 23586711
DOI: 10.1021/jm400288z

実験手法

X-RAY DIFFRACTION (2.9 Å)