7KS8

Crystal structure of human CYP3A4 with the caged inhibitor

7KS8 の概要

• エントリーDOI: 10.2210/pdb7ks8/pdb
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57414.54

構造登録者

Sevrioukova, I.S. (登録日: 2020-11-21, 公開日: 2021-06-02, 最終更新日: 2023-10-18)

主引用文献

Toupin, N.,Steinke, S.J.,Nadella, S.,Li, A.,Rohrabaugh Jr., T.N.,Samuels, E.R.,Turro, C.,Sevrioukova, I.F.,Kodanko, J.J.
Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.
J.Am.Chem.Soc., 143:9191-9205, 2021

PubMed Abstract: We report the synthesis and photochemical and biological characterization of the first selective and potent metal-based inhibitors of cytochrome P450 3A4 (CYP3A4), the major human drug metabolizing enzyme. Five Ru(II)-based derivatives were prepared from two analogs of the CYP3A4 inhibitor ritonavir, and : [Ru(tpy)(L)()]Cl (tpy = 2,2':6',2″-terpyridine) with L = 6,6'-dimethyl-2,2'-bipyridine (Mebpy; ), dimethylbenzo[]dipyrido[3,2-:2',3'-]phenazine (Medppn; ) and 3,6-dimethyl-10,15-diphenylbenzo[]dipyrido[3,2-:2',3'-]phenazine (MePhdppn; ), [Ru(tpy)(Mebpy)()]Cl () and [Ru(tpy)(Medppn)()]Cl (). Photochemical release of or from - was demonstrated, and the spectrophotometric evaluation of showed that it behaves similarly to free (type II heme ligation) after irradiation with visible light but not in the dark. Unexpectedly, the intact Ru(II) complexes and were found to inhibit CYP3A4 potently and specifically through direct binding to the active site without heme ligation. Caged inhibitors - showed dual action properties by combining photoactivated dissociation of or with efficient O production. In prostate adenocarcinoma DU-145 cells, compound had the best synergistic effect with vinblastine, the anticancer drug primarily metabolized by CYP3A4 . Thus, our study establishes a new paradigm in CYP inhibition using metalated complexes and suggests possible utilization of photoactive CYP3A4 inhibitory compounds in clinical applications, such as enhancement of therapeutic efficacy of anticancer drugs.

PubMed: 34110801
DOI: 10.1021/jacs.1c04155

実験手法

X-RAY DIFFRACTION (2.5 Å)