3NXU

Crystal structure of human cytochrome P4503A4 bound to an inhibitor ritonavir

3NXU の概要

• エントリーDOI: 10.2210/pdb3nxu/pdb
• 関連するPDBエントリー: 1TQN 1W0E 1W0F 1W0G 2J0D 2V0M
• 関連するBIRD辞書のPRD_ID: PRD_001001
• 分子名称: Cytochrome P450 3A4, DIMETHYL SULFOXIDE, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: alpha beta protein, cytochrome p450 fold, hemoprotein, monooxygenase, cytochrome p450 reductase, endoplasmic reticulum, 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: 2
• 化学式量合計: 114106.62

構造登録者

Sevrioukova, I.F.,Poulos, T.L. (登録日: 2010-07-14, 公開日: 2010-10-20, 最終更新日: 2023-09-06)

主引用文献

Sevrioukova, I.F.,Poulos, T.L.
Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.
Proc.Natl.Acad.Sci.USA, 107:18422-18427, 2010

PubMed Abstract: Ritonavir is a HIV protease inhibitor routinely prescribed to HIV patients that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. By inhibiting CYP3A4, ritonavir increases plasma concentrations of other anti-HIV drugs oxidized by CYP3A4 thereby improving clinical efficacy. Despite the importance and wide use of ritonavir in anti-HIV therapy, the precise mechanism of CYP3A4 inhibition remains unclear. The available data are inconsistent and suggest that ritonavir acts as a mechanism-based, competitive or mixed competitive-noncompetitive CYP3A4 inactivator. To resolve this controversy and gain functional and structural insights into the mechanism of CYP3A4 inhibition, we investigated the ritonavir binding reaction by kinetic and equilibrium analysis, elucidated how the drug affects redox properties of the hemoprotein, and determined the 2.0 Å X-ray structure of the CYP3A4-ritonavir complex. Our results show that ritonavir is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase.

PubMed: 20937904
DOI: 10.1073/pnas.1010693107

実験手法

X-RAY DIFFRACTION (2 Å)