4ENH

Crystal Structure of Human Cytochrome P450 CYP46A1 with Fluvoxamine Bound

4ENH の概要

• エントリーDOI: 10.2210/pdb4enh/pdb
• 関連するPDBエントリー: 2Q9F 2Q9G 3MDM 3MDR 3MDT 3MDV
• 分子名称: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, Fluvoxamine, ... (4 entities in total)
• 機能のキーワード: enzyme, p450, fluvoxamine, oxidoreductase, endoplasmic reticulum
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Single-pass membrane protein: Q9Y6A2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53059.91

構造登録者

Stout, C.D.,Mast, N.,Pikuleva, I.A. (登録日: 2012-04-13, 公開日: 2012-08-22, 最終更新日: 2023-09-13)

主引用文献

Mast, N.,Linger, M.,Clark, M.,Wiseman, J.,Stout, C.D.,Pikuleva, I.A.
In Silico and Intuitive Predictions of CYP46A1 Inhibition by Marketed Drugs with Subsequent Enzyme Crystallization in Complex with Fluvoxamine.
Mol.Pharmacol., 82:824-834, 2012

PubMed Abstract: Cytochrome P450 46A1 (cholesterol 24-hydroxylase) is an important brain enzyme that may be inhibited by structurally distinct pharmaceutical agents both in vitro and in vivo. To identify additional inhibitors of CYP46A1 among U.S. Food and Drug Administration-approved therapeutic agents, we used in silico and intuitive predictions and evaluated some of the predicted binders in the enzyme and spectral binding assays. We tested a total of 298 marketed drugs for the inhibition of CYP46A1-mediated cholesterol hydroxylation in vitro and found that 13 of them reduce CYP46A1 activity by >50%. Of these 13 inhibitors, 7 elicited a spectral response in CYP46A1 with apparent spectral K(d) values in a low micromolar range. One of the identified tight binders, the widely used antidepressant fluvoxamine, was cocrystallized with CYP46A1. The structure of this complex was determined at a 2.5 Å resolution and revealed the details of drug binding to the CYP46A1 active site. The NH(2)-containing arm of the Y-shaped fluvoxamine coordinates the CYP46A1 heme iron, whereas the methoxy-containing arm points away from the heme group and has multiple hydrophobic interactions with aliphatic amino acid residues. The CF(3)-phenyl ring faces the entrance to the substrate access channel and has contacts with the aromatic side chains. The crystal structure suggests that only certain drug conformers can enter the P450 substrate access channel and reach the active site. Once inside the active site, the conformer probably further adjusts its configuration and elicits the movement of the protein side chains.

PubMed: 22859721
DOI: 10.1124/mol.112.080424

実験手法

X-RAY DIFFRACTION (2.5 Å)