2Q9G

Crystal structure of human cytochrome P450 46A1

2Q9G の概要

• エントリーDOI: 10.2210/pdb2q9g/pdb
• 関連するPDBエントリー: 2q9f
• 分子名称: Cytochrome P450 46A1, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: cyp46a1, p450 46a1, p450, monooxygenase, cholesterol metabolic enzyme, oxidoreductase, heme
• 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: 52925.76

構造登録者

White, M.A.,Mast, N.V.,Johnson, E.F.,Stout, C.D.,Pikuleva, I.A. (登録日: 2007-06-12, 公開日: 2008-06-17, 最終更新日: 2023-08-30)

主引用文献

Mast, N.,White, M.A.,Bjorkhem, I.,Johnson, E.F.,Stout, C.D.,Pikuleva, I.A.
Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain.
Proc.Natl.Acad.Sci.Usa, 105:9546-9551, 2008

PubMed Abstract: By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-A structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-A resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B'-C loop insertion (residues 116-120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics.

PubMed: 18621681
DOI: 10.1073/pnas.0803717105

実験手法

X-RAY DIFFRACTION (2.4 Å)