3GPH

Human cytochrome P450 2E1 in complex with omega-imidazolyl-decanoic acid

3GPH の概要

• エントリーDOI: 10.2210/pdb3gph/pdb
• 関連するPDBエントリー: 3E4E 3E6I
• 分子名称: Cytochrome P450 2E1, PROTOPORPHYRIN IX CONTAINING FE, 10-(1H-imidazol-1-yl)decanoic acid, ... (4 entities in total)
• 機能のキーワード: cyp2e1, p450 2e1, monooxygenase, acetaminophen, oxidoreductase, heme, fatty acid hydroxylase, metal-binding
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein: P05181
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 111826.60

構造登録者

Porubsky, P.R.,Battaile, K.P.,Scott, E.E. (登録日: 2009-03-23, 公開日: 2010-05-12, 最終更新日: 2023-09-06)

主引用文献

Porubsky, P.R.,Battaile, K.P.,Scott, E.E.
Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode.
J.Biol.Chem., 285:22282-22290, 2010

PubMed Abstract: Human microsomal cytochrome P450 (CYP) 2E1 is widely known for its ability to oxidize >70 different, mostly compact, low molecular weight drugs and other xenobiotic compounds. In addition CYP2E1 oxidizes much larger C9-C20 fatty acids that can serve as endogenous signaling molecules. Previously structures of CYP2E1 with small molecules revealed a small, compact CYP2E1 active site, which would be insufficient to accommodate medium and long chain fatty acids without conformational changes in the protein. In the current work we have determined how CYP2E1 can accommodate a series of fatty acid analogs by cocrystallizing CYP2E1 with omega-imidazolyl-octanoic fatty acid, omega-imidazolyl-decanoic fatty acid, and omega-imidazolyl-dodecanoic fatty acid. In each structure direct coordination of the imidazole nitrogen to the heme iron mimics the position required for native fatty acid substrates to yield the omega-1 hydroxylated metabolites that predominate experimentally. In each case rotation of a single Phe(298) side chain merges the active site with an adjacent void, significantly altering the active site size and topology to accommodate fatty acids. The binding of these fatty acid ligands is directly opposite the channel to the protein surface and the binding observed for fatty acids in the bacterial cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium. Instead of the BM3-like binding mode in the CYP2E1 channel, these structures reveal interactions between the fatty acid carboxylates and several residues in the F, G, and B' helices at successive distances from the active site.

PubMed: 20463018
DOI: 10.1074/jbc.M110.109017

実験手法

X-RAY DIFFRACTION (2.7 Å)