2NNJ

CYP2C8dH complexed with felodipine

2NNJ の概要

• エントリーDOI: 10.2210/pdb2nnj/pdb
• 関連するPDBエントリー: 2NNH 2NNI
• 分子名称: Cytochrome P450 2C8, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• 機能のキーワード: cyp2c8; human p450 2c8; monooxygenases; felodipine; plendil; inhibitor complex; palmitic acid, oxidoreductase, electron transport
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein: P10632
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55599.51

構造登録者

Schoch, G.A.,Yano, J.K.,Stout, C.D.,Johnson, E.F. (登録日: 2006-10-24, 公開日: 2007-10-23, 最終更新日: 2023-08-30)

主引用文献

Schoch, G.A.,Yano, J.K.,Sansen, S.,Dansette, P.M.,Stout, C.D.,Johnson, E.F.
Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid.
J.Biol.Chem., 283:17227-17237, 2008

PubMed Abstract: Although a crystal structure and a pharmacophore model are available for cytochrome P450 2C8, the role of protein flexibility and specific ligand-protein interactions that govern substrate binding are poorly understood. X-ray crystal structures of P450 2C8 complexed with montelukast (2.8 A), troglitazone (2.7 A), felodipine (2.3 A), and 9-cis-retinoic acid (2.6 A) were determined to examine ligand-protein interactions for these chemically diverse compounds. Montelukast is a relatively large anionic inhibitor that exhibits a tripartite structure and complements the size and shape of the active-site cavity. The inhibitor troglitazone occupies the upper portion of the active-site cavity, leaving a substantial part of the cavity unoccupied. The smaller neutral felodipine molecule is sequestered with its dichlorophenyl group positioned close to the heme iron, and water molecules fill the distal portion of the cavity. The structure of the 9-cis-retinoic acid complex reveals that two substrate molecules bind simultaneously in the active site of P450 2C8. A second molecule of 9-cis-retinoic acid is located above the proximal molecule and can restrain the position of the latter for more efficient oxygenation. Solution binding studies do not discriminate between cooperative and noncooperative models for multiple substrate binding. The complexes with structurally distinct ligands further demonstrate the conformational adaptability of active site-constituting residues, especially Arg-241, that can reorient in the active-site cavity to stabilize a negatively charged functional group and define two spatially distinct binding sites for anionic moieties of substrates.

PubMed: 18413310
DOI: 10.1074/jbc.M802180200

実験手法

X-RAY DIFFRACTION (2.28 Å)