1NR6

MICROSOMAL CYTOCHROME P450 2C5/3LVDH COMPLEX WITH DICLOFENAC

1NR6 の概要

• エントリーDOI: 10.2210/pdb1nr6/pdb
• 関連するPDBエントリー: 1DT6 1N6B
• 分子名称: CYTOCHROME P450 2C5, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: membrane protein, progesterone 21-hydroxylase, benzo(a), pyrene hydroxylase, estradiol 2-hydroxylase, p450, cyp2c5, diclofenac complex, oxidoreductase
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• 細胞内の位置: Endoplasmic reticulum membrane (By similarity): P00179
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54989.01

構造登録者

Wester, M.R.,Johnson, E.F.,Stout, C.D. (登録日: 2003-01-23, 公開日: 2003-08-12, 最終更新日: 2023-08-16)

主引用文献

WESTER, M.R.,JOHNSON, E.F.,Marques-Soares, C.,Dijols, S.,Dansette, P.M.,Mansuy, D.,STOUT, C.D.
Structure of Mammalian Cytochrome P450 2C5 Complexed with Diclofenac at 2.1 A Resolution: Evidence for an Induced Fit Model of Substrate Binding
Biochemistry, 42:9335-9345, 2003

PubMed Abstract: The structure of the anti-inflammatory drug diclofenac bound in the active site of rabbit microsomal cytochrome P450 2C5/3LVdH was determined by X-ray crystallography to 2.1 A resolution. P450 2C5/3LVdH and the related enzyme 2C5dH catalyze the 4'-hydroxylation of diclofenac with apparent K(m) values of 80 and 57 microM and k(cat) values of 13 and 16 min(-1), respectively. Spectrally determined binding constants are similar to the K(m) values. The structure indicates that the pi-electron system of the dichlorophenyl moiety faces the heme Fe with the 3'- and 4'-carbons located 4.4 and 4.7 A, respectively, from the Fe. The carboxyl moiety of the substrate is hydrogen bonded to a cluster of waters that are also hydrogen bonded to the side chains of N204, K241, S289, and D290 as well as the backbone of the protein. The proximity of the diclofenac carboxylate to the side chain of D290 together with an increased binding affinity at lower pH suggests that diclofenac is protonated when bound to the enzyme. The structure exhibits conformational changes indicative of an adaptive fit to the substrate reflecting both the hydration and size of the substrate. These results indicate how structurally diverse substrates are recognized by drug-metabolizing P450 enzymes.

PubMed: 12899620
DOI: 10.1021/bi034556l

実験手法

X-RAY DIFFRACTION (2.1 Å)