7LYX

Crystal structure of human CYP8B1 in complex with (S)-tioconazole

7LYX の概要

• エントリーDOI: 10.2210/pdb7lyx/pdb
• 分子名称: 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, (S)-Tioconazole, ... (6 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58265.13

構造登録者

Liu, J.,Scott, E.E. (登録日: 2021-03-08, 公開日: 2022-08-17, 最終更新日: 2023-10-25)

主引用文献

Liu, J.,Carlson, H.A.,Scott, E.E.
The structure and characterization of human cytochrome P450 8B1 supports future drug design for nonalcoholic fatty liver disease and diabetes.
J.Biol.Chem., 298:102344-102344, 2022

PubMed Abstract: Human cytochrome P450 8B1 (CYP8B1) is involved in conversion of cholesterol to bile acids. It hydroxylates the steroid ring at C12 to ultimately produce the bile acid cholic acid. Studies implicated this enzyme as a good drug target for nonalcoholic fatty liver disease and type 2 diabetes, but there are no selective inhibitors known for this enzyme and no structures to guide inhibitor development. Herein, the human CYP8B1 protein was generated and used to identify and characterize interactions with a series of azole inhibitors, which tend to be poorly selective P450 inhibitors. Structurally related miconazole, econazole, and tioconazole bound with submicromolar dissociation constants and were effective inhibitors of the native reaction. CYP8B was cocrystallized with S-tioconazole to yield the first X-ray structure. This inhibitor bound in the active site with its azole nitrogen coordinating the heme iron, consistent with inhibitor binding and inhibition assay data. Additionally, the CYP8B1 active site was compared with similar P450 enzymes to identify features that may facilitate the design of more selective inhibitors. Selective inhibitors should promote a better understanding of the role of CYP8B1 inhibition in normal physiology and disease states and provide a possible treatment for nonalcoholic fatty liver disease and type 2 diabetes.

PubMed: 35944583
DOI: 10.1016/j.jbc.2022.102344

実験手法

X-RAY DIFFRACTION (2.6 Å)