8EOH

crystal structure of human Cytochrome P450 8B1 in complex with a C12-Pyridine Containing Steroid

8EOH の概要

• エントリーDOI: 10.2210/pdb8eoh/pdb
• 分子名称: 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, 12-(pyridin-3-yl)-8alpha,10alpha,13alpha,14beta-androsta-4,11-diene-3,17-dione, ... (4 entities in total)
• 機能のキーワード: monooxygenase, sterol 12-hydroxylase, 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: 58107.70

構造登録者

Liu, J.,Scott, E.E. (登録日: 2022-10-03, 公開日: 2023-08-02, 最終更新日: 2024-05-22)

主引用文献

Liu, J.,Offei, S.D.,Yoshimoto, F.K.,Scott, E.E.
Pyridine-containing substrate analogs are restricted from accessing the human cytochrome P450 8B1 active site by tryptophan 281.
J.Biol.Chem., 299:103032-103032, 2023

PubMed Abstract: The human oxysterol 12α-hydroxylase cytochrome P450 8B1 (CYP8B1) is a validated drug target for both type 2 diabetes and nonalcoholic fatty liver disease, but effective selective inhibitors are not yet available. Herein, steroidal substrate-mimicking compounds with a pyridine ring appended to the C12 site of metabolism were designed as inhibitors, synthesized, and evaluated in terms of their functional and structural interactions with CYP8B1. While the pyridine nitrogen was intended to coordinate the CYP8B1 active site heme iron, none of these compounds elicited shifts in the CYP8B1 Soret absorbance consistent with this type of interaction. However, when CYP8B1 was cocrystallized with the pyridine-containing compound with the 3-keto-Δ4 steroid backbone most similar to the endogenous substrate, it was apparent that this ligand was bound in a channel leading to the active site, instead of near the heme iron. Inspection of this structure suggested that tryptophan 281 directly above the heme might restrict active site binding of potential inhibitors with this design. This hypothesis was supported when a CYP8B1 W281F mutation did allow all three compounds to coordinate the heme iron as designed. These results indicated that the design of next-generation CYP8B1 inhibitors should be compatible with the low-ceiling tryptophan immediately above the heme iron.

PubMed: 36806682
DOI: 10.1016/j.jbc.2023.103032

実験手法

X-RAY DIFFRACTION (2.65 Å)