4J14

Crystal Structure of Human Cytochrome P450 CYP46A1 with Posaconazole Bound

4J14 の概要

• エントリーDOI: 10.2210/pdb4j14/pdb
• 関連するPDBエントリー: 3MDM 3MDR 3MDT 3MDV 4ENH 4FIA
• 分子名称: Cholesterol 24-hydroxylase, PROTOPORPHYRIN IX CONTAINING FE, POSACONAZOLE, ... (5 entities in total)
• 機能のキーワード: enzyme, p450, posaconazole, oxidoreductase, endoplasmic reticulum, cholesterol 24-hydroxylase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Single-pass membrane protein: Q9Y6A2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53534.44

構造登録者

Stout, C.D.,Mast, N.,Pikuleva, I.A. (登録日: 2013-01-31, 公開日: 2014-01-15, 最終更新日: 2023-09-20)

主引用文献

Mast, N.,Zheng, W.,Stout, C.D.,Pikuleva, I.A.
Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.
Mol.Pharmacol., 84:86-94, 2013

PubMed Abstract: Although there are currently three generations of antifungal azoles on the market, even the third-generation agents show undesirable interactions with human cytochrome P450 (P450) enzymes. CYP46A1 is a cholesterol-metabolizing P450 in the brain that tightly binds a number of structurally distinct azoles. Previously, we determined the crystal structures of CYP46A1 in complex with voriconazole and clotrimazole, and in the present work we cocrystallized the P450 with posaconazole at 2.5 Å resolution. This long antifungal drug coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface. Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1. We compared the crystal structure of posaconazole-bound CYP46A1 with those of the P450 in complex with other drugs, including the antifungal voriconazole and clotrimazole. We also analyzed the accommodation of posaconazole in the active site of the target enzymes, CYPs 51, from several pathogenic species. These and the solution studies with different marketed azoles, collectively, allowed us to identify the determinants of tight azole binding to CYP46A1 and generate an overall picture of azole binding to this important P450. The data obtained suggest that development of CYP51-specific antifungal agents will continue to be a challenge. Therefore, structural understanding of the azole binding not only to CYPs 51 from the pathogenic species but also to different human P450s is required to deal efficiently with this challenge.

PubMed: 23604141
DOI: 10.1124/mol.113.085902

実験手法

X-RAY DIFFRACTION (2.5 Å)