1EA1

Cytochrome P450 14 alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with fluconazole

1EA1 の概要

• エントリーDOI: 10.2210/pdb1ea1/pdb
• 関連するPDBエントリー: 1E9X
• 分子名称: CYTOCHROME P450 51-LIKE RV0764C, PROTOPORPHYRIN IX CONTAINING FE, 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, cytochrome p450, 14 alpha-sterol demethylase, azole inhibitors
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52422.09

構造登録者

Podust, L.M.,Poulos, T.L.,Waterman, M.R. (登録日: 2000-11-02, 公開日: 2000-11-06, 最終更新日: 2023-12-13)

主引用文献

Podust, L.M.,Poulos, T.L.,Waterman, M.R.
Crystal Structure of Cytochrome P450 14Alpha -Sterol Demethylase (Cyp51) from Mycobacterium Tuberculosis in Complex with Azole Inhibitors
Proc.Natl.Acad.Sci.USA, 98:3068-, 2001

PubMed Abstract: Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. The 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target. MTCYP51 exhibits the P450 fold with the exception of two striking differences-a bent I helix and an open conformation of BC loop-that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.

PubMed: 11248033
DOI: 10.1073/PNAS.061562898

実験手法

X-RAY DIFFRACTION (2.21 Å)