5TZ1

Crystal structure of sterol 14-alpha demethylase (CYP51) from Candida albicans in complex with the tetrazole-based antifungal drug candidate VT1161 (VT1)

5TZ1 の概要

• エントリーDOI: 10.2210/pdb5tz1/pdb
• 関連するPDBエントリー: 5FSA
• 分子名称: Sterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, (R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol, ... (4 entities in total)
• 機能のキーワード: cyp51, cytochrome p450, heme, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Candida albicans (Yeast)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115158.14

構造登録者

Hargrove, T.,Wawrzak, Z.,Lepesheva, G. (登録日: 2016-11-21, 公開日: 2017-03-15, 最終更新日: 2023-10-04)

主引用文献

Hargrove, T.Y.,Friggeri, L.,Wawrzak, Z.,Qi, A.,Hoekstra, W.J.,Schotzinger, R.J.,York, J.D.,Guengerich, F.P.,Lepesheva, G.I.
Structural analyses of Candida albicans sterol 14 alpha-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis.
J. Biol. Chem., 292:6728-6743, 2017

PubMed Abstract: With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: ()-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against and , pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals.

PubMed: 28258218
DOI: 10.1074/jbc.M117.778308

実験手法

X-RAY DIFFRACTION (2 Å)