3KHM

Crystal structure of sterol 14alpha-demethylase (CYP51) from Trypanosoma cruzi in complex with inhibitor fluconazole

3KHM の概要

• エントリーDOI: 10.2210/pdb3khm/pdb
• 関連するPDBエントリー: 3K1O
• 分子名称: Sterol 14 alpha-demethylase, PROTOPORPHYRIN IX CONTAINING FE, 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL (3 entities in total)
• 機能のキーワード: sterol 14-alpha demethylase, cyp51, cytochrome p450, heme, oxidoreductase, monooxygenase, endoplasmic reticulum, transmembrane protein, sterol biosynthesis, lipids, membrane, iron, heme thiolate protein
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53848.10

構造登録者

Lepesheva, G.I.,Hargrove, T.Y.,Anderson, S.,Wawrzak, Z.,Waterman, M.R. (登録日: 2009-10-30, 公開日: 2009-11-10, 最終更新日: 2023-09-06)

主引用文献

Lepesheva, G.I.,Hargrove, T.Y.,Anderson, S.,Kleshchenko, Y.,Furtak, V.,Wawrzak, Z.,Villalta, F.,Waterman, M.R.
Structural Insights into Inhibition of Sterol 14{alpha}-Demethylase in the Human Pathogen Trypanosoma cruzi.
J.Biol.Chem., 285:25582-25590, 2010

PubMed Abstract: Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)biphenyl-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.

PubMed: 20530488
DOI: 10.1074/jbc.M110.133215

実験手法

X-RAY DIFFRACTION (2.85 Å)