4CKA

STEROL 14-ALPHA DEMETHYLASE (CYP51)FROM TRYPANOSOMA CRUZI IN COMPLEX WITH (S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 4- isopropylphenylcarbamate (LFS)

4CKA の概要

• エントリーDOI: 10.2210/pdb4cka/pdb
• 関連するPDBエントリー: 4CK8 4CK9
• 分子名称: STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, (1S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 4-isopropylphenylcarbamate, ... (4 entities in total)
• 機能のキーワード: heme, oxidoreductase, monooxygenase, sterol biosynthesis, eukaryotic membranes, cytochrome p450 fold, endoplasmic reticulum membrane
• 由来する生物種: TRYPANOSOMA CRUZI
• 細胞内の位置: Membrane; Single-pass membrane protein (Potential): Q7Z1V1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53536.80

構造登録者

Friggeri, L.,Wawrzak, Z.,Tortorella, S.,Lepesheva, G.I. (登録日: 2013-12-31, 公開日: 2014-07-30, 最終更新日: 2023-12-20)

主引用文献

Friggeri, L.,Hargrove, T.Y.,Rachakonda, G.,Williams, A.D.,Wawrzak, Z.,Di Santo, R.,De Vita, D.,Waterman, M.R.,Tortorella, S.,Villalta, F.,Lepesheva, G.I.
Structural Basis for Rational Design of Inhibitors Targeting Trypanosoma Cruzi Sterol 14Alpha-Demethylase: Two Regions of the Enzyme Molecule Potentiate its Inhibition.
J.Med.Chem., 57:6704-, 2014

PubMed Abstract: Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50=1.2 nM, vs (S)-2/(S)-3, EC50=1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.

PubMed: 25033013
DOI: 10.1021/JM500739F

実験手法

X-RAY DIFFRACTION (2.7 Å)