7RTQ

Sterol 14alpha demethylase (CYP51) from Naegleria fowleri in complex with an inhibitor R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide

7RTQ の概要

• エントリーDOI: 10.2210/pdb7rtq/pdb
• 分子名称: Protein CYP51, PROTOPORPHYRIN IX CONTAINING FE, N-[(1R)-2-(1H-imidazol-1-yl)-1-(3,4',5-trifluoro[1,1'-biphenyl]-4-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, ... (4 entities in total)
• 機能のキーワード: cytochrome p450, cyp51, sterol 14 alpha- demethylase, oxidoreductase
• 由来する生物種: Naegleria fowleri (Brain eating amoeba)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 218968.10

構造登録者

Lepesheva, G.I.,Hargrove, T.Y.,Wawrzak, Z. (登録日: 2021-08-13, 公開日: 2021-11-24, 最終更新日: 2023-10-18)

主引用文献

Hargrove, T.Y.,Wawrzak, Z.,Rachakonda, G.,Nes, W.D.,Villalta, F.,Guengerich, F.P.,Lepesheva, G.I.
Relaxed Substrate Requirements of Sterol 14 alpha-Demethylase from Naegleria fowleri Are Accompanied by Resistance to Inhibition.
J.Med.Chem., 64:17511-17522, 2021

PubMed Abstract: is the protozoan pathogen that causes primary amoebic meningoencephalitis (PAM), with the death rate exceeding 97%. The amoeba makes sterols and can be targeted by sterol biosynthesis inhibitors. Here, we characterized sterol 14-demethylase, including catalytic properties and inhibition by clinical antifungal drugs and experimental substituted azoles with favorable pharmacokinetics and low toxicity. None of them inhibited the enzyme stoichiometrically. The highest potencies were displayed by posaconazole (IC = 0.69 μM) and two of our compounds (IC = 1.3 and 0.35 μM). Because both these compounds penetrate the brain with concentrations reaching minimal inhibitory concentration (MIC) values in an cellular assay, we report them as potential drug candidates for PAM. The 2.1 Å crystal structure, in complex with the strongest inhibitor, provides an explanation connecting the enzyme weaker substrate specificity with lower sensitivity to inhibition. It also provides insight into the enzyme/ligand molecular recognition process and suggests directions for the design of more potent inhibitors.

PubMed: 34842434
DOI: 10.1021/acs.jmedchem.1c01710

実験手法

X-RAY DIFFRACTION (2.11 Å)