5ESF

Saccharomyces cerevisiae CYP51 (Lanosterol 14-alpha demethylase) G73E mutant complexed with fluconazole

5ESF の概要

• エントリーDOI: 10.2210/pdb5esf/pdb
• 関連するPDBエントリー: 5ESE 5ESG 5ESH 5ESI 5ESJ 5ESK 5ESL 5ESM 5ESN
• 分子名称: Lanosterol 14-alpha demethylase, 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: cyp51, oxidoreductase-oxidoreducatse inhibitor complex, mutation, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (strain YJM789) (Baker's yeast)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62880.03

構造登録者

Sagatova, A.,Keniya, M.V.,Wilson, R.K.,Sabherwal, M.,Tyndall, J.D.A.,Monk, B.C. (登録日: 2015-11-16, 公開日: 2016-11-23, 最終更新日: 2023-09-27)

主引用文献

Sagatova, A.A.,Keniya, M.V.,Tyndall, J.D.A.,Monk, B.C.
Impact of Homologous Resistance Mutations from Pathogenic Yeast on Saccharomyces cerevisiae Lanosterol 14 alpha-Demethylase.
Antimicrob.Agents Chemother., 62:-, 2018

PubMed Abstract: Fungal infections frequently affect immunodeficient individuals and are estimated to kill 1.35 million people per annum. Azole antifungals target the membrane-bound cytochrome P450 monooxygenase lanosterol 14α-demethylase (CYP51; Erg11p). Mutations in CYP51 can render the widely used triazole drugs less effective. The CYP51 mutation G464S and the double mutation Y132F G464S (Y140F and G464S by numbering) as well as the CYP51A G54E/R/W mutations of (G73E/R/W by numbering) have been reproduced in a recombinant C-terminal hexahistidine-tagged version of CYP51 (ScErg11p6×His). Phenotypes and X-ray crystal structures were determined for the mutant enzymes. Liquid microdilution assays showed that the G464S mutation in ScErg11p6×His conferred no difference in the susceptibility of yeast to triazole drugs but in combination with the Y140F mutation gave a 4-fold reduction in susceptibility to the short-tailed triazole fluconazole. The ScErg11p6×His Y140F G464S mutant was unstable during purification and was not crystallized. The ScErg11p6×His G73E/R/W mutations conferred increased susceptibly to all triazoles tested in liquid microdilution assays. High-resolution X-ray crystal structures reveal two different conformations of the ligand itraconazole, including a previously unseen conformation, as well as interactions between the tail of this triazole and the E/W73 residue. This study shows that CYP51 adequately represents some but not all mutations in CYP51s of pathogenic fungi. Insight into the molecular mechanisms of resistance mutations in CYP51 will assist the development of inhibitors that will overcome antifungal resistance.

PubMed: 29263059
DOI: 10.1128/AAC.02242-17

実験手法

X-RAY DIFFRACTION (2.25 Å)