5UL0

S. CEREVISIAE CYP51 COMPLEXED WITH VT-1161

5UL0 の概要

• エントリーDOI: 10.2210/pdb5ul0/pdb
• 関連するPDBエントリー: 4WMZ 5U1F
• 分子名称: Lanosterol 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, ... (5 entities in total)
• 機能のキーワード: vt-1161, cyp51, oxidoreductase-oxidoreducatse inhibitor complex, sterol biosynthesis, oxidoreductase
• 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: 61969.90

構造登録者

Tyndall, J.D.,Keniya, M.V.,Sabherwal, M.,Monk, B.C. (登録日: 2017-01-23, 公開日: 2017-02-15, 最終更新日: 2023-10-04)

主引用文献

Monk, B.C.,Keniya, M.V.,Sabherwal, M.,Wilson, R.K.,Graham, D.O.,Hassan, H.F.,Chen, D.,Tyndall, J.D.A.
Azole Resistance Reduces Susceptibility to the Tetrazole Antifungal VT-1161.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: Tetrazole antifungals designed to target fungal lanosterol 14α-demethylase (LDM) appear to be effective against a range of fungal pathogens. In addition, a crystal structure of the catalytic domain of LDM in complex with the tetrazole VT-1161 has been obtained. We have addressed concern about artifacts that might arise from crystallizing VT-1161 with truncated recombinant CYP51s and measured the impact on VT-1161 susceptibility of genotypes known to confer azole resistance. A yeast system was used to overexpress recombinant full-length LDM with a C-terminal hexahistidine tag (ScLDM6×His) for phenotypic analysis and crystallographic studies with VT-1161 or with the widely used triazole drug posaconazole (PCZ). We determined the effect of characterized mutations in LDM on VT-1161 activity and identified drug efflux pumps from fungi, including key fungal pathogens, that efflux VT-1161. The relevance of these yeast-based observations on drug efflux was verified using clinical isolates of and VT-1161 binding elicits a significant conformational difference between the full-length and truncated enzymes not found when posaconazole is bound. Susceptibility to VT-1161 is reduced by ATP-binding cassette (ABC) and major facilitator superfamily (MFS) drug efflux pumps, the overexpression of LDM, and mutations within the drug binding pocket of LDM that affect interaction with the tertiary alcohol of the drug.

PubMed: 30397057
DOI: 10.1128/AAC.02114-18

実験手法

X-RAY DIFFRACTION (2.2 Å)