5JLC

Structure of CYP51 from the pathogen Candida glabrata

5JLC の概要

• エントリーDOI: 10.2210/pdb5jlc/pdb
• 分子名称: Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, 2-[(2R)-butan-2-yl]-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one, ... (7 entities in total)
• 機能のキーワード: pathogen, candida glabrata, cyp51, itraconazole, oxidoreductase-oxidoreducatse inhibitor complex, oxidoreductase/oxidoreducatse inhibitor
• 由来する生物種: Candida glabrata (strain ATCC 2001 / CBS 138 / JCM 3761 / NBRC 0622 / NRRL Y-65) (Yeast)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61109.33

構造登録者

Keniya, M.V.,Sabherwal, M.,Wilson, R.K.,Sagatova, A.A.,Tyndall, J.D.A.,Monk, B.C. (登録日: 2016-04-26, 公開日: 2016-05-25, 最終更新日: 2023-09-27)

主引用文献

Keniya, M.V.,Sabherwal, M.,Wilson, R.K.,Woods, M.A.,Sagatova, A.A.,Tyndall, J.D.A.,Monk, B.C.
Crystal Structures of Full-Length Lanosterol 14 alpha-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery.
Antimicrob.Agents Chemother., 62:-, 2018

PubMed Abstract: Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed the need to improve the potency, spectrum, and specificity for azoles by expressing in functional, recombinant, hexahistidine-tagged, full-length LDM (CaLDM6×His) and LDM (CgLDM6×His) and determining their X-ray crystal structures. The crystal structures of CaLDM6×His, CgLDM6×His, and ScLDM6×His have the same fold and bind itraconazole in nearly identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6×His catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single-site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

PubMed: 30126961
DOI: 10.1128/AAC.01134-18

実験手法

X-RAY DIFFRACTION (2.4 Å)