6CJI

Candida albicans Hsp90 nucleotide binding domain

6CJI の概要

• エントリーDOI: 10.2210/pdb6cji/pdb
• 分子名称: Heat shock protein 90 homolog, 1,2-ETHANEDIOL (3 entities in total)
• 機能のキーワード: hsp90. atpase, structural genomics, structural genomics consortium, sgc, chaperone
• 由来する生物種: Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26643.12

構造登録者

Hutchinson, A.,Loppnau, P.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Hui, R.,STRUCTURAL GENOMICS CONSORTIUM, S.G.C.,Pizarro, J.C.,Structural Genomics Consortium (SGC) (登録日: 2018-02-26, 公開日: 2019-01-30, 最終更新日: 2023-10-04)

主引用文献

Whitesell, L.,Robbins, N.,Huang, D.S.,McLellan, C.A.,Shekhar-Guturja, T.,LeBlanc, E.V.,Nation, C.S.,Hui, R.,Hutchinson, A.,Collins, C.,Chatterjee, S.,Trilles, R.,Xie, J.L.,Krysan, D.J.,Lindquist, S.,Porco Jr., J.A.,Tatu, U.,Brown, L.E.,Pizarro, J.,Cowen, L.E.
Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus.
Nat Commun, 10:402-402, 2019

PubMed Abstract: New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans. Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe's species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy.

PubMed: 30679438
DOI: 10.1038/s41467-018-08248-w

実験手法

X-RAY DIFFRACTION (1.64 Å)