6CJR

Candida albicans Hsp90 nucleotide binding domain in complex with SNX-2112

Summary for 6CJR

• Entry DOI: 10.2210/pdb6cjr/pdb
• Related: 6CJI 6CJJ 6CJL 6CJP
• Descriptor: Heat shock protein 90 homolog, 4-[6,6-dimethyl-4-oxidanylidene-3-(trifluoromethyl)-5,7-dihydroindazol-1-yl]-2-[(4-oxidanylcyclohexyl)amino]benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: hsp90. atpase, chaperone
• Biological source: Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast)
• Total number of polymer chains: 2
• Total formula weight: 52943.83

Authors

Kirkpatrick, M.G.,Pizarro, J.C. (deposition date: 2018-02-26, release date: 2019-01-30, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)