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Nat Commun. 2019 Jan 24;10(1):402. doi: 10.1038/s41467-018-08248-w.

Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus.

Author information

1
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada.
2
Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
3
Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA, 02215, USA.
4
Department of Tropical Medicine, School of Public Health and Tropical Medicine and Vector-Borne Infectious Disease Research Center, Tulane University, New Orleans, LA, 70112, USA.
5
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
6
Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
7
Departments of Pediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.
8
Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
9
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada. leah.cowen@utoronto.ca.

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.

PMID:
30679438
PMCID:
PMC6345968
DOI:
10.1038/s41467-018-08248-w
[Indexed for MEDLINE]
Free PMC Article

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