Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus
Luke Whitesell,
Nicole Robbins,
David S. Huang,
Catherine A. McLellan,
Tanvi Shekhar-Guturja,
Emmanuelle V. LeBlanc,
Catherine S. Nation,
Raymond Hui,
Ashley Hutchinson,
Cathy Collins,
Sharanya Chatterjee,
Richard Trilles,
Jinglin L. Xie,
Damian J. Krysan,
Susan Lindquist,
John A. Porco,
Utpal Tatu,
Lauren E. Brown,
Juan Pizarro and
Leah E. Cowen ()
Additional contact information
Luke Whitesell: University of Toronto
Nicole Robbins: University of Toronto
David S. Huang: Boston University
Catherine A. McLellan: Whitehead Institute for Biomedical Research
Tanvi Shekhar-Guturja: University of Toronto
Emmanuelle V. LeBlanc: University of Toronto
Catherine S. Nation: Tulane University
Raymond Hui: University of Toronto
Ashley Hutchinson: University of Toronto
Cathy Collins: University of Toronto
Sharanya Chatterjee: Indian Institute of Science
Richard Trilles: Boston University
Jinglin L. Xie: University of Toronto
Damian J. Krysan: University of Iowa
Susan Lindquist: Whitehead Institute for Biomedical Research
John A. Porco: Boston University
Utpal Tatu: Indian Institute of Science
Lauren E. Brown: Boston University
Juan Pizarro: Tulane University
Leah E. Cowen: University of Toronto
Nature Communications, 2019, vol. 10, issue 1, 1-17
Abstract:
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.
Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08248-w
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DOI: 10.1038/s41467-018-08248-w
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