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

Whitesell, Luke; Robbins, Nicole; Huang, David S.; McLellan, Catherine A.; Shekhar-Guturja, Tanvi; LeBlanc, Emmanuelle V.; Nation, Catherine S.; Hui, Raymond; Hutchinson, Ashley; Collins, Cathy; Chatterjee, Sharanya; Trilles, Richard; Xie, Jinglin L.; Krysan, Damian J.; Lindquist, Susan; Porco, Jr., John A.; Tatu, Utpal; Brown, Lauren E.; Pizarro, Juan; Cowen, Leah E.

doi:10.1038/s41467-018-08248-w

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

Journal Article · 23 January 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-018-08248-w · OSTI ID:1497179

Whitesell, Luke ^[1]; Robbins, Nicole ^[2]; Huang, David S. ^[3]; McLellan, Catherine A. ^[4]; Shekhar-Guturja, Tanvi ^[2]; LeBlanc, Emmanuelle V. ^[2]; Nation, Catherine S. ^[5]; Hui, Raymond ^[2]; Hutchinson, Ashley ^[2]; Collins, Cathy ^[2]; Chatterjee, Sharanya ^[6]; Trilles, Richard ^[3]; Xie, Jinglin L. ^[2]; Krysan, Damian J. ^[7]; Lindquist, Susan ^[8]; Porco, Jr., John A. ^[3]; Tatu, Utpal ^[6];

^[3];

^[5]; Cowen, Leah E. ^[2]

Univ. of Toronto, ON (Canada); Whitehead Inst. for Biomedical Research, Cambridge, MA (United States)
Univ. of Toronto, ON (Canada)
Boston Univ., MA (United States)
Whitehead Inst. for Biomedical Research, Cambridge, MA (United States)
Tulane Univ., New Orleans, LA (United States)
Indian Inst. of Science, Bangalore (India)
Univ. of Iowa, Iowa City, IA (United States)
Whitehead Inst. for Biomedical Research, Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Canadian Institutes of Health Research (CIHR); Grand Challenges Canada Star in Global Health; National Institutes of Health (NIH)

OSTI ID:: 1497179

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Global proteomic analyses define an environmentally contingent Hsp90 interactome and reveal chaperone-dependent regulation of stress granule proteins and the R2TP complex in a fungal pathogen O’Meara, Teresa R.; O’Meara, Matthew J.; Polvi, Elizabeth J. PLOS Biology, Vol. 17, Issue 7 https://doi.org/10.1371/journal.pbio.3000358	journal	July 2019

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