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 Jr; Utpal Tatu; Lauren E Brown; Juan Pizarro; Leah E Cowen

doi:10.1038/s41467-018-08248-w

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.10(1), pp.402-402

01/24/2019

DOI: 10.1038/s41467-018-08248-w

PMCID: PMC6345968

PMID: 30679438

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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.

Virulence - drug effects

Humans

Candida albicans - metabolism

Recombinant Proteins

Candida albicans - genetics

Heterocyclic Compounds, 4 or More Rings - antagonists & inhibitors

Candida albicans - drug effects

HSP90 Heat-Shock Proteins - chemistry

Protein Domains

HSP90 Heat-Shock Proteins - genetics

Antifungal Agents - pharmacology

Candida albicans - pathogenicity

Cell Line

Molecular Chaperones

Isoxazoles - antagonists & inhibitors

Drug Resistance, Fungal - drug effects

HSP90 Heat-Shock Proteins - drug effects

Models, Molecular

Triazoles - antagonists & inhibitors

Fungal Proteins - drug effects

Animals

Signal Transduction - drug effects

Protein Binding

Protein Conformation

Resorcinols - antagonists & inhibitors

Mice

Fungal Proteins - metabolism

Details

Title: Subtitle: Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus
Creators: Luke Whitesell - Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA
Nicole Robbins - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada
David S Huang - Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA, 02215, USA
Catherine A McLellan - Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA
Tanvi Shekhar-Guturja - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada
Emmanuelle V LeBlanc - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada
Catherine S Nation - 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
Raymond Hui - Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
Ashley Hutchinson - Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada
Cathy Collins - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada
Sharanya Chatterjee - Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
Richard Trilles - Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA, 02215, USA
Jinglin L Xie - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada
Damian J Krysan - Departments of Pediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Susan Lindquist - Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
John A Porco Jr - Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA, 02215, USA
Utpal Tatu - Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
Lauren E Brown - Department of Chemistry, Center for Molecular Discovery, Boston University, Boston, MA, 02215, USA
Juan Pizarro - 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
Leah E Cowen - Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1M1, Canada. leah.cowen@utoronto.ca
Resource Type: Journal article
Publication Details: Nature communications, Vol.10(1), pp.402-402
DOI: 10.1038/s41467-018-08248-w
PMID: 30679438
PMCID: PMC6345968
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R01AI120958-01A1 / NIH HHS R01 AI120958 / NIAID NIH HHS
Language: English
Date published: 01/24/2019
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093362002771

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