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

• DOI: 10.1038/s41467-018-08248-w
• Publication Date: 2019-01-24T11:05:12Z
• Authors: Luke Whitesell; Nicole Robbins; David S. Huang; Catherine A. McLe...; Tanvi Shekhar-Gut...; Emmanuelle V. LeB...; 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; Leah E. Cowen
• Keywords: Pathogenic fungus; Antifungal drugs; Hsp90 inhibitor

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 under development as anticancer therapeutics, however, exert host toxicities that preclude their use antifungals. Seeking route species-selectivity, we investigate nucleotide-binding domain (NBD) from most common fungal pathogen, Candida albicans . Here report structures for this NBD alone, in complex with ADP or known inhibitors. Encouraged conformational flexibility revealed these structures, synthesize an inhibitor >25-fold binding-selectivity NBD. Comparing co-crystals occupied probe vs. inhibitors major, previously unreported rearrangements. These insights our probe’s species-selectivity culture support feasibility targeting antifungal strategy.