PDBsum entry 6cjs

Chaperone

PDB id: 6cjs

Contents

Protein chain

218 a.a.

Ligands

2GJ

EDO

Waters ×151

PDB id:

6cjs

Name:

Chaperone

Title:

Candida albicans hsp90 nucleotide binding domain in complex with auy922

Structure:

Heat shock protein 90 homolog. Chain: a. Engineered: yes

Source:

Candida albicans (strain sc5314 / atcc mya- 2876). Yeast. Organism_taxid: 237561. Strain: sc5314 / atcc mya-2876. Gene: hsp90, caalfm_c702030wa, caj7.0234, cao19.13868, cao19.6515. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.167 R-free: 0.193

Authors:

M.G.Kirkpatrick,J.C.Pizarro

Key ref:

L.Whitesell et al. (2019). Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus. Nat Commun, 10, 402. PubMed id: 30679438 DOI: 10.1038/s41467-018-08248-w

Date:

26-Feb-18 Release date: 30-Jan-19

Protein chain

P46598  (HSP90_CANAL) -  Heat shock protein 90 homolog from Candida albicans (strain SC5314 / ATCC MYA-2876)

Seq: 707 a.a.

Struc: 218 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

DOI no: 10.1038/s41467-018-08248-w

Nat Commun 10:402 (2019)

PubMed id: 30679438

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

L.Whitesell, N.Robbins, D.S.Huang, C.A.McLellan, T.Shekhar-Guturja, E.V.LeBlanc, C.S.Nation, R.Hui, A.Hutchinson, C.Collins, S.Chatterjee, R.Trilles, J.L.Xie, D.J.Krysan, S.Lindquist, J.A.Porco, U.Tatu, L.E.Brown, J.Pizarro, L.E.Cowen.

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.