7K9S

Cryptococcus neoformans Hsp90 nucleotide binding domain in complex with NVP-AUY922

Summary for 7K9S

• Entry DOI: 10.2210/pdb7k9s/pdb
• Related: 7K9R
• Descriptor: Hsp90-like protein, 5-[2,4-DIHYDROXY-5-(1-METHYLETHYL)PHENYL]-N-ETHYL-4-[4-(MORPHOLIN-4-YLMETHYL)PHENYL]ISOXAZOLE-3-CARBOXAMIDE (2 entities in total)
• Functional Keywords: cryptococcus, hsp90, atp-binding, inhibitor, chaperone
• Biological source: Cryptococcus neoformans
• Total number of polymer chains: 6
• Total formula weight: 146703.85

Authors

Kuntz, D.A.,Prive, G.G. (deposition date: 2020-09-29, release date: 2021-01-27, Last modification date: 2023-10-18)

Primary citation

Marcyk, P.T.,LeBlanc, E.V.,Kuntz, D.A.,Xue, A.,Ortiz, F.,Trilles, R.,Bengtson, S.,Kenney, T.M.G.,Huang, D.S.,Robbins, N.,Williams, N.S.,Krysan, D.J.,Prive, G.G.,Whitesell, L.,Cowen, L.E.,Brown, L.E.
Fungal-Selective Resorcylate Aminopyrazole Hsp90 Inhibitors: Optimization of Whole-Cell Anticryptococcal Activity and Insights into the Structural Origins of Cryptococcal Selectivity.
J.Med.Chem., 64:1139-1169, 2021

PubMed Abstract: The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal (, ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure-property optimization toward RAPs capable of inhibiting growth in culture. In addition, we report the first X-ray crystal structures of Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.

PubMed: 33444025
DOI: 10.1021/acs.jmedchem.0c01777

Experimental method

X-RAY DIFFRACTION (3.21 Å)