7K9S

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

7K9S の概要

• エントリーDOI: 10.2210/pdb7k9s/pdb
• 関連するPDBエントリー: 7K9R
• 分子名称: 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)
• 機能のキーワード: cryptococcus, hsp90, atp-binding, inhibitor, chaperone
• 由来する生物種: Cryptococcus neoformans
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 146703.85

構造登録者

Kuntz, D.A.,Prive, G.G. (登録日: 2020-09-29, 公開日: 2021-01-27, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.21 Å)