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Proteins. 2019 May 29. doi: 10.1002/prot.25750. [Epub ahead of print]

Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity.

Author information

1
Hauptman-Woodward Medical Research Institute, Buffalo, New York.
2
Department of Structural Biology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York.
3
Program in Chemical Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Abstract

Hsp90α and Hsp90β are implicated in a number of cancers and neurodegenerative disorders but the lack of selective pharmacological probes confounds efforts to identify their individual roles. Here, we analyzed the binding of an Hsp90α-selective PU compound, PU-11-trans, to the two cytosolic paralogs. We determined the co-crystal structures of Hsp90α and Hsp90β bound to PU-11-trans, as well as the structure of the apo Hsp90β NTD. The two inhibitor-bound structures reveal that Ser52, a nonconserved residue in the ATP binding pocket in Hsp90α, provides additional stability to PU-11-trans through a water-mediated hydrogen-bonding network. Mutation of Ser52 to alanine, as found in Hsp90β, alters the dissociation constant of Hsp90α for PU-11-trans to match that of Hsp90β. Our results provide a structural explanation for the binding preference of PU inhibitors for Hsp90α and demonstrate that the single nonconserved residue in the ATP-binding pocket may be exploited for α/β selectivity.

KEYWORDS:

Hsp90alpha; Hsp90beta; inhibitor; paralog selectivity

PMID:
31141217
DOI:
10.1002/prot.25750

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