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

Huck, John D.; Que, Nanette S.; Sharma, Sahil; Taldone, Tony; Chiosis, Gabriela; Gewirth, Daniel T.

doi:10.1002/prot.25750

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

Journal Article · Wed Jun 12 00:00:00 EDT 2019 · Proteins

DOI:https://doi.org/10.1002/prot.25750· OSTI ID:1577176

Huck, John D. ^[1]; Que, Nanette S. ^[2]; Sharma, Sahil ^[3]; Taldone, Tony ^[3]; Chiosis, Gabriela ^[3];

^[1]

Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States); Univ. at Buffalo, NY (United States)
Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: P01-CA186866; R01-CA095130.

OSTI ID:: 1577176

Journal Information:: Proteins, Vol. 87, Issue 10; ISSN 0887-3585

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 6 works

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

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