Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity Journal Article
| Authors: | Huck, J. D.; Que, N. L. S.; Sharma, S.; Taldone, T.; Chiosis, G.; Gewirth, D. T. |
| Article Title: | Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity |
| 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. © 2019 Wiley Periodicals, Inc. |
| Keywords: | inhibitor; hsp90alpha; hsp90beta; paralog selectivity |
| Journal Title: | Proteins: Structure, Function and Bioinformatics |
| Volume: | 87 |
| Issue: | 10 |
| ISSN: | 0887-3585 |
| Publisher: | Wiley Liss |
| Date Published: | 2019-10-01 |
| Start Page: | 869 |
| End Page: | 877 |
| Language: | English |
| DOI: | 10.1002/prot.25750 |
| PUBMED: | 31141217 |
| PROVIDER: | scopus |
| PMCID: | PMC6718336 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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