Structures of Hsp90α and Hsp90β bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity.
Hsp90alpha
Hsp90beta
inhibitor
paralog selectivity
Journal
Proteins
ISSN: 1097-0134
Titre abrégé: Proteins
Pays: United States
ID NLM: 8700181
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
09
01
2019
revised:
24
04
2019
accepted:
22
05
2019
pubmed:
30
5
2019
medline:
1
7
2020
entrez:
30
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31141217
doi: 10.1002/prot.25750
pmc: PMC6718336
mid: NIHMS1530291
doi:
Substances chimiques
Amino Acids
0
HSP90 Heat-Shock Proteins
0
HSP90AA2P protein, human
0
HSP90AB1 protein, human
0
Purines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
869-877Subventions
Organisme : NCI NIH HHS
ID : P01-CA186866
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032969
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA095130
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA192937
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172546
Pays : United States
Organisme : NCI NIH HHS
ID : R01-CA095130
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA186866
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG061869
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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