6OLX

Hsp90-alpha S52A bound to PU-11-trans

Summary for 6OLX

• Entry DOI: 10.2210/pdb6olx/pdb
• Related: 6N8W 6N8X 6N8Y
• Descriptor: Heat shock protein HSP 90-alpha, 9-[(2E)-but-2-en-1-yl]-8-[(3,4,5-trimethoxyphenyl)methyl]-9H-purin-6-amine (3 entities in total)
• Functional Keywords: hsp90, chaperone, cytosol, cancer, inhibitor, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29126.56

Authors

Gewirth, D.T.,Huck, J.D. (deposition date: 2019-04-17, release date: 2019-07-03, Last modification date: 2024-03-06)

Primary citation

Huck, J.D.,Que, N.L.S.,Sharma, S.,Taldone, T.,Chiosis, G.,Gewirth, D.T.
Structures of Hsp90 alpha and Hsp90 beta bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity.
Proteins, 87:869-877, 2019

PubMed 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.

PubMed: 31141217
DOI: 10.1002/prot.25750

Experimental method

X-RAY DIFFRACTION (1.43760580022 Å)