6olx | pdb_00006olx
Hsp90-alpha S52A bound to PU-11-trans
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedHsp90alpha and Hsp90beta 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 Hsp90alpha-selective PU compound, PU-11-trans, to the two cytosolic paralogs. We determined the co-crystal structures of Hsp90alpha and Hsp90beta bound to PU-11-trans, as well as the structure of the apo Hsp90beta NTD. The two inhibitor-bound structures reveal that Ser52, a nonconserved residue in the ATP binding pocket in Hsp90alpha, provides additional stability to PU-11-trans through a water-mediated hydrogen-bonding network. Mutation of Ser52 to alanine, as found in Hsp90beta, alters the dissociation constant of Hsp90alpha for PU-11-trans to match that of Hsp90beta. Our results provide a structural explanation for the binding preference of PU inhibitors for Hsp90alpha and demonstrate that the single nonconserved residue in the ATP-binding pocket may be exploited for alpha/beta selectivity. Structures of Hsp90alpha and Hsp90beta bound to a purine-scaffold inhibitor reveal an exploitable residue for drug selectivity.,Huck JD, Que NLS, Sharma S, Taldone T, Chiosis G, Gewirth DT Proteins. 2019 May 29. doi: 10.1002/prot.25750. PMID:31141217[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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