8SBT

Structure of human Hsp90-alpha bound to purine inhibitor PU-H36

Summary for 8SBT

• Entry DOI: 10.2210/pdb8sbt/pdb
• Descriptor: Heat shock protein HSP 90-alpha, MAGNESIUM ION, 9-(pent-4-yn-1-yl)-8-[(2,4,6-trimethylphenyl)sulfanyl]-9H-purin-6-amine, ... (4 entities in total)
• Functional Keywords: chaperone, inhibitor, complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29148.92

Authors

Que, N.S.,Gewirth, D.T. (deposition date: 2023-04-04, release date: 2024-10-09, Last modification date: 2025-02-19)

Primary citation

Que, N.L.S.,Seidler, P.M.,Aw, W.J.,Chiosis, G.,Gewirth, D.T.
Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding.
Proteins, 93:654-672, 2025

PubMed Abstract: Grp94 is the endoplasmic reticulum paralog of the hsp90 family of chaperones, which have been targeted for therapeutic intervention via their highly conserved ATP binding sites. The design of paralog-selective inhibitors relies on understanding the protein structural elements that drive higher affinity in selective inhibitors. Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94-selective inhibitor PU-H36, and of Grp94 with the non-selective inhibitor PU-H71. In Grp94, PU-H36 derives its higher affinity by utilizing Site 2, a Grp94-specific side pocket adjoining the ATP binding cavity, but in Hsp90 PU-H36 occupies Site 1, a side pocket that is accessible in all paralogs with which it makes lower affinity interactions. The structure of Grp94 in complex with PU-H71 shows only Site 1 binding. While changes in the conformation of helices 4 and 5 in the N-terminal domain occur when ligands bind to Site 1 of both Hsp90 and Grp94, large conformational shifts that also involve helix 1 are associated with the engagement of the Site 2 pocket in Grp94 only. Site 2 in Hsp90 is blocked and its helix 1 conformation is insensitive to ligand binding. To understand the role of helix 1 in ligand selectivity, we tested the binding of PU-H36 and other Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 is the major determinant of selectivity for Site 2 targeted ligands and also influences the rate of ATPase activity in Hsp90 paralogs.

PubMed: 39473058
DOI: 10.1002/prot.26756

Experimental method

X-RAY DIFFRACTION (1.5 Å)