8TF0
Crystal structure of Grp94 N-terminal domain bound to the purine inhibitor PU-H36
Summary for 8TF0
| Entry DOI | 10.2210/pdb8tf0/pdb |
| Descriptor | Endoplasmin, MAGNESIUM ION, 9-(pent-4-yn-1-yl)-8-[(2,4,6-trimethylphenyl)sulfanyl]-9H-purin-6-amine, ... (7 entities in total) |
| Functional Keywords | chaperone, inhibitor, grp94 |
| Biological source | Canis lupus familiaris (dog) |
| Total number of polymer chains | 4 |
| Total formula weight | 109401.41 |
| Authors | Que, N.L.S.,Gewirth, D.T. (deposition date: 2023-07-07, release date: 2024-11-06, 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 Cited by 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: 39473058DOI: 10.1002/prot.26756 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.79 Å) |
Structure validation
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