8tf0

Crystal structure of Grp94 N-terminal domain bound to the purine inhibitor PU-H36

spinqualitylabelsall models 8tf0, resolution 2.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tf0 is a 4 chain structure with sequence from Canis lupus familiaris. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.79Å Ligands: GOL, MG, MN, SO4, ZUY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ENPL_CANLF Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity (By similarity). Publication Abstract from PubMed 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. Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding.,Que NLS, Seidler PM, Aw WJ, Chiosis G, Gewirth DT Proteins. 2024 Oct 29. doi: 10.1002/prot.26756. PMID:39473058 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA