6hv0

IRE1 kinase/RNase in complex with imidazo[1,2-b]pyridazin-8-amine compound 33

spinqualitylabelsall models 6hv0, resolution 2.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hv0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.73Å Ligands: GUK Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ERN1_HUMAN Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis. [UniProtKB:Q9EQY0] Publication Abstract from PubMed A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors was discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1alpha (IRE1alpha), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1alpha oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1alpha kinase domain that would be incompatible with back-to-back dimerization of the IRE1alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1alpha kinase site that allosterically inhibit the endoribonuclease. Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1alpha kinase-endoribonuclease.,Colombano G, Caldwell JJ, Matthews TP, Bhatia C, Joshi A, McHardy T, Mok NY, Newbatt Y, Pickard L, Strover J, Hedayat S, Walton MI, Myers S, Jones AM, Saville H, McAndrew C, Burke R, Eccles S, Davies F, Bayliss R, Collins I J Med Chem. 2019 Feb 19. doi: 10.1021/acs.jmedchem.8b01721. PMID:30779566 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ire1

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