6HV0

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

Summary for 6HV0

• Entry DOI: 10.2210/pdb6hv0/pdb
• Descriptor: Serine/threonine-protein kinase/endoribonuclease IRE1, 6-chloranyl-3-(2~{H}-indazol-5-yl)-~{N}-propan-2-yl-imidazo[1,2-b]pyridazin-8-amine (3 entities in total)
• Functional Keywords: unfolded protein response allosteric inhibitor, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 48082.60

Authors

Bayliss, R.,Bhatia, C.,Collins, I. (deposition date: 2018-10-09, release date: 2019-02-27, Last modification date: 2024-01-24)

Primary citation

Colombano, G.,Caldwell, J.J.,Matthews, T.P.,Bhatia, C.,Joshi, A.,McHardy, T.,Mok, N.Y.,Newbatt, Y.,Pickard, L.,Strover, J.,Hedayat, S.,Walton, M.I.,Myers, S.M.,Jones, A.M.,Saville, H.,McAndrew, C.,Burke, R.,Eccles, S.A.,Davies, F.E.,Bayliss, R.,Collins, I.
Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1 alpha Kinase-Endoribonuclease.
J.Med.Chem., 62:2447-2465, 2019

PubMed Abstract: A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), 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 IRE1α 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 IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.

PubMed: 30779566
DOI: 10.1021/acs.jmedchem.8b01721

Experimental method

X-RAY DIFFRACTION (2.73 Å)