An unusual inactive kinase conformation identified

A series of  kinase inhibitors was discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), 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 IRE1 alpha oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. Xray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1 alpha kinase domain that would be incompatible with back-toback dimerization of the IRE1 alpha protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1 alpha protein conformations and can guide the discovery of highly selective ligands for the IRE1 alpha kinase site that allosterically inhibit the endoribonuclease. Read more.