Structural distortions induced by Kinase Inhibiting RNase Attenuator (KIRA) compounds prevent the formation of face-to-face dimers of Inositol Requiring Enzyme 1α

In the present work, computational analysis, protein-protein and protein-ligand docking studies, and molecular dynamics simulations were applied to different IRE1 dimer systems to provide structural insights into the perturbation of IRE1 dimers by small molecules kinase inhibitors that regulate the RNase activity. By analyzing structural deviations, energetic components and number of hydrogen bonds in the interface region, we propose that the KIRA inhibitors act at an early stage of IRE1 activation by interfering with IRE1 face-to-face dimer formation, thus disabling the activation of the RNase domain. The work sheds light on the mechanism of action of KIRA compounds and may assist in development of further compounds in e.g. cancer therapeutics. The work also provides information on the sequence of events and protein-protein interactions initiating the unfolded protein response.