Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

• DOI: 10.1038/s41467-020-19974-5
• Publication Date: 2020-12-14T11:13:36Z
• Authors: Elena Ferri; Adrien Le Thomas; Heidi Ackerly Wal...; Eric S. Day; Benjamin T. Walters; Susan E. Kaufman; Marie-Gabrielle B...; Kevin R. Clark; Maureen H. Beresini; Kyle Mortara; Yung-Chia A. Chen; Breanna Canter; Wilson Phung; Peter S. Liu; Alfred Lammens; Avi Ashkenazi; Joachim Rudolph; Weiru Wang
• Keywords: Endoribonuclease

Abstract Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in ER lumen induce dimerization oligomerization IRE1, triggering trans-autophosphorylation RNase activation. Known ATP-competitive small-molecule inhibitors either allosterically disrupt or stabilize active dimeric unit, accordingly inhibiting stimulating activity. Previous allosteric activators display poor selectivity and/or weak cellular In this study, we describe class possessing high strong This binds front pocket, leading to distinct conformation activation loop. Our findings reveal exquisitely precise interdomain regulation within advancing mechanistic understanding important enzyme its investigation as potential therapeutic target.