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- Title
Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.
- Authors
Ferri, Elena; Le Thomas, Adrien; Wallweber, Heidi Ackerly; Day, Eric S.; Walters, Benjamin T.; Kaufman, Susan E.; Braun, Marie-Gabrielle; Clark, Kevin R.; Beresini, Maureen H.; Mortara, Kyle; Chen, Yung-Chia A.; Canter, Breanna; Phung, Wilson; Liu, Peter S.; Lammens, Alfred; Ashkenazi, Avi; Rudolph, Joachim; Wang, Weiru
- Abstract
Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target. The RNase activity of Inositol-Requiring Enzyme 1 (IRE1) can be allosterically regulated by ATP-competitive inhibitors of the IRE1 kinase domain. Here, the authors identify ATP-competitive IRE1 RNase activators with improved selectivity and cellular activity, and elucidate their mechanism of action.
- Subjects
UNFOLDED protein response; LIGANDS (Biochemistry); ENDOPLASMIC reticulum; KINASE inhibitors
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-19974-5