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

Elena Ferri, Adrien Thomas, Heidi Ackerly Wallweber, Eric S. Day, Benjamin T. Walters, Susan E. Kaufman, Marie-Gabrielle Braun, 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 () and Weiru Wang ()
Additional contact information
Elena Ferri: Structural Biology, Genentech, Inc., 1 DNA Way
Adrien Thomas: Cancer Immunology, Genentech, Inc., 1 DNA Way
Heidi Ackerly Wallweber: Structural Biology, Genentech, Inc., 1 DNA Way
Eric S. Day: Pharmaceutical Development, Genentech, Inc., 1 DNA Way
Benjamin T. Walters: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way
Susan E. Kaufman: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way
Marie-Gabrielle Braun: Discovery Chemistry, Genentech, Inc., 1 DNA Way
Kevin R. Clark: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way
Maureen H. Beresini: Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way
Kyle Mortara: BioMolecular Resources, Genentech, Inc., 1 DNA Way
Yung-Chia A. Chen: Cancer Immunology, Genentech, Inc., 1 DNA Way
Breanna Canter: Discovery Chemistry, Genentech, Inc., 1 DNA Way
Wilson Phung: Microchemistry, Proteomics & Lipidomics, Genentech, Inc., 1 DNA Way
Peter S. Liu: Microchemistry, Proteomics & Lipidomics, Genentech, Inc., 1 DNA Way
Alfred Lammens: Proteros Biostructures GmbH
Avi Ashkenazi: Cancer Immunology, Genentech, Inc., 1 DNA Way
Joachim Rudolph: Discovery Chemistry, Genentech, Inc., 1 DNA Way
Weiru Wang: Structural Biology, Genentech, Inc., 1 DNA Way

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19974-5

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