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

Autor:	Ferri E; Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Le Thomas A; Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Wallweber HA; Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Day ES; Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Walters BT; Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Kaufman SE; Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Braun MG; Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Clark KR; Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Beresini MH; Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Mortara K; BioMolecular Resources, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Chen YA; Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Canter B; Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Phung W; Microchemistry, Proteomics & Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Liu PS; Microchemistry, Proteomics & Lipidomics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Lammens A; Proteros Biostructures GmbH, Bunsenstr. 7a, D - 82152, Martinsried, Germany., Ashkenazi A; Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA., Rudolph J; Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. rudolph.joachim@gene.com., Wang W; Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. wang.weiru@gene.com.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Dec 14; Vol. 11 (1), pp. 6387. Date of Electronic Publication: 2020 Dec 14.
DOI:	10.1038/s41467-020-19974-5
Abstrakt:	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.
Databáze:	MEDLINE
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