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Nat Commun ; 11(1): 6387, 2020 12 14.
Article in English | MEDLINE | ID: mdl-33318494

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.


Subject(s)
Adenosine Triphosphate/metabolism , Endoribonucleases/metabolism , Protein Serine-Threonine Kinases/metabolism , Ribonucleases/metabolism , Adenosine Triphosphate/chemistry , Allosteric Site/drug effects , Crystallography, X-Ray , Endoplasmic Reticulum/metabolism , Endoribonucleases/chemistry , Gene Knockout Techniques , Humans , Ligands , Models, Molecular , Phosphorylation , Protein Conformation , Protein Folding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Multimerization , Protein Serine-Threonine Kinases/chemistry , Ribonucleases/chemistry , Unfolded Protein Response
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