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

Nat Commun. 2020 Dec 14;11(1):6387. doi: 10.1038/s41467-020-19974-5.


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.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism*
  • Allosteric Site / drug effects
  • Crystallography, X-Ray
  • Endoplasmic Reticulum / metabolism
  • Endoribonucleases / chemistry
  • Endoribonucleases / metabolism*
  • 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
  • Protein Serine-Threonine Kinases / metabolism*
  • Ribonucleases / chemistry
  • Ribonucleases / metabolism*
  • Unfolded Protein Response


  • Ligands
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases
  • Ribonucleases