Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors

Likun Wang, B. Gayani K. Perera, Sanjay B. Hari, Barun Bhhatarai, Bradley J. Backes, Markus A. Seeliger, Stephan C. Schürer, Scott A. Oakes, Feroz R. Papa, Dustin J. Maly

Research output: Contribution to journalArticlepeer-review

134 Scopus citations


Under endoplasmic reticulum stress, unfolded protein accumulation leads to activation of the endoplasmic reticulum transmembrane kinase/endoRNase (RNase) IRE1α. IRE1α oligomerizes, autophosphorylates and initiates splicing of XBP1 mRNA, thus triggering the unfolded protein response (UPR). Here we show that IRE1α's kinase-controlled RNase can be regulated in two distinct modes with kinase inhibitors: one class of ligands occupies IRE1α's kinase ATP-binding site to activate RNase-mediated XBP1 mRNA splicing even without upstream endoplasmic reticulum stress, whereas a second class can inhibit the RNase through the same ATP-binding site, even under endoplasmic reticulum stress. Thus, alternative kinase conformations stabilized by distinct classes of ATP-competitive inhibitors can cause allosteric switching of IRE1α's RNase - either on or off. As dysregulation of the UPR has been implicated in a variety of cell degenerative and neoplastic disorders, small-molecule control over IRE1α should advance efforts to understand the UPR's role in pathophysiology and to develop drugs for endoplasmic reticulum stress-related diseases.

Original languageEnglish (US)
Pages (from-to)982-989
Number of pages8
JournalNature Chemical Biology
Issue number12
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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