Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors

Mario Sanches, Nicole M. Duffy, Manisha Talukdar, Nero Thevakumaran, David Chiovitti, Marella D. Canny, Kenneth Lee, Igor Kurinov, David Uehling, Rima Al-Awar, Gennadiy Poda, Michael Prakesch, Brian Wilson, Victor Tam, Colleen Schweitzer, Andras Toro, Julie L. Lucas, Danka Vuga, Lynn Lehmann, Daniel DurocherQingping Zeng, John B. Patterson, Frank Sicheri

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1a is a transmembrane kinase endoribonuclease (RNase) that cleaves mRNA substrates to re-establish ER homeostasis. Aromatic ring systems containing hydroxy-aldehyde moieties, termed hydroxy-aryl-aldehydes (HAA), selectively inhibit IRE1a RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1a in complex with three HAA inhibitors. HAA inhibitors engage a shallow pocket at the RNase-active site through pi-stacking interactions with His910 and Phe889, an essential Schiff base with Lys907 and a hydrogen bond with Tyr892. Structure-activity studies and mutational analysis of contact residues define the optimal chemical space of inhibitors and validate the inhibitor-binding site. These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1a using small molecule inhibitors and suggest new avenues for inhibitor design.

Original languageEnglish (US)
Article number4202
JournalNature communications
StatePublished - Aug 28 2014

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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