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

نویسندگان

  • 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 Durocher
  • Qingping Zeng
  • John B. Patterson
  • Frank Sicheri
چکیده

Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1α 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 IRE1α RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1α 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 IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design.

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عنوان ژورنال:

دوره 5  شماره 

صفحات  -

تاریخ انتشار 2014