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Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202.

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

Author information

1
1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2].
2
1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3].
3
1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
4
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
5
1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
6
NE-CAT APS, Building 436E, Argonne National Lab, 9700 S.Cass Avenue, Argonne, Illinois 60439, USA.
7
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
8
1] Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3 [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
9
MannKind Corporation, 28903 North Avenue Paine, Valencia, California 91355, USA.
10
NanoTemper Technologies, Inc., 395 Oyster Point Boulevard, Suite 135, South San Francisco, California 94080, USA.
11
1] Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Abstract

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.

PMID:
25164867
PMCID:
PMC4486471
DOI:
10.1038/ncomms5202
[Indexed for MEDLINE]
Free PMC Article

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