期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5202
关键词
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资金
- Canadian Institutes of Health Research [MOP 84370]
- Multiple Myeloma Research Foundation Biotech Investment Award
- National Institute of General Medical Sciences from the National Institutes of Health [P41 GM103403]
- U.S. DOE [DE-AC02-06CH11357]
- Canadian Cancer Society Postdoctoral Fellowship
Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1 alpha 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 IRE1 alpha RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1 alpha 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 IRE1 alpha using small molecule inhibitors and suggest new avenues for inhibitor design.
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