Abstract
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 language | English (US) |
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Article number | 4202 |
Journal | Nature communications |
Volume | 5 |
DOIs | |
State | Published - Aug 28 2014 |
All Science Journal Classification (ASJC) codes
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy