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

Publication Type:

Journal Article


Nat Commun, Volume 5, p.4202 (2014)


Aldehydes, Antigens, CD59, Benzaldehydes, Binding Sites, Catalytic Domain, Cell Line, Tumor, Coumarins, Crystallography, X-Ray, DNA Mutational Analysis, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Membrane Proteins, Molecular Structure, Morpholines, Plasmacytoma, Protein Conformation, Protein-Serine-Threonine Kinases, Regulatory Factor X Transcription Factors, Ribonucleases, Small Molecule Libraries, Structure-Activity Relationship, Transcription Factors


<p>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.</p>

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