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Sanches, M, Duffy, NM, Talukdar, M, Thevakumaran, N, Chiovitti, D, Canny, MD, Lee, K, Kurinov, I, Uehling, D, Al-awar, R, Poda, G, Prakesch, M, Wilson, B, Tam, V, Schweitzer, C, Toro, A, Lucas, JL, Vuga, D, Lehmann, L, Durocher, D, Zeng, Q, Patterson, JB and Sicheri, F (2014) Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun 5:4202


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.


PubMed PMC4486471 Online version:10.1038/ncomms5202


Aldehydes/chemistry; Aldehydes/pharmacology; Benzaldehydes/chemistry; Benzaldehydes/pharmacology; Binding Sites; CD59 Antigens/metabolism; Catalytic Domain; Cell Line, Tumor/drug effects; Coumarins/chemistry; Coumarins/pharmacology; Crystallography, X-Ray; DNA Mutational Analysis; DNA-Binding Proteins/genetics; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Enzyme Inhibitors/pharmacology; Humans; Membrane Proteins/antagonists & inhibitors; Membrane Proteins/chemistry; Membrane Proteins/genetics; Membrane Proteins/metabolism; Molecular Structure; Morpholines/chemistry; Morpholines/pharmacology; Plasmacytoma/drug therapy; Plasmacytoma/pathology; Protein Conformation; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Regulatory Factor X Transcription Factors; Ribonucleases/metabolism; Small Molecule Libraries/chemistry; Small Molecule Libraries/pharmacology; Structure-Activity Relationship; Transcription Factors/genetics