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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.
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