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  • Title: Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.
    Author: 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, Sicheri F.
    Journal: Nat Commun; 2014 Aug 28; 5():4202. PubMed ID: 25164867.
    Abstract:
    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.
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