| First Author | Sanches M | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 4202 | PubMed ID | 25164867 |
| Mgi Jnum | J:255334 | Mgi Id | MGI:6114871 |
| Doi | 10.1038/ncomms5202 | Citation | Sanches M, et al. (2014) Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun 5:4202 |
| abstractText | Endoplasmic reticulum (ER) stress activates the unfolded protein response and its dysfunction is linked to multiple diseases. The stress transducer IRE1alpha 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 IRE1alpha RNase and thus represent a novel chemical series for therapeutic development. We solved crystal structures of murine IRE1alpha 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 IRE1alpha using small molecule inhibitors and suggest new avenues for inhibitor design. |
