4PL3
Crystal structure of murine IRE1 in complex with MKC9989 inhibitor
Summary for 4PL3
| Entry DOI | 10.2210/pdb4pl3/pdb |
| Related | 4PL4 4PL5 |
| Descriptor | Serine/threonine-protein kinase/endoribonuclease IRE1, 7-hydroxy-6-methoxy-3-[2-(2-methoxyethoxy)ethyl]-4,8-dimethyl-2H-chromen-2-one, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total) |
| Functional Keywords | schiff base, hydroxy aryl aldehydes (haa), inhibitor complex, unfolded protein response, endoribonuclease, transferase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 102210.48 |
| Authors | Sanches, M.,Duffy, N.,Talukdar, M.,Thevakumaran, N.,Chiovitti, D.,Al-awar, R.,Patterson, J.B.,Sicheri, F. (deposition date: 2014-05-16, release date: 2014-09-03, Last modification date: 2023-09-27) |
| Primary citation | Sanches, M.,Duffy, N.M.,Talukdar, M.,Thevakumaran, N.,Chiovitti, D.,Canny, M.D.,Lee, K.,Kurinov, I.,Uehling, D.,Al-Awar, R.,Poda, G.,Prakesch, M.,Wilson, B.,Tam, V.,Schweitzer, C.,Toro, A.,Lucas, J.L.,Vuga, D.,Lehmann, L.,Durocher, D.,Zeng, Q.,Patterson, J.B.,Sicheri, F. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun, 5:4202-4202, 2014 Cited by PubMed 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. PubMed: 25164867DOI: 10.1038/ncomms5202 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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