4pl3: Difference between revisions
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pl3 PDBsum]</span></td></tr> | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pl3 PDBsum]</span></td></tr> | ||
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== Publication Abstract from PubMed == | |||
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. | |||
Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.,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 Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202. PMID:25164867<ref>PMID:25164867</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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== References == | |||
<references/> | |||
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</StructureSection> | </StructureSection> | ||
Revision as of 10:18, 10 September 2014
Crystal structure of murine IRE1 in complex with MKC9989 inhibitorCrystal structure of murine IRE1 in complex with MKC9989 inhibitor
Structural highlights
Publication Abstract from PubMedEndoplasmic 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. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors.,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 Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202. PMID:25164867[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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