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| | <StructureSection load='4pl3' size='340' side='right'caption='[[4pl3]], [[Resolution|resolution]] 2.90Å' scene=''> | | <StructureSection load='4pl3' size='340' side='right'caption='[[4pl3]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pl3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PL3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PL3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pl3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PL3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PL3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=31J:7-HYDROXY-6-METHOXY-3-[2-(2-METHOXYETHOXY)ETHYL]-4,8-DIMETHYL-2H-CHROMEN-2-ONE'>31J</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=31J:7-HYDROXY-6-METHOXY-3-[2-(2-METHOXYETHOXY)ETHYL]-4,8-DIMETHYL-2H-CHROMEN-2-ONE'>31J</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pl4|4pl4]], [[4pl5|4pl5]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4pl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pl3 OCA], [https://pdbe.org/4pl3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [https://www.ebi.ac.uk/pdbsum/4pl3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pl3 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ern1, Ire1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | |
| - | <tr id='resources'><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://pdbe.org/4pl3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pl3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pl3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pl3 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ERN1_MOUSE ERN1_MOUSE]] Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.<ref>PMID:11850408</ref> | + | [https://www.uniprot.org/uniprot/ERN1_MOUSE ERN1_MOUSE] Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.<ref>PMID:11850408</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Al-awar, R]] | + | [[Category: Al-awar R]] |
| - | [[Category: Chiovitti, D]] | + | [[Category: Chiovitti D]] |
| - | [[Category: Duffy, N]] | + | [[Category: Duffy N]] |
| - | [[Category: Patterson, J B]] | + | [[Category: Patterson JB]] |
| - | [[Category: Sanches, M]] | + | [[Category: Sanches M]] |
| - | [[Category: Sicheri, F]] | + | [[Category: Sicheri F]] |
| - | [[Category: Talukdar, M]] | + | [[Category: Talukdar M]] |
| - | [[Category: Thevakumaran, N]] | + | [[Category: Thevakumaran N]] |
| - | [[Category: Endoribonuclease]]
| + | |
| - | [[Category: Hydrolase-inhibitor complex]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Schiff base]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Unfolded protein response]]
| + | |
| Structural highlights
Function
ERN1_MOUSE Senses unfolded proteins in the lumen of the endoplasmic reticulum via its N-terminal domain which leads to enzyme auto-activation. The active endoribonuclease domain splices XBP1 mRNA to generate a new C-terminus, converting it into a potent unfolded-protein response transcriptional activator and triggering growth arrest and apoptosis.[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002 Feb 15;16(4):452-66. PMID:11850408 doi:http://dx.doi.org/10.1101/gad.964702
- ↑ 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. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun. 2014 Aug 28;5:4202. doi: 10.1038/ncomms5202. PMID:25164867 doi:http://dx.doi.org/10.1038/ncomms5202
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