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| | <StructureSection load='4z7h' size='340' side='right'caption='[[4z7h]], [[Resolution|resolution]] 2.90Å' scene=''> | | <StructureSection load='4z7h' size='340' side='right'caption='[[4z7h]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4z7h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z7H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Z7H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4z7h]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z7H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z7H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4L5:2-METHOXY-4-[6-(PROPAN-2-YLAMINO)IMIDAZO[1,2-B]PYRIDAZIN-3-YL]BENZAMIDE'>4L5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</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=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4L5:2-METHOXY-4-[6-(PROPAN-2-YLAMINO)IMIDAZO[1,2-B]PYRIDAZIN-3-YL]BENZAMIDE'>4L5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4z7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z7h OCA], [http://pdbe.org/4z7h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z7h RCSB], [http://www.ebi.ac.uk/pdbsum/4z7h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4z7h ProSAT]</span></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=4z7h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z7h OCA], [https://pdbe.org/4z7h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z7h RCSB], [https://www.ebi.ac.uk/pdbsum/4z7h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z7h ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ERN1_HUMAN ERN1_HUMAN]] 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:9637683</ref> <ref>PMID:11175748</ref> <ref>PMID:12637535</ref> [UniProtKB:Q9EQY0] | + | [https://www.uniprot.org/uniprot/ERN1_HUMAN ERN1_HUMAN] 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:9637683</ref> <ref>PMID:11175748</ref> <ref>PMID:12637535</ref> [UniProtKB:Q9EQY0] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bayliss, R]] | + | [[Category: Bayliss R]] |
| - | [[Category: Joshi, A]] | + | [[Category: Joshi A]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Rnase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Unfolded protein response]]
| + | |
| Structural highlights
Function
ERN1_HUMAN 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] [2] [3] [UniProtKB:Q9EQY0]
Publication Abstract from PubMed
IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged. Structure-function analysis reveals that IRE1 is autoinhibited through a Tyr-down mechanism related to that found in the unrelated Ser/Thr protein kinase Nek7. We have developed a compound that potently inhibits human IRE1 kinase activity while stimulating XBP1 splicing. A crystal structure of the inhibitor bound to IRE1 shows an increased ordering of the kinase activation loop. The structures of hIRE in apo and ligand-bound forms are consistent with a previously proposed model of IRE1 regulation in which formation of a back-to-back dimer coupled to adoption of a kinase-active conformation drive RNase activation. The structures provide opportunities for structure-guided design of IRE1 inhibitors.
Molecular mechanisms of human IRE1 activation through dimerization and ligand binding.,Joshi A, Newbatt Y, McAndrew PC, Stubbs M, Burke R, Richards MW, Bhatia C, Caldwell JJ, McHardy T, Collins I, Bayliss R Oncotarget. 2015 Apr 18. PMID:25968568[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998 Jun 15;12(12):1812-24. PMID:9637683
- ↑ Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, Tsuru A, Kohno K. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol. 2001 Feb;3(2):158-64. PMID:11175748 doi:10.1038/35055065
- ↑ Liu CY, Xu Z, Kaufman RJ. Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha. J Biol Chem. 2003 May 16;278(20):17680-7. Epub 2003 Mar 13. PMID:12637535 doi:10.1074/jbc.M300418200
- ↑ Joshi A, Newbatt Y, McAndrew PC, Stubbs M, Burke R, Richards MW, Bhatia C, Caldwell JJ, McHardy T, Collins I, Bayliss R. Molecular mechanisms of human IRE1 activation through dimerization and ligand binding. Oncotarget. 2015 Apr 18. PMID:25968568
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