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7bmk
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==ATP-Competitive Partial Antagonists-'PAIR's-Rheostatically Modulate IRE1alpha's Kinase Helix-alphaC to Segregate its RNase-Mediated Biological Outputs== | |
| + | <StructureSection load='7bmk' size='340' side='right'caption='[[7bmk]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7bmk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BMK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BMK FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=U4N:2,2,2-tris(fluoranyl)-~{N}-[4-[3-[2-[[(3~{S})-piperidin-3-yl]amino]pyrimidin-4-yl]pyridin-2-yl]oxynaphthalen-1-yl]ethanesulfonamide'>U4N</scene></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=7bmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bmk OCA], [https://pdbe.org/7bmk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bmk RCSB], [https://www.ebi.ac.uk/pdbsum/7bmk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bmk ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1alpha. We previously found that the RNase of IRE1alpha can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1alpha RNase (PAIRs), that partially antagonize the IRE1alpha RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix alphaC in the IRE1alpha kinase domain. In insulin-producing beta-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1alpha, captures a desirable conformation for drugging this master UPR sensor/effector. | ||
| - | + | ATP-competitive partial antagonists of the IRE1alpha RNase segregate outputs of the UPR.,Feldman HC, Ghosh R, Auyeung VC, Mueller JL, Kim JH, Potter ZE, Vidadala VN, Perera BGK, Olivier A, Backes BJ, Zikherman J, Papa FR, Maly DJ Nat Chem Biol. 2021 Nov;17(11):1148-1156. doi: 10.1038/s41589-021-00852-0. Epub, 2021 Sep 23. PMID:34556859<ref>PMID:34556859</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 7bmk" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Ire1|Ire1]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Auyeung, V]] | ||
| + | [[Category: Backes, B J]] | ||
| + | [[Category: Feldman, H C]] | ||
| + | [[Category: Ghosh, R]] | ||
| + | [[Category: Maly, D J]] | ||
| + | [[Category: Mueller, J L]] | ||
| + | [[Category: Olivier, A]] | ||
| + | [[Category: Papa, F R]] | ||
| + | [[Category: Vidadala, V N]] | ||
| + | [[Category: Zikherman, J]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Kinase inhibitor]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Transferase inhibitor]] | ||
| + | [[Category: Unknown function]] | ||
Current revision
ATP-Competitive Partial Antagonists-'PAIR's-Rheostatically Modulate IRE1alpha's Kinase Helix-alphaC to Segregate its RNase-Mediated Biological Outputs
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