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| | <StructureSection load='7mx3' size='340' side='right'caption='[[7mx3]], [[Resolution|resolution]] 3.23Å' scene=''> | | <StructureSection load='7mx3' size='340' side='right'caption='[[7mx3]], [[Resolution|resolution]] 3.23Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7mx3]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MX3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MX3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7mx3]] is a 4 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=7MX3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MX3 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=ZOV:3-(1,3-benzothiazol-5-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-c]pyridin-4-amine'>ZOV</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]] 3.23Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=ZOV:3-(1,3-benzothiazol-5-yl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)thieno[3,2-c]pyridin-4-amine'>ZOV</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=7mx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx3 OCA], [https://pdbe.org/7mx3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx3 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx3 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=7mx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx3 OCA], [https://pdbe.org/7mx3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx3 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/RIPK3_HUMAN RIPK3_HUMAN]] Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.<ref>PMID:19498109</ref> <ref>PMID:19524512</ref> <ref>PMID:19524513</ref> <ref>PMID:22265413</ref> <ref>PMID:22265414</ref> <ref>PMID:22421439</ref>
| + | [https://www.uniprot.org/uniprot/RIPK3_HUMAN RIPK3_HUMAN] Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.<ref>PMID:19498109</ref> <ref>PMID:19524512</ref> <ref>PMID:19524513</ref> <ref>PMID:22265413</ref> <ref>PMID:22265414</ref> <ref>PMID:22421439</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL.
| + | |
| | | | |
| - | Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis.,Meng Y, Davies KA, Fitzgibbon C, Young SN, Garnish SE, Horne CR, Luo C, Garnier JM, Liang LY, Cowan AD, Samson AL, Lessene G, Sandow JJ, Czabotar PE, Murphy JM Nat Commun. 2021 Nov 22;12(1):6783. doi: 10.1038/s41467-021-27032-x. PMID:34811356<ref>PMID:34811356</ref>
| + | ==See Also== |
| - | | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 7mx3" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Czabotar PE]] |
| - | [[Category: Czabotar, P E]] | + | [[Category: Davies KA]] |
| - | [[Category: Davies, K A]] | + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase-inhibitor complex]]
| + | |
| Structural highlights
Function
RIPK3_HUMAN Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.[1] [2] [3] [4] [5] [6]
See Also
References
- ↑ Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009 Jul 17;325(5938):332-6. doi: 10.1126/science.1172308. Epub 2009 Jun, 4. PMID:19498109 doi:http://dx.doi.org/10.1126/science.1172308
- ↑ He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009 Jun 12;137(6):1100-11. doi: 10.1016/j.cell.2009.05.021. PMID:19524512 doi:10.1016/j.cell.2009.05.021
- ↑ Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12;137(6):1112-23. doi: 10.1016/j.cell.2009.05.037. PMID:19524513 doi:10.1016/j.cell.2009.05.037
- ↑ Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012 Jan 20;148(1-2):213-27. doi: 10.1016/j.cell.2011.11.031. PMID:22265413 doi:http://dx.doi.org/10.1016/j.cell.2011.11.031
- ↑ Wang Z, Jiang H, Chen S, Du F, Wang X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell. 2012 Jan 20;148(1-2):228-43. doi: 10.1016/j.cell.2011.11.030. PMID:22265414 doi:http://dx.doi.org/10.1016/j.cell.2011.11.030
- ↑ Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5322-7. doi:, 10.1073/pnas.1200012109. Epub 2012 Mar 15. PMID:22421439 doi:http://dx.doi.org/10.1073/pnas.1200012109
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