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| | ==Solution structure of unliganded MLKL executioner domain== | | ==Solution structure of unliganded MLKL executioner domain== |
| - | <StructureSection load='6zle' size='340' side='right'caption='[[6zle]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='6zle' size='340' side='right'caption='[[6zle]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zle]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZLE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZLE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zle]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZLE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZLE FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MLKL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </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=6zle FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zle OCA], [https://pdbe.org/6zle PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zle RCSB], [https://www.ebi.ac.uk/pdbsum/6zle PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zle ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zle FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zle OCA], [http://pdbe.org/6zle PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zle RCSB], [http://www.ebi.ac.uk/pdbsum/6zle PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zle ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MLKL_HUMAN MLKL_HUMAN]] Required for the execution of programmed necrosis.<ref>PMID:22265414</ref> | + | [https://www.uniprot.org/uniprot/MLKL_HUMAN MLKL_HUMAN] Required for the execution of programmed necrosis.<ref>PMID:22265414</ref> |
| | <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: Bauer, M]] | + | [[Category: Bauer M]] |
| - | [[Category: Nar, H]] | + | [[Category: Nar H]] |
| - | [[Category: Ruebbelke, M]] | + | [[Category: Ruebbelke M]] |
| - | [[Category: Zeeb, M]] | + | [[Category: Zeeb M]] |
| - | [[Category: Lipid binding protein]]
| + | |
| - | [[Category: Necroptosis]]
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| Structural highlights
Function
MLKL_HUMAN Required for the execution of programmed necrosis.[1]
Publication Abstract from PubMed
As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix alpha6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.
Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.,Rubbelke M, Fiegen D, Bauer M, Binder F, Hamilton J, King J, Thamm S, Nar H, Zeeb M Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ Rubbelke M, Fiegen D, Bauer M, Binder F, Hamilton J, King J, Thamm S, Nar H, Zeeb M. Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis. Proc Natl Acad Sci U S A. 2020 Dec 14. pii: 2017406117. doi:, 10.1073/pnas.2017406117. PMID:33318170 doi:http://dx.doi.org/10.1073/pnas.2017406117
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