View source for 6zpr


==Solution structure of MLKL executioner domain in complex with a covalent inhibitor==
<StructureSection load='6zpr' size='340' side='right'caption='[[6zpr]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6zpr]] 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=6ZPR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZPR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QOK:7-(2-methoxyethoxymethyl)-1,3-dimethyl-purine-2,6-dione'>QOK</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6zle|6zle]]</div></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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zpr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zpr OCA], [http://pdbe.org/6zpr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zpr RCSB], [http://www.ebi.ac.uk/pdbsum/6zpr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zpr ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/MLKL_HUMAN MLKL_HUMAN]] Required for the execution of programmed necrosis.<ref>PMID:22265414</ref>  
<div style="background-color:#fffaf0;">
== 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<ref>PMID:33318170</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6zpr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Bauer, M]]
[[Category: Binder, F]]
[[Category: Hamilton, J]]
[[Category: Nar, H]]
[[Category: Ruebbelke, M]]
[[Category: Zeeb, M]]
[[Category: Lipid binding protein]]
[[Category: Necroptosis]]