6zz1: Difference between revisions
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New page: '''Unreleased structure''' The entry 6zz1 is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of MLKL executioner domain in complex with a covalent inhibitor== | ||
<StructureSection load='6zz1' size='340' side='right'caption='[[6zz1]], [[Resolution|resolution]] 1.64Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6zz1]] 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=6ZZ1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZZ1 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64Å</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zz1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zz1 OCA], [https://pdbe.org/6zz1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zz1 RCSB], [https://www.ebi.ac.uk/pdbsum/6zz1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zz1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6zz1" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bauer M]] | |||
[[Category: Fiegen D]] | |||
[[Category: Nar H]] | |||
Latest revision as of 12:00, 1 February 2024
Crystal structure of MLKL executioner domain in complex with a covalent inhibitor
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