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==Solution structure of MLKL executioner domain in complex with a fragment==
==Solution structure of MLKL executioner domain in complex with a fragment==
<StructureSection load='7nm2' size='340' side='right'caption='[[7nm2]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='7nm2' size='340' side='right'caption='[[7nm2]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7nm2]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NM2 FirstGlance]. <br>
<table><tr><td colspan='2'>Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NM2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UJ5:2-[(~{S})-methoxy-(4-propan-2-ylphenyl)methyl]-3~{H}-benzimidazole-5-carboxylic+acid'>UJ5</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UJ5:2-[(~{S})-methoxy-(4-propan-2-ylphenyl)methyl]-3~{H}-benzimidazole-5-carboxylic+acid'>UJ5</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=7nm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nm2 OCA], [https://pdbe.org/7nm2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nm2 RCSB], [https://www.ebi.ac.uk/pdbsum/7nm2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nm2 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=7nm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nm2 OCA], [https://pdbe.org/7nm2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nm2 RCSB], [https://www.ebi.ac.uk/pdbsum/7nm2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nm2 ProSAT]</span></td></tr>
</table>
</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 ==
Necroptosis is a form of programmed cell death that in case of misregulation can lead to inflammatory diseases. Mixed lineage kinase domain-like protein (MLKL), the effector protein in the canonical necroptosis signaling pathway, becomes activated by phosphorylation. Here, we report the identification of novel reversible binders of the MLKL executioner domain by a protein NMR-detected fragment-based screen. Determination of protein fragment costructures using NMR spectroscopy revealed a small molecule binding site that is distinct from the previously identified binding site of covalent MLKL inhibitors. Affinity optimization of the initially prioritized hit with millimolar affinity was achieved by NMR-guided structure-based design and yielded fragment-like molecules with a KD of 50 muM. Furthermore, we demonstrate that the improved fragment competes for the same binding site as nonyl-maltoside, a detergent that in conjunction with phytic acid activates the MLKL executioner domain.
Discovery and Structure-Based Optimization of Fragments Binding the Mixed Lineage Kinase Domain-like Protein Executioner Domain.,Rubbelke M, Hamilton J, Binder F, Bauer M, King J, Nar H, Zeeb M J Med Chem. 2021 Nov 11;64(21):15629-15638. doi: 10.1021/acs.jmedchem.1c00686., Epub 2021 Oct 21. PMID:34672548<ref>PMID:34672548</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7nm2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bauer, M]]
[[Category: Bauer M]]
[[Category: Binder, F]]
[[Category: Binder F]]
[[Category: Hamilton, J]]
[[Category: Hamilton J]]
[[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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