6o5z
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Crystal Structure of the human MLKL pseudokinase domain bound to compound 2== | ==Crystal Structure of the human MLKL pseudokinase domain bound to compound 2== | ||
| - | <StructureSection load='6o5z' size='340' side='right'caption='[[6o5z]]' scene=''> | + | <StructureSection load='6o5z' size='340' side='right'caption='[[6o5z]], [[Resolution|resolution]] 2.29Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O5Z OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6o5z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O5Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O5Z FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </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=LN4:1-[2-fluoranyl-5-(trifluoromethyl)phenyl]-3-[4-[methyl-[2-[(3-sulfamoylphenyl)amino]pyrimidin-4-yl]amino]phenyl]urea'>LN4</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MLKL ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6o5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o5z OCA], [https://pdbe.org/6o5z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o5z RCSB], [https://www.ebi.ac.uk/pdbsum/6o5z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o5z 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 an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS). | ||
| + | |||
| + | Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.,Pierotti CL, Tanzer MC, Jacobsen AV, Hildebrand JM, Garnier JM, Sharma P, Lucet IS, Cowan AD, Kersten WJA, Luo MX, Liang LY, Fitzgibbon C, Garnish SE, Hempel A, Nachbur U, Huang DCS, Czabotar PE, Silke J, van Delft MF, Murphy JM, Lessene G ACS Chem Biol. 2020 Oct 16;15(10):2702-2713. doi: 10.1021/acschembio.0c00482., Epub 2020 Sep 22. PMID:32902249<ref>PMID:32902249</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6o5z" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Cowan | + | [[Category: Cowan, A D]] |
| - | [[Category: Czabotar | + | [[Category: Czabotar, P E]] |
| - | [[Category: Lessene | + | [[Category: Lessene, G L]] |
| - | [[Category: Murphy | + | [[Category: Murphy, J M]] |
| - | [[Category: Pierotti | + | [[Category: Pierotti, C L]] |
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Necroptosis]] | ||
| + | [[Category: Pseudokinase]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 14:54, 3 March 2021
Crystal Structure of the human MLKL pseudokinase domain bound to compound 2
| |||||||||||
