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6bwk

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Crystal structure of the human MLKL pseudokinase domain T357E/S358E mutant

Structural highlights

6bwk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.79Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MLKL_HUMAN Required for the execution of programmed necrosis.^[1]

Publication Abstract from PubMed

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain alphaC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.

Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.,Petrie EJ, Sandow JJ, Jacobsen AV, Smith BJ, Griffin MDW, Lucet IS, Dai W, Young SN, Tanzer MC, Wardak A, Liang LY, Cowan AD, Hildebrand JM, Kersten WJA, Lessene G, Silke J, Czabotar PE, Webb AI, Murphy JM Nat Commun. 2018 Jun 21;9(1):2422. doi: 10.1038/s41467-018-04714-7. PMID:29930286^[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
↑ Petrie EJ, Sandow JJ, Jacobsen AV, Smith BJ, Griffin MDW, Lucet IS, Dai W, Young SN, Tanzer MC, Wardak A, Liang LY, Cowan AD, Hildebrand JM, Kersten WJA, Lessene G, Silke J, Czabotar PE, Webb AI, Murphy JM. Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis. Nat Commun. 2018 Jun 21;9(1):2422. doi: 10.1038/s41467-018-04714-7. PMID:29930286 doi:http://dx.doi.org/10.1038/s41467-018-04714-7

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6bwk"

Categories: Homo sapiens | Large Structures | Cowan AD | Czabotar PE | Murphy JM

@@ Line 3: / Line 3: @@
 <StructureSection load='6bwk' size='340' side='right'caption='[[6bwk]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6bwk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BWK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BWK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6bwk]] is a 1 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=6BWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BWK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.79&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bwk OCA], [http://pdbe.org/6bwk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bwk RCSB], [http://www.ebi.ac.uk/pdbsum/6bwk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bwk 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=6bwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bwk OCA], [https://pdbe.org/6bwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bwk RCSB], [https://www.ebi.ac.uk/pdbsum/6bwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bwk 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>
+[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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Cowan, A C]]
+[[Category: Cowan AD]]
-[[Category: Czabotar, P E]]
+[[Category: Czabotar PE]]
-[[Category: Murphy, J M]]
+[[Category: Murphy JM]]
-[[Category: Necroptosis]]
-[[Category: Pseudokinase]]
-[[Category: Transferase]]

6bwk

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Current revision

Crystal structure of the human MLKL pseudokinase domain T357E/S358E mutant

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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