7nm5: Difference between revisions

Revision as of 11:17, 14 June 2023

Solution structure of MLKL executioner domain in complex with a fragment

Structural highlights

7nm5 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	UJ2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

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^[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:https://dx.doi.org/10.1016/j.cell.2011.11.030
↑ Rubbelke M, Hamilton J, Binder F, Bauer M, King J, Nar H, Zeeb M. Discovery and Structure-Based Optimization of Fragments Binding the Mixed Lineage Kinase Domain-like Protein Executioner Domain. J Med Chem. 2021 Nov 11;64(21):15629-15638. doi: 10.1021/acs.jmedchem.1c00686., Epub 2021 Oct 21. PMID:34672548 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c00686

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OCA

[1] 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:https://dx.doi.org/10.1016/j.cell.2011.11.030

[2] Rubbelke M, Hamilton J, Binder F, Bauer M, King J, Nar H, Zeeb M. Discovery and Structure-Based Optimization of Fragments Binding the Mixed Lineage Kinase Domain-like Protein Executioner Domain. J Med Chem. 2021 Nov 11;64(21):15629-15638. doi: 10.1021/acs.jmedchem.1c00686., Epub 2021 Oct 21. PMID:34672548 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c00686

[1]

[2]

@@ Line 1: / Line 1: @@
 ==Solution structure of MLKL executioner domain in complex with a fragment==
-<StructureSection load='7nm5' size='340' side='right'caption='[[7nm5]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='7nm5' size='340' side='right'caption='[[7nm5]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7nm5]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NM5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NM5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7nm5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NM5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NM5 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UJ2:2-[(~{S})-methoxy-(4-phenylphenyl)methyl]-3~{H}-benzimidazole-5-carboxylic+acid'>UJ2</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=7nm5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nm5 OCA], [https://pdbe.org/7nm5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nm5 RCSB], [https://www.ebi.ac.uk/pdbsum/7nm5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nm5 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>
+[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 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[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]]

7nm5: Difference between revisions

Revision as of 11:17, 14 June 2023

Solution structure of MLKL executioner domain in complex with a fragment

Structural highlights

Function

Publication Abstract from PubMed

References

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