6O5Z
Crystal Structure of the human MLKL pseudokinase domain bound to compound 2
Summary for 6O5Z
| Entry DOI | 10.2210/pdb6o5z/pdb |
| Descriptor | Mixed lineage kinase domain-like protein, 1,2-ETHANEDIOL, 1-[2-fluoranyl-5-(trifluoromethyl)phenyl]-3-[4-[methyl-[2-[(3-sulfamoylphenyl)amino]pyrimidin-4-yl]amino]phenyl]urea, ... (4 entities in total) |
| Functional Keywords | pseudokinase, inhibitor, necroptosis, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 66359.38 |
| Authors | Cowan, A.D.,Murphy, J.M.,Pierotti, C.L.,Lessene, G.L.,Czabotar, P.E. (deposition date: 2019-03-04, release date: 2020-09-16, Last modification date: 2023-10-11) |
| Primary citation | Pierotti, C.L.,Tanzer, M.C.,Jacobsen, A.V.,Hildebrand, J.M.,Garnier, J.M.,Sharma, P.,Lucet, I.S.,Cowan, A.D.,Kersten, W.J.A.,Luo, M.X.,Liang, L.Y.,Fitzgibbon, C.,Garnish, S.E.,Hempel, A.,Nachbur, U.,Huang, D.C.S.,Czabotar, P.E.,Silke, J.,van Delft, M.F.,Murphy, J.M.,Lessene, G. Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway. Acs Chem.Biol., 15:2702-2713, 2020 Cited by PubMed Abstract: Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound is a more potent analogue of the published compound 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 . These target engagement studies demonstrate that compound 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 and in cells. Compound also shows efficacy in a murine model of systemic inflammatory response syndrome (SIRS). PubMed: 32902249DOI: 10.1021/acschembio.0c00482 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.285 Å) |
Structure validation
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