6O5Z

Crystal Structure of the human MLKL pseudokinase domain bound to compound 2

6O5Z の概要

• エントリーDOI: 10.2210/pdb6o5z/pdb
• 分子名称: 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)
• 機能のキーワード: pseudokinase, inhibitor, necroptosis, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66359.38

構造登録者

Cowan, A.D.,Murphy, J.M.,Pierotti, C.L.,Lessene, G.L.,Czabotar, P.E. (登録日: 2019-03-04, 公開日: 2020-09-16, 最終更新日: 2023-10-11)

主引用文献

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

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: 32902249
DOI: 10.1021/acschembio.0c00482

実験手法

X-RAY DIFFRACTION (2.285 Å)