7mx3
From Proteopedia
Crystal structure of human RIPK3 complexed with GSK'843
Structural highlights
Function[RIPK3_HUMAN] Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL. Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis.,Meng Y, Davies KA, Fitzgibbon C, Young SN, Garnish SE, Horne CR, Luo C, Garnier JM, Liang LY, Cowan AD, Samson AL, Lessene G, Sandow JJ, Czabotar PE, Murphy JM Nat Commun. 2021 Nov 22;12(1):6783. doi: 10.1038/s41467-021-27032-x. PMID:34811356[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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