| Structural highlights
Function
[RIPK3_MOUSE] Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 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 (By similarity).[1]
Publication Abstract from PubMed
Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.
Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.,Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065., eCollection 2020 Mar 12. PMID:32184955[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 2009 Aug;10(8):916-22. doi: 10.1038/embor.2009.109. Epub 2009 Jul 10. PMID:19590578 doi:http://dx.doi.org/10.1038/embor.2009.109
- ↑ Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ, Weigelt C, Pokross M, Kish K, Kim KS, Cornelius L, Douglas AE, Calambur D, Zhang P, Carpenter B, Pitts WJ. Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Med Chem Lett. 2019 May 6;11(3):266-271. doi: 10.1021/acsmedchemlett.9b00065., eCollection 2020 Mar 12. PMID:32184955 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00065
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