气候变化领域集成服务门户(CCPortal): Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

CCPortal

DOI	10.1073/PNAS.2017406117
	Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis
	Rübbelke M.; Fiegen D.; Bauer M.; Binder F.; Hamilton J.; King J.; Thamm S.; Nar H.; Zeeb M.
发表日期	2021
ISSN	00278424
起始页码	33272
结束页码	33281
卷号	117 期号:52
英文摘要	As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix α6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Drug discovery; Necroptosis; NMR; X-ray
语种	英语
scopus关键词	MLKL protein, human; protein kinase; protein kinase inhibitor; xanthine; chemistry; human; IC50; Jurkat cell line; metabolism; molecular model; necroptosis; nuclear magnetic resonance spectroscopy; protein domain; protein multimerization; U-937 cell line; Humans; Inhibitory Concentration 50; Jurkat Cells; Magnetic Resonance Spectroscopy; Models, Molecular; Necroptosis; Protein Domains; Protein Kinase Inhibitors; Protein Kinases; Protein Multimerization; U937 Cells; Xanthine
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179624
作者单位	Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, 88397, Germany; Bioprocess Development Biologicals, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, 88397, Germany; Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, United States; Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss, 88397, Germany
推荐引用方式 GB/T 7714	Rübbelke M.,Fiegen D.,Bauer M.,et al. Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis[J],2021,117(52).
APA	Rübbelke M..,Fiegen D..,Bauer M..,Binder F..,Hamilton J..,...&Zeeb M..(2021).Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Rübbelke M.,et al."Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).