Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that   Blocks RIP3-dependent Necroptosis

doi:10.1016/j.chembiol.2015.08.018

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	Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis
	Li, Dianrong ; Li, Chao ; Li, Lin ; Chen, She ; Wang, Lei ; Li, Qiang ; Wang, Xiaodong ; Lei, Xiaoguang ; Shen, Zhirong
刊名	Cell Chemical Biology
	2016
关键词	MIXED LINEAGE KINASE DOMAIN-LIKE PROTEIN CELL-DEATH PROGRAMMED NECROSIS BIOORTHOGONAL LIGATION MOLECULAR CHAPERONE RIP3 CANCER MLKL COMPLEX
DOI	10.1016/j.chembiol.2015.08.018
英文摘要	RIP3-dependent necroptosis has recently garnered significant interest because of the unique signaling mechanisms and pathologic functions involved in this process. Accordingly, a number of chemical screens have identified several effective small-molecule inhibitors that specifically block necroptosis. Here, we report the discovery that kongensin A (KA), a natural product isolated from Croton kongensis, is a potent inhibitor of necroptosis and an inducer of apoptosis. Using a new bioorthogonal ligation method (TQ ligation), we reveal that the direct cellular target of KA is heat shock protein 90 (HSP90). Further studies demonstrate that KA covalently binds to a previously uncharacterized cysteine 420 in the middle domain of HSP90 and dissociates HSP90 from its cochaperone CDC37, which leads to inhibition of RIP3-dependent necroptosis and promotion of apoptosis in multiple cancer cell lines. Collectively, our findings demonstrate that KA is an effective HSP90 inhibitor that has potential anti-necroptosis and anti-inflammation applications.; National Basic Science 973 grants from the Chinese Ministry of Science and Technology [2013CB530805, 2015CB856200]; National Natural Science Foundation of China (NNSFC) [21561142002, 21472010, 91313303, 81571385]; Beijing Nova Program grant from the Beijing Municipal Commission of Science and Technology [xx2012070/Z121102002512077]; Special Research Foundation of State Key Laboratory of Medical Genomics; SCI(E); ARTICLE; xglei@pku.edu.cn; shenzhirong@nibs.ac.cn; 2; 257-266; 23
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/492362]
专题	化学与分子工程学院生命科学学院
推荐引用方式 GB/T 7714	Li, Dianrong,Li, Chao,Li, Lin,et al. Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis[J]. Cell Chemical Biology,2016.
APA	Li, Dianrong.,Li, Chao.,Li, Lin.,Chen, She.,Wang, Lei.,...&Shen, Zhirong.(2016).Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis.Cell Chemical Biology.
MLA	Li, Dianrong,et al."Natural Product Kongensin A is a Non-Canonical HSP90 Inhibitor that Blocks RIP3-dependent Necroptosis".Cell Chemical Biology (2016).