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

Cell Chemical Biology(2016)

引用 98|浏览21
暂无评分
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.
更多
查看译文
关键词
hsp90,inhibitor,non-canonical
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要