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Structural Basis of RIP1 Inhibition by Necrostatins

renchunxiao 添加于 2013/3/19 15:56:49  1608次阅读 | 0次推荐 | 0个评论

Necroptosis is a cellular mechanism that mediates necrotic cell death. The receptor-interacting serine/threonine protein kinase 1 (RIP1) is an essential upstream signaling molecule in tumor-necrosis-factor-α-induced necroptosis. Necrostatins, a series of small-molecule inhibitors, suppress necroptosis by specifically inhibiting RIP1 kinase activity. Both RIP1 structure and the mechanisms by which necrostatins inhibit RIP1 remain unknown. Here, we report the crystal structures of the RIP1 kinase domain individually bound to necrostatin-1 analog, necrostatin-3 analog, and necrostatin-4. Necrostatin, caged in a hydrophobic pocket between the N- and C-lobes of the kinase domain, stabilizes RIP1 in an inactive conformation through interactions with highly conserved amino acids in the activation loop and the surrounding structural elements. Structural comparison of RIP1 with the inhibitor-bound oncogenic kinase B-RAF reveals partially overlapping binding sites for necrostatin and for the anticancer compound PLX4032. Our study provides a structural basis for RIP1 inhibition by necrostatins and offers insights into potential structure-based drug design.

作 者:Tian Xie1, 4, Wei Peng1, 4, Yexing Liu1, 4, Chuangye Yan1, Jenny Maki2, Alexei Degterev2, Junying Yuan3, Yigong Shi1, ,
期刊名称: Structure
期卷页: 第卷 第期 页
学科领域:生命科学 » 生物物理、生物化学与分子生物学 » 生物大分子结构与功能
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原文链接:http://www.sciencedirect.com/science/article/pii/S0969212613000245
DOI: 10.1016/j.str.2013.01.016
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