Small molecules that target phosphorylation dependent protein-protein interaction
Small molecules that target phosphorylation dependent protein-protein interaction
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DOI：
10.1016/j.bmc.2016.03.023
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发表时间：
2016-08-01
影响因子：
3.5
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
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作者：
Watanabe, Nobumoto;Osada, Hiroyuki
蛋白质-蛋白质相互作用是信号转导途径中的关键事件之一。这种相互作用改变了蛋白质的构象、活性、定位和稳定性，并将信号转导至下一步。通常，这种相互作用发生在蛋白质磷酸化时。当上游信号受到刺激时，蛋白激酶被激活并磷酸化其底物，并诱导磷酸化依赖的蛋白质-蛋白质相互作用。对于这种相互作用，已知蛋白质中的几个结构域可以特异性识别靶蛋白的磷酸化残基。这些相互作用的特定结构域对于信号转导紊乱引起的疾病（例如癌症）的进展非常重要。因此，调节这种相互作用的小分子是治疗此类疾病的有吸引力的先导化合物。在这篇综述中，我们重点关注了磷酸化依赖性蛋白质-蛋白质相互作用模块的三个例子（14-3-3、Plk1 的 polo box 结构域和 SCF 泛素连接酶中的 F-box 蛋白），并总结了调节它们相互作用的小分子。我们还引入了我们原创的筛选系统来识别此类小分子。 (C) 2016 Elsevier Ltd. 保留所有权利。
Protein-protein interaction is one of the key events in the signal transduction pathway. The interaction changes the conformations, activities, localization and stabilities of the proteins, and transduces the signal to the next step. Frequently, this interaction occurs upon the protein phosphorylation. When upstream signals are stimulated, protein kinase(s) is/are activated and phosphorylate(s) their substrates, and induce the phosphorylation dependent protein-protein interaction. For this interaction, several domains in proteins are known to specifically recognize the phosphorylated residues of target proteins. These specific domains for interaction are important in the progression of the diseases caused by disordered signal transduction such as cancer. Thus small molecules that modulate this interaction are attractive lead compounds for the treatment of such diseases. In this review, we focused on three examples of phosphorylation dependent protein-protein interaction modules (14-3-3, polo box domain of Plk1 and F-box proteins in SCF ubiquitin ligases) and summarize small molecules that modulate their interaction. We also introduce our original screening system to identify such small molecules. (C) 2016 Elsevier Ltd. All rights reserved.