Switching Aurora-A kinase on and off at an allosteric site
Switching Aurora-A kinase on and off at an allosteric site
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DOI：
10.1111/febs.14069
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发表时间：
2017-09-01
期刊：
影响因子：
5.4
通讯作者：
McIntyre, Patrick J.
中科院分区：
文献类型：
--
作者：
Bayliss, Richard;Burgess, Selena G.;McIntyre, Patrick J.
蛋白激酶是细胞周期和信号通路调节的核心参与者。它们的催化活性通过翻译后修饰和蛋白质-蛋白质相互作用受到严格调节，控制非活性和活性状态之间的切换。尽管蛋白激酶的动态性质使得捕获所有相关状态变得困难，但已经使用蛋白质晶体学对这些状态进行了广泛研究。在这里，我们描述了 Aurora-A 激酶的两种最新结构，它们捕获了其活性和非活性状态。在这两种情况下，Aurora-A 通过与合成蛋白相互作用而被捕获，合成蛋白可以是抑制激酶的单域抗体，也可以是激活激酶的碳氢化合物肽。这些结构显示了不同的合成蛋白如何靶向相同的变构袋，并对活性产生相反的影响。这些研究为开发探测细胞中这些变构机制的工具铺平了道路。
Protein kinases are central players in the regulation of cell cycle and signalling pathways. Their catalytic activities are strictly regulated through post-translational modifications and protein-protein interactions that control switching between inactive and active states. These states have been studied extensively using protein crystallography, although the dynamic nature of protein kinases makes it difficult to capture all relevant states. Here, we describe two recent structures of Aurora-A kinase that trap its active and inactive states. In both cases, Aurora-A is trapped through interaction with a synthetic protein, either a single-domain antibody that inhibits the kinase or a hydrocarbon-stapled peptide that activates the kinase. These structures show how the distinct synthetic proteins target the same allosteric pocket with opposing effects on activity. These studies pave the way for the development of tools to probe these allosteric mechanisms in cells.