Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, UK.
Department of Molecular and Cell Biology, University of Leicester, UK.
FEBS J. 2017 Sep;284(18):2947-2954. doi: 10.1111/febs.14069. Epub 2017 Apr 18.
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.
蛋白激酶是细胞周期和信号通路调控的核心分子。它们的催化活性受到严格的翻译后修饰和蛋白-蛋白相互作用的调控，这些调控控制着激酶在无活性和有活性状态之间的转换。尽管蛋白激酶的动态性质使得很难捕捉到所有相关的状态，但这些状态已经通过蛋白质晶体学得到了广泛的研究。在这里，我们描述了两个最近的 Aurora-A 激酶结构，它们捕获了激酶的活性和无活性状态。在这两种情况下，Aurora-A 都是通过与合成蛋白的相互作用而被捕获的，这些合成蛋白要么是抑制激酶的单域抗体，要么是激活激酶的碳氢化合物订书肽。这些结构显示了不同的合成蛋白如何以相反的方式靶向相同的变构口袋，从而对活性产生影响。这些研究为开发在细胞中探测这些变构机制的工具铺平了道路。
