McClendon Christopher L, Kornev Alexandr P, Gilson Michael K, Taylor Susan S
Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, and.
Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093 Department of Pharmacology,
Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):E4623-31. doi: 10.1073/pnas.1418402111. Epub 2014 Oct 15.
Protein kinases are dynamically regulated signaling proteins that act as switches in the cell by phosphorylating target proteins. To establish a framework for analyzing linkages between structure, function, dynamics, and allostery in protein kinases, we carried out multiple microsecond-scale molecular-dynamics simulations of protein kinase A (PKA), an exemplar active kinase. We identified residue-residue correlated motions based on the concept of mutual information and used the Girvan-Newman method to partition PKA into structurally contiguous "communities." Most of these communities included 40-60 residues and were associated with a particular protein kinase function or a regulatory mechanism, and well-known motifs based on sequence and secondary structure were often split into different communities. The observed community maps were sensitive to the presence of different ligands and provide a new framework for interpreting long-distance allosteric coupling. Communication between different communities was also in agreement with the previously defined architecture of the protein kinase core based on the "hydrophobic spine" network. This finding gives us confidence in suggesting that community analyses can be used for other protein kinases and will provide an efficient tool for structural biologists. The communities also allow us to think about allosteric consequences of mutations that are linked to disease.
蛋白激酶是动态调节的信号蛋白，通过磷酸化靶蛋白在细胞中起开关作用。为了建立一个分析蛋白激酶结构、功能、动力学和变构之间联系的框架，我们对典型的活性激酶蛋白激酶A（PKA）进行了多次微秒级分子动力学模拟。我们基于互信息的概念确定了残基-残基相关运动，并使用Girvan-Newman方法将PKA划分为结构上连续的“群落”。这些群落大多包含40-60个残基，并与特定的蛋白激酶功能或调节机制相关，基于序列和二级结构的知名基序常常被分割到不同的群落中。观察到的群落图谱对不同配体的存在很敏感，并为解释长距离变构偶联提供了一个新框架。不同群落之间的通讯也与先前基于“疏水脊柱”网络定义 的蛋白激酶核心结构一致。这一发现让我们有信心认为群落分析可用于其他蛋白激酶，并将为结构生物学家提供一个有效的工具。这些群落还使我们能够思考与疾病相关的突变的变构后果。
