Effector-Binding-Directed Dimerization and Dynamic Communication between Allosteric Sites of Ribonucleotide Reductase.
Effector-Binding-Directed Dimerization and Dynamic Communication between Allosteric Sites of Ribonucleotide Reductase.
复制标题
效应器结合定向二聚化和核糖核苷酸还原酶变构位点之间的动态通讯。
DOI：
10.1021/acs.biochem.8b01131
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发表时间：
2019
期刊：
影响因子：
2.9
通讯作者：
Shen,Tongye
中科院分区：
文献类型：
--
作者：
Pham,Bill;Lindsay,RichardJ;Shen,Tongye
形成二聚体或更大复合体的蛋白质会受到效应器结合状态的强烈影响。我们通过计算机模拟研究了效应器结合事件是如何与界面形成耦合的，并量化了两种类型的接触相互作用的相关性：效应器与其结合口袋之间以及蛋白质单体之间。这是通过将单体水平上的蛋白质动力学与低聚物界面信息联系起来实现的。我们将这种方法应用于核糖核苷酸还原酶(RNR)，这是从头合成DNA的关键酶。RnR含有两个重要的变构位点，即S位点(专一性位点)和a位点(活性位点)，它们结合不同的效应子。我们用原子模拟研究了这些不同的结合状态，并利用它们的粗粒度接触信息来分析蛋白质的动力学。结果表明，S位点的效应器-蛋白质动力学与二聚体界面的形成是正耦合的。我们进一步量化了这两个事件之间的共振水平，这可以应用于其他类似的系统。在a位，不同的效应器结合状态(三磷酸腺苷和二磷酸腺苷)极大地改变了蛋白质的动力学，影响了酶的活性。在这些结果的基础上，我们提出了a-位点如何调节酶活性的新机制。
Proteins forming dimers or larger complexes can be strongly influenced by their effector-binding status. We investigated how the effector-binding event is coupled with interface formation via computer simulations, and we quantified the correlation of two types of contact interactions: between the effector and its binding pocket and between protein monomers. This was achieved by connecting the protein dynamics at the monomeric level with the oligomer interface information. We applied this method to ribonucleotide reductase (RNR), an essential enzyme for de novo DNA synthesis. RNR contains two important allosteric sites, the s-site (specificity site) and the a-site (activity site), which bind different effectors. We studied these different binding states with atomistic simulation and used their coarse-grained contact information to analyze the protein dynamics. The results reveal that the effector–protein dynamics at the s-site and dimer interface formation are positively coupled. We further quantify the resonance level between these two events, which can be applied to other similar systems. At the a-site, different effector-binding states (ATP vs dATP) drastically alter the protein dynamics and affect the activity of the enzyme. On the basis of these results, we propose a new mechanism of how the a-site regulates enzyme activation.