Exploring the molecular basis of domain-domain communication in aminoacyl-tRNA sy

描述（由申请人提供）：氨酰基-tRNA 合成酶（ARS）在最重要的细胞过程之一（即蛋白质生物合成）中发挥关键作用。它们催化氨基酸与其同源转移 RNA (tRNA) 的共价连接，这是遗传密码翻译的重要步骤。 ARS 是多结构域蛋白质，其结构域在 tRNA 氨酰化和维持蛋白质合成的高精度方面具有独特的作用。这些域以高度协调的方式履行其特定职能。因此，它们的功能协调需要域与域之间的通信。各种生化和结构研究提供的证据表明 ARS 中明显存在域间通信。一般来说，多结构域蛋白质中相距较远的结构域之间的通讯被认为是通过结构元件的耦合运动网络传播的。然而，对于 ARS，信号从一个域传播到另一个域的分子机制仍然知之甚少。该提案旨在探索两种不同类别的 ARS 中域间通信的分子基础。特别是，我们将研究残基的进化耦合网络在促进结构域动态方面的作用，从而维持蛋白质生物合成的保真度。鉴于该问题的多学科性质，我们的研究将采用计算和实验方法。首席研究员和由四名本科生组成的研究团队将开展一系列涉及生物信息学、统计耦合分析和模拟（正则模式和分子动力学）的计算研究，以深入了解 ARS 中的进化-结构-动力学关系。将进行特定残基的补充诱变研究，并评估它们在酶功能中的作用。这些实验研究将提供沟通途径的更多细节。在分子水平上了解 ARS 的域间通信对于药物设计具有重要意义。 ARS 在蛋白质合成中的重要作用使其成为潜在的药物靶点。非催化位点变构残基的鉴定可用于开发针对致病性 ARS 的新一代疗法。我们的研究结果可用于设计靶向远距离位点的小分子，这些位点与氨酰化和/或编辑活性位点能量耦合。公共卫生相关性：声明在分子水平上了解 ARS 的域间通信对药物设计具有重大意义。 ARS 在蛋白质合成中的重要作用使其成为潜在的药物靶点。我们的研究结果可用于设计靶向远距离位点的小分子，这些位点与氨酰化和/或编辑活性位点能量耦合。

DESCRIPTION (provided by applicant): Aminoacyl-tRNA synthetases (ARSs) play a key role in one of the most important cellular processes, namely protein biosynthesis. They catalyze the covalent attachment of amino acids to their cognate transfer RNAs (tRNAs), an essential step in the translation of the genetic code. ARSs are multi-domain proteins, with domains that have distinct roles in aminoacylation of tRNA and maintaining high accuracy in protein synthesis. These domains carry out their specific functions in a highly coordinated manner. The coordination of their function, therefore, requires domain-domain communication. Various biochemical and structural studies provide evidence to suggest that domain-domain communication clearly exists in ARSs. In general, communication between distantly located domains in multi-domain proteins is believed to be propagated through networks of coupled motions of structural elements. However, for ARSs, the molecular mechanism of signal propagation from one domain to another domain remains poorly understood. This proposal aims to explore the molecular basis of domain-domain communication in two different classes of ARSs. In particular, we will examine the role of evolutionarily coupled networks of residues in facilitating domain dynamics, thereby maintaining the fidelity of protein biosynthesis. Given the multidisciplinary nature of the problem, our study will employ both computational and experimental methods. The principal investigator and a research team of four undergraduate students will carry out a number of computational studies involving bioinformatics, statistical coupling analysis, and simulations (normal mode and molecular dynamics) to gain insight into the evolution-structure-dynamics relationships in ARSs. Complementary mutagenesis studies of specific residues will be conducted and their role in enzyme function will be evaluated. These experimental studies will provide further details of the communication pathway. Understanding domain-domain communication of ARSs at the molecular level has significant implications for drug design. The essential role of ARSs in protein synthesis has made them potential drug targets. The identification of allosteric residues at a non-catalytic site can be exploited to develop a new generation of therapeutics targeted against pathogenic ARSs. Results of our studies can be used in the design of small molecules targeting distant sites that are energetically coupled to the aminoacylation and/or the editing active site(s). PUBLIC HEALTH RELEVANCE: Statement Understanding domain-domain communication of ARSs at the molecular level has significant implications for drug design. The essential role of ARSs in protein synthesis has made them potential drug targets. Results of our studies can be used in the design of small molecules targeting distant sites that are energetically coupled to the aminoacylation and/or the editing active site(s).