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

描述(申请人提供)：氨基酰-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起着关键作用。它们催化氨基酸与其同源转移RNA(TRNAs)的共价结合，这是遗传密码翻译的关键步骤。ARS是一种具有多结构域的蛋白质，其结构域在tRNA的氨基酰化和维持蛋白质合成的高准确性中具有不同的作用。这些领域以高度协调的方式履行其特定职能。因此，它们功能的协调需要域与域之间的沟通。各种生化和结构研究提供了证据，表明在ARS中明显存在域-域通信。一般来说，多结构域蛋白质中位于较远位置的结构域之间的通信被认为是通过结构元件的耦合运动网络来传播的。然而，对于ARSS来说，信号从一个结构域传播到另一个结构域的分子机制仍然知之甚少。这一建议旨在探索两类不同类型的ARS中域-域通信的分子基础。特别是，我们将研究进化上耦合的残基网络在促进结构域动态方面的作用，从而保持蛋白质生物合成的保真度。考虑到这个问题的多学科性质，我们的研究将使用计算和实验方法。首席研究员和一个由四名本科生组成的研究团队将进行一系列涉及生物信息学、统计耦合分析和模拟(正常模式和分子动力学)的计算研究，以深入了解ARSS中的进化-结构-动力学关系。将进行特定残基的互补性突变研究，并评估它们在酶功能中的作用。这些实验研究将提供交流途径的进一步细节。在分子水平上理解ARSS的结构域-结构域通讯对于药物设计具有重要的意义。ARS在蛋白质合成中的重要作用使其成为潜在的药物靶点。识别非催化部位的变构残基可以被用来开发针对致病ARSS的新一代疗法。我们的研究结果可用于设计靶向与氨基酰化和/或编辑活性中心(S)能量偶联的远距离位点的小分子。公共卫生相关性：在分子水平上理解ARS的域-域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。我们的研究结果可用于设计靶向与氨基酰化和/或编辑活性中心(S)能量偶联的远距离位点的小分子。

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).