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

探索氨酰-tRNA 系统中域间通讯的分子基础

基本信息

批准号：
8005166
负责人：
Sanchita Hati
金额：
$ 5.63万
依托单位：
UNIVERSITY OF WISCONSIN EAU CLAIRE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-05 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005166
关键词：
Active Sites Advanced Development Amino Acid Sequence Amino Acids Amino Acyl Transfer RNA Amino Acyl-tRNA Synthetases Aminoacylation Anti-Infective Agents Architecture Binding Biochemical Bioinformatics Catalysis Catalytic Domain Cell physiology Communication Complex Coupled Coupling Distant Drug Delivery Systems Drug Design Elements Enzymes Escherichia coli Evolution Free Energy Generations Genetic Code Goals Indium Lead Leucine Ligase Maps Methods Molecular Motion Movement Mutagenesis Nature Pathway interactions Peptide Sequence Determination Play Principal Investigator Proline Protein Biosynthesis Protein Dynamics Proteins Research Role Signal Transduction Site Structure Students Tertiary Protein Structure Thermus thermophilus Time Transfer RNA Transfer RNA Aminoacylation Translations Work X-Ray Crystallography Zinc adenylate analog base computer studies conformational conversion design flexibility insight leucine-tRNA molecular dynamics multidisciplinary mutant novel polypeptide proline-tRNA public health relevance research study simulation small molecule therapeutic target transmission process

项目摘要

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).

描述（由申请人提供）：氨基酰基trna合成酶（ARSs）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是一种多结构域蛋白，其结构域在tRNA的氨基酰化中发挥着不同的作用，在蛋白质合成中保持着很高的准确性。这些领域以高度协调的方式执行其特定功能。因此，它们的功能协调需要域与域之间的通信。各种生物化学和结构研究表明，域域通信在ars中明显存在。一般来说，在多结构域蛋白质中，距离较远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传播的。然而，对于ars，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。本文旨在探讨两种不同类型的ars中域-域通信的分子基础。特别是，我们将研究进化偶联的残基网络在促进结构域动力学中的作用，从而保持蛋白质生物合成的保真度。鉴于这个问题的多学科性质，我们的研究将采用计算和实验两种方法。首席研究员和一个由四名本科生组成的研究小组将开展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ars的进化-结构-动力学关系。将对特定残基进行互补诱变研究，并评估其在酶功能中的作用。这些实验研究将提供进一步的细节的通信途径。在分子水平上理解ARSs的域-域通信对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。鉴定非催化位点的变构残基可用于开发针对致病性急性呼吸道综合征的新一代治疗方法。我们的研究结果可用于设计靶向与氨基酰化和/或编辑活性位点能量偶联的远端位点的小分子。公共卫生相关性：声明在分子水平上理解ars的域-域通信对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/或编辑活性位点能量偶联的远端位点的小分子。