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关键作用。它们催化氨基酸与同源转移RNA（TRNA）的共价附着，这是遗传密码翻译的重要步骤。 ARS是多域蛋白，其结构域在tRNA的氨基化中具有不同的作用，并且在蛋白质合成中保持高精度。这些领域以高度协调的方式执行其特定功能。因此，其功能的协调需要域域通信。各种生化和结构研究提供了证据，以表明ARS中有区域障碍沟通清楚。通常，多域蛋白中远处的域之间的通信被认为通过结构元素的耦合运动网络传播。然而，对于ARS，从一个结构域到另一个域的信号传播的分子机制仍然很少理解。该提案旨在探索两种不同类别的ARS类别域通信的分子基础。特别是，我们将研究残基的进化耦合网络在促进域动力学中的作用，从而维持蛋白质生物合成的忠诚度。鉴于问题的多学科性质，我们的研究将同时采用计算方法和实验方法。主要研究人员和由四名本科生组成的研究团队将进行许多涉及生物信息学，统计耦合分析以及模拟（正常模式和分子动力学）的计算研究，以深入了解ARSS中进化结构界限的关系。将对特定残基进行互补的诱变研究，并将评估它们在酶功能中的作用。这些实验研究将为通信途径提供更多细节。了解ARS在分子水平上的域域通信对药物设计具有重要意义。 ARS在蛋白质合成中的基本作用使它们成为潜在的药物靶标。可以利用在非催化部位的变构残基的鉴定来开发针对致病性ARS的新一代治疗剂。我们的研究结果可用于靶向遥远位点的小分子的设计，这些分子在能量耦合到氨基酰基化和/或编辑活性位点（S）。公共卫生相关性：了解ARS在分子层的域域通信的陈述对药物设计具有重要意义。 ARS在蛋白质合成中的基本作用使它们成为潜在的药物靶标。我们的研究结果可用于靶向遥远位点的小分子的设计，这些分子在能量耦合到氨基酰基化和/或编辑活性位点（S）。