Structure and function of cloverleaf RNA in enterovirus

肠道病毒三叶草RNA的结构和功能

基本信息

批准号：
10414132
负责人：
Kyung H Choi
金额：
$ 2.65万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2022-09-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414132
关键词：
Acute Myocarditis Affinity Antiviral Agents Antiviral Therapy Basic Science Binding Binding Proteins Binding Sites Biochemical Clinical Trials Code Common Cold Communicable Diseases Complex Coxsackie Viruses Crystallization Development Dilated Cardiomyopathy Disease Ensure Enterovirus Equilibrium Family Picornaviridae Fluorescence Foundations Genome Goals Heart Transplantation Heart failure Human Immunity Individual Inflammation Intervention KH Domain Label Lead Length Molecular Molecular Conformation Mutation Myocarditis Myocardium Persons Poliomyelitis Process Protein Biosynthesis Proteins RNA RNA Viruses RNA chemical synthesis RNA replication RNA-Protein Interaction Replication-Associated Process Resolution Rhinovirus Roentgen Rays Role Site Specificity Structure Therapeutic Transfer RNA Translations United States United States National Institutes of Health Vaccines Viral Viral Genome Viral Proteins Virus Virus Replication Work antiviral drug development biophysical techniques genomic RNA immunoregulation insight novel promoter response scaffold stem therapeutic target three dimensional structure viral RNA virology

项目摘要

Abstract Human enteroviruses are responsible for diseases that range from mild conditions like the common cold to severe diseases such as poliomyelitis and myocarditis. For example, the inflammation and weakening of the heart muscle (myocarditis) caused by coxsackie B3 virus (CBV3) can lead to heart failure. Approximately 10-15 million people are infected with enteroviruses in the US each year, yet no antiviral therapies are currently available. Our long-term goal is to obtain detailed structural and biochemical information regarding the enterovirus replication process, and to use this information for the development of antiviral therapeutics and vaccines. In enteroviruses and other positive-strand RNA viruses, the RNA genome is used as a template for both protein translation and RNA synthesis, and thus these viruses need a mechanism to balance the relative extents of these two processes. Enteroviruses use a ‘cloverleaf’ four-way junction RNA structure at the 5’ ends of their genomes to serve as a binding site for the host protein, poly(rC)-binding protein 2 (PCBP2) and the virally encoded protein 3CD, and to modulate the relative levels of viral protein translation and RNA genome synthesis. The goal of the project is to understand how the cloverleaf RNA interacts with these host and virus proteins to balance protein translation and genome synthesis to ensure efficient replication. To accomplish these goals, we will determine the structure of 5’ cloverleaf of the coxsackie virus genome and characterize its interactions with PCBP2 using complementary structural, biochemical, and biophysical approaches. The structure of cloverleaf is predicted to be conserved in enterovirus, rhinovirus, and other picornaviruses, and hence our studies will inform how the 3D structure of cloverleaf RNA regulates viral replication in this large class of viruses.

抽象的人肠病毒是导致疾病的原因严重疾病，例如脊髓灰质炎和心肌炎。例如，炎症和减弱由Coxsackie B3病毒（CBV3）引起的心肌（心肌炎）会导致心力衰竭。约10-15 每年美国有百万人感染肠病毒，但目前尚无抗病毒疗法可用的。我们的长期目标是获得有关该的详细结构和生化信息肠病毒复制过程，并将此信息用于开发抗病毒疗法和疫苗。在肠病毒和其他阳性RNA病毒中，RNA基因组用作模板蛋白质翻译和RNA合成，因此这些病毒需要一种机制来平衡相对这两个过程的范围。肠病毒在5'末端使用“三叶草”四向连接RNA结构它们的基因组作为宿主蛋白的结合位点，poly（rc）结合蛋白2（PCBP2）和虚拟的结合位点编码的蛋白3CD，并调节病毒蛋白翻译和RNA基因组合成的相对水平。该项目的目的是了解三叶草RNA如何与这些宿主和病毒蛋白相互作用平衡蛋白质翻译和基因组合成，以确保有效复制。为了实现这些目标，我们将确定Coxsackie病毒基因组的5'三叶草的结构，并表征其与 PCBP2使用完整的结构，生化和生物物理方法。三叶草的结构预计将构成肠病毒，鼻病毒和其他Picornavires，因此我们的研究将告知三叶草RNA的3D结构如何调节这种大类病毒中的病毒复制。