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Assembly of Picornaviral Replication Complexes

小核糖核酸病毒复制复合物的组装

基本信息

批准号：
8090406
负责人：
Olve Breien Peersen
金额：
$ 29.11万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8090406
关键词：
ATP phosphohydrolase Active Sites Acute Hepatitis Affect Antiviral Agents Back Binding Biochemical Biochemistry Catalysis Cell membrane Cells Cellular Membrane Common Cold Complex Coxsackie Viruses DNA Sequence Rearrangement DNA-Directed RNA Polymerase Data Detergents Development Disease Endoplasmic Reticulum Engineering Family Family Picornaviridae Funding Future Genome Genomics Goals Heart Diseases Hepatitis A Virus Human poliovirus In Vitro Individual Length Life Cycle Stages Maps Membrane Membrane Proteins Membrane Structure and Function Methods Molecular Motor Mutation Nucleotides Paralysed Peptide Hydrolases Play Polioviruses Polymerase Polyproteins Positioning Attribute Protein Precursors Proteins Proteolytic Processing RNA RNA Viruses RNA chemical synthesis RNA replication RNA-Binding Proteins RNA-Directed RNA Polymerase Reaction Replication-Associated Process Research Research Project Grants Resolution Rhinovirus Site Staging Structure Surface System Testing Translations Update Vaccines Vesicle Viral Viral Genome Virus Virus Diseases Virus Replication base cost helicase in vitro activity in vivo member mutant nanodisk porin protein activation protein function public health relevance reconstitution research study viral RNA

项目摘要

DESCRIPTION (provided by applicant): The picornaviruses are a family of small positive sense single stranded RNA viruses that cause a wide range of diseases at an annual cost well into the hundreds of million dollars. Members include acute hepatitis A virus, the heart disease causing coxsackie B3 virus, rhinoviruses that cause more than half the occurrences of the common cold, and the paralyzing poliovirus. These viruses share a life cycle where RNA replication and viral assembly occurs in large membrane anchored replication complexes assembled on the surfaces of vesicles derived from the endoplasmic reticulum. The replication process is driven by a virally encoded RNA dependent RNA polymerase, the 3Dpol protein, that is responsible for the synthesis of all viral RNA. This research project is focused on the structure and assembly of viral replication centers, where we use poliovirus and coxsackievirus as our main experimental systems. We have previously solved the crystal structures of the 3Dpol proteins from both these viruses and elucidated the molecular mechanism behind the proteolytic activation of these proteins upon cleavage from the viral 3CDpro precursor protein. We are continuing our studies of picornaviral replication proteins by focusing on the structural changes associated with the formation of the 3Dpol elongation complex and on understanding how mutations in the polymerase affect viral RNA replication rate and fidelity both in vitro and in vivo. A new aspect of the project is focused on the structure and function of the membrane associated viral 2C and 2BC proteins that are responsible for host cell membrane rearrangements resulting in the formation of the vesicles upon which the viral replication complexes assemble. PUBLIC HEALTH RELEVANCE: Poliovirus is a member of a large family of viruses containing a specific RNA dependent RNA polymerase protein that is responsible for replicating the viral genome. The focus of this research project is to understand how this protein functions during virus replication and find ways to interfere with its function, which can open the door to the development of antiviral drugs.

描述（由申请人提供）：小核糖核酸病毒是一类小型正链单链RNA病毒，可引起多种疾病，每年造成的损失高达数亿美元。其成员包括急性甲型肝炎病毒、引起心脏病的柯萨奇 B3 病毒、导致一半以上普通感冒发生的鼻病毒以及麻痹性脊髓灰质炎病毒。这些病毒具有相同的生命周期，其中RNA复制和病毒组装发生在源自内质网的囊泡表面组装的大膜锚定复制复合物中。复制过程由病毒编码的 RNA 依赖性 RNA 聚合酶（3Dpol 蛋白）驱动，该酶负责所有病毒 RNA 的合成。该研究项目的重点是病毒复制中心的结构和组装，我们使用脊髓灰质炎病毒和柯萨奇病毒作为主要实验系统。我们之前已经解析了这两种病毒的 3Dpol 蛋白的晶体结构，并阐明了这些蛋白从病毒 3CDpro 前体蛋白裂解后蛋白水解激活背后的分子机制。我们正在继续研究小核糖核酸病毒复制蛋白，重点关注与 3Dpol 延伸复合物形成相关的结构变化，并了解聚合酶的突变如何影响病毒 RNA 体外和体内复制速率和保真度。该项目的一个新方面侧重于膜相关病毒 2C 和 2BC 蛋白的结构和功能，这些蛋白负责宿主细胞膜重排，从而形成病毒复制复合物在其上组装的囊泡。公共卫生相关性：脊髓灰质炎病毒是病毒大家族的一员，含有特定的 RNA 依赖性 RNA 聚合酶蛋白，负责复制病毒基因组。该研究项目的重点是了解这种蛋白质在病毒复制过程中如何发挥作用，并找到干扰其功能的方法，这可以为抗病毒药物的开发打开大门。