The Mechanism and Regulation of ATP Hydrolysis in a Viral Genome Packaging Motor

病毒基因组包装马达中 ATP 水解的机制和调控

• 批准号: 9327813
• 负责人: Janelle Hayes
• 金额: $ 3.07万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327813
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; ATPase Domain; Address; Antiviral Agents; Bacteriophages; Binding; Biochemical; Biological; Biological Assay; Biological Models; Capsid; Capsid Proteins; Communication; Complex; Cryoelectron Microscopy; Crystallization; DNA; DNA Binding; DNA Packaging; Dependence; Double Stranded DNA Virus; Double Stranded RNA Virus; Drug Targeting; Drug resistance; Engineering; Event; Family; Genome; Herpesviridae; Human; Imagery; In Vitro; Individual; Joints; Knowledge; Measures; Modeling; Molecular Conformation; Molecular Machines; Molecular Sieve Chromatography; Motor; Motor Activity; Mutagenesis; Mutation; Nucleic Acids; Pharmaceutical Preparations; Positioning Attribute; Proteins; Publishing; Reaction; Regulation; Research; Rest; Role; Schools; Side; Site; Solubility; Speed; Structural Models; Structure; System; Therapeutic; Time; Training; Viral; Viral Genome; Viral Packaging; X-Ray Crystallography; base; crosslink; design; design and construction; experience; flexibility; human disease; improved; insight; interfacial; light scattering; multidisciplinary; nanodevice; novel; pathogen; small molecule; small molecule inhibitor; terminase

Project Summary/ Abstract Many dsDNA and dsRNA viruses package their genomes into preformed protein capsids using a powerful molecular machine known as a viral packaging motor. One viral motor family, the terminase motor, is associated with both bacteriophage and human pathogens. Terminase motors have three components: the Portal that connects the rest of the motor to the capsid, the Large Terminase (TerL) which has the enzymatic activity of the motor, and the Small Terminase (TerS), which recognizes the viral genome. Although viral genome packaging has been studied for over 30 years, several questions regarding viral motor ATPase mechanism and regulation remain unanswered. Filling these gaps is critical for improving the small-molecule inhibitors that target the motor for treating human pathogens, such as herpesviruses. Additionally, answering these questions will improve the design of the viral motor-powered nanodevices currently being developed as nucleic acid-based therapeutic delivery systems. These gaps have not been properly addressed due of the limitations of commonly used mesophilic model systems. To avoid the shortcomings of mesophilic systems, this project employs an improved novel thermophilic bacteriophage P74-26 model system. This proposal aims to elucidate the mechanism and regulation of TerL ATPase activity. Addressing these gaps in current knowledge will provide insight as to how viral motors translocate DNA during viral genome packaging.

项目摘要/摘要 许多dsDNA和dsRNA病毒将它们的基因组包装成预先形成的蛋白质衣壳 强大的分子机器被称为病毒包装马达。一种病毒运动家族，终止酶运动，是 与噬菌体和人类病原体有关。终端机电机有三个组件： 连接发动机其余部分和衣壳的门户，即具有酶的大终端酶(TERL) 马达的活性，以及识别病毒基因组的小末端酶(TERS)。 尽管病毒基因组打包已经研究了30多年，但关于病毒的几个问题 运动型ATPase的作用机制和调控机制尚不清楚。填补这些差距对于改善 针对马达的小分子抑制剂，用于治疗人类病原体，如疱疹病毒。 此外，回答这些问题将改进病毒电机驱动的纳米设备的设计 目前正被开发为基于核酸的治疗给药系统。这些差距还没有 由于常用的中温模式系统的局限性，适当地解决了这一问题。为了避免 针对中温系统的缺点，本项目采用了一种改进的新型嗜热噬菌体 P74-26模型系统。本研究旨在阐明端粒酶ATPase活性的调控机制。 解决现有知识中的这些差距将为深入了解病毒马达如何在 病毒基因组包装。