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.

项目概要/摘要 许多 dsDNA 和 dsRNA 病毒使用 强大的分子机器，称为病毒包装马达。一种病毒马达家族，即终止酶马达，是 与噬菌体和人类病原体有关。终止酶电机具有三个组件： 将电机其余部分连接到衣壳的门户，即具有酶促作用的大终止酶 (TerL) 马达的活动，以及识别病毒基因组的小终止酶（TerS）。 尽管病毒基因组包装的研究已超过 30 年，但有关病毒基因组包装的几个问题 运动 ATP 酶机制和调节仍未得到解答。填补这些空白对于改善 针对电机的小分子抑制剂，用于治疗人类病原体，例如疱疹病毒。 此外，回答这些问题将改进病毒马达驱动的纳米设备的设计 目前正在开发基于核酸的治疗递送系统。这些差距还没有被 由于常用的中温模型系统的局限性，已得到适当解决。为了避免 针对嗜温系统的缺点，该项目采用了改进的新型嗜热噬菌体 P74-26模型系统。该提案旨在阐明 TerL ATPase 活性的机制和调节。 解决当前知识中的这些空白将提供关于病毒马达如何在病毒传播过程中易位的见解。 病毒基因组包装。