Structural analysis of the Legionella pneumophila type IV secretion system by single particle cryo-electron microscopy.

通过单颗粒冷冻电子显微镜对嗜肺军团菌 IV 型分泌系统进行结构分析。

• 批准号: 2367541
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2367541
• 关键词: Structural; analysis; Legionella; pneumophila; type

Legionella pneumophila, (the causative agent of Legionnaires' disease) developed a specialized type IV secretion system (T4SS), to transport >300 toxins, into host cells (Costa et al, Nat Rev Micro, 2015). Some of the characterized translocated toxins play a critical role in hijacking host cellular pathways to establish the intracellular niche where the bacteria survive, replicate and ultimately cause disease.The goal of the project is to investigate the atomic structure of the L. pneumophila T4SS using cutting-edge single particle cryo-electron microscopy (cryo-EM) (Costa et al, Methods in Molecular Biology, 2017). The near-atomic details obtained from the 3D structure will provide unique insights into how toxins are recruited by the secretion system, how is the secretion system gated, and which is the toxins route within the secretion system. The project will pave the way for rational design of drugs that will abolish toxin secretion preventing bacterial survival and disease. The project will provide training in the biochemical isolation and characterization of large membrane protein complexes, cutting-edge single particle cryo-EM data collection and processing (Costa et al, Cell, 2016). This work will take advantage of the state-of-the-art electron microscopy infrastructures located at the Francis Crick Institute and Diamond Light Source.

嗜肺军团菌（Legionella pneumophila）（军团病的病原体）开发了一种专门的IV型分泌系统（T4 SS），以将>300种毒素转运到宿主细胞中（Costa等人，Nat Rev Micro，2015）。一些特征性的易位毒素在劫持宿主细胞通路以建立细菌生存、复制并最终导致疾病的细胞内生态位中起着关键作用。使用尖端的单颗粒冷冻电子显微镜（cryo-EM）对嗜肺菌T4 SS进行了细胞学和细胞生物学研究（Costa et al，Methods in Molecular Biology，2017）。从3D结构中获得的近原子细节将为毒素如何被分泌系统招募，分泌系统如何被门控以及分泌系统内的毒素途径提供独特的见解。该项目将为合理设计药物铺平道路，这些药物将消除毒素分泌，防止细菌存活和疾病。该项目将提供大型膜蛋白复合物的生化分离和表征，尖端单颗粒冷冻EM数据收集和处理方面的培训（Costa et al，Cell，2016）。这项工作将利用位于弗朗西斯克里克研究所和钻石光源的最先进的电子显微镜基础设施。