Towards a molecular, mechanistic, understanding of bacterial type three secretion

向环境中分泌蛋白质是细菌生命的基本特征。这种机制允许病原菌通过分泌毒素和组装分泌的蛋白质以形成运动所需的纳米机器来引起疾病。许多重要的人类病原体使用3型分泌系统（简称T3SS）来执行这些功能，其中T3SS的缺失使细菌非致病性。T3SS对于世界卫生组织强调的12个细菌家族中的8个家族特别重要，因为它们是世界范围内的疾病负担，我们迫切需要开发新的抗生素。 T3SS组装了一个大型的纳米机器，我们早期的计划资助所产生的工作最近已经确定了控制分泌的门的结构，并位于其核心。这个结构揭示了门在组装机器中的一个意想不到的位置，现在需要对我们之前关于T3SS功能的假设进行重大的重新设计。这些结构信息构成了理解T3SS如何运作的实验的基础。我们特别想了解纳米机器是如何运作的，将货物从细菌中推出，尽管油膜定义了有机体。这一过程需要能量，但目前还不清楚如何使用能量来精确输出正确的蛋白质。通过确定分子结构，我们希望能够通过了解所涉及的分子如何排列和重新排列以实现输出步骤来深入了解这一关键过程。 这项工作有可能通过提供有关这种纳米机器力学的分子细节的信息来帮助设计攻击致病细菌家族的药物，这些信息可能会建议使用药物样分子来破坏系统的新途径。

Secretion of proteins into the environment is a fundamental feature of bacterial life. This mechanism allows pathogenic bacteria to cause disease both by secretion of toxins and also by assembling the secreted proteins to form the nano-machines required for motility. Many important human pathogens use type 3 secretion systems, T3SS for short, to perform these functions with deletion of the T3SS rendering the bacteria non-pathogenic. The T3SS is particularly important for eight of the twelve bacterial families highlighted by the World Health Organisation as those for which we critically need to develop novel antibiotics due to their world-wide disease burden. T3SSs assemble a large nano-machine and work arising from our earlier Programme Grant has recently determined the structure of the gate that controls secretion and lies at its core. This structure has revealed an unexpected location for the gate within the assembled machine that now requires significant redrawing of our previous hypotheses about how T3SS function. This structural information forms the basis for experiments to understand how T3SSs operate. In particular we want to understand how the nano-machine operates to push the cargo out of the bacteria, though the oily membrane that defines the organism. This process requires energy, but it is currently completely opaque how that energy is used to achieve export of precisely the right proteins. By determining molecular structures we hope to be able to gain insight into this critical process by understanding how the molecules involved are arranged and re-arranged to achieve the export step. This work has the potential to aid the design of drugs to attack pathogenic bacterial families by providing information about molecular detail of the mechanics of this nano-machine that may suggest novel routes to break the system using drug-like molecules.