Structure/function studies of information flow in M. tuberculosis

这个拟议的协作项目的长期目标是确定结构基础和机制 分枝杆菌毒力和持久性所必需的信息流中介系统的原理 结核病(Mtb)。在结核病结构基因组学联盟(TBSGC)的框架内，我们将重点关注 关于四个过程的结构、生化、计算、遗传和微阵列方法--DMA复制 修复、转录、磷酸化丝氨酸/苏氨酸/酪氨酸信号转导和硫代谢。这项研究有四个方面 具体目标： 1.确定介导DMA复制和修复的Mtb蛋白的结构和功能。 2.确定Mtb RNA聚合酶抑制Rho转录的结构和机制 终止因子和几个核糖核酸酶。 3.确定丝氨酸/苏氨酸蛋白激酶和蛋白酪氨酸磷酸酶的结构和信号通路 在Mtb。 4.确定硫磺转运酶的结构和在结核杆菌生长和持久性中的作用。 实现这些目标所需的基因组观点和广泛的攻击依赖于与 其他TBSGC组件。克隆和蛋白质生产的核心设施将使许多 用于分析的表达载体和蛋白质。结晶核心设施将识别结晶 数据收集核心将为快速确定结构提供必要的数据。 该项目中的微阵列实验将有助于确定所有TBSGC组件的途径和靶点。 项目1将使用选定的高分辨率结构进行抑制剂的协作虚拟筛选。我们会 与其他项目合作，分析关键的磷酸化蛋白质的结构和功能。 协调需要TBSGC网站(项目2)和行政框架。 这一项目和整个TBSGC对人类健康具有很高的意义。结核分枝杆菌感染了三分之一的 全球每年有200多万人死于此病。通过揭示信号如何调节 MTB代谢和确定抗生素和抑制剂结合的机制，该项目将刺激 有效治愈持续结核分枝杆菌感染的新疗法的开发。

The long-term goal of this proposed collaborative project is to define the structural basis and mechanistic principles of systems that mediate information flow essential for virulence and persistence of Mycobacterium tuberculosis (Mtb). Within the framework of the TB Structural Genomics Consortium (TBSGC), we will focus structural, biochemical, computational, genetic and microarray methods on four processes?DMA replication and repair, transcription, phospho-Ser/Thr/Tyr signaling and sulfur metabolism. This research has four specific aims: 1. Define the structures and functions of Mtb proteins that mediate DMA replication and repair. 2. Determine the structures and mechanisms of inhibition of Mtb RNA polymerase, the Rho transcription termination factor and several RNases. 3. Determine the structures and signaling pathways of Ser/Thr kinases and protein tyrosine phosphatases in Mtb. 4. Establish the structures and the roles sulfotransfer enzymes in Mtb growth and persistence. The genomic perspective and broad attack needed to achieve these aims rest on strong collaborations with the other TBSGC components. The Core Facilities for Cloning and Protein Production will make many expression vectors and proteins for analysis. The crystallization core facilities will identify crystallization conditions, and the Data Collection Core will provide essential data for rapid structure determination. Microarray experiments in this project will help identify pathways and targets for all TBSGC components. Project 1 will use selected high-resolution structures for collaborative virtual screens for inhibitors. We will collaborate with the other Projects to analyze the structures and functions of key phosphorylated proteins. Coordination requires the TBSGC web site (Project 2) and administrative framework. This project and the TBSGC as a whole have high significance for human health. Mtb infects one third of the world's population and annually kills over two million people worldwide. By revealing how signals regulate Mtb metabolism and defining the mechanisms of antibiotic and inhibitor binding, this project will stimulate development of new therapeutics to efficiently cure persistent Mtb infections.