Structure-based Discovery of Critical Vulnerabilities of Micobacteria

整体课程说明(由申请人提供)： 结核结构基因组学联盟的总体任务是确定结核分枝杆菌蛋白质(Mtb)的三维结构，根据它们与药物发现的相关性进行优先排序。结核分枝杆菌是结核病的病原体，仍然是世界范围内的主要健康威胁，迫切需要有关蛋白质的结构信息来支持未来的药物开发。我们的计划项目不仅专注于解决脆弱途径中的蛋白质结构，而且还关注药物靶标与抑制剂结合的复合体，这将为药物设计提供关于活性部位相互作用的重要见解。 四个项目中的每一个都选择将重点放在对东道国的生存至关重要的目标和进程上。项目1(UCB：PI：ALBER)的重点是定义对细胞生长和分裂至关重要的结核杆菌细胞壁生物合成和重塑过程的新机制范例。项目2(TAMU：PI：Sacchettini)将解决核心代谢酶的晶体结构，包括那些与能量产生、氨基酸和辅因子的生物合成以及细胞壁脂肪成分的生物合成有关的酶。项目3(加州大学洛杉矶分校：PI：艾森伯格)将进行调查 蛋白质复合体家族的结构，包括PE/PPE和ESX蛋白质，以及毒素/抗毒素对。项目4(UCI，PI：Goulding)将重点研究与代谢物运输和二硫键异构化有关的蛋白质的结构特征。我们方法的一个新方面是使用两个核心项目来帮助我们的小组项目确定结构并为其目标获取有价值的生物信息。我们的结构确定核心将生产重组蛋白质和晶体，并通过高效的管道确定它们的结构。我们的化学和遗传核心将使用遗传方法来评估单个目标的重要性、功能和相互作用，并进行HTS来识别我们目标的小分子抑制剂。这些抑制剂将作为共结晶素的配体，并将成为探测细胞功能和验证靶点的有价值的化学工具。我们收集的所有结构和生化数据都将提供给公众；以促进学术和制药行业未来的药物发现工作。

DESCRIPTION OF THE OVERALL PROGRAM (provided by applicant): The overall mission of the TB Structural Genomics Consortium is to determine the three-dimensional structures of proteins from M. tuberculosis (Mtb), prioritized by their relevance for drug discovery. Mtb, the causative agent of tuberculosis, remains a major-health threat worldwide, and structural information on relevant proteins is critically needed to support future drug discovery. Our Program Project focuses not only on solving structures of proteins in vulnerable pathways, but also complexes of drug targets with inhibitors bound, which will yield important insights about active-site interactions for drug design. Each of the four projects has chosen to focus on targets and processes that are essential to survival in the host. Project 1 (UCB: PI: Alber) is focused on defining new mechanistic paradigms to Mtb cell-wall biosynthesis and remodeling processes that are essential for cell growth and division. Project 2 (TAMU: PI: Sacchettini) will solve the crystal structures of core metabolic enzymes, including those involved in energy production, biosynthesis of amino acids and co-factors, and biosynthesis of lipid components of the cell wall. Project 3 (UCLA: Pi: Eisenberg) will investigate structures of families of protein complexes, including PE/PPE and ESX proteins, as well as toxin/anti-toxin pairs. Project 4 (UCI, PI: Goulding) will focus on structural characterization of proteins involved in metabolite transport and disulfide-bond isomerization. A novel aspect of our approach is the use of the two Core projects to aid our group projects in structure determination and to gain valuable biological information for their targets. Our Structure Determination Core will produce recombinant protein and crystals, and determine their structures through a high-efficiency pipeline. Our Chemical and Genetic Core will use genetic methods to evaluate the essentiality, function, and interactions of individual targets and also conduct HTS to identify small-molecule inhibitors of our targets. The inhibitors will serve as ligands for co-crystallizatin, and will be valuable chemical tools for probing function in cells and validating targets. All of th structural and biochemical data we collect will be provided to the public; to foster future drug discovery efforts in the academic and pharmaceutical industries.