Structure-based Discovery of Critical Vulnerabilities of Micobacteria

基于结构的微生物关键漏洞发现

• 批准号: 8340374
• 负责人: JAMES C SACCHETTINI
• 金额: $ 197.34万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340374
• 关键词: Active Sites; Alleles; Anabolism; Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Area; Binding; Biochemical; Biological; Biology; Cell Wall; Cell division; Cells; Chemicals; Complex; Core Facility; Crystallization; Cycloserine; Data; Development; Drug Delivery Systems; Drug Design; Drug Industry; Drug resistance; Energy Metabolism; Enzymes; Ethambutol; Fatty Acids; Fostering; Future; Genetic; Genetic Screening; Genus Mycobacterium; Goals; Health; Hydrolase; Individual; Infection; Lead; Life; Ligands; Metabolic; Metabolism; Methods; Mission; Mycobacterium tuberculosis; Pathogenesis; Pathway interactions; Peptidoglycan; Pharmaceutical Preparations; Physiology; Process; Production; Property; Protein Family; Proteins; Recombinant Proteins; Roentgen Rays; Role; Services; Structure; Testing; Toxin; Tuberculosis; aminoacid biosynthesis; arabinogalactan; base; cell growth; chemical genetics; disulfide bond; drug discovery; enzyme structure; expression cloning; extracellular; family structure; glycosyltransferase; high throughput screening; human ELF3 protein; inhibitor/antagonist; insight; interest; isoniazid; isoprenoid; lipid biosynthesis; mutant; mycobacterial; novel; programs; protein complex; protein structure; resistant strain; small molecule; structural biology; structural genomics; three dimensional structure; tool

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.

总体说明（由申请人提供）： TB结构基因组学联盟的总体使命是确定M.结核病（Mtb），优先考虑其与药物发现的相关性。结核病的病原体，结核病，仍然是世界范围内的主要健康威胁，和相关蛋白质的结构信息是迫切需要支持未来的药物发现。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物，这将为药物设计提供有关活性位点相互作用的重要见解。 四个项目中的每一个都选择把重点放在对在东道国生存至关重要的目标和进程上。项目1（UCB：主要研究者：阿尔伯）专注于定义对细胞生长和分裂至关重要的Mtb细胞壁生物合成和重塑过程的新机制范例。项目2（TAMU：主要研究者：Sacchettini）将解决核心代谢酶的晶体结构，包括参与能量生产、氨基酸和辅因子生物合成以及细胞壁脂质成分生物合成的酶。项目3（UCLA：Pi：Eisenberg）将调查 蛋白质复合物家族的结构，包括PE/PPE和ESX蛋白，以及毒素/抗毒素对。项目4（UCI，PI：Goulding）将侧重于参与代谢物转运和二硫键异构化的蛋白质的结构表征。我们的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进行结构测定，并为其目标获得有价值的生物信息。我们的Structure Determination Core将生产重组蛋白和晶体，并通过高效管道确定其结构。我们的化学和遗传核心将使用遗传方法来评估单个靶标的重要性，功能和相互作用，并进行HTS以识别我们靶标的小分子抑制剂。这些抑制剂将作为共结晶的配体，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物化学数据将提供给公众;以促进学术和制药行业未来的药物发现工作。