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: 8711232
• 负责人: JAMES C SACCHETTINI
• 金额: $ 191.51万
• 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/8711232
• 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 Design; Drug Industry; Drug Targeting; 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.

整体计划的描述（由申请人提供）： 结合结构基因组学联盟的总体使命是确定结核分枝杆菌（MTB）的蛋白质的三维结构，优先考虑其与药物发现的相关性。 MTB是结核病的病因，仍然是全世界的主要健康威胁，有关相关蛋白质的结构信息至关重要，以支持未来的药物发现。我们的计划项目不仅侧重于探索弱势途径中蛋白质的结构，而且还着重于抑制剂构成的药物靶标的复合物，这将产生有关药物设计的主动位点相互作用的重要见解。 四个项目中的每个项目都选择将重点放在目标中生存至关重要的目标和过程上。项目1（UCB：PI：ALBER）的重点是将新的机械范式定义为MTB细胞壁生物合成和重塑过程，这对于细胞生长和分裂至关重要。项目2（TAMU：PI：Sacchettini）将解决核心代谢酶的晶体结构，包括参与能源生产的酶，氨基酸和副因素的生物合成以及细胞壁脂质成分的生物合成。项目3（加州大学洛杉矶分校：PI：Eisenberg）将调查 包括PE/PPE和ESX蛋白在内的蛋白质复合物家族的结构，以及毒素/抗毒素对。项目4（UCI，PI：Goulding）将集中于代谢物转运和二硫键键异构化的蛋白质的结构表征。我们方法的一个新颖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确定，并为其目标获得有价值的生物学信息。我们的结构测定核心将产生重组蛋白和晶体，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本质，功能和相互作用，并进行HTS以鉴定我们靶标的小分子抑制剂。抑制剂将用作共结晶素的配体，并将是探测细胞功能和验证靶标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向公众提供；促进学术和制药行业的未来药物发现工作。