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: 8534693
• 负责人: JAMES C SACCHETTINI
• 金额: $ 179.95万
• 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/8534693
• 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.

总体计划描述（由申请人提供）： 结核病结构基因组学联盟的总体使命是确定结核分枝杆菌 (Mtb) 蛋白质的三维结构，并根据其与药物发现的相关性确定优先顺序。 Mtb 是结核病的病原体，仍然是全世界的主要健康威胁，迫切需要相关蛋白质的结构信息来支持未来的药物发现。我们的项目不仅关注于解决脆弱途径中的蛋白质结构，还关注于药物靶点与抑制剂结合的复合物，这将为药物设计的活性位点相互作用提供重要的见解。 这四个项目中的每一个都选择关注对宿主生存至关重要的目标和过程。项目 1（UCB：PI：Alber）专注于为 Mtb 细胞壁生物合成和重塑过程定义新的机制范式，这对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，包括那些参与能量产生、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）将进行调查 蛋白质复合物家族的结构，包括 PE/PPE 和 ESX 蛋白质，以及毒素/抗毒素对。项目 4（UCI，PI：Goulding）将重点关注参与代谢物转运和二硫键异构化的蛋白质的结构表征。我们方法的一个新颖之处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。我们的结构测定核心将生产重组蛋白和晶体，并通过高效管道测定其结构。我们的化学和遗传核心将使用遗传方法来评估单个靶点的必要性、功能和相互作用，并进行 HTS 来识别我们靶点的小分子抑制剂。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标的有价值的化学工具。我们收集的所有结构和生化数据将向公众提供；促进学术和制药行业未来的药物发现工作。