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Structure-based Discovery of Critical Vulnerabilities of Micobacteria

基于结构的微生物关键漏洞发现

基本信息

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
项目类别：
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

项目摘要

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.

整体课程描述（由申请人提供）：