GENETIC REGULATION THROUGH STRUCTURAL STUDIES OF RIBOSWITCH-METABOLITE COMPLEXES

通过核糖开关代谢物复合物的结构研究进行遗传调控

• 批准号: 8167503
• 负责人: JEFF SOUKUP
• 金额: $ 5.12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167503
• 关键词: Agonist; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Base Pairing; Binding; Binding Sites; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallization; Development; Distal; Elements; Funding; Gene Expression Regulation; Genes; Genetic; Grant; Guanine; Institution; Ligands; Metabolic; Metabolism; Molecular Probes; Process; RNA; Regulation; Research; Research Personnel; Resources; Source; United States National Institutes of Health; X-Ray Crystallography; analog; aptamer; base; combat; design; fighting; novel; novel strategies

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The emergence of antibiotic resistance has required that new approaches be applied in order to effectively fight a host of medically relevant bacterial infections. The currently used, imprecise antibiotics need to be replaced with novel, rigorous, and safe treatments in order to combat the evolved bacterium of today. One way to destroy bacteria is to target one of their most essential processes, metabolism. The discovery of RNA structural elements, termed riboswitches, that bind cellular metabolites and control expression of essential metabolic genes provides a unique and distinct target for development of artificial agonists to fight bacterial infections. In order to rationally design and develop effective artificial agonists/antibiotics that target bacterial riboswitches, an understanding of the structural and functional details of the riboswitch-metabolite complex is essential. The aims of this grant focus on (1) probing the molecular contribution of a conserved base pair distal to the metabolite binding site within a riboswitch that binds guanine, (2) designing a crystallization construct for structural characterization of the newly discovered pre-queuosine1 riboswitch, and (3) determining the molecular interactions between the metabolite pre-queuosine1 and its riboswitch aptamer domain. The studies described here will provide atomic level detail of the interactions between riboswitches and their ligands. Structural studies of riboswitches are essential in order to gain detailed information about how the RNA interacts with its metabolite and to ultimately design non-natural metabolite analogs that can act as antibiotics. The X-ray crystallography studies described here will also have a high impact on understanding RNA-based gene regulation.

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