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: 8360016
• 负责人: JEFF SOUKUP
• 金额: $ 5.07万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360016
• 关键词: Agonist; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Base Pairing; Binding; Binding Sites; Complex; Crystallization; Development; Distal; Elements; Funding; Gene Expression Regulation; Genes; Genetic; Grant; Guanine; Ligands; Metabolic; Metabolism; Molecular Probes; National Center for Research Resources; Nebraska; Principal Investigator; Process; RNA; Regulation; Research; Research Infrastructure; Resources; Source; United States National Institutes of Health; X-Ray Crystallography; analog; aptamer; base; combat; cost; design; fighting; functional genomics; novel; novel strategies

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抗生素耐药性的出现需要采用新方法，以有效地抵抗许多与医学相关的细菌感染。 目前使用的不精确的抗生素需要被新颖，严格和安全的治疗替代，以便对抗当今的进化细菌。 消灭细菌的一种方法是针对其最重要的过程之一，即代谢。 RNA结构元素的发现，称为核糖开关，结合细胞代谢物和基本代谢基因的控制表达，为人工激动剂的发展提供了独特而独特的靶标，以抵抗细菌感染。 为了合理设计和开发靶向细菌核糖开关的有效人工激动剂/抗生素，对核糖开关 - 米代谢物复合物的结构和功能细节的理解是必不可少的。 这项赠款的目的集中在（1）探测一对距离鸟嘌呤的核糖开关内的一对远端与代谢物结合位点远端的分子贡献，（2）设计一种结晶构建体，以实现新发现的Queosine1 rocoswitch的结构表征，并确定其核糖核能之间的核糖和核糖核酸核心核糖核苷的核糖核体核心，并确定（3） 领域。此处描述的研究将提供核糖开关及其配体之间相互作用的原子水平细节。核糖开关的结构研究对于获得有关RNA如何与代谢物相互作用的详细信息至关重要的，并最终设计了可以充当抗生素的非天然代谢产物类似物。此处描述的X射线晶体学研究也将对理解基于RNA的基因调节产生很大的影响。