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Catalysis and Cooperativity in Regulatory RNAs

调控RNA的催化和协同作用

基本信息

批准号：
7446461
负责人：
Daniel Klein
金额：
$ 3.89万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2008-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446461
关键词：
5&apos Untranslated Regions Address Adopted Affect Antibiotics Architecture Award Bacillus anthracis Bacteria Base Pairing Binding Binding Sites Biochemical Biology Catalysis Catalytic RNA Cell Wall Cell physiology Class Complex Daily Development Elements Energy-Generating Resources Environment Enzymatic Biochemistry Essential Genes Fluorescence Spectroscopy Gene Expression Genes Genetic Genetic Transcription Genetic Translation Glutamine Glycine Goals Hepatitis Delta Virus Human Ions Kinetics Laboratories Length Life Ligand Binding Ligands Measurement Mentors Messenger RNA Metals Molecular Mutagenesis Nucleotides Organism Participant Peptidoglycan Pharmaceutical Preparations Phase Play Property Proteins Public Health RNA RNA Splicing Relative (related person)Research Research Personnel Research Training Resolution Roentgen Rays Role Specificity Staphylococcus aureus Structure Structure-Activity Relationship Techniques Testing Thermodynamics Thinking Training Vibrio cholerae Work X-Ray Crystallography aptamer bacterial resistance base career fructose-6-phosphate glucosamine 6-phosphate in vivo interest member novel pathogen programs protein expression research study retinal rods skills small molecule stem success synergism varkud satellite ribozyme

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY: RNA, once thought of as a passive intermediate in the flow of genetic information, is now recognized as an active participant in the control of gene expression. The focus of this research program is to understand the structural, biophysical, and biochemical properties of riboswitches, a widespread class of cis-acting regulatory RNAs that sense cellular metabolites. Riboswitches are relevant to public health because they directly affect the cellular processes of transcription, translation, and mRNA splicing. Moreover, many riboswitches are promising targets for novel antibiotics because they regulate essential genes in human pathogens such as Staphylococcus aureus, Bacillus anthracis, and Vibrio cholerae. I am focusing on two riboswitches, the glmS ribozyme and the glycine riboswitch, that are distinguished from currently known natural RNAs by their respective catalytic and cooperative ligand binding mechanisms. The research I propose capitalizes on the synergism of high-resolution structural studies and detailed biochemical analyses. The specific aims of this research are: (1) to determine the catalytic mechanism of the glmS ribozyme, (2) to elucidate the molecular basis of cooperative ligand binding by the glycine riboswitch, and (3) to determine a high-resolution crystal structure of the glycine riboswitch. This research program will allow me to complete my training and provide me with new skills in fluorescence spectroscopy, ribozyme kinetics and thermodynamic analyses of RNA. The proposed training is connected to my long-term objective of establishing an independent research program dedicated to understanding the structure-function relationships of RNAs that play important catalytic and regulatory roles in biology. The laboratory of Dr. Adrian Ferre-D'Amare provides an exceptional environment for this research and training, owing to the laboratory's past success in structural and biophysical studies of catalytic RNA. RELEVANCE: All living organisms must precisely control the activation, or expression, of thousands of genes. This research program aims to address how gene expression is controlled by a specific set of RNA molecules that are thought to be necessary for the survival of harmful bacteria. With an urgent need to develop new drugs to combat the rise of bacteria that are resistant to current antibiotics, this work will provide a starting point to develop novel antibiotics that inhibit these RNA molecules.

描述（由申请人提供）：项目摘要：RNA曾经被认为是遗传信息流中的被动中间体，现在被认为是基因表达控制的积极参与者。该研究项目的重点是了解核糖开关的结构、生物物理和生化特性，核糖开关是一类广泛分布的顺式作用调节 RNA，可感知细胞代谢物。核糖开关与公共卫生相关，因为它们直接影响转录、翻译和 mRNA 剪接的细胞过程。此外，许多核糖开关是新型抗生素有希望的靶标，因为它们调节人类病原体（如金黄色葡萄球菌、炭疽杆菌和霍乱弧菌）的必需基因。我主要关注两种核糖开关，glmS 核酶和甘氨酸核糖开关，它们通过各自的催化和协同配体结合机制与目前已知的天然 RNA 区分开来。我提出的研究利用了高分辨率结构研究和详细生化分析的协同作用。本研究的具体目的是：（1）确定glmS核酶的催化机制，（2）阐明甘氨酸核糖开关协同配体结合的分子基础，（3）确定甘氨酸核糖开关的高分辨率晶体结构。这个研究项目将使我能够完成培训，并为我提供荧光光谱、核酶动力学和 RNA 热力学分析方面的新技能。拟议的培训与我的长期目标有关，即建立一个独立的研究计划，致力于了解在生物学中发挥重要催化和调节作用的 RNA 的结构功能关系。 Adrian Ferre-D'Amare 博士的实验室过去在催化 RNA 的结构和生物物理研究方面取得了成功，为这项研究和培训提供了优越的环境。相关性：所有生物体都必须精确控制数千个基因的激活或表达。该研究项目旨在解决一组特定 RNA 分子如何控制基因表达，这些分子被认为是有害细菌生存所必需的。由于迫切需要开发新药来对抗对现有抗生素产生耐药性的细菌的增加，这项工作将为开发抑制这些 RNA 分子的新型抗生素提供一个起点。