权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Factors Stabilizing RNA Structures

稳定 RNA 结构的因素

基本信息

批准号：
8606857
负责人：
DAVID E. DRAPER
金额：
$ 0.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606857
关键词：
Address Adenine Adopted Affect Antibiotics Area Bacteria Binding Proteins Biochemical Bioinformatics Catalytic RNA Cations Cell physiology Cells Charge Chemicals Collaborations Complex Drug Targeting Effectiveness Electrostatics Environment Equilibrium Escherichia coli Eukaryota Functional RNA Gene Expression Genes Genetic Transcription Goals Grant Growth Human body Hydration status In Vitro Ions Kinetics Ligands Measures Mediation Molecular Chaperones Molecular Conformation Nature Pharmaceutical Preparations Process Protein Biosynthesis Proteins Putrescine RNA RNA Folding RNA Sequences RNA Stability Reliance Resolution Ribosomal RNA Ribosomes Role Signal Transduction Solutions Solvents Stream Structure Surface System Testing Thermodynamics Time Transcriptional Regulation Transfer RNA Translations Universities Washington Water Work cell growth design in vivo inorganic phosphate pathogen planetary Atmosphere research study response small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The folding of RNA molecules into specific tertiary structures is important for many cellular processes relating to gene expression: the protein synthesis machinery depends on intricate transfer and ribosomal RNA structures, processing of messenger and other RNAs requires specific structures, and the regulation of transcription and translation depend on the ability of RNA sequences to adopt specific structures in response to protein or metabolite signals. The chemical nature of RNA limits its structural possibilities; the negative charge causes sensitivity to the types and concentrations of ions present, and the high degree of hydration induces sensitivity to neutral solution components (osmolytes). The long term goals of the proposed studies are to investigate all the naturally-occurring solution factors that might influence RNA stability and identify the different strategies an RNA might use to accomplish a specific function in vivo. Specific questions will be investigated in each of three general areas: At a fundamental level, we will pursue our finding that some osmolytes stabilize RNA structures by affecting the hydration of RNA surfaces to obtain a more detailed picture of RNA hydration changes that accompany tertiary structure formation, and expand our studies of ions to include organic ions of in vivo relevance. Detailed studies will be made of the kinetics and energetics of conformational switches between alternative structures in two different RNAs in which the switch controls gene expression in response to changes in intracellular levels of free Mg2+ or a small metabolite (so-called "riboswitch" RNAs). These two RNAs use very different strategies to achieve stable tertiary structures, and probably function by different mechanisms as well; the studies are intended as explorations of these contrasting possibilities for functional RNAs. The physical studies of riboswitch RNAs will serve as a springboard for in vivo studies that will aim to elucidate the functional mechanism in the cellular environment, for example, how thermodynamic stability is balanced versus the kinetic rate of folding in determining functional response of RNA to cell signals, the reliance of RNAs on various ions found in vivo, and how changes in ion and osmolyte concentrations made by bacterial cells in response to changing growth conditions affect RNA function. These studies will help elucidate how RNAs function in a cellular environment, with potential applications in devising ways to block key RNA functions or design RNAs with specific regulatory functions. Bacterial pathogens are particularly reliant on riboswitch RNAs to survive in different environments inside and outside the human body, and are thus candidates for RNA-targeted therapeutics.

描述RNA分子折叠成特定的三级结构对于与基因表达相关的许多细胞过程是重要的：蛋白质合成机制依赖于复杂的转运和核糖体RNA结构，信使和其它RNA的加工需要特定的结构，转录和翻译的调节依赖于RNA序列响应蛋白质或代谢物信号而采用特定结构的能力。RNA的化学性质限制了其结构的可能性;负电荷导致对存在的离子的类型和浓度的敏感性，并且高度水合诱导对中性溶液组分（渗透剂）的敏感性。拟议研究的长期目标是研究可能影响RNA稳定性的所有天然存在的溶液因素，并确定RNA可能用于实现体内特定功能的不同策略。具体的问题将在三个一般领域的每一个进行调查：在一个基本的水平上，我们将追求我们的发现，一些渗透剂稳定RNA结构，通过影响RNA表面的水合作用，以获得更详细的图片RNA水合作用的变化，伴随着三级结构的形成，并扩大我们的研究离子，包括在体内相关的有机离子。将详细研究两种不同RNA中替代结构之间的构象开关的动力学和能量学，其中开关控制基因表达以响应细胞内游离Mg 2+或小代谢物（所谓的“核糖开关”RNA）水平的变化。这两种RNA使用非常不同的策略来实现稳定的三级结构，并且可能通过不同的机制发挥作用;这些研究旨在探索功能性RNA的这些对比可能性。核糖开关RNA的物理研究将作为体内研究的跳板，体内研究的目的是阐明细胞环境中的功能机制，例如，在确定RNA对细胞信号的功能响应中，热力学稳定性如何与折叠的动力学速率平衡，RNA对体内发现的各种离子的依赖性，以及细菌细胞对变化的生长条件的反应是如何改变离子和渗压剂浓度的，从而影响RNA的功能。这些研究将有助于阐明RNA如何在细胞环境中发挥作用，并可能应用于设计阻断关键RNA功能或设计具有特定调控功能的RNA的方法。细菌病原体特别依赖核糖开关RNA在人体内外的不同环境中生存，因此是RNA靶向治疗的候选者。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Application of a time-dependent coalescence process for inferring the history of population size changes from DNA sequence data.

DOI：
10.1073/pnas.95.10.5456
发表时间：
1998-05
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
A. Polański;M. Kimmel;R. Chakraborty
通讯作者：
A. Polański;M. Kimmel;R. Chakraborty

Tertiary structure of an RNA pseudoknot is stabilized by "diffuse" Mg2+ ions.