Structure, function, and dynamics of viral RNAs and RNA-containing complexes

病毒 RNA 和含 RNA 复合物的结构、功能和动力学

• 批准号: 9753272
• 负责人: Jeffrey S Kieft
• 金额: $ 61.81万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753272
• 关键词: Adopted; Architecture; Biochemistry; Biological; Biology; Biophysics; Cell physiology; Cells; Cellular Structures; Complex; Data; Disease; Enzymes; Goals; Health; Human; Infection; Knowledge; Learning; Link; Machine Learning; Modeling; Molecular; Molecular Conformation; Outcome; Protein Biosynthesis; RNA; Research; Resolution; Structure; Travel; United States National Institutes of Health; Virus; Virus Diseases; Work; base; biological systems; effective therapy; human disease; interest; macromolecule; new therapeutic target; novel; novel therapeutics; pandemic disease; programs; public health relevance; structural biology; therapy development; viral RNA; virology

 DESCRIPTION (provided by applicant): RNA is a central molecule in biology, performing a large number of diverse and essential tasks. The diversity of RNA function is conferred, in part, by its ability to adopt many different architectures. This includes the ability to form compactly folded structures that interact with other macromolecules to achieve a biological outcome. The discovery of RNAs with novel functions is accelerating, but our understanding of the diversity of RNA structure and how these structures drive function is not keeping pace. Given the importance of RNA in biology, this is an important knowledge gap. The research program described here focuses on understanding important, diverse, biologically active RNAs produced by viruses. This program is motivated by the fact that many viruses use RNA-based mechanisms to manipulate host cell components, altering cellular conditions to favor infection. Thus, viral RNAs are powerful models to discover new RNA structures, to understand how these structures fold, to examine how they interact with and manipulate other macromolecules, and ultimately to describe how the structure drives a specific function. In addition, by studying how viral RNAs manipulate cellular machines, we learn about the machinery itself and we may find new important fundamental RNA-based cellular processes. Finally, viral disease remains a substantial threat to human health, but for most viral infections there is no effective therapy. Learning how viral RNAs work reveals the molecular basis of virus-induced disease, a necessary understanding for developing needed therapies. The number of unexplored viral RNAs is vast, therefore our strategy is to study a set of model viral RNAs with diverse functions. This includes viral RNAs that manipulate the protein synthesis machinery, RNAs that interfere with or co-opt the function of cellular enzymes, and viral RNAs that mimic cellular RNAs and may be molecular "hijackers". For each, we aim to understand the details of their structure-based mechanisms by linking atomic-resolution structural data with the function of these structures within cells. In addition, we are particularly interested in understanding how these RNAs may use programmed conformational dynamics to regulate their function. To achieve this understanding we are using quantitative biochemistry, biophysics, structural biology, and virology in an integrated approach. Our overarching goal is to discover important fundamental rules of RNA-based mechanisms of high impact and with broad applicability to many biological systems, simultaneously characterizing new therapeutic targets to inform the development of treatments for human disease.

 描述（由申请人提供）：RNA是生物学中的中心分子，执行大量不同和基本的任务。RNA功能的多样性部分是由于它能够采用许多不同的结构。这包括形成与其他大分子相互作用以实现生物学结果的复合折叠结构的能力。具有新功能的RNA的发现正在加速，但我们对RNA结构的多样性以及这些结构如何驱动功能的理解并没有跟上。鉴于RNA在生物学中的重要性，这是一个重要的知识空白。这里描述的研究计划侧重于了解病毒产生的重要的，多样的，具有生物活性的RNA。该计划的动机是许多病毒使用基于RNA的机制来操纵宿主细胞成分，改变细胞条件以利于感染。因此，病毒RNA是发现新的RNA结构，了解这些结构如何折叠，检查它们如何与其他大分子相互作用和操纵其他大分子，并最终描述结构如何驱动特定功能的强大模型。此外，通过研究病毒RNA如何操纵细胞机器，我们了解了机器本身，我们可能会发现新的重要的基于RNA的基本细胞过程。最后，病毒性疾病仍然是对人类健康的重大威胁，但对于大多数病毒感染，没有有效的治疗方法。了解病毒RNA如何工作揭示了病毒诱导疾病的分子基础，这是开发所需疗法的必要理解。未开发的病毒RNA的数量是巨大的，因此我们的策略是研究一组具有不同功能的模型病毒RNA。这包括操纵蛋白质合成机制的病毒RNA、干扰或吸收细胞酶功能的RNA以及模拟细胞RNA并可能是分子“劫持者”的病毒RNA。对于每一个，我们的目标是通过将原子分辨率的结构数据与细胞内这些结构的功能联系起来，来了解它们基于结构的机制的细节。此外，我们特别感兴趣的是了解这些RNA如何使用程序化的构象动力学来调节它们的功能。为了实现这一理解，我们正在使用定量生物化学，生物物理学，结构生物学和病毒学的综合方法。我们的总体目标是发现基于RNA的机制的重要基本规则，这些机制具有高度影响力，并广泛适用于许多生物系统，同时表征新的治疗靶点，以告知人类疾病治疗的发展。