Interactions of Transition Metal Ions with RNA: Structure and Function

过渡金属离子与 RNA 的相互作用：结构和功能

• 批准号: 1710721
• 负责人: Victoria DeRose
• 金额: $ 47.72万
• 依托单位: University of Oregon Eugene
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1710721&HistoricalAwards=false
• 关键词: Interactions; Transition; Metal; Ions; RNA

The Chemistry of Life Processes Program in the Chemistry Division funds this award. Professor Victoria J. DeRose from the University of Oregon investigates the structures of complex ribonucleic acid (RNA) biopolymers. RNA takes part in a wide variety of life sustaining processes. It adopts complex and dynamic structures that are challenging to monitor and predict with current methods. In this research, new platinum compounds are developed as RNA structure probes and used to determine RNA structures in cells. The outcomes of this project are novel methods and reagents for RNA structure analysis, and new information about large RNA structures in cells. The breadth of methods applied to this project supports a unique interdisciplinary training environment for workforce development, including summer undergraduate training for women and other underrepresented groups in science, technology, engineering and mathematics (STEM). The goals of this research are to develop methods for long-range tertiary interactions in large RNAs and to understand determinants for targeting compounds to complex RNA structures. The project develops exchange-inert platinum (Pt(II)) complexes as RNA crosslinking reagents and incorporates them into approaches for RNA structure determination. Pt(II) compounds crosslink purine-rich but noncanonical regions in RNA such as internal loops and junctions and are robust through RNA isolation methods. To enable crosslink analysis, novel modified Pt(II) click reagents are synthesized with installed handles for selective post-treatment modification of Pt(II) RNA species. Structure analysis protocols based on the unique chemistry of these Pt(II) complexes and high-throughput sequencing methods are developed, along with methods to directly image crosslinked species. The specificity of small-molecule RNA interactions is probed through design of enhanced Pt ligands. These approaches are used to predict structures of RNAs in vitro and in-cell, including tertiary structures in long non-coding RNAs.

化学部的生命过程化学计划资助该奖项。 俄勒冈大学的 Victoria J. DeRose 教授研究了复杂核糖核酸 (RNA) 生物聚合物的结构。 RNA 参与多种生命维持过程。它采用复杂且动态的结构，用当前的方法来监测和预测具有挑战性。在这项研究中，新的铂化合物被开发为RNA结构探针并用于确定细胞中的RNA结构。该项目的成果是用于 RNA 结构分析的新方法和试剂，以及有关细胞中大 RNA 结构的新信息。该项目采用了广泛的方法，为劳动力发展提供了独特的跨学科培训环境，包括针对女性和其他科学、技术、工程和数学 (STEM) 领域代表性不足群体的暑期本科培训。这项研究的目标是开发大 RNA 中长程三级相互作用的方法，并了解将化合物靶向复杂 RNA 结构的决定因素。该项目开发交换惰性铂 (Pt(II)) 络合物作为 RNA 交联试剂，并将其纳入 RNA 结构测定方法中。 Pt(II) 化合物可交联 RNA 中富含嘌呤但非规范的区域，例如内部环和连接点，并且通过 RNA 分离方法具有稳健性。为了实现交联分析，合成了新型修饰的 Pt(II) 点击试剂，并安装了手柄，用于对 Pt(II) RNA 物质进行选择性后处理修饰。开发了基于这些 Pt(II) 复合物的独特化学性质和高通量测序方法的结构分析方案，以及直接对交联物质进行成像的方法。通过设计增强的 Pt 配体来探究小分子 RNA 相互作用的特异性。这些方法用于预测体外和细胞内 RNA 的结构，包括长非编码 RNA 的三级结构。

项目成果

Editorial overview: Bioinorganic chemistry: Metals in biology: approaching the big picture

编辑概述：生物无机化学：生物学中的金属：接近大局

• DOI: 10.1016/j.cbpa.2020.03.002
• 发表时间: 2020
• 期刊: Current Opinion in Chemical Biology
• 影响因子: 7.8
• 作者: DeRose, Victoria;Michel, Sarah
• 通讯作者: Michel, Sarah

Monofunctional platinum(II) compounds and nucleolar stress: is phenanthriplatin unique?

• DOI: 10.1007/s00775-019-01707-9
• 发表时间: 2019-09
• 期刊: Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry
• 作者: McDevitt CE;Yglesias MV;Mroz AM;Sutton EC;Yang MC;Hendon CH;DeRose VJ
• 通讯作者: DeRose VJ