NMR structures of components from human telomerase RNP

人端粒酶 RNP 成分的 NMR 结构

• 批准号: 6888087
• 负责人: THOMAS C LEEPER
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-26 至 2007-04-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888087
• 关键词: RNA; binding sites; enzyme activity; enzyme structure; nuclear magnetic resonance spectroscopy; nucleic acid structure; postdoctoral investigator; protein biosynthesis; protein localization; protein structure; ribonucleoproteins; structural biology; telomerase; telomere

DESCRIPTION (provided by applicant): The ribonucleoprotein enzyme telomerase plays a major role in the cellular homeostasis and its regulation is believed to be one a key step in malignant transformation. This project seeks to study the structures of two regions from human telomerase RNA (hTR) with the long-term goal of presenting a framework from which drugs that fight cancer may be discovered. Protein accessory factors that interact with, and stabilize, one of these two domains will also be studied. The primary technique proposed is Nuclear Magnetic Resonance spectroscopy (NMR), which can be used to determine at atomic resolution the contacts formed within a biomolecule, such as a domain of hTR, and between molecules such as between hTR and the accessory protein NHP2. The specific domains to be studied are the 60-nucleotide CR4/CR5 domain of hTR that is crucial for activation of the telomerase holoenzyme, and the box H/ACA snoRNA-like domain. This second domain interacts with the four protein factors (Nhp2, Nop10, Gar1, and Diskerin) that stabilize hTR in vivo. Obtaining the structures of these domains would provide crucial insight into telomerase function and ultimately allow for the design of drugs that can interact with the RNA and thus attenuate tumor growth.

描述（由申请人提供）： 核糖核蛋白酶端粒酶在细胞稳态中起主要作用，其调节被认为是恶性转化的关键一步。该项目旨在研究人类端粒酶RNA（HTR）的两个区域的结构，其长期目标是提出一个框架，可以从中发现与癌症作斗争的药物。还将研究与这两个结构域之一相互作用并稳定的蛋白质附件因子。提出的主要技术是核磁共振光谱（NMR），可用于在原子分辨率下确定生物分子内形成的接触，例如HTR的结构域，以及在HTR和HTR之间的分子之间形成的接触。要研究的特定结构域是HTR的60-核苷酸CR4/CR5结构域，该结构域对于激活端粒酶全酶和盒子H/ACA SNORNA样域至关重要。该第二个结构域与稳定在体内HTR的四个蛋白质因子（NHP2，NOP10，GAR1和盘）相互作用。获得这些结构域的结构将提供对端粒酶功能的关键见解，并最终允许设计可以与RNA相互作用并因此减弱肿瘤生长的药物。