NMR structures of components from human telomerase RNP

描述(由申请人提供)： 核糖核蛋白酶端粒酶在细胞内稳态中起重要作用，其调控被认为是恶性转化的关键步骤之一。该项目旨在研究人类端粒酶RNA(HTR)的两个区域的结构，长期目标是提供一个框架，从中可能发现抗癌药物。与这两个结构域中的一个相互作用并稳定的蛋白质辅助因子也将被研究。提出的主要技术是核磁共振波谱，它可以用来在原子分辨率下确定生物分子内形成的接触，如HTR结构域，以及分子之间，如HTR和辅助蛋白NHP2之间。要研究的特定结构域是hTR的60个核苷酸的CR4/CR5结构域，它是端粒酶全酶激活的关键，以及Box H/ACA snoRNA样结构域。这第二个结构域与体内稳定HTR的四个蛋白质因子(Nhp2、Nop10、Gar1和Diskerin)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洞察，并最终允许设计能够与RNA相互作用从而抑制肿瘤生长的药物。

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.