STRUCTURAL ANALYSIS OF THE MTOR KINASE PATHWAY BY SOLUTION X-RAY SCATTERING

通过溶液 X 射线散射对 MTOR 激酶通路进行结构分析

• 批准号: 7370630
• 负责人: Seong Woo Anthony Kang
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370630
• 关键词: STRUCTURAL; ANALYSIS; MTOR; KINASE; PATHWAY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell growth is a fundamental biological process that determines the sizes of cells, organs, and organisms, and is often perturbed in human cancers. By integrating signals derived from nutrients, energy status, and growth factors, the mammalian target of rapamycin (mTOR) signaling network regulates the growth mechanisms. To this end, the long-term goal of our research is to determine the structures of several components within the mTOR pathway and to understand the basis for protein-protein interactions and their implications on the function of this growth regulation. To accomplish our goals, we plan to design and apply multidisciplinary experimental approaches, combining tools of structural biology, cell biology, and biochemistry. We aim to understand in molecular detail how mTOR complexes propagate signals and then adapt to inputs from nutrients and growth factors. Therefore, in addition to determining the structures of the individual proteins and their functional domains with high-resolution x-ray diffraction, we will use SAXS to construct intermediate-resolution envelopes of high molecular weight complexes, as well as to track associations and domain motions in solution. We underscore the importance of synchrotron radiation to our structural studies of the mTOR pathway. With the results obtained through successful SAXS experiments, we will create an adequate framework in which the high-resolution models that are generated by protein crystallography can be meaningfully fitted. Moreover, this study will provide new insights into understanding the protein-protein interactions, docking geometries, and stoichiometry of binding within the mTOR signaling pathway.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。细胞生长是决定细胞、器官和生物体大小的基本生物学过程，并且在人类癌症中经常受到干扰。哺乳动物雷帕霉素靶蛋白（mTOR）信号网络通过整合来自营养、能量状态和生长因子的信号来调节生长机制。为此，我们研究的长期目标是确定mTOR通路中几种组分的结构，并了解蛋白质-蛋白质相互作用的基础及其对这种生长调节功能的影响。为了实现我们的目标，我们计划设计和应用多学科的实验方法，结合结构生物学，细胞生物学和生物化学的工具。我们的目标是从分子上详细了解mTOR复合物如何传播信号，然后适应营养素和生长因子的输入。因此，除了用高分辨率X射线衍射确定单个蛋白质及其功能结构域的结构外，我们还将使用SAXS构建高分子量复合物的中间分辨率包络，以及跟踪溶液中的缔合和结构域运动。我们强调同步辐射的重要性，我们的mTOR通路的结构研究。通过成功的SAXS实验获得的结果，我们将创建一个适当的框架，在其中可以有意义地拟合由蛋白质晶体学生成的高分辨率模型。此外，这项研究将为理解mTOR信号通路中的蛋白质-蛋白质相互作用、对接几何形状和结合化学计量提供新的见解。