Structural Cell Biology Core

结构细胞生物学核心

• 批准号: 7152390
• 负责人: John A. Tainer
• 金额: $ 43.51万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152390
• 关键词: DNA repair; X ray; cell biology; neoplasm /cancer; proteins

The Structural Cell Biology (SCB) Core provides critical technologies and support for the Structural Cell Biology of DNA Repair Machines (SBDR) Program. Major challenges of SBDR stem from the dynamic and coordinated assembly of large protein complexes involved in DNA repair processes. These complexes undergo functionally important conformational changes and modifications. The SCB Core will provide structural expertise and technologies suitable for SBDR project and program Aims, create a functional bridge between atomic resolution structures and molecular envelopes, and help close the gap between static crystal structures and biologically relevant, multi-component macromolecular machines. In particular, the SCB Core will provide SBDR with three distinct and complementary methods for structural analyses. (1) Multiwavelength single crystal X-ray diffraction will provide high-resolution structures of discrete states. (2) Small Angle X-ray Scattering (SAXS) will characterize the solution dynamics of protein complexes by visualizing flexible regions and induced conformational changes. (3) Scanning Force Microscopy (SFM) of single molecules, available through the Wyman lab, will provide information about DNA and protein dynamics, and will reveal structural insight into heterogeneous mixtures previously inaccessible using crystallographic or SAXS techniques. The SCB Core is designed to supply the SBDR projects with the necessary tools and proficiency to overcome the structural biology challenges inherent to analysis of large complexes. The requested funding provides staff to maximize interaction with the EMB Core and for SBDR use of the Structurally Integrated Biology for Life Sciences (SIBYLS) beamline at the Advanced Light Source (ALS) at the Lawrence Berkeley National Laboratories (LBNL). The SIBYLS beamline is a unique synchrotron resource that provides tunable wavelengths for both single crystal X-ray diffraction and SAXS. The SCB Core will develop software that addresses current limitations in the analysis of DNA repair proteins including software that will combine results from high and low resolution techniques through the systematic and objective fitting of X-ray crystal structures into molecular envelopes generated by EM and SAXS experiments. The SCB Core will test, develop, and provide advanced tools to detect and measure posttranslational modifications. Understanding the dynamic structures of macromolecular machines for DNA repair will generate insights into multi-component systems that have remained elusive through the study of individual component biomolecules. The results from the SCB Core will be applied to the understanding of cancer etiology and potential cancer diagnostics and prognostics through interactions with the UCSF Comprehensive Cancer Center.

结构细胞生物学（SCB）核心为结构细胞提供关键技术和支持 DNA 修复机器生物学 (SBDR) 计划。 SBDR 的主要挑战源于动态和 参与 DNA 修复过程的大型蛋白质复合物的协调组装。这些复合体 经历功能上重要的构象变化和修饰。 SCB 核心将提供 适合 SBDR 项目和计划的结构专业知识和技术 目标，创建一座功能桥梁 原子分辨率结构和分子包络之间，并有助于缩小静态晶体之间的差距 结构和生物相关的多组分高分子机器。特别是，SCB 核心 将为 SBDR 提供三种不同且互补的结构分析方法。 (1) 多波长 单晶X射线衍射将提供离散态的高分辨率结构。 (2) 小 角 X 射线散射 (SAXS) 将通过可视化来表征蛋白质复合物的溶液动力学 柔性区域并诱导构象变化。 (3) 单晶的扫描力显微镜 (SFM) 怀曼实验室提供的分子将提供有关 DNA 和蛋白质动力学的信息，以及 将揭示以前使用晶体学或无法获得的异质混合物的结构洞察 SAXS 技术。 SCB 核心旨在为 SBDR 项目提供必要的工具和 熟练地克服大型复合物分析所固有的结构生物学挑战。这 所请求的资金使工作人员能够最大限度地与 EMB 核心互动，并为 SBDR 使用 先进光源 (ALS) 的生命科学结构集成生物学 (SIBYLS) 光束线 劳伦斯伯克利国家实验室 (LBNL)。 SIBYLS 光束线是一种独特的同步加速器 为单晶 X 射线衍射和 SAXS 提供可调波长的资源。渣打银行 Core 将开发软件来解决当前 DNA 修复蛋白分析的局限性，包括 软件将通过系统和低分辨率技术结合结果 将 X 射线晶体结构客观拟合到 EM 和 SAXS 生成的分子包膜中 实验。 SCB 核心将测试、开发并提供先进的工具来检测和测量翻译后 修改。了解 DNA 大分子机器的动态结构 修复将产生对多组件系统的深入了解，而这些系统通过研究仍然难以捉摸 单个组成的生物分子。 SCB 核心的结果将应用于理解 通过与 UCSF 的互动进行癌症病因学以及潜在的癌症诊断和预后 综合癌症中心。