COMBINED SAXS AND THEORETICAL DETERMINATION OF THE STRUCTURAL ENSEMBLE

组合萨克斯管和结构合奏的理论确定

• 批准号: 8362370
• 负责人: PATRICIA A JENNINGS
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362370
• 关键词: Biological; Biology; Data; Enzymes; Funding; Grant; Methodology; Molecular Conformation; National Center for Research Resources; Play; Population; Principal Investigator; Process; Proteins; Radiation; Regulation; Research; Research Infrastructure; Resources; Roentgen Rays; Role; Solutions; Source; System; United States National Institutes of Health; conformer; cost; experimental analysis; macromolecule; protein folding; protein function; simulation; structural biology; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is becoming clear that regulation of protein function is often acheived via shifts in the populations of active and inactive conformers. X-ray crystallographic analysis gives only snapshots of possible configurations populated in solution. Taking advantage of our expertises in theoretical and experimental analysis of protein folding and assembly, we seek to use a combined SAXS and theoretical approach to define the structural ensembles present in the functional landscapes of multidomain proteins. This approach extends beyond current simulation analysis of SAXS data to include local and global folding/unfolding transitions that are important in function. Our initial choice in developing this methodology is the enzyme Csk as it is not only an important therapeutic target but also is a system we have characterized in terms of the optimal enzymatic and folding conditions. There is growing evidence that biases in the structural ensemble may play an important role in the regulation of Csk. The methodology developed here is broadly applicable to biological macromolecules and will provide useful information about what ensembles of conformations are consistent with the experimental data as well as the the ubiquitous dynamic reversible folding/assembly processes inherent in biology.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 越来越清楚的是，蛋白质功能的调节通常是通过活性构象体和非活性构象体的变化来实现的。X射线晶体学分析仅给出溶液中可能的构型的快照。 利用我们在蛋白质折叠和组装的理论和实验分析的专业知识，我们试图使用相结合的SAXS和理论方法来定义存在于多结构域蛋白质的功能景观的结构合奏。这种方法超出了目前的模拟分析SAXS数据，包括本地和全球的折叠/展开的过渡，是重要的功能。 我们在开发这种方法的最初选择是酶Csk，因为它不仅是一个重要的治疗靶点，而且是我们在最佳酶促和折叠条件方面表征的系统。 越来越多的证据表明，结构合奏中的偏见可能在调节Csk中发挥重要作用。这里开发的方法是广泛适用于生物大分子，并将提供有用的信息，什么合奏的构象是一致的实验数据，以及无处不在的动态可逆折叠/组装过程中固有的生物学。