Structural Dynamics at LCLS

LCLS 结构动力学

• 批准号: 10379228
• 负责人: Sebastien Boutet
• 金额: $ 6.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379228
• 关键词: Active Sites; Adenine; Antibiotics; Area; Automobile Driving; Beds; Binding; Biochemical Reaction; Communities; Development; Emerging Technologies; Equilibrium; Goals; Life Cycle Stages; Light; Macromolecular Complexes; Membrane Proteins; Methodology; Methods; Molecular Conformation; Motivation; Neisseria gonorrhoeae; Process; RNA Polymerase II; Research; Research Personnel; Ribonucleotide Reductase; Roentgen Rays; Selection Criteria; Signal Transduction; Source; Specificity; Structure; Technology; Testing; Time; Training; United States National Institutes of Health; Variant; base; beta-Lactamase; cytochrome c oxidase; experimental study; improved; interest; macromolecule; metalloenzyme; method development; programs; technology development; temporal measurement; tool; willingness; x-ray free-electron laser

ABSTRACT: DRIVING BIOMEDICAL PROJECTS PORTFOLIO Nine Driving Biomedical Projects (DBP) are selected in this component of the proposed BTRR. These DBPs were selected based on high scientific merit as well as their need for X-ray methods to obtain structural and dynamic information that will reveal the detailed function of various biomolecules of interest. As such, they fulfil the primary purpose of providing scientific context and motivation for the technologies to be developed by the proposed BTRR. The DBPs will also provide necessary test beds for the developed technologies and create a virtuous cycle of iterative technology development that will lead to new broadly available capabilities for the biomedical community. The DBPs are organized along three themes. 1-Structure determination of large macromolecules and membrane proteins. 2-The determination of accurate active site structures of metalloenzymes, such as ribonucleotide reductase and cytochrome c oxidase, and complex macromolecular machines, such as RNA polymerase-II. 3-A common research area of all DBPs involve time-resolved (TR) studies that include research to follow dynamic processes involved in adenine riboswitch signaling, the transport mechanism of N. gonorrhoeae MtrF, antibiotic binding to β-lactamase and examination of interaction specificity of CypA variants. These DBPs will drive method developments in efficient structure determination using the Linac Coherent Light Source (LCLS). They will also drive the development of robust rapid mixing capabilities that will reveal antibiotic binding dynamics or enzymatic reactions with high spatial and temporal resolution, as well as new methods in light activated caged compound release and understanding conformational space dynamics in biomolecules using light to push them out of equilibrium. Overall, the proposed DBPs cover a breadth of scientific problems of high interest to the biomedical community and NIH and they represent a strong set of requirements that will push the BTRR technologies towards tools that will serve the biomedical community for the long term.

摘要：推动生物医学项目组合 在拟议的 BTRR 的这一部分中选择了九个驱动生物医学项目 (DBP)。 这些 DBP 的选择基于较高的科学价值以及对 X 射线方法的需求 获得结构和动态信息，揭示各种的详细功能 因此，它们实现了提供科学背景的主要目的。 DBP 还将提议 BTRR 开发技术的动机和动机。 为已开发的技术提供必要的测试平台，并形成迭代的良性循环 技术的发展将为生物医学带来新的广泛可用的能力 社区。 DBP 围绕三个主题进行组织：1-大分子的结构测定。 和膜蛋白2-准确的活性位点结构的测定。 金属酶，例如核糖核苷酸还原酶和细胞色素c氧化酶，以及复合物 大分子机器，例如RNA聚合酶-II。3-所有DBP的共同研究领域。 涉及时间分辨（TR）研究，其中包括跟踪涉及的动态过程的研究 腺嘌呤核糖开关信号传导、淋病奈瑟菌 MtrF 的转运机制、抗生素结合 β-内酰胺酶并检查 CypA 变体的相互作用特异性。 这些 DBP 将推动使用直线加速器进行有效结构测定的方法开发 它们还将推动稳健快速混合的发展。 能够揭示抗生素结合动力学或高空间酶促反应的能力 和时间分辨率，以及光激活笼状化合物释放和释放的新方法 利用光将生物分子推出来了解生物分子的构象空间动力学 平衡。 总体而言，拟议的 DBP 涵盖了人们高度感兴趣的广泛科学问题。 生物医学界和 NIH，它们代表了一系列强有力的要求，将推动 BTRR 技术致力于为生物医学界提供长期服务的工具。