Structural biology core

结构生物学核心

• 批准号: 10512622
• 负责人: DAVID A. AGARD
• 金额: $ 566.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512622
• 关键词: 2019-nCoV; Affinity; Algorithmic Analysis; Artificial Intelligence; Automobile Driving; Binding Proteins; Biological Process; Biology; COVID-19 pandemic; Cells; Classification; Collaborations; Collection; Complex; Cryo-electron tomography; Cryoelectron Microscopy; Crystallization; Crystallography; Data; Data Collection; Databases; Defect; Development; Docking; Drops; Drug Design; Drug Screening; Ensure; Essential Drugs; Generations; Goals; Grant; High Performance Computing; Image; In Situ; Laboratories; Lead; Lipids; Mass Spectrum Analysis; Membrane Proteins; Microscope; Modeling; Molecular; Molecular Conformation; Molecular Structure; Nucleoproteins; Oxides; Pharmacologic Substance; Phase; Play; Process; Proteins; Proteomics; Publications; RNA Viruses; Rapid screening; Reagent; Recording of previous events; Research Personnel; Resolution; Robot; Robotics; Roentgen Rays; Role; Sampling; Science; Services; Source; Structure; Surface; Techniques; Technology; Therapeutic; Time; Viral; Viral Proteins; Virus Assembly; Virus-like particle; Visualization; Western Blotting; Work; X-Ray Crystallography; base; beamline; cluster computing; denoising; design; detector; drug development; drug discovery; drug mechanism; experience; experimental study; field emission gun; graphene; high throughput screening; imaging detector; inhibitor; insight; large datasets; meetings; nanolitre; nanometer resolution; new technology; novel; novel therapeutics; pandemic disease; particle; programs; protein complex; protein structure; relating to nervous system; response; screening; small molecule; structural biology; therapeutic development; urinary gonadotropin fragment

CORE 4: SRUCTURAL BIOLOGY SUMMARY Structural biology plays a key role in elucidating molecular mechanisms of biological processes and in therapeutic development. De novo structure elucidation can delineate novel interaction interfaces guiding fundamentally new drug screening campaigns. Molecular structures can be used as targets for computational docking to obtain novel chemotypes that can then be optimized to become potent inhibitors. Visualizing protein structures bound to inhibitor hits or leads at a high resolution is invaluable for the chemists rationally optimizing compounds based on the protein binding pocket. The central role of structural biology in developing therapeutics is underlined by the fact that it is involved in three stages of the QCRG Drug Discovery Platform and every Project. The goal of the Structural Biology Core is to provide cutting-edge X-ray crystallography and cryo- electron microscopy (Cryo-EM) services to the Projects. Core Investigators have a track record of technological development in both X-ray and Cryo-EM fields and a history of very effectively working together. A testament to this is that at the start of the COVID-19 pandemic, we formed the QCRG Structural Biology Consortium (QCRG SBC), which in the span of a year yielded five structure-based publications on SARS-CoV-2. This experience allowed for fine tuning the practical aspects of working together like sharing common facilities, having regular project focused meetings and online spaces for continued project discussions, databases for reagents and project progress, etc. Therefore, the Structural Biology Core will present a seamless one stop solution for the structural biology needs of this proposal. Specifically, in Aim 1, we will provide support on X-ray crystallography based structural studies for proteins that express in suitable quantities. Crystallography will be especially important for visualizing hit and lead compounds bound to their targets at the highest possible resolutions to drive structure-based drug design. Our robotized high-throughput screening facilities allow for setting up and inspecting tens of thousands of nanoliter sized crystal drops (including membrane proteins), enabling rapid condition screening. We share beamline 8.3.1 at Lawrence Berkeley National Laboratory (LBNL) with regular time slots available for data collection, allowing for regular and easy access to a high flux X-ray source. In Aim 2, we will leverage our state-of-the-art facilities to enable Cryo-EM studies of viral proteins and complexes. We have fully staffed facilities with five Field Emission Gun (FEG) microscopes equipped with the latest direct detector cameras and access to high performance computing clusters and GPU workstations for processing. For Cryo-EM studies, we will leverage our recent advances in grid technology, denoising and incorporation of artificial intelligence (AI) predicted protein structures, to resolve previously unseen viral protein interactions. In addition, we have set up the UCSF Center for Cellular Structural Analysis enabling high-resolution in situ cryo-EM tomographic studies of virus-like particles. Overall, the Structural Biology Core will provide atomic resolution insights to the proposal at all scales and resolutions, driving therapeutic development at all stages of the Project.

核心4：外科生物学 总结 结构生物学在阐明生物学过程的分子机制和 治疗发展从头结构解析可以描绘新的相互作用界面， 从根本上说是新的药物筛选活动。分子结构可以用作计算的目标。 对接，以获得新的化学型，然后可以优化成为有效的抑制剂。可视化蛋白质 以高分辨率与抑制剂命中物或先导物结合的结构对于化学家合理优化 基于蛋白质结合口袋的化合物。结构生物学在开发治疗方法中的核心作用 它参与了QCRG药物发现平台的三个阶段， 项目结构生物学核心的目标是提供尖端的X射线晶体学和低温， 电子显微镜（Cryo-EM）服务。核心调查人员有技术跟踪记录， 在X射线和冷冻EM领域的发展和非常有效地合作的历史。证明了 这就是在COVID-19大流行开始时，我们成立了QCRG结构生物学联盟（QCRG SBC），在一年的时间里产生了五篇关于SARS-CoV-2的基于结构的出版物。这段经历 允许对合作的实际方面进行微调，如共享公共设施，定期 以项目为重点的会议和在线空间，用于继续项目讨论，试剂数据库， 项目进展等。因此，结构生物学核心将提出一个无缝一站式解决方案， 生物学的需要。具体来说，在目标1中，我们将提供X射线晶体学方面的支持 基于蛋白质的结构研究，以适当的数量表达。晶体学将特别 重要的是可视化命中和铅化合物结合到他们的目标在尽可能高的分辨率， 驱动基于结构的药物设计。我们的自动化高通量筛选设施允许设置和 检测数万纳升大小的晶体液滴（包括膜蛋白）， 条件筛选我们在劳伦斯伯克利国家实验室（LBNL）与常规的 数据收集的时间段，允许定期和方便地访问高通量X射线源。在Aim中 2.我们将利用我们最先进的设施，对病毒蛋白和复合物进行Cryo-EM研究。我们 拥有配备齐全的设施，拥有五台场发射枪（FEG）显微镜，配备最新的直接 探测器摄像头和访问高性能计算集群和GPU工作站进行处理。为 Cryo-EM研究，我们将利用我们最近在网格技术，去噪和人工 人工智能（AI）预测蛋白质结构，以解决以前看不见的病毒蛋白质相互作用。此外，本发明还提供了一种方法， 我们建立了加州大学旧金山分校细胞结构分析中心， 病毒样颗粒的断层扫描研究。总体而言，结构生物学核心将提供原子分辨率 对所有规模和分辨率的提案的见解，推动项目各个阶段的治疗开发。