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：术生物学 概括 结构生物学在阐明生物过程的分子机制以及在 治疗发展。从头结构阐明可以描绘出新的相互作用界面引导 从根本上讲，新的药物筛查运动。分子结构可以用作计算的目标 对接获得新的化学型，然后可以优化成为有效抑制剂。可视化蛋白质 与抑制剂击中或高分辨率结合的结构对于化学家合理优化是宝贵的 基于蛋白质结合袋的化合物。结构生物学在开发治疗学中的核心作用 它是由QCRG药物发现平台的三个阶段和每个阶段所涉及的事实所强调的。 项目。结构生物学核心的目的是提供尖端的X射线晶体学和冷冻 - 电子显微镜（Cryo-EM）服务。核心调查人员有技术的记录 X射线和冷冻EM领域的发展以及非常有效合作的历史。证明 这是在COVID-19大流行病开始时，我们组成了QCRG结构生物学联盟（QCRG SBC），在一年的时间里，它在SARS-COV-2上产生了五个基于结构的出版物。这个经历 可以微调共同努力的实际方面，例如共享共同的设施，定期 以项目为中心的会议和在线空间进行持续的项目讨论，试剂数据库和 因此，项目进度等。因此，结构生物学核心将为 该建议的结构生物学需求。具体而言，在AIM 1中，我们将为X射线晶体学提供支持 基于适当量表达的蛋白质的基于结构研究。晶体学尤其是 对于以最高的分辨率绑定到目标的命中和铅化合物至关重要 基于驱动结构的药物设计。我们的机器人高通量筛选设施允许设置和 检查成千上万的纳米尺寸晶体滴（包括膜蛋白），使能够快速 条件筛查。我们在劳伦斯·伯克利国家实验室（LBNL）与梁线8.3.1共享 可用于数据收集的时间插槽，可定期且轻松访问高通量X射线源。目标 2，我们将利用我们的最先进的设施来实现对病毒蛋白和复合物的冷冻EM研究。我们 配备了配备最新直接的五个现场排放枪（FEG）显微镜 检测器摄像机并访问高性能计算簇和GPU工作站进行处理。为了 冷冻EM研究，我们将利用我们最近在网格技术上的进展 智力（AI）预测蛋白质结构，以解决以前看不见的病毒蛋白相互作用。此外， 我们已经建立了UCSF的细胞结构分析中心，实现了高分辨率原位冷冻EM 病毒样颗粒的层析成像研究。总体而言，结构生物学核心将提供原子分辨率 在各个规模和决议方面对该提案的见解，在项目的各个阶段推动治疗性开发。