Structural biology core

核心4：结构生物学 摘要 结构生物学在阐明生物过程的分子机制方面发挥着关键作用。 治疗方面的发展。从头结构解析可以描绘出新的相互作用界面 全新的药物筛选活动。分子结构可以作为计算的靶标 对接，以获得新的化学类型，然后可以优化成为有效的抑制剂。将蛋白质可视化 在高分辨率下与缓蚀剂结合的结构对于化学家合理优化是非常宝贵的。 基于蛋白质结合口袋的化合物。结构生物学在发展治疗学中的核心作用 突出表现在它参与了QCRG药物发现平台的三个阶段，并且每个阶段 项目。结构生物学核心的目标是提供尖端的X射线结晶学和冷冻- 电子显微镜(Cryo-EM)为这些项目提供服务。核心调查人员在技术方面有良好的记录 在X射线和低温电磁领域的发展，以及非常有效地合作的历史。对…的证明 这是在新冠肺炎大流行开始的时候，我们成立了QCRG结构生物学联盟(QCRG (SBC)，在一年的时间里，它制作了五份关于SARS-CoV-2的结构化出版物。这段经历 允许微调合作的实际方面，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、试剂数据库和 因此，结构生物学核心将提供无缝的一站式解决方案 结构生物学需要这一提议。具体地说，在目标1中，我们将提供X射线结晶学方面的支持 以适量表达的蛋白质为基础的结构研究。结晶学将特别 对于可视化以尽可能高的分辨率绑定到其目标的命中和引导化合物非常重要 推动以结构为基础的药物设计。我们的自动化高通量筛查设施允许设置和 检测数万纳升大小的晶滴(包括膜蛋白)，使快速 条件筛查。我们在劳伦斯伯克利国家实验室(LBNL)与Regular共享光束线8.3.1 可用于数据收集的时隙，允许定期、轻松地访问高通量X射线源。在AIM 2，我们将利用我们最先进的设施来实现对病毒蛋白质和复合体的冷冻-EM研究。我们 设施配备齐全，配备5台场发射枪(FEG)显微镜，配备最新的DIRECT 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 低温电磁研究，我们将利用我们在网格技术、去噪和融合人工智能方面的最新进展 智能(AI)预测蛋白质结构，以解决以前未见过的病毒蛋白质相互作用。此外, 我们已经建立了加州大学旧金山分校的细胞结构分析中心，实现了高分辨率的原位冷冻-EM 病毒样颗粒的断层扫描研究。总的来说，结构生物学核心将提供原子分辨率 在所有规模和决议下对该提案的见解，推动项目所有阶段的治疗发展。

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.