Structural biology core

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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.