Electron cryo-microscopy (cryo-EM), especially single-particle cryo-EM, has experienced tremendous successes in pushing achievable resolution and biological impact. We can now determine atomic resolution structures of a broad range of biomolecules without crystals?from as large as viruses with icosahedral symmetry, to ribosomal particles without symmetry, to integral membrane proteins as small as ion channels?and the technological limits of detection and resolution are still improving. UCSF has made a remarkable number of contributions to cryo- EM technological breakthroughs. Our successes helped generate an unprecedented revolution in structural biology and a flourishing of insights into long-intractable biological questions. Now it is imperative for us to increase access for the entire research community, especially for UC biochemists and structural biologists who are prepared to make full use of the technology for their NIH funded projects. Unfortunately, we are scheduled to lose one of our most useful instruments, the TF30 Polara, which is no longer under service contract and which we anticipate decommissioning 2019 or possibly in 2020. We have analyzed our microscope user workflows and determined that the best replacement for the Polara is a microscope capable of screening cryogenic samples for high-resolution quality and of reaching atomic-resolution for single particle samples. Acquiring such a microscope will improve overall throughout for UCSF scientists and will maximize the impactful use of our highest-resolution and most in-demand instruments, including those equipped with specialized equipment like the Volta phase plate or the BioQuantum energy filter. We, therefore, propose to acquire a high performance and automated electron cryo-microscope system for efficient sample screening for the most substantial number of possible users. Adding such an instrument to the UCSF Center for Advanced CryoEM will enable us to spread the advantages of recent UCSF technological breakthroughs, including the advent of improved motion correction algorithms and expanded surface area and faster direct electron detectors, to study challenging biological macromolecules.
Structural biology has a long track record of illuminating the mechanisms governing life, including pathogenic mechanisms that lead to disease and the restorative activities of therapeutic small molecules. Recent technological breakthroughs, contributed by laboratories at the University of California, San Francisco, transformed electron cryo-microscopy (cryo-EM) for high-resolution structure determination. As hoped, success has led to unprecedented demand?the user community has grown by more than a factor of four?for access to the technology. This application proposes to advance at least 32 NIH-funded research programs by replacing a critical and now failing high-performance electron cryo-microscope system with a new one that is optimal for efficient sample screening and for capable of atomic-resolution single particle imaging.