This proposal requests support for the acquisition of a state-of-the-art 100 kV screening cryo-EM instrument. This instrument will be housed in a geographically central location at the University of Connecticut Health Center (UCHC) in Farmington, CT, thereby ensuring facile access for all participating research groups. The cryo-EM will be integrated into the established UCHC EM facility, which has a proven tradition of research excellence for over 30 years. The UCHC EM facility is operated by a full-time manager and an assistant director, supported by UCHC. As typical for shared instrumentation, this instrument will be available not only to the core research groups, but also to others throughout New England that will benefit from it. This proposal combines researchers from 3 universities, with a total of 18 research groups forming the core user group. Research areas include virology, signal-transduction, immunobiology, DNA repair among many others, with key implications for a broad variety of diseases. The proposed research projects are well supported with exciting preliminary data. Many of the 18 core research groups have gained extensive cryo-EM experience over the last years and have a strong external funding portfolio. While access to high powered cryo-EM instruments is available, the access to affordable, easy-to-use screening cryo-EM’s that allow for the careful optimization of samples for structure determination are either non-existent or expensive and thus out of reach for many research groups. The requested Tundra 100 kV cryo-EM will solve this limitation, and enable rapid, cost-effective and easy access for the investigation of large, highly complex biological systems. Furthermore, it will enhance the training capabilities of students and post-doctoral research scientists for cryo-EM. In summary, the so-called ‘resolution-revolution’ has highlighted the capabilities of novel cryo-EM instruments for the structure determination of critical biological samples to answer fundamental biological questions. However, as for all structural biology techniques, sample optimization is the key essential step for gaining these new insights. The requested instrument will fill this gap for a significant number of researchers throughout New England. Further, significant institutional investments will guarantee the long-term success and will allow key biological functions to be determined. We are confident that this cryo-EM instrument will not only provide a necessary nucleus for the research of the core participating laboratories specifically but will also provide a long-lasting impact for New England, as well as the US research community, generally.