The Center for Structural Biology at the University of Michigan (CSB) is developing a state-of-the-art regional X- ray facility for the state of Michigan and are requesting funds to purchase a single crystal X-ray diffraction system with cutting edge technology in both X-ray production and photon detection to be the cornerstone of this new facility. This system will pair the MetalJet D2+ microfocus X-ray source which produces the hottest beam outside a synchrotron with the latest hybrid photon counting detector, Eiger2 R 4M. The VariMax-VHF Ga confocal optics will focus the beam to conform to our smallest crystal size and a Cryostream 800 will keep the crystals cool. At this time, there are no functioning macromolecular X-ray diffraction systems operating at any of the major academic institutions in the state of Michigan or Northwest Ohio. Eleven of the 12 macromolecular crystallography groups at the University of Michigan along with those at Wayne State University, Michigan State University and Grand Valley State University have frequent access to synchrotron radiation through the Life Science Collaborative Access Team, which currently operates three insertion device beamlines in Sector 21 in the Advanced Photon Source (APS) at the Argonne National Laboratory. The other U-M crystallography group has continuous access to the General Medical Sciences and National Cancer Institute Structural Biology Facility, which operates two insertion device beamlines at APS. Starting in 2022, APS will shut down for over 18 months for a major upgrade. During this downtime, our research that depends on macromolecular crystallography (membrane protein structure determination, cryo-EM, protein design, structure-based drug design and a variety of basic science research projects) will suffer greatly without an in-house high flux X-ray source. The majority of the NIH funded research involving X-ray crystallography at U-M involves the development of new therapeutics to treat cancer, cardiovascular disease, obesity, macular degeneration, neuropathies, HIV and chronic kidney disease as well as the development of new antibiotics and antivirals. To run a successful drug development program, of which U-M is a leader having contributed to the development of the most FDA approved drugs of any University in the US, constant access to high flux X-rays is required to solve the structures of targets bound to new iterations of drug-like molecules to ensure proper target engagement during the designing phase. The proposed X-ray system will produce a flux density of 1011, which is on the same order of magnitude of X-rays produced from a bending magnet line at APS. Coupled with shutterless data collection, small sample focal point (80 um) and the ability to tune the divergence of the beam to accommodate large cell axes, the proposed system will afford data collection on small (50-70 um)3 weakly diffracting crystals with unit cell axes > 200 . Based on the survey filled out by the crystallography groups, this configuration will accommodate >75% of the crystallography projects ensuring continuity in our research.
X-ray crystallography is a technique that offers the research community 3-D snapshots of biologically relevant macromolecules and their complexes at atomic resolution. By studying the form and interactions of these molecules, their cellular functions can be determined, which is vital for identifying the basis and progression of diseases, such as cancer, HIV, macular degeneration and cardiovascular and gastrointestinal diseases. Using the structural information gained from X-ray crystallography, new therapeutics can be developed to treat these diseases.
