Synergy-R Diffractometer for Southeastern Wisconsin - Abstract We request funds to purchase a new single-crystal X-ray diffractometer (scXRD) equipped with a Cu-anode rotating source, VariMaxHF computer-controlled optics and a hybrid photon counting detector. This equipment will be installed in the Department of Biochemistry at the Medical College of Wisconsin (MCW) as a shared resource. The department has a long history of supporting macromolecular crystallography dating back to 1992. The requested equipment will replace an outdated 18-year-old diffractometer that has been a workhorse for the collection of macromolecular X-ray diffraction data by numerous NIH-funded investigators. Structural biology has long been a cornerstone for a diverse group of NIH-funded researchers at MCW and in southeastern Wisconsin. This is demonstrated by the continued support of the Biomolecular NMR Facility (Est. 2000), the formation of the Program in Chemical Biology (PCB) in 2017, and the acquisition of a Thermo Glacios cryo-EM installing on MCW’s campus in 2023. The continued expansion of drug discovery on campus has recently benefited from over a $5M investment in infrastructure and the commitment to hire 2 to 3 tenure- track faculty into the PCB. Additionally, the Department of Biochemistry has hired two structural biologists within the past four years. Consistent with a 30-year track record of supporting scXRD systems, MCW has committed space to house the requested system, funds for service contracts/consumables, and salary support for technical staff to ensure training of the users. We describe projects for six major users with NIH-funding and ten minor users (seven with NIH-funding). These user projects aim to understand a wide range of human diseases: cancer, psychiatric disorders such as Parkinson’s, ischemia, viral infectivity by cytomegalovirus and coronavirus, obesity, and non-alcoholic fatty-acid liver disease. Many of these projects involve developing small molecules for future therapeutics. The proteins are as diverse (soluble, transmembrane, integral membrane) as their functions and require an scXRD capable of handling this diversity. The requested system from Rigaku has the versatility to handle these projects. These researchers will rely on its increased sensitivity and the ability to collect data directly from crystallization trays. Our user group will also benefit from this instrument's ability to determine the absolute configuration of small molecules, a capability lacking in the local community. When installed, the requested diffractometer will be the only one in Wisconsin and one of less than five installed at academic institutions in the United States. A staff with more than 18 years of experience in X- ray crystallography and 10 years of experience operating and maintaining scXRD instrumentation will oversee the new system. Users will be trained in the operation of this system, and instrument time will be allocated using a web-based scheduling system. An advisory committee will provide oversight of operations and conflict resolution. Acquisition of the scXRD system requested in this S10 application will significantly accelerate NIH- funded biomedical research programs at MCW and other institutions in the region.
