This proposal requests funds for an x-ray diffraction data collection system consisting of a high intensity rotating anode x-ray source with focusing mirrors, image plate detector, cryocooling accessory and computer to be used in biological macromolecule structure determination in a number of studies in our laboratories. This instrument will serve a community of macromolecule crystallographers and their collaborators, most of whom are housed in the Institute of Structural Biology and Drug Discovery of Virginia Commonwealth University. The structural studies to be carried out with this instrument are all coordinated with broad projects of basic, biomedical significance drawing on the skills of biochemists, molecular biologists and medicinal chemists as well as crystallographers. These studies include: enzymes of fatty acid biosynthesis and intermediary metabolism, which are targets for new drug discovery in such diseases as tuberculosis; enzymes of pyridoxal phosphate and folate metabolism that are potential targets for new cancer chemotherapeutic agents and cardiovascular treatment; development of anti-sickling agents for sickle cell hemoglobin; serpins and their complexes with heparin and other ligands, which play critical roles in fibrinolysis, thrombosis and Alzheimer's disease; RNA methylases, which are new potential drug targets in infectious diseases; and pathogenic bacterial transcriptional factors. The determination of macromolecule structures is an essential component of these projects and is carried out by a team of 6 experienced x-ray crystallographers. The instrument for which funds are requested will replace a 15 year old x-ray diffraction data collection system that has been in continuous and heavy use throughout that period and which is now suffering frequent failures with consequent delays in structure determination and disruptions of the research projects for which those structures are required. The instrument will be housed and maintained in the Institute of Structural Biology and Drug Discovery, to which Virginia Commonwealth University has made a long term commitment of provision of infrastructure and maintenance support.
