Ttie Structural Biology Shared Resource brings togethier Crystallograpfiy, NMR, and Protein Production & Analysis into a single facility, with Dr. Liddington as its Scientific Director and two Facility Directors/Managers who oversee day-to-day operations. This merger has brought the two complementary techniques for determining 3-dimensional structures of biological macromolecules at atomic resolution together with facilities for the large-scale production and biophysical characterization of proteins, technologies that are not available in individual Cancer Center laboratories owing to their expense and complexity. These developments have created a seamless Resource that is transforming the ability of scientists with little prior experience in structural biology to incorporate structural and structure-function studies as well as chemical biology into their research programs. The expanded facility has served the needs of more than 40 Cancer Center investigators over the last few years. The Institute has provided major equipment upgrades in crystallography, including a high brilliance generator fully equipped for data collection on two ports, together with a crystallization robot and storage/imaging 'hotels'; a new cryoprobe for the 600 MHz NMR instrument and a new 'walk-up' 400 MHz instrument optimized for rapidly tuning to different nuclei and high-throughput sample-changing; and a complete laboratory suite for large-scale protein expression and purification in bacterial, insect and mammalian cells, together with state-of-the-art instrumentation for biophysical analysis, including an Analytical Ultracentrifuge, Differential Scanning and Isothermal Titration Calorimetry and stopped-flow fluorescence spectrometer for measurement of molecular size, shape, folded integrity, and thermodynamic and kinetic binding constants. The Resource directly supported Cancer Center investigator's work in the past funding period that led to the publication of at least 83 peer-reviewed papers, including 5 in Nature, Cell or Science, as well as more than 40 review articles on various aspects of structural biology and structure-function studies. Future priorities include the full integration of the crystallization robot facility into drug discovery efforts; additional instrumentation to measure binding kinetics of protein-small molecule interactions, and to measure mechanical forces within and between molecules and their interplay with chemical forces in processes such as cell migration; and further upgrades in eukaryotic protein expression and purification systems. Overall, $139,456 in CCSG support is requested in the first year, representing 12% of the total projected Structural Biology operating budget.
Structural biology plays a central and critical role in many aspects of cancer research, from understanding the molecular bases of normal and aberrant cell behavior to the discovery and refinement of new inhibitors and probes. The Structural Biology Shared Resource provides expertise, training and sophisticated instrumentation that is well beyond the scope of individual laboratories but critical to their science.
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