MOLECULAR ANALYSIS / TRANSLATION GROUP STRUCTURAL BIOLOGY SHARED FACILITY (SBSF) ABSTRACT The Structural Biology Shared Facility (SBSF) provides CCC members access to critical biophysical facilities including: 1) X-ray crystallographic data collection (via in-house x-ray systems and dedicated access to two synchrotron beam lines via membership in the Southeastern Collaborative Access Team (SERCAT) at the Argonne Synchrotron Facility; 2) high-throughput nano-crystallization services for aqueous and membrane proteins, 3) Nuclear Magnetic Resonance (NMR) instrumentation ranging from 850 MHz to 300 MHz and 4) biophysical measurements including high-throughput differential scanning and isothermal micro-calorimeters. In addition to providing access to the state-of-the-art instrumentation, the SBSF supports the Cancer Center members through service and consultation over a wide array of structural biology projects ranging from: 1) structural determination of proteins, protein-protein and protein-ligand complexes of interest in different cancers; 2) structure-based virtual screening of compound libraries; 3) drug discovery research in general including structure-based chemical syntheses; 4) fragment-based design of new inhibitors; 5) screening of compound libraries by NMR and crystallography; 6) applications of NMR-metabolomics in cancer research, and on membrane proteins as drug targets. The SBSF works closely with the Alabama Drug Discovery Alliance (ADDA) to support the research efforts of the CCC members developing novel drugs to treat multiple forms of cancer. During the past funding period the facility was used to support fundamental and translational research for 105 users, 78 of which are CCC members with NIH funding exceeding $60 million. SBSF usage resulted in more than 50 different novel protein structures published in a variety of journals including Science, PNAS, Biochemistry, JBC, JMB, Cell Biology, Molecular Pharmacology, Trends in Biotechnology, Acta-D, Acta-F and Structure. Examples of value added via the shared facility include: a) determination of more than 20 x-ray structures of the retinoid X receptor, RXR, a protein implicated in breast cancer and cutaneous T-cell lymphoma. A clinical drug candidate is currently in human phase 1b trials at NCI; b) Identification of novel Src kinase inhibitors (initial hits) that target the Src/calmodulin interaction and exhibit anti-pancreatic cancer activity. This project is utilizing both NMR and x-ray crystallographic techniques in developing new inhibitors from these initial hits; c) x-ray structure information was produced for several inhibitors bound to the drug- binding pocket of P-glycoprotein, one of the multi-drug resistance transporters that often become over-active in cancer cells causing resistance to chemotherapy.
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