The parent P41 Center grant (5 P41 RR001209, A Synchrotron Radiation Structural Biology Resource, K.O. Hodgson, P.l.) has as its overall aim to develop new and enhanced approaches for the investigation of biomolecular structure and function using synchrotron radiation at Stanford Synchrotron Radiation Lightsource (SSRL). One of the Center's three methodologies and technical research and development (TR&D) areas is macromolecular crystallography. Since the submission of the competitive renewal in May, 2009, a revolutionary new x-ray light source has become available that could well have a transformative impact in macromolecular crystallography (and other areas of structural biology). This light source, an x-ray free electron laser named LCLS, located at the SLAC National Accelerator Laboratory (and in close proximity to SSRL) is now in full operation. Several key proof-of-principle experiments have been carried out and published, demonstrating the feasibility of obtaining high quality, potentially radiation damage free diffraction data from nanocrystals. Data on such samples cannot be obtained from any other source. There are several key technical R&D areas, which need to be addressed, and problems that need to be solved, for this innovative new approach to be successful and applicable to important biomedical problems and made widely available to the biomedical research community. Three TR&D areas are the focus of this Revision Application, in response to the NIH FOA PAR-12-046. The P41 Center, in close partnership with the LCLS scientific team and with the Physical Biosciences Division at Lawrence Berkeley National Laboratory (LBNL) will build upon existing core capabilities, augmented with proposed staff and instrumentation, to address nanocrystal growth, characterization and manipulation, data reduction and analysis, and structure solution, to provide an integrated capability for nanocrystallography using the LCLS. Also key is significant integration with specific facilities and beam lines at SSRL for technology development and characterization. The TR&D projects will be driven strongly by research collaborations (Driving Biomedical Projects).
As with the parent grant and Center, relevance is to a number of important biological problems including membrane-bound proteins such as G-coupled receptors;the structure of metalloproteins involved in metabolism;and how these structures change in different states or evolve in time. Such information is more broadly important to the health-related areas of drug discovery, cancer research, and cell development.
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