(Taken from the Application): Structural genomics has the potential to impact modern biology profoundly by building on the foundation laid by the genome projects. However, no proof of concept for such a systematic approach to high throughput 3-D structural determination has yet been demonstrated. The Joint Center for Structural Genomics (JCSG) has been formed to promote methodological, technological and computational advances for the rapid, efficient, and cost effective determination of novel protein structures. The JCSG will be managed by a consortium of three primary institutions, The Scripps Research Institute (TSRI), the University of California at San Diego (UCSD) and Stanford Synchrotron Research Laboratory (SSRL), with key collaborations that include the San Diego Supercomputer Center; Salk Institute; the Genomics Institute of the Novartis Research Foundation (GNF); the University of California, Irvine; the California Institute of Technology; the Advanced Light Source (ALS); and Stanford University. In addition, numerous other individual investigators and groups will participate in the Center. The main aims of the JCSG are to develop and integrate high-throughput robotic technologies for target selection, protein expression, crystal production and structure determination. The goal is to automate all of these processes so that the NIH target of 10,000 new structures (approximately 2,000 per center) is in reach within five years. To achieve these objectives, three cores have been established - Bioinformatics, Crystallomics, and Structure Determination. Analysis of both successes and failures at each experimental step will enhance the learning process for optimization of the entire system. The initial focus will be on the C. elegans genome in order to provide a suitable number of targets to optimize each component of the system. Sequences that are likely to have novel folds and that are implicated in cell signaling will be selected. The successful structure determinations will advance understanding of structure-function relationships and structure families and provide essential feedback for refinement of the target selection process. Movement to Drosophila, mouse, and human genomes will be rapid as their entire sequences become available. The proposal builds on the substantial foundation already laid in high-throughput protein expression, purification, crystallization and crystal image collection and analysis. The investigators expect to build upon their individual successes by combining their substantial expertise in bioinformatics, macromolecular crystallography and synchrotron radiation. They expect to refine the essential tools and develop new ones when bottlenecks are uncovered. Such progress is essential for the successful operation of a second generation Structural Genomics Center that can exploit the tremendous opportunities in structural biology and medicine that arise from the human and other genome projects.
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