(Taken from the Application): This proposal is a joint application from the Argonne National Laboratory (ANL), Northwestern University (NWU), the University of Toronto, Washington University, University College London (UCL), the University of Virginia (UVA), and the University of Texas to establish the Midwest Center for Structural Genomics. The research program will develop and implement integrated robotic and automated technologies that will allow rapid, large-scale determination of new protein structures using x-ray crystallography, third-generation synchrotrons, and advanced software and computing facilities. It is expected that these new, high-throughput methods will reduce the time typically invested in solving new protein structures from months to days. The DNA sequences of known complete genomes (prokaryotic, archaeal, and eukaryotic) will be used to identify protein genes and cluster them into homologous families. Protein families with no confident homology to other proteins of known structure will be selected for experimental studies to determine the 3D structure of a family member. Some of these studies may reveal a new protein fold; in all cases, new sequence-fold relationships will be established and will improve future homology modeling efforts. The selection of targets will be biased toward proteins from pathogenic organisms that are relevant to human health. An expected consequence of this analysis will be the identification of a set of core protein structural motifs that can be used to ascertain, by homology, the structures of other proteins. The long-term goal is to correlate these folding units to their primary amino acid sequences in a database, enabling virtually all protein structures to be derived by genome sequence analysis and 3D modeling. First, there must be significant improvement of the cost-effectiveness of the methods used to (a) generate pure proteins for structural analysis, and (b) obtain and process crystallographic data to render accurate models that are useful for further studies. The Midwest Center for Structural Genomics will develop high-throughput methods that emphasize the use of robotics and automation to analyze genomes, clone selected genes, and overexpress, purify, and crystallize proteins. By using highly efficient undulator beamlines at the Advanced Photon Source (APS), anomalous diffraction data will be collected from protein crystals. Approaches will be developed to improve the anomalous data collection strategies and data analysis. Advanced crystallographic software and high-throughput crystallographic methods will be applied to solve and refine protein crystal structures. There will be interactions with other structural genomic centers and research activities will be coordinated with them. All approaches, methods, data, and results developed in the course of this study will be readily available to the scientific community.
Showing the most recent 10 out of 140 publications
