The Midwest Center for Structural Genomics (MCSG) was established in 2000 as a part of the Protein Structure Initiative (PSI) and for the past decade has collaborated with the biological community and developed enabling technology to address problems related to microbial pathogenesis, microbial metabolism, microbe-host interactions, and human disease. The MCSG is multi-disciplinary and multi-institutional organization with a broad scientific network, and as such has been able to initiate and participate in effective interactions with the community. In the PSI:Biology, we continue to maintain our collaborative focus, while operating and improving our high-throughput pipeline.
The primary objective of the MCSG is to apply its structure determination pipeline to collaboratively determine the structures of targets nominated by the PSI:Biology Network and the broader biology community. The MCSG will devote a smaller fraction of its effort to contribute, together with its PSI colleagues, to a broader coverage of protein fold space by targeting proteins whose structures would provide the greatest insight into the relationships between protein sequence and structure. The MCSG will continue to drive three scientific programs to study: proteins associated with virulence in human pathogens, proteins overrepresented and associated with disease in human microbiomes and proteins involved in signaling and transcription regulation - areas that we are pursuing in collaboration with the scientific community.
Our long-term goals are to provide high-quality structural models for a significant number of biomedically and biologically important proteins and protein families, to improve the structure determination pipeline so that it can also be applied to challenging proteins and protein complexes, and to develop advanced protein production methods for these protein families. As part of its mandate, the MCSG will also continue to develop and improve technology, and to refine rapid, highly integrated, and cost-effective methods for de novo structure determination by X-ray crystallography using high-efficiency beamlines at third-generation synchrotron sources. Our ultimate goal is to build, together with our PSI colleagues and structural biology community, a foundation for 21st century structural biology where the structures of virtually any protein or protein complex is available to the biology community through the Protein Data Bank (PDB).
The MCSG consortium is organized around seven highly integrated Core-Technology Units: Bioinformatics, Gene Cloning and Protein Expression, Eukaryotic and Viral Proteins Expression, Purification and Crystallization, Data Collection and Analysis, Structure Determination and Databases and LIMS. Members come from: the Argonne National Laboratory (ANL), European Bioinformatics Institute (EBI), Northwestern University (NU), University of Toronto (UT), University College London (UCL), University of Virginia (UVA), and University of Texas Southwestern Medical Center (UT-SWMC).
The MCSG objectives are addressed by the following specific aims:
- Structure determination: Operate the high-throughput pipeline starting from gene to structure that was developed in PSI and determine the high-quality structures of proteins nominated by scientific community by X-ray crystallography using synchrotron radiation. Conduct structure determination on proteins selected as part of the coordinated PSI:Biology network and those proteins within the MCSG biomedical themes to achieve coarse sequence coverage of unique protein families of biomedical interest.
- Collaborative research: Conduct collaborative research on protein targets proposed by the PSI:Biology network and to contribute to the expanding PSI:Biology research portfolio. Enable collaborative research by providing research facilities for community-nominated projects, by hosting visiting scientists and by developing informatics gateways to facilitate collaborations with the biology community.
- Development of structural biology technologies: Continue development of high-throughput technologies in protein expression, purification and crystallization to tackle all classes of proteins and protein complexes proposed by the PSI:Biology network.
- Development of structure determination technologies: Continue development of high-throughput technologies for semi-automated structure determination using synchrotron radiation that includes real-time structure solution, automated model building, accelerated structure refinement, rapid model validation, and deposition into the PDB.
- Development of bioinformatics tools: Develop and apply advanced sequence- and structure-based bioinformatics tools to annotate solved structures; to create high-quality models based on solved structures; to prioritize potential protein targets from single genomes or a collection of genomes (metagenomes); and to apply data mining techniques to advance the pipeline
- Data dissemination: Disseminate the information through peer-reviewed publications and the PSI-Knowledgebase (PSI:KB), and disseminate the materials via the PSI-Materials Repository (PSI MR).