The Joint Center for Structural Genomics (P.I. Ian A. Wilson; JCSG; www.jcsg.org) that pioneers new high throughput methodologies and technologies for protein production, structure determination and functional analysis in order to investigate the Expanding Protein Universe and the human gut microbiome and other high-value targets in the regulation of stem cells, T cells and nuclear receptors. The JCSG is a multi-institutional consortium based at The Scripps Research Institute, with major components the Genomics Institute of the Novartis Research Foundation, the University of California San Diego, the Sanford-Burnham Medical Research Institute, and the Stanford Synchrotron Radiation Lightsource (SSRL) at Stanford University. These Cores work in concert to develop new methodologies, determine the best strategies for processing diverse targets, efficiently operate as a PSI:Biology Center for High-Throughput Structure Determination.
Mission of the Joint Center for Structural Genomic
The JCSG high-throughput (HTP) platform, assembled over the past 15 years, has delivered a large numbers of protein structures to the community by both X-ray crystallography and NMR on a wide range of targets from bacteria to human, including challenging targets, such as eukaryotic proteins, protein-protein and other macromolecular complexes. Our primary approach to HTP structural biology involves processing sets of targets through an extensive combination of bioinformatics and biophysical analyses to efficiently characterize each target in order to optimize its path through our pipeline. Our primary mission as a PSI:Biology Center for High-Throughput Structure Determination is to provide a robust, flexible HTP structure determination pipeline that meets the challenges and embraces the opportunities that arise from PSI:Biology Partnerships projects and the community through (PSI Community Nominated Target) CNTs. The JCSG is leveraging its HTP platform to promote the biological and biomedical impact of all of our structures through extensive functional and bioinformatics analyses both internally and in collaboration with our Partnerships, CNTs and via other collaborations within the PSI:Biology network, as well as the general scientific community. Using a more focused approach, in close collaboration with our assigned Partnership Centers, we are tackling much more challenging targets, such as protein-protein and protein-nucleic acid complexes and capitalizing on our extensive experience to develop the best strategies to enhance chances of success. In parallel, we continue to process our internal biomedical and structure coverage targets in a HTP mode. These target sets are initially focused on the microbial communities that inhabit specific niches and environments of the human body. Interactions of commensal bacteria with the human body are profound and have a significant impact on maintenance of general human health, as well as being associated with disease. The human microbiota are dominated by poorly characterized bacterial phyla, which contain an unusually high number of uncharacterized proteins that so far remain largely unstudied. Thus, this biological theme project serves a dual purpose in also addressing coverage of novel sequence space as a component of the central PSI structural coverage theme. The influence of the microbiome upon human development, physiology, immunity, and nutrition is only starting to surface and, thus, represents an exciting new frontier for high throughput structural biology where we can investigate the contributions of these microorganisms to human health, as well as to disease. We are mainly focusing at present on the human gut microbiome. As part of the PSI:Biology Network, we strive to promote widespread use of PSI resources, materials, methodologies and data to the general scientific community. The JCSG also continues to develop new technologies and methodologies, both experimental and computational, to address a wide spectrum of targets, while keeping the cost per structure to a minimum and quality to the highest standard. We also continue to contribute to the original PSI mission of structural coverage of the expanding protein universe.
- Slabinski L, Jaroszewski L, Rodrigues AP, Rychlewski L, Wilson IA, Lesley SA, Godzik A. The challenge of protein structure determination – lessons from structural genomics. Protein Sci. 16: 2472-2482 (2007).
- Slabinski L, Jaroszewski L, Rychlewski L, Wilson IA, Lesley SA, Godzik A. XtalPred: a web server for prediction of protein crystallizability. Bioinformatics 23: 3403-3405 (2007).
- Soltis SM, Cohen AE, Deacon A, Eriksson T, González A, McPhillips S, Chui H, Dunten P, Hollenbeck M, Mathews I, Miller M, Moorhead P, Phizackerley RP, Smith C, Song J, van dem Bedem H, Ellis P, Kuhn P, McPhillips T, Sauter N, Sharp K, Tsyba I, Wolf G. New paradigm for macromolecular crystallography experiments at SSRL: automated crystal screening and remote data collection. Acta Crystallogr. D Biol. Crystallogr. 64: 1210-1221 (2008).
- Nair R, Liu J, Soong TT, Acton TB, Everett JK, Kouranov A, Fiser A, Godzik A, Jaroszewski L, Orengo C, Montelione GT, Rost B. Structural genomics is the largest contributor of novel structural leverage. J Struct. Funct. Genomics 10: 181-91 (2009).
- Jaroszewski L, Li Z, Krishna SS, Bakolitsa C, Wooley J, Deacon AM, Wilson IA, Godzik A. Exploration of uncharted regions of the protein universe. PLoS Biol. 7:e1000205 (2009).
- Zhang Y, Thiele I, Weekes D, Li Z, Jaroszewski L, Ginalski K, Deacon AM, Wooley J, Lesley SA, Wilson IA, Palsson B, Osterman A, Godzik A. Three-dimensional structural view of the central metabolic network of Thermotoga maritima. Science 325: 1544-1549 (2009). Koehn EM, Fleischmann T, Conrad JA, Palfey BA, Lesley SA, Mathews II, Kohen A. An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene. Nature 458: 919-923 (2009).
- Ellrott K, Zmasek CM, Weekes D, Sri Krishna S, Bakolitsa C, Godzik A, Wooley J. TOPSAN: a dynamic web database for structural genomics. Nucleic Acids Res. 39: D494-496 (2011).
- van den Bedem H, Wolf G, Xu Q, Deacon AM. Distributed structure determination at the JCSG. Acta Crystallogr. D Biol. Crystallogr. 67: 368-375 (2011).
- Xu, Q., Chiu, H. – J., Farr, C. L., Jaroszewski, L., Knuth, M. W., Miller, M. D., et al. (2014). Structures of a Bifunctional Cell Wall Hydrolase CwlT Containing a Novel Bacterial Lysozyme and an NlpC/P60 dl-Endopeptidase. J Mol Biol, 426(1), 169–184.
- Das, D., Herve, M., Elsliger, M. – A., Kadam, R. U., Grant, J., Chiu, H. – J., et al. (2013). Structure and function of a novel LD-carboxypeptidase A involved in peptidoglycan recycling. J Bacteriol, .
- Das, D., Lee, W. – S., Grant, J. C., Chiu, H. – J., Farr, C. L., Vance, J., et al. (2013). Structure and function of the DUF2233 domain in bacteria and in the human mannose 6-phosphate uncovering enzyme. J Biol Chem, 288(23), 16789–16799.