Joint Center for Structural Genomics funded to advance high-throughput protein structure determination

San Diego 24 September 2000To deliver on the promise of the genome project for health care, scientists must understand the information implicit in the genome, and specifically, the functions of the proteins encoded by the genes. The Joint Center for Structural Genomics (JCSG), a consortium of California scientific research organisations, has received a National Institutes of Health (NIH) grant of $24 million over a five-year period, in order to expand on the body of knowledge made available by the completion of the human and other genome sequencing projects. Its goal is to determine the 3D structure of up to 2000 proteins by developing state-of-the-art high-throughput technology, thereby advancing efforts to understand structure-function relationships important for diseases and their treatments.

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The main organisations comprising the JCSG consortium are The Scripps Research Institute (TSRI) including the Genomics Institute for the Novartis Research Foundation (GNF); the San Diego Supercomputer Center (SDSC) at University of California, San Diego (UCSD); and the Stanford Synchrotron Radiation Laboratory (SSRL, a Division of the Stanford Linear Accelerator Center, SLAC) at Stanford University. Associated with the JCSG are also 29 scientific collaborators from other institutions around the world, including the Salk Institute and Syrrx Inc. in La Jolla, California.

Principal investigator Ian Wilson, professor in the Department of Molecular Biology and The Skaggs Institute for Chemical Biology at TSRI, stated that this initiative in structural genomics is the next step beyond the sequencing of the human and other genomes as well as an opportunity to gain a more profound understanding of how individual proteins work in the body. The consortium represents a close synergy between the academic and research institutions, along with their biotechnology partners, who want to combine their expertise in a large-scale effort with enormous potential benefits.

Co-principal investigator of the centre is Dr. John Wooley, who is associate vice-chancellor for research at UCSD. Dr. Wooley, together with the other senior investigators at UCSD will direct the bio-informatics component for JCSG. "Today biology is a data-driven science and bio-informatics is the sine qua non of modern biology", Dr. Wooley stated. "Data emerging from this project will provide us comprehensive knowledge in atomic detail of the molecular machines which are driving the cellular processes."

There are five major steps in high-throughput protein structure determination:

  1. Selection of the best protein targets
  2. Expression and purification of proteins
  3. Crystallisation of proteins
  4. Collection of x-ray diffraction data
  5. Structure determination at high resolution
The primary aim of the JCSG is to develop and integrate high-throughput robotic technologies for these steps, ultimately providing researchers with key insights about biological function. Automating each step is JCSG's goal for its contribution to the NIH target of 10.000 protein structures in ten years.

"Structural genomics has the potential to impact contemporary biology in a substantial way by building on the foundation of the sequencing genome projects", Dr. Ian Wilson explained. For rapid, efficient, cost-effective determination of novel protein structures through advances in experimental and computational methods, JCSG has established 3 collaborative teams. The bio-informatics team directs target selection, informatics, and validation; the crystallomics team is responsible for production of protein samples and crystallisation; and the structure determination team orchestrates x-ray data collection and analysis, structure determination, and refinement.

The initial focus of the JCSG will be on the complete worm genome, called C. elegans, and its 18.000 genes, as to provide a suitable number of targets in order to optimise each component of the system. The JCSG's target selection committee is chaired by Dr. Susan Taylor, professor of Chemistry and Bio-chemistry at UCSD and HHMI investigator. "We will focus on proteins implicated in cell signalling, which is the information transmission within and between cells", she stated, "because these provide clues to many aspects of disease." Utilising C. elegans signalling proteins as templates, JCSG will investigate genetically related proteins in the fruitfly or Drosophila, mouse and human. Bio-informatics will be essential to identify the most promising targets and ascertain genetically related proteins among the various organisms.

For protein expression, purification and crystallisation, JCSG will make use of breakthrough robotic technologies pioneered by Raymond Stevens and Peter Schultz at the Genomics Institute of the Novartis Research Foundation, Lawrence Berkeley National Laboratory and Syrrx Inc. JCSG will equally incorporate SSRL's novel technologies for synchrotron-based data collection and structure solution. Similarly, JCSG will develop new structural bio-informatics methods, exploiting SDSC cutting-edge research in the Biology WorkBench, the Protein Data Bank, the SDSC Storage Resource Broker and other informatics activities. In addition to improving and integrating these technologies, JCSG will construct novel systems resulting in a complete, highly automated "pipeline" within a knowledge-based feedback system.

A key enabling technology for the high-throughput structure determination component is the combination of synchrotron x-rays and robotic crystal mounting being developed at SSRL and the Advanced Light Source (ALS) in Berkeley. According to Dr. Keith Hodgson, professor and director of SSRL, synchrotron-based macro-molecular crystallography has revolutionised the ability to determine structures with much higher quality and at a much faster rate than before. As Dr. Hodgson added: "SSRL was the site of the first pioneering protein crystallography experiments in the mid-to-late seventies, and we look forward to helping the JCSG reach its goal of high-throughput structure determination as a means to remarkable discoveries in the biological and biomedical sciences."

The JCSG will build on the foundation which its members and collaborators have already laid in high-throughput protein expression, crystallisation, purification, and crystallographic data collection and analysis. According to Dr. Wilson, the JCSG expects to refine essential tools and develop new ones. "Such progress is imperative for the successful operation of a second-generation structural genomics centre that is able to exploit the tremendous opportunities in structural biology and medicine arising from the sequencing of the human genome."

Genes are the blueprint, whereas the proteins they encode are the workers, the molecular machinery, in all living organisms. They digest food; provide us with energy; allow the blood to carry oxygen; fight infections; enable us to think, reason and speak; and perform a variety of other critical activities. A protein's function depends on the exquisitely fine details of its structure and shape, including the grooves, ridges, and pockets on or near its surface. By studying thousands of molecules in this project, the researchers will deepen their understanding of how protein structure and function are interrelated. Scientists will better understand how each protein functions normally, and how defective proteins malfunction and cause disease. Ultimately, this knowledge will lead to new diagnostic techniques and therapeutics.

The JCSG is funded by the National Institute of General Medical Sciences (NIGMS), one of the main supporters of basic biomedical research within the National Institutes of Health (NIH). NIGMS is funding seven such projects throughout the United States, and the Joint Center for Structural Genomics is one of three such centres in the Western United States. NIGMS anticipates spending a total of $140 to $175 million over five years. According to NIGMS Director Marvin Cassman, the JCSG project can be viewed as an inventory of all the protein structure families that exist in nature. "We expect that this effort will yield major biological findings which will shed light on health and disease."

Preliminary results laying the foundation for the centres were supported by the NIH, the National Science Foundation (NSF), the Department of Energy Office of Biological and Environmental Research (DOE-BER), the Genomics Institute for the Novartis Research Foundation and Syrrx Inc. Dr. Hodgson noted that all seven new centres will use synchrotron radiation, an essential component of these technologies made available because of the sustained funding provided by DOE and NSF in operating these user facilities. Another one of these initiatives constitutes the Alliance for Cellular Signalling (AFCS). You can read more about it in the VMW October 2000 article US National Institute of General Medical Sciences awards "glue grant" to create virtual cells. For more information on the JCSG project, you can contact David Hart.


Leslie Versweyveld

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