ARGONNE, Ill. (Sept. 26, 2000) A quicker and more efficient method to determine protein structures is the goal of a new research center based at the U.S. Department of Energy's Argonne National Laboratory.
The Midwest Center for Structural Genomics (MCSG), funded by the National Institutes of Health, will receive approximately $4 million each year for five years. The center is part of an initiative to determine the structures of thousands of proteins over the next decade.
Structural genomics is a new field dedicated to a broad understanding of protein structures and functions in relation to gene sequences. It grew out of the Genome Project, the effort that sequenced the human and dozens of other genomes. Researchers now want to use that one-dimensional information to help them determine the structure and function of every single human protein.
"Being able to read a genome is a crucial first step, but knowing the structure and function are the keys to using the information to cure, treat and prevent the disease," said Andrzej Joachimiak, the MCSG principal researcher. For example, the structure of a disease-related protein can provide insight into how the protein works normally and how a faulty structure can cause disease. This same structure may reveal how to design drugs to treat that disease.
The Midwest Center for Structural Genomics combines the talents of researchers at Argonne, Northwestern University, University of Toronto, University of Virginia, University College of London, University of Texas Southwestern Medical Center in Dallas and Washington University School of Medicine in St. Louis.
The center's goal is to cut the average cost for determining the three-dimensional structures of proteins from $100,000 to $20,000. Researchers will also work to slice the time it takes to analyze a protein from months and years to days and hours. The group will also select protein targets from all three kingdoms of life - Eukarya, Archaea and Bacteria - with an emphasis on new protein folds and proteins from disease-causing organisms.
"Argonne is one of the initiators of the structural genomics program in the United States, and this center allows us to continue the research we started four years ago," said Joachimiak.
Argonne researchers have been working to improve productivity in all areas of structural genomics. Biologists first clone proteins by snipping pieces of the genome and add them to bacteria to make copies. Then they coax these proteins to grow single crystals. Researchers shine X-rays through the crystal and end up with an X-ray diffraction pattern that computers read and manipulate into a three-dimensional structure.
Argonne's major contribution to the center's efforts is its Structural Biology Center at the Advanced Photon Source, a synchrotron facility that provides the country's most brilliant X-rays for research. This X-ray crystallography center allows rapid data collection and supplies the highest-resolution images of protein structures available anywhere. Joachimiak directs Argonne's Structural Biology Center, which in 1999 determined more new protein structures than at any other synchrotron beam line. He predicts 200 protein structures will be solved next year. Such high-throughput facilities are essential to the success of a structural genomic program.
"The accurate and high resolution data collected at the Structural Biology Center make a huge difference in cutting the time necessary to recreate the three-dimensional structure with computer programs," said Midwest Center member Wayne Anderson, a professor of molecular pharmacology and biological chemistry at Northwestern. Anderson and his colleagues are working to automate the time-consuming steps of creating a three-dimensional image of a protein from an X-ray diffraction pattern.
"The Northwestern University investigators are very excited to be involved in this collaborative venture. Each institution brings research groups with their own special expertise to the effort," Anderson said.
Argonne researchers are automating the protein cloning and crystal production with robots. The Robotic Molecular Biology facility can produce 400 to 800 clones a week. Manual methods produce only 20 to 40. Plans to quadruple production are in the works.
Computer researchers also sift through data to point researchers toward what could be the most important proteins to study.
The center will first organize all known proteins into structural families based on their genetic sequences. They will then determine the structure of one or more proteins from each family, for a total of about 10,000 protein structures in 10 years. This information will form the foundation of a public resource linking sequence, structural and functional information. The resource will also allow scientists to use gene sequences to predict the approximate structures of all other proteins.
"The importance of understanding the function of every protein in an organism cannot be understated," said Lee Makowski, director of Argonne's Biosciences Division. "The challenge we face is to use the information we gather to construct a detailed, coherent and complete picture of a living organism and to use this picture to develop methods for manipulating and engineering biomolecular systems and predicting their response to complex environmental stimuli."
The National Institute for General Medical Sciences of the National Institutes of Health is awarding almost $30 million this year to seven projects, each totaling around $4 million for the first year. The Institute anticipates spending a total of approximately $150 million on these projects over five years, making NIGMS the world's single largest funder of structural genomics.
The six other projects are based at Rutgers University, Rockefeller University, University of Georgia, Scripps Research Institute and Lawrence Berkeley and Los Alamos national laboratories.
The nation's first national laboratory, Argonne National Laboratory supports basic and applied scientific research across a wide spectrum of disciplines, ranging from high energy physics to climatology and biotechnology. Since 1990, Argonne has worked with more than 600 companies and numerous federal agencies and other organizations to help advance America's scientific leadership and prepare the nation for the future. Argonne is operated by the University of Chicago as part of the U.S. Department of Energy national laboratory system.
Editor's note: Andrzej Joachimiak is a resident of Bolingbrook, Ill. Lee Makowski is a resident of Hinsdale, Ill.
More information about Argonne is available at http://www.anl.gov , and about Argonne's Structural Biology Center at http://www.sbc.anl.gov .
More information about the NIGMS Protein Structure Initiative is available at http://www.nih.gov/nigms/funding/psi.html .