The Midwest Center for Structural Genomics, housed at Argonne National Laboratory, received a $31 million grant to continue its effort to solve structures of important proteins

October 12, 2010

Argonne receives $31 million for pathogen protein studies
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September 30, 2010.

ARGONNE, Ill. (Sept. 30, 2010) — The U.S. Department of Energy’s Argonne National Laboratory will continue to feed the national research community a steady diet of new protein structures, thanks to a $31 million grant over five years from the newest phase of the National Institutes of Health’s Protein Structure Initiative, PSI:Biology.

The grant will fund new work by the Midwest Center for Structural Genomics (MCSG), a consortium led by Argonne that also includes the European Bioinformatics Institute, Northwestern University, University of Toronto, University College of London, University of Virginia and the University of Texas. Since 2000, the MCSG has contributed more than 1,300 structures — more than three-quarters of which were unique — to the Protein Data Bank, a repository of all known protein structures. These new funds will allow researchers to better understand the relationships between proteins in terms of both their structure and their function, said MCSG Director and Argonne Distinguished Fellow Andrzej Joachimiak.

According to Joachimiak, the funds will support a renewed focus by Argonne, the MCSG and other laboratories around the country on protein targets that hold promise as candidates for biomedical breakthroughs. “This funding represents a new phase in the evolution of the Protein Structure Initiative — one that is committed to finding the biophysical building blocks of new cures,” he said.

The NIH grant will specifically fund two biology partnership initiatives that will examine proteins potentially responsible for the virulence of three of the world’s most dangerous bacteria: staphylococcus, tuberculosis and salmonella.

The tuberculosis and staphylococcus research will pair MCSG researchers with a team led by Jim Sacchettini at Texas A&M University to focus on new drug targets to combat these deadly diseases. Many strains of tuberculosis and staphylococcus have evolved to resist conventional antibiotics, which heightens the urgency of new research into their biochemistry, Joachimiak said.

In the salmonella study, Joachimiak and a team led by Josh Atkins at Pacific Northwest National Laboratory will try to find and analyze the structure of the bacterium’s effector protein, which is what the pathogen uses to infect and reprogram a host cell. “Eventually, we hope that all of these studies will lead to the development of new drugs that can target and interfere with particular regions of the proteins that we are working to identify,” Joachimiak said.

Proteins are responsible for the regulation and functioning of virtually all biological systems. The base-pairs of DNA in our genetic sequence—the blueprints of our bodies—are translated bit-by-bit within all cells into chains of amino acids that eventually fold into long and complex proteins.

“The experiments we will be able to do, thanks to this grant, will give us a much clearer picture of how proteins with similar structures can have highly divergent functions, and vice versa,” Joachimiak said. “We hope that this funding will enable us to understand and identify most of the largest fundamental protein families that exist across nature.”

According to Joachimiak, roughly 100,000 protein families are believed to exist in nature. Each protein family can comprise hundreds or even thousands of individual proteins with different structures. However, Joachimiak believes that fewer than 2,000 unique protein folding patterns exist in nature, so thousands of individual structures and many different protein families may be related to each other.

An individual protein, in turn, forms from an assembly of distinct protein “domains” — large regions that can reappear in many different configurations across different proteins. “You can think of a protein family as similar to a class of animals, like mammals or birds,” Joachimiak said. “Every protein within a family has many features in common, but each protein is adapted to fill a slightly different niche.”

“We’re working to find the basic structural and biochemical templates and patterns that are used repeatedly throughout nature as the foundation for life on the cellular level,” he added.

In order to analyze a protein, Joachimiak and his colleagues at the MCSG and Argonne’s Structural Biology Center must first produce a pure, small and perfectly ordered crystal of it. Argonne’s crystallographers can then place each crystal in the path of one of the beamlines at the laboratory’s Advanced Photon Source (APS), a high-energy X-ray synchrotron supported by DOE’s Office of Science. The X-rays generated by the APS strike the protein crystal and, upon contact, scatter in different directions before hitting a detector, which produces a pattern from which researchers can reconstruct the protein’s structure.

All protein structures identified and catalogued by the MCSG are entered into the Protein Data Bank, where they are available to the public without charge. “The MCSG has been a leader in developing efficient methods to determine protein structures,” said Ward Smith, director of the Protein Structure Initiative at NIH. “Now it will take full advantage of these methods to partner with other labs to deepen our understanding of how pathogen and host proteins interact and lead to potential new drug targets.”

More information about the MCSG can be found at mcsg.anl.gov, and additional information about the PSI can be found at http://www.nigms.nih.gov/Initiatives/PSI.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America ‘s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.
By Jared Sagoff.