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Structural Genomics Research at SSRL Begins Exciting New Chapter

Ashley Deacon loads samples of crystallized proteins into an automated sample mounting system. (Photo by Elizabeth Buchen.)

Thanks to a $37.6 million grant from the National Institutes of Health, researchers at the Joint Center for Structural Genomics—including a 12-member team at SLAC's Stanford Synchrotron Radiation Lightsource—will continue to map the structures of proteins for the next five years.

The funding comes from the third phase of the National Institute of General Medical Sciences' Protein Structure Initiative, called PSI:Biology. Under the first two phases of the initiative, which began in 2000, JCSG contributed more than 1,000 new structures to the Protein Data Bank, a free, publicly available repository of all known protein structures.

In this third phase, SSRL researchers in the JCSG Structure Determination Core will continue their collaboration with the Bioinformatics Core at the Sanford-Burnham Medical Research Institute and the University of California-San Diego, and the Crystallomics Core at the Genomics Institute for the Novartis Research Foundation and The Scripps Research Institute. Together, these groups will map protein structures using SSRL's X-ray protein crystallography beamlines. By placing crystallized protein samples in the X-ray beam and recording how the beam diffracts off the atoms within each protein molecule, the researchers can reconstruct the three-dimensional structure of each protein.

In addition, this new phase of the initiative will partner JCSG researchers with groups of biologists who need to know many protein structures to better understand important biological processes or molecular functions. This collaboration will help researchers leverage structural information for use in biology and medicine.

"PSI was very successful in developing high-throughput technology and rapidly learning what the structures of novel proteins in the protein universe look like," said SLAC researcher Ashley Deacon, who leads the JCSG Structure Determination Core. Now, with PSI:Biology, "We're going to focus on determining structures of proteins and protein complexes in challenging biological systems that can have a profound biomedical impact."

"PSI has mapped out large areas of the protein universe, as well as many proteins from the human gut microbiome," Deacon continued. "The ultimate goal is to better understand the role these proteins play in health and disease."

Proteins, linear chains of amino acids folded into a three-dimensional form, play an essential role in just about every process that happens within a living organism's cells. While many of the estimated 100,000 protein families have been sequenced—in other words, scientists have determined the order of the amino acids that make up the protein—researchers know the folding patterns of relatively few of those proteins. That's important knowledge; a protein's three-dimensional structure can provide indications of how the protein performs its function.

In total, the NIH awarded 23 grants as part of the Protein Structure Initiative, totaling $290 million over five years. These grants include funding for four large-scale structure determination centers—including JCSG, which is led by Professor Ian Wilson at The Scripps Research Institute—and nine membrane-protein centers.

SSRL is also involved in one of the membrane-protein centers, centered at Caltech, through SSRL's Structural Molecular Biology program, which is led by Britt Hedman and Keith Hodgson. This collaboration, called the Center for X-ray Structure Determination of Human Transporters, seeks to determine the structures of cell membrane proteins, which mediate the transfer of matter, information and energy between the inside of a cell and the outside environment.

The new membrane-protein center, for which Caltech Professor Doug Rees serves as principal investigator, includes researchers from SSRL, The Scripps Research Institute, University of Colorado, Sanford-Burnham Medical Research Institute, UC San Diego, Texas Tech and Caltech.

"Through this collaboration, we will be working with Doug on developing the microbeam methodology needed to map the structure of membrane proteins," Hedman said. "SSRL's beamline 12-2 is specialized for this type of work, and we're looking forward to improving the structural determination process by developing even more advanced instrumentation on that beamline."

More information about the recent funding can be found in the NIH press release "NIH grants will advance studies of the form and function of proteins." Information on all of the structures solved and deposited by the JCSG can be found at the JCSG Structure Gallery.

In addition, more information on JCSG can be found in a recently released special issue of the journal Acta Crystallographica Section F. This issue of the peer-reviewed crystallography and structural biology journal focuses entirely on JCSG.

JCSG is funded by the NIH National Institute of General Medical Sciences, Protein Structure Initiative U54GM094586.

The SSRL Structural Molecular Biology program is funded by the Department of Energy's Biological and Environmental Research program, the NIH National Center for Research Resources and the NIH National Institute of General Medical Sciences.

—Kelen Tuttle
SLAC Today, October 25, 2010