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In Vivo

Major Protein Structure Initiative

Researchers Awarded $25 Million  to Envision Proteins of Life

The structure of resistin, a protein produced by fat cells, may reveal how obesity and diabetes are connected.

The structure of resistin, a protein produced by fat cells, may reveal how obesity and diabetes are connected. The structure, part of PSI's first phase, was published last year by Lawrence Shapiro.

The NIH's Protein Structure Initiative kicked off its second phase in July with the creation of 10 new centers, including the New York Consortium on Membrane Protein Structure led by Wayne Hendrickson, Ph.D., University Professor of Biochemistry and Molecular Biophysics. The Protein Structure Initiative (PSI) is a national effort to determine the 3-D shapes of thousands of different proteins with new high-throughput techniques.

"The overall idea of PSI is a bit like the Human Genome Project in that the information gained from these large-scale efforts will underpin a more efficient approach to medical research in the future," Dr. Hendrickson says. "Drug discovery has been lagging in recent years, and many of us believe that the development of drugs based on a protein's structure is a much more efficient way to find the drugs we'd like to have."

The first phase of PSI began in 2000 when pilot centers were established to develop innovative approaches and tools, such as robotic instruments, that streamline and speed many steps of generating protein structures.

Columbia researchers are also taking part in two other PSI centers, the Northeast Structural Genomics Research Consortium (NESG) and the New York Structural Genomics Research Consortium, and will receive about $25 million over the next five years to fund their research in all three centers.

The focus now shifts to a production phase during which the new centers will use methods developed during the pilot period to rapidly determine thousands of protein structures found in organisms ranging from bacteria to humans. All together, the 10 centers are aiming for 5,000 structures in the next five years. (The nine centers of PSI's first phase solved 1,100 structures in five years).

The project's ultimate goal is even more ambitious.

"We hope that the PSI will allow us to develop a new view of the relationships between protein sequence, protein structure, and protein function that will ultimately make the three-dimensional structures and functions of most proteins predictable from the protein sequence," said Barry Honig, Ph.D., professor of biochemistry and molecular biophysics and NESG bioinformatics leader.

Another CUMC participating researcher in NESG (led by Gaetano Montelione of Rutgers University) is Burkhard Rost, Ph.D., associate professor of biochemistry and molecular biophysics. Dr. Hendrickson is the consortium's director of crystallography.

Lawrence Shapiro, Ph.D., associate professor in the Departments of Ophthalmology and Biochemistry & Molecular Biophysics, is heading a project in the New York Structural Genomics Research Consortium, led by Structural GenomiX, Inc.

Drs. Rost, Honig, and Shapiro are also participating in the New York Consortium on Membrane Protein Structure along with CUMC's Eric Gouaux, Ph.D., professor of biochemistry and biophysics; Ming Zhou, Ph.D., assistant professor of physiology and cellular biophysics; and Filippo Mancia, Ph.D., associate research scientist in biochemistry and biophysics.

—Susan Conova

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