The Shapes of Life: NIGMS Project Yields More Than 1,000 Protein Structures

The Protein Structure Initiative (PSI), a national program aimed at determining the three-dimensional shapes of a wide range of proteins, has now determined more than 1,000 different structures. These structures will shed light on how proteins function in many life processes and could lead to targets for the development of new medicines.

The PSI is a 10-year, approximately $600 million project funded largely by the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health. The first half of this project—a pilot phase that started in 2000—has centered on developing new tools and processes that enable researchers to quickly, cheaply, and reliably determine the shapes of many proteins found in nature.

“One thousand protein structures is a significant milestone for the PSI, and it shows an impressive return on the investment in the technology and methods for rapid structure determination,” said Jeremy M. Berg, Ph.D., director of NIGMS. “These structures are interesting in their own right and provide the basis for modeling many important proteins.”

Some of the newly determined structures are of proteins found in plants, mice, yeast, and bacteria, including the pathogenic types that cause pneumonia, anthrax, and tuberculosis.

The nine PSI pilot centers have transformed protein structure determination from a mostly manual process to a highly automated one. Robotic instruments rapidly clone, express, purify, crystallize, and analyze many proteins simultaneously, cutting the time it takes to determine a single protein structure from months to days. For example, a robotic arm drops protein solution into thousands of tiny wells for crystallization trials, and an imaging system quickly scans the wells looking for signs of crystal formation—key to capturing protein structures.

“At this large scale, it would be unthinkable to do all these steps by hand,” said John Norvell, Ph.D., director of the PSI at NIGMS and a scientist trained in protein structure determination. He noted that some robotics and automated tools have been refined and are now marketed by companies for general structural biology applications.

As the PSI pilot centers have put automated structure determination pipelines in place, the number of protein structures they have solved has increased significantly. In the second, third, and fourth years of the pilot phase, the centers in aggregate reported 109, 217, and 348 structures, respectively. Now, halfway through the fifth year, they’ve surpassed a total of 1,000. Many of these structures are very different from previously known structures, said Norvell.

The findings contribute to the initiative’s ultimate goal of providing structural information on 4,000-6,000 unique proteins that represent the variety found in organisms ranging from bacteria to humans. Researchers can use these structures, which are determined experimentally, to build computer models of the structures of other proteins with related amino acid sequences.

Although the main focus of the second phase of the PSI will be on solving protein structures, Norvell said there will be continued development of new technology: “As we reach for higher-hanging fruit—protein structures that are more complex and harder to solve—we will need to develop additional tools and methods.”

As part of the PSI effort, all the structures determined by the centers are collected, stored, and made publicly available by the Protein Data Bank (PDB), http://www.rcsb.org/pdb/, a repository of three-dimensional biological structure data.

“The protein structures solved by the PSI are more than a scientific stamp collection,” explained Norvell. “They will help researchers better understand the function of proteins, predict the shape of unknown proteins, quickly identify targets for drug development, and compare protein structures from normal and diseased tissues.” In general, a broad range of biomedical researchers will benefit from the PSI’s technical advances, experimental data, and availability of new materials, such as reagents.

“There are a lot of proteins that are incredibly important to understanding human biology and medicine, yet we know very little about most of them,” said Norvell. “The PSI will provide important information about these molecules so vital to life.”

The nine pilot centers participating in the first phase of the PSI are:

• The Berkeley Structural Genomics Center,
  http://www.strgen.org/
• The Center for Eukaryotic Structural Genomics,
  http://www.uwstructuralgenomics.org/
• The Joint Center for Structural Genomics,
  http://www.jcsg.org/
• The Midwest Center for Structural Genomics,
  http://www.mcsg.anl.gov/
• The New York Structural Genomics Research Consortium,
  http://www.nysgrc.org/
• The Northeast Structural Genomics Consortium,
  http://www.nesg.org/
• The Southeast Collaboratory for Structural Genomics,
  http://www.secsg.org/

The Structural Genomics of Pathogenic Protozoa Consortium, http://www.sgpp.org/

The TB Structural Genomics Consortium, http://www.doe-mbi.ucla.edu/TB/
The pilot phase of the PSI will end in mid-2005. Centers for the second phase will be announced in July 2005.

In addition to NIGMS, the PSI currently receives funding from the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health.

For more information about the PSI, please visit http://www.nigms.nih.gov/psi/. To schedule an interview with Jeremy M. Berg, Ph.D., or John Norvell, Ph.D., please contact the NIGMS Office of Communications and Public Liaison at 301-496-7301.

NIGMS is one of the 27 components of NIH, the premier federal agency for biomedical research. The NIGMS mission is to support basic biomedical research that lays the foundation for advances in disease diagnosis, treatment and prevention.