If genes are the recipes for life, then proteins are the culinary result--the very stuff of life. Proteins control many biological processes in organisms ranging from bacteria to plants and humans. One way to understand proteins--and perhaps find ways to control their action--is to decipher their three-dimensional structures.
The National Institute of General Medical Sciences (NIGMS) has developed a major new initiative to determine the structures of thousands of proteins over the next decade. Work toward this goal will be divided into two phases: a five-year pilot stage and a subsequent five-year full-scale production phase. The initial phase begins with today's announcement of the first awards for pilot research centers in structural genomics, a new field dedicated to a broad understanding of protein structures and functions in relation to gene sequences.
NIGMS 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 around $150 million on these projects over five years, making NIGMS the world's single largest funder of structural genomics.
"This project can be viewed as an inventory of all the protein structure families that exist in nature," said Dr. Marvin Cassman, NIGMS Director. "We expect that this effort will yield major biological findings that will improve our understanding of health and disease."
Structural genomics, which builds on genome sequencing efforts, can teach us fundamental lessons about biology and can advance efforts in structure-based drug design. 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.
Although structure determination techniques--chiefly X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy--have advanced dramatically in recent years, they are still time-consuming and labor-intensive. The research centers funded by NIGMS seek to streamline and automate these techniques, as well as every other task in structural genomics, ranging from selecting proteins for structure determination to analyzing the final data.
"These research centers are true pilots," said Dr. John Norvell, director of the NIGMS Protein Structure Initiative. "Each will include every experimental and computational task of structural genomics and will develop strategies for use in the subsequent large-scale research networks. By the fifth year of the award, we expect each pilot center to reach a production level of 100 to 200 protein structures annually, which is significantly greater than the current rate of protein structure determination."
The centers will begin their work by organizing 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 awards are listed below alphabetically by the name of the principal investigator.
- Five institutions in the New York City area have joined to form the New York Structural Genomics Research Consortium, which will develop techniques to streamline every step of structural genomics. The consortium expects to solve several hundred protein structures from humans and model organisms ranging from bacteria to humans. (Stephen K. Burley*, The Rockefeller University)
*As of February 2002, Jeffrey Bonanno of The Rockefeller University is Acting Director, as Stephen Burley moves to Structural GenomiX.
- The Midwest Center for Structural Genomics, a consortium of seven institutions, seeks to reduce the average cost to determine a protein structure from $100,000 to $20,000. The group will select protein targets from all three kingdoms of life (Eukarya, Archaea, and Bacteria), with an emphasis on previously unknown folds and on proteins from disease-causing organisms. (Andrzej Joachimiak, Argonne National Laboratory)
- Berkeley Structural Genomic Center aims to speed up structure determination by X-ray crystallography. It will focus on two bacteria with extremely small genomes to study proteins essential for independent life. The bacteria, Mycoplasma genitalium and Mycoplasma pneumoniae, are closely related. The former contains the smallest genome of any free-living organism and infects the human genital and respiratory tracts. The latter causes a form of pneumonia. (Sung-Hou Kim, Lawrence Berkeley National Laboratory)
- Researchers in New Jersey, New York, Connecticut, Washington State, and Ontario, Canada have formed the Northeast Structural Genomics Consortium, which will target proteins from various model organisms--including the fruit fly, yeast, and the roundworm--and related human proteins. This consortium will use both X-ray crystallography and NMR spectroscopy to determine protein structures. (Gaetano Montelione, Rutgers University)
- A collaboration of scientists in six countries have formed the TB Structural Genomics Consortium to determine and analyze the structures of about 400 proteins from Mycobacterium tuberculosis. The group seeks to optimize the technical and managerial underpinnings of high-throughput structure determination and will develop a database of structures and functions. NIH's National Institute of Allergy and Infectious Diseases, which is cofunding this project with NIGMS, anticipates that this information also will lead to the design of new and improved drugs and vaccines for tuberculosis. (Thomas Terwilliger, Los Alamos National Laboratory)
- The Southeast Collaboratory for Structural Genomics, with its core in Georgia and Alabama, will analyze part of the human genome and the entire genomes of two representative organisms--the roundworm Caenorhabditis elegans and its more primitive microbial ancestor, Pyrococcus furiosus. The group emphasizes technology development, especially for automated crystallography and NMR techniques. (Bi-Cheng Wang, University of Georgia)
- The Joint Center for Structural Genomics, centered in California, is developing high-throughput methods for protein production, crystallization, and structure determination. It will initially focus on novel structures from C. elegans and on human proteins thought to be involved in cell signaling. It will also determine the structures of similar proteins from other organisms to ensure the inclusion of the greatest number of different protein folds. (Ian Wilson, The Scripps Research Institute)
To arrange an interview with Dr. Marvin Cassman, NIGMS Director, or with Dr. John Norvell, director of the Protein Structure Initiative, call Alisa Machalek in the NIGMS Office of Communications and Public Liaison at (301) 496-7301.
More information about the NIGMS Protein Structure Initiative is available at http://www.nih.gov/nigms/funding/psi.html.