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Vol. LVII, No. 15
July 29, 2005
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Protein Structures Take the Stage

With genomics getting so much media attention, researchers working on proteins could be excused for grumbling that it is proteins, after all, that actually do most of the work in the cell. Technology has enabled an accelerating stream of genome sequences, and powerful new methods like gene expression arrays have identified countless genes involved in virtually every disease and condition under the sun. The study of proteins has been advancing as well, albeit more quietly, and just passed a milestone as the Protein Structure Initiative (PSI, an NIGMS effort) completed its first 5-year phase and moved into its second.

The goal of the PSI is basically to make it easier to figure out the three-dimensional shapes of proteins, with the long-term goal of being able to predict most protein structures from their DNA sequences. A genetic mutation is, to use an analogy, like a spelling change in one letter of a long word. To understand how that mutation leads to disease, it helps to know how it changes a protein's structure. How proteins work, put simply, depends on their three-dimensional structure.

But it's more than a better understanding of biology that's at stake. For example, NIGMS-funded researchers at Yale recently identified the structural changes that enable bacteria to become resistant to some antibiotics. Researchers knew that a mutation in a ribosome gene led to the resistance, but by analyzing the structure, they now know exactly why the antibiotics don't bind as well. They are already using this information to try to design new antibiotics. These kinds of protein structure studies can guide the way in designing medicines to target defective proteins that cause all kinds of disease.

PSI's first phase was dedicated to figuring out how to process proteins and determine their three-dimensional structures more efficiently. Its focus was on developing innovative approaches and tools such as robotic instruments. Nine pilot centers created what is now a collection of more than 1,100 protein structures, which serve as templates for modeling related sequences. Software developed by the PSI can now compare a structure against three-dimensional structural templates and identify functionally important motifs.

Phase 2 is the production phase, in which thousands more protein structures will be solved and put into the Protein Data Bank (http://www.rcsb.org/pdb/), a public repository with powerful tools for processing protein structure information. Some centers will also work to develop new methods — for instance, for solving the structure of membrane proteins.

For more information, including some provocative images, see http://www.nigms.nih.gov/psi/.

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