Ten Thousand Protein Structures: The First Goal of Structural Genomics

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Ten thousand protein structures in 10 years. That's the initial goal of a new international effort involving scientists in at least nine countries. The U.S. portion of the project is being organized by the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health.

Why Should We Care About Protein Structure?
Proteins are the worker molecules in every living thing. They help us digest our food, allow our blood to carry oxygen, fight infections, and carry out many other critical jobs. They come in many sizes and shapes. Often, a protein's function depends on tiny details of its structure--the grooves, ridges, and pockets on its surface. By determining the detailed, three-dimensional structures of proteins, we are better able to understand how each protein functions normally and how faulty protein structures can cause disease. Scientists can use the structures of disease-related proteins to help develop new medicines and diagnostic techniques.

Why Are We Doing This Now?
Scientists have studied protein structures for more than 40 years and NIGMS has and continues to play a major role in supporting these studies. Several factors-- including the explosion of available gene sequences and advances in the methods for determining protein structures--make the time right for NIGMS to launch its protein structure initiative.

Determining protein structures is often a difficult, time-consuming task. By comparison, determining gene sequences--the "recipes" for proteins--is quick and easy. So for decades, researchers have sought a shortcut to protein structure determination by predicting these structures from gene sequences. The complete gene sequences of several organisms, including humans, have been deciphered recently and enable researchers to approach this goal in an organized way.

In the international protein structure project, scientists are starting by organizing all known proteins into families based on their genetic sequence. They will then determine the structure of one or more proteins from each family, for a total of about 10,000. These structures will teach the researchers valuable lessons about the relationship between gene sequence and protein structure. With this knowledge as a guide, scientists hope to use gene sequences to predict the structures of all other proteins. Scientists are calling the effort "structural genomics."

The time is ripe for the structural genomics effort for another reason. A number of advances in the two main techniques used to determine molecular structures--X-ray crystallography and nuclear magnetic resonance spectroscopy--allow researchers to obtain protein structures faster than ever before.

What's Next?
Because details of a protein's structure reveal aspects of its function, a main goal of these structural studies is to better understand how individual proteins work in the body. Scientists learn much from comparing the structures of different proteins. Often--but not always--two similarly shaped proteins have similar biological functions. By studying thousands of molecules in an organized way in this project, researchers will deepen their understanding of how protein structure and function are interrelated.

NIGMS' Role in Structural Genomics
Because the structural genomics project is so ambitious, NIGMS envisions that it will eventually be accomplished not by individual researchers, but by efficient, large-scale research networks. Toward this end, NIGMS is offering two types of grants. The first spurs individual scientists to develop new techniques that will accelerate any aspect of protein structure determination. The second supports the formation of pilot centers to develop and test techniques for high-throughput operations by subsequent, larger research networks.

For a more detailed description of the NIGMS structural genomics initiatives, see /Initiatives/PSI/.

The Promises of Structural Genomics
The medical incentives for understanding protein structure are great. Several diseases, including cystic fibrosis and sickle cell disease, are caused by defects in a single protein. Other diseases, such as Alzheimer's and "mad cow" disease, result from proteins with an incorrect structure. If scientists could decipher the structures of proteins involved in such diseases, they might be a step closer to improving disease treatment, diagnosis, or prevention. Beyond such specific medical applications, the project will teach fundamental lessons about the structural basis of all living things.