Structural Biology

Overview

A healthy mind and body require the coordinated action of billions of tiny molecular workers called proteins. Our genes contain the DNA scripts for manufacturing these proteins. Some proteins build our cells and other proteins work to allow us to think, smell, eat and breathe. Proteins are indispensable molecules in our bodies, and each has a unique three-dimensional shape that is well suited for its particular job. And if the shape of even one protein happens to go awry, there can be major consequences for human health. Misshapen proteins, especially those that make up part of the cell surface or cell membranes, are the culprits behind many diseases, including cystic fibrosis, Alzheimer's disease and countless others.

The Structural Biology Roadmap is a strategic effort to create a "picture" gallery of the molecular shapes of proteins in the body. This research investment will involve the development of rapid, efficient, and dependable methods to produce protein samples that scientists can use to determine the three-dimensional structure, or shape, of a protein. The new effort will catalyze what is currently a hit-or-miss process into a organized, coordinated, systematic and streamlined routine, helping researchers clarify the role of protein shape in health and disease.

A limiting step in the determination of protein structures is the production of purified samples of the proteins in sufficient quantities for structural determination. Proteins that are tightly bound to the membranes of our cells have been the most difficult to study and were chosen for special Roadmap attention. Membrane proteins which account for about 30% of the proteins in a cell also turn out to be one of the most important classes of proteins for health. They are major drug targets for the development of disease treatments.

During the first phase of the Structural Biology Roadmap (FY2004-2008), the NIH Roadmap funded two Centers for Innovation in Membrane Protein Production that enabled interdisciplinary groups of scientists to develop innovative methods for producing large quantities of membrane proteins. In addition, a number of small exploratory (R21) and regular research grants (R01) were awarded to individual investigators to broaden the base of innovative ideas under development.

These investments in Centers and in investigator-initiated research projects have produced considerable advances in methods and several important solved structures, including that of the beta-2 adrenergic receptor. This protein is the target of numerous drugs and a prime example of a large family of important cell regulatory molecules known as G-protein coupled receptors (GPCRs). However, thus far, most work has been done on relatively simple membrane proteins that contain only one subunit or multiple copies of the identical protein subunit (homo-oligomers).

Many membrane proteins are complex biological machines consisting of several interlocking proteins working together. To understand how these machines work—and to learn how to fix them when they don't—researchers need to view the protein complexes in several different orientations, mimicking the way these assemblies twist and bend inside living cells. Extremely large amounts of high-quality protein are needed to perform these difficult experiments. NIH anticipates that scientists will require about a decade of intense work to achieve the project's most ambitious goal: the ability to routinely predict the shape and action of a biological machine from its DNA script.

During the next phase of the NIH Structural Biology Roadmap (FY2009-2013), the goals are to develop additional innovative approaches for membrane protein production and structure determination that can be applied to more complicated membrane proteins containing multiple subunits of differing structure (hetero-oligomers). Another goal is to be able to determine structures for complexes that are formed between membrane proteins and their soluble partner proteins (for example, complexes of G-proteins with GPCRs) or membrane proteins and proteins of the intracellular and extracellular matrix.

During this next phase, pipelines will also be established to make the solution of simple membrane protein structures much more routine. Methods developed through the Roadmap will be disseminated and networks of collaborations with other groups will be established. A mix of 2–3 center grants and 10–12 individual research awards will be made for a total of approximately $45 million over the next five years. Co-funding outside of the Roadmap and development of public-private partnerships between the NIH-funded researchers and industry will be encouraged.

For more information on the Structural Biology Roadmap, contact John Norvell, Ph.D., National Institute of General Medical Sciences, (301) 594-0533, norvellj@mail.nih.gov.

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