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’Crystal engineering’ helps scientists solve 3-D protein structures

07.04.2004


Research aids drug design; sheds light on plague and other diseases



A new technique for engineering protein crystals is helping scientists figure out the three-dimensional structures of some important biological molecules, including a key plague protein whose structure has eluded researchers until now. The technique, developed with support from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH), promises to help pharmaceutical companies develop more effective drugs to treat various diseases by tailor-making molecules to "fit" a protein’s shape.

Featured in the cover article of the April 2004 issue of Structure, University of Virginia School of Medicine researcher Zygmunt Derewenda, Ph.D., describes how his group was able to coax certain proteins to crystallize by carefully altering their surfaces using "targeted mutagenesis." In effect, the technique substitutes a small amino acid for certain large ones. This effectively shrinks bulky groups of atoms on protein surfaces that might otherwise prevent the proteins from crystallizing.


"In order to determine a high-resolution structure of a protein, we need to study it in its crystal form," Derewenda explained. "Yet many proteins do not crystallize easily, or even at all, with current laboratory techniques. Using our approach, we can now make some of these proteins more amenable to crystallization without seriously affecting their overall structure or function."

Already, the crystal engineering technique has helped solve the structures of some particularly stubborn proteins, including the so-called V antigen of Yersinia pestis, the bacterium that causes the plague. Despite numerous attempts, researchers had been unsuccessful in unlocking the secrets of this protein, which plays a key role in the bacterium’s ability to cause the plague. Working with Derewenda’s group, David S. Waugh, Ph.D., of the NIH’s National Cancer Institute in Frederick, Md., was able to crystallize the protein and then determine its structure by X-ray diffraction. (The results were published in the February 2004 issue of Structure.)

Other large biological molecules whose structures were recently solved thanks to the new technique include an important protein complex containing ubiquitin, which is involved in a wide range of cellular processes (discovered by a research team led by James H. Hurley, Ph.D., of the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases). The technique was also used by a team at Merck Research Laboratories to yield a much more accurate structure of a potential anticancer drug target called insulin-like growth factor-1 receptor.

Development of the technique was made possible by funding from NIGMS’ Protein Structure Initiative (PSI)--an ambitious 10-year project, launched in 2000, aimed at dramatically reducing the time and cost of solving protein structures. PSI researchers around the world are now working to determine the structures of thousands of proteins experimentally, using highly automated systems, and to produce computer-based tools for ultimately modeling the structure of any protein from its genetic spelling, or sequence.

"This crystallization method has the potential to become a powerful new tool for structural biology and is a great example of the kind of innovation that the Protein Structure Initiative is intended to foster," said NIGMS director Jeremy M. Berg, Ph.D. "Technologies such as this are crucial to realizing the promise of structural biology and accelerating the development of more effective medicines to treat both new and re-emerging diseases."


NIGMS is one of the 27 components of the National Institutes of Health, the premier federal agency for biomedical research. Its mission is to support basic biomedical research that lays the foundation for advances in disease diagnosis, treatment and prevention. For more about NIGMS’ Protein Structure Initiative, visit the PSI Web site at http://www.nigms.nih.gov/psi.

CONTACTS

To arrange an interview with NIGMS director Jeremy M. Berg, Ph.D., contact the NIGMS Office of Communications and Public Liaison at 301-496-7301.

For high-resolution images to illustrate the research, contact the NIGMS Office of Communications and Public Liaison at 301-496-7301.

Dan Hogan | EurekAlert!
Further information:
http://www.nigms.nih.gov/psi

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