|Crystal Engineering Helps Scientists
Solve 3-D Protein Structures
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.
To arrange an interview with NIGMS director Jeremy M. Berg, Ph.D.,
contact the NIGMS Office of Communications and Public Liaison at
For high-resolution images to illustrate the research, contact
the NIGMS Office of Communications and Public Liaison at 301-496-7301.