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Crystallizing Moment

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The Noble Research Institute's x-ray crystallography laboratory works to uncover the hidden structures of plant proteins
X.Q. Wang, Ph.D., associate professor
X.Q. Wang, Ph.D., associate professor, discusses ongoing research with a postdoctoral fellow in his laboratory.
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Xiaoqiang Wang is probably one of the few plant structural biologists who started his career by looking at fish. In the late 1980s, Wang was a master's student at Wuhan University in central China, measuring the heat that radiates from a fertilized loach egg as it transforms into a striped - a swimming version of its former self. The particulars of loach embryology did not make an impression on him. Instead, he became fascinated with the chemicals that cued each step of the animal's development. Without the right enzymes appearing at the right time, he realized, the fish darting around in the tank would have remained a microscopic cluster of cells.

He wanted to know more about the most basic mechanics of life itself. He learned that the function of every enzyme in the plant and animal world depends on how it looks. Like paper airplanes, biological molecules work only when they are folded into their correct shapes.

Now an associate professor heading up a structural biology laboratory at the Noble Research Institute, Wang has devoted his life to figuring out what molecules look like - an undertaking that would be easier if anyone could really see them. But even the most powerful microscope cannot look at the arrangement of atoms in a protein. So scientists have to rely on an indirect method called x-ray crystallography. The technique has simple steps: purify the protein, coax it to solidify into a crystal, bombard it with x-rays and piece together a three-dimensional structure based on the pattern of x-rays as they bounce off the crystal. If this sounds straightforward, know that it is, in fact, so difficult that Nobel Prizes are awarded for the task. It was x-ray crystallography that revealed the double helix of DNA - the fundamental building block of all life. Despite the advanced technology involved, the shape for a typical molecule (if any one could be considered typical) takes years to emerge.

Among the challenges - aside from the fact that many key molecules in cells are stubbornly resistant to forming crystals - structural biologists also have to become experts at decoding the x-ray patterns, which appear simply as dots scattered across a page. "Even for a small molecule, we may need thousands of dots to get the shape," Wang said. To the rest of us, patterns produced by the x-rays look like little more than a Xerox gone wrong.

Wang has focused much of his work on enzymes that orchestrate the attachment of "sugars" to molecules - this action being known as glycosylation. Glycosylation is the most frequent chemical reaction in nature and is usually the final step in a long chain of reactions that a plant uses to make key compounds involved in defending the host plant from pests and disease, as well as undertaking basic plant functions. A group of enzymes called uridine diphosphate glycosyltransferases (UGTs) are the most significant for glycosylation in both human and plant physiology. Humans have about 20 UGT versions. However, plants contain a much greater diversity of UGTs since their survival depends on chemical warfare. A focus of research at the Noble Research Institute, the model legume Medicago truncatula is thought to contain more than 100 UGT versions.

Despite years of intense study, the function of UGTs has remained largely a mystery. While better understanding of these enzymes could provide insight into ways of enhancing plant defenses, the field also has implications for human health - glycosylation can affect the potency of antioxidants and antibiotics, or could one day aid in the synthesis of pharmaceuticals from simple natural compounds. But none of this can happen until scientists obtain a clear three-dimensional picture of each molecule.

Of the five plant UGTs for which a structure is known, three have come from the Wang laboratory. The first was published in 2005 and the last one in 2009. "It is groundbreaking work with significant implications for plant science research," said Richard Dixon, D.Phil., senior vice president and director of the Plant Biology Division. "We hope Dr. Wang's research will generate knowledge on in areas as diverse as plant defense and biofuel production. This could lead to improved varieties of plants, including forages for livestock, in the future."

In addition to determining the crystal structure of UGTs, Wang's laboratory has determined the crystal structure of two other types of enzymes vital in plant biology. One is a cytochrome P450, an enzyme that exists throughout nature and assists with a wide range of chemical reactions. Because cytochrome P450s are so difficult to extract and isolate from the membranes of a plant cell, Wang's research marked the first published description of the structure of a P450 enzyme in plants.

The Wang laboratory has also determined the crystal structures of two enzymes critical to the production of isoflavonoids - compounds involved in plant defenses that also have a significant benefit to human health. After obtaining the structure for both of these enzymes, Wang also determined the sites on the molecules critical to their function.

"From this information," he said, "we can understand how the enzyme works to catalyze its chemicle reaction."

While extraordinary, the discoveries of the Wang laboratory are merely a starting point that provides fundamental understanding. Eventually this information could lead to altering natural enzymes to improve their efficiency or expand their functionality.

Much like a child adjusts the folds on a paper airplane, trying to improve the way it flies, Wang and his research group are providing the plant science community with information that may one day benefit plant productivity or even improve animal or human health.

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