Team Solves X-ray Structure Of Powerful Enzyme

September 28, 1998

MADISON, Wis. -- Researchers at the University of Wisconsin Medical School and the National Institutes of Health have determined the three dimensional molecular structure of a powerful enzyme responsible for activating many cell functions.

Reported in the current issue of the journal Cell, the new information is a crucial step in the potential development of drugs that may be used to control unchecked cell growth leading to cancer as well as the spread of cancer throughout the body.

The research represents a milestone in an on-going UW Medical School effort to fully understand the large family of enzymes known as phosphoinositide kinases. The enzymes are usually located on the cell membrane, where they receive signals from outside the cell. They relay the signals by generating "second messengers," which in turn pass them along to proteins that initiate and control various kinds of cellular activity.

"The enzymes regulate a cascade of events related to almost every aspect of cell function in our bodies, including the ability of cells to move and secrete neurotransmitters and hormones, and their ability to divide and grow," said UW Medical School professor of pharmacology Richard Anderson, who directed the research. "When the second-messenger signalling system doesn't function properly, cells can proliferate wildly, causing cancers, or travel to distant parts of the body, resulting in cancer metastasis."

UW Medical School's pharmacology department has a deep and long-running interest in phosphoinositide kinases. More than 50 years ago Dr. Lowell Hokin was the first to discover the enzymes and the signalling cascade they initiate in cells. Following this tradition, scientists in Anderson's laboratory were the first to isolate the gene underlying these enzymes, and to purify them and define their biochemical composition.

For the current Cell (Sept. 18) study, the Anderson team genetically engineered bacterial cells to produce large quantities of one member of the enzyme family exactly as it is found in its natural state. The large, accurate quantities were required for collaborator James Hurley of the NIH to determine the three-dimensional X-ray crystal structure of the enzyme. The technique entails growing a crystal of the enzyme, taking an X-ray picture of it and then processing the X-ray image through a computer.

"Understanding the structure of the enzyme at the molecular level, as we have done with this X-ray crystallography, will help scientists figure out how to manipulate it," said Anderson. "Using these studies as a foundation, we will be able to modify the enzyme, either genetically or by developing therapeutic drugs that can block the generation of second messengers."

Anderson said the next step for his laboratory will be to use the structural information to study the way the enzymes control activities that result in functions such as cell growth and movement.
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Dian Land, medical/science writer
University of Wisconsin-Madison
610 Walnut St., room 746
Madison, WI 53705
ph: 608/263-9893
fx: 608/263-6394
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University of Wisconsin-Madison

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