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Structure of key breast cancer receptor determined

A team of scientists from Johns Hopkins and the biotechnology company Genitope has unlocked the 3-D structure of a receptor that goes awry in 20 percent to 30 percent of breast cancers. Reporting in the Feb. 13 issue of the journal Nature, the scientists also figured out how the receptor, known as HER2, interacts with an antibody, sold as Herceptin, that is used to treat thousands of breast cancer patients each year.

"Now we know exactly which building blocks of the Herceptin antibody interact with which building blocks of HER2," says Dan Leahy, Ph.D., professor of biophysics and a Howard Hughes Medical Institute investigator at the Johns Hopkins School of Medicine. "When you understand the properties of receptors and antibodies in terms of their structural interaction, you can begin to explain their effects and use the information to design better drugs."

Developed by Genentech, Herceptin kills cancer cells carrying excess HER2. But even though Herceptin was approved as a breast cancer treatment by the U.S. Food and Drug Administration in September 1998, until now no one has known precisely how it interacted with the receptor.

The findings also explain why the HER2 receptor behaves so differently from its relatives HER1, HER3 and HER4, says Leahy, in whose laboratory the structure of HER3 was deciphered last summer. While all four proteins are similar in the sequence of their building blocks, only excess HER2 leads to uncontrolled cell growth in the lab and breast cancer in people.

Like its relatives, the HER2 receptor is stuck in the cell membrane, partially outside the cell, and partially inside. The extracellular part, whose structure the scientists determined, is the receptor's "on switch." Through this region, HER receptors join into pairs to become fully active and trigger events that eventually result in cell division.

Comparisons of HER family structures reveal that a few key changes in the sequence make all th
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
12-Feb-2003


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