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Using a combination of techniques, including x-ray crystallography, Daniel
Leahy, Ph.D., a Howard Hughes Medical Institute investigator at the Johns Hopkins
University School of Medicine, and colleagues have determined the extracellular
structure of several of these receptors, answering some fundamental questions
about how the receptors operate. These structures suggest new approaches for
interfering with their signals and may lead to the design of novel anticancer
agents.
EGF receptors have a unique arm that remains folded when the receptor is inactive. The arm pivots open in a dramatic rearrangement when growth factors come to bind with it. The one receptor that stands out as different is HER2, which has its coupling arm always exposed, ready for action.
Over the past two years, groups in the United States, Japan, and Australia solved the crystal structures of different segments of these receptors. The groups came together to write a review article in September 2003, and "the picture
that emerged was really very exciting," Leahy says. "The review was needed to fit all the puzzle pieces into the big picture."
Today, they have seven different crystal structures, with distinct arrangements of the receptor domains, representing snapshots of both inactive and activated configurations. This wealth of data has revolutionized the view of how HER receptors are regulated.
"This explains a lot about HER2's unique properties," says Leahy. "It explains how HER2 is so promiscuous - readily partnering with each of the other EGF receptors - because it's always in the open state." When HER2 acts as a coreceptor to the other activated EGF receptors, growth signals are invariably enhanced, which likely underlies its role in several human cancers, he added.
Using the new information about the receptors' structures, researchers have begun work on new drugs that they hope will be more widely effective than Herceptin because they directly block the signaling between HER2 and its sister receptors.
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