Structure
of HER2 receptor explains why Herceptin therapy is effective against
breast cancer tumors with excess receptor
Discovery
of the three-dimensional structure of the HER2 receptor, which is
overexpressed in 20 to 30 percent of breast cancer cases, explains
why antibody therapy with Herceptin is effective against those tumors,
according to an article in the February 13th issue of Nature. The
discovery also explains why overexpression of that receptor can
result in cancer, whereas overexpression of other receptors in the
same family does not result in tumors.
"Now we know exactly which building blocks of the Herceptin
antibody interact with which building blocks of HER2," said
Dan Leahy, Ph.D., a coauthor of the article. "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."
Herceptin, which was approved for use in the
U.S. in 1998, kills cancer cells carrying excess HER2 receptor;
however, the current study marks the first time anyone has understood
precisely how the antagonist interacts physically with the receptor.
The findings also explain why the HER2 receptor
behaves so differently from related growth factor receptors called
HER1, HER3, and HER4, according to Leahy, whose team determined
the structure of the HER3 receptor last summer. Although all four
proteins are similar in amino acid sequence, only excess HER2 receptor
leads to uncontrolled cell growth in both laboratory and human studies.
All of the receptors are transmembrane proteins,
with part outside the cell and part inside the cell. Binding of
the extracellular part causes HER receptors to form pairs, become
fully active, and trigger events that result in cell division.
Comparison of HER receptor structures reveals
that a few changes in amino acid sequence are the basis for the
difference between HER2 and other HER receptors as stimulators of
cell growth. Specifically, the HER2 receptor does not need to be
opened through binding of a molecule before it can pair with another
receptor. This is why the mere presence of extra receptors can cause
cancer without the presence of ligands that bind to them, said Leahy.
"We can see now that it's unlikely any
natural ligands for HER2 exist -- it just doesn't need one to work,"
added Leahy.
Led by Hyun-Soo Cho, Ph.D., the research team
grew crystals of the extracellular part of the HER2 protein. After
bombarding the crystals with radiation, the team interpreted the
data to create the protein's structure. The team went through the
same process with crystals of HER2 receptor bound to Herceptin antibody.
The researchers found that all of the
HER receptors have extracellular regions made up of four structurally
distinct sequences, or domains. HER 1 and HER3 receptors have a
bracelet-shaped loop that connects the second and fourth domains.
However, HER2 has a tight connection between the first and third
domains, which prevents formation of the bracelet-shaped loop and
opens the fourth domain for potential binding with Herceptin antibody.
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