Structure Of Key Receptor Unlocked; Related Proteins Will Fall Like Dominoes

"It took us more than two years to interpret the data and get HER3's structure," says Dan Leahy, Ph.D., a Howard Hughes Medical Institute investigator and a professor of biophysics in Hopkins' Institute for Basic Biomedical Sciences. "Now that we have it, it might take only weeks to figure out its relatives."

Reporting the structure in the Aug. 1 online version of Science, Leahy says finding out the shapes of the entire HER family of proteins, HER1, HER2 and HER4, will provide the first opportunity to rationally design new drugs to interfere with them, possibly preventing or treating select forms of cancer.

HER2, for example, is the target of the breast cancer treatment Herceptin, an antibody. But while it's an effective life-prolonging treatment in certain breast cancer patients, different strategies targeting HER2 might also prove effective. Having a protein's structure allows scientists to conceive new strategies and pursue new classes of drugs, says Leahy.

A focus of many scientists because of the proteins' involvement in cell growth, the HER family are receptors for "epidermal growth factor" (EGF) and other chemicals. Although the DNA sequences of HER proteins have been known for some time, technical problems dogged efforts to understand how the proteins are shaped, Leahy says.

"Until we know proteins' structures, we're very limited in figuring out how a molecule or possible drug might bind," says Leahy. "We now have a starting point to see how molecules binding to HER3 change its shape and turn it on."

Stuck in the cell membrane, each HER protein consists of three parts: a region outside the cell that recognizes and binds certain molecules; a region that anchors the protein in the cell membrane; and a region inside the cell that, when activated, adds phosphates to various proteins. Leahy and postdoctoral fellow Hyun-Soo Cho determined the structure of the first of these regions for HER3.

Combining a number of available methods, Leahy, Cho and technician Patti Longo purified large amounts of the HER3 receptor region and formed uniform crystals, crucial for figuring out protein structures. By bombarding the crystals with X-rays at the National Synchrotron Light Source at Brookhaven National Laboratory in New York, Cho got the information he needed to start figuring out how the protein looks in space.

In each crystal there are billions of protein molecules, organized in a careful pattern. As the X-rays travel through the crystal, they hit individual atoms in the protein and are bounced back or bent, depending on the 3-D arrangement of the atoms. Others travel through unaffected. By analyzing where the X-rays end up, the scientists can reconstruct how the protein is put together.

One unexpected aspect of the protein's structure is what Leahy and Cho call the "snap" region -- two finger-like loops that reach out toward one another and interact, stabilizing the structure.

"While it's all speculation right now, it's easy to imagine how losing the "snap" interaction might be involved in binding or activation," Leahy says.

HER1 and HER4 have the same sequence of building blocks in the "snap" region, but HER2 does not, which may help explain why HER2 is the only one of the four receptors that interacts only with other HER proteins.

The experiments were funded by the Howard Hughes Medical Institute and the National Institutes of Health.