Structure of key receptor unlocked; Related proteins will fall like dominoes

After two years of stubborn persistence, scientists at Johns Hopkins have determined the 3-D structure of part of a protein called HER3, which should speed efforts to interfere with abnormal growth and cancer.

"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 re

Contact: Joanna Downer
Johns Hopkins Medical Institutions

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