Qing Fan and Wayne Hendrickson solved the structure of follicle-stimulating hormone (FSH), which is central to reproduction in mammals.

WHY DO RESEARCHERS work so hard to make three-dimensional crystal structures of molecules and their minuscule kin? “Most of these structures end up being a wellspring of ideas,” says HHMI investigator Wayne A. Hendrickson. “They are often filled with unexpected things.”

So it was with Hendrickson’s recent work to solve the crystal structure of a particular complex—follicle-stimulating hormone (FSH) binding to its receptor. The structure not only yielded clues about how the interaction works, but opened new research avenues for fertility treatments as well as contraception. Medical practitioners already use FSH injections for treating infertility, but researchers think that if they learn how FSH binds to its receptor on the surface of cells, they may be able to improve such therapies.

One of a family of signaling molecules—including luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone—FSH is a key regulator in human reproduction, controlling egg development in women and sperm production in men. Each of these hormones is composed of an α and a β subunit. Because they all use the same α subunit, researchers thought the specificity they have for their own receptors had to come from the β subunit.

Hints that this might not be strictly true had already come from the xray crystal structure of FSH alone, which James Dias and colleagues at the Wadsworth Center in the New York State Department of Health solved in 2001. But knowledge of that structure left open some big mysteries, including how an apparently disordered (flexible) C-terminal tail in the α subunit fit into the complex.

Now that Hendrickson, a professor of biochemistry and molecular biophysics at Columbia University College of Physicians and Surgeons, and Qing Fan, a postdoctoral fellow in his laboratory, have solved the structure of the hormone bound to the extracellular domain of the receptor, it’s clear why the α-subunit tail is so important. If it is mutated or deleted, the hormone can’t bind to the receptor. The researchers reported their results in the January 20, 2005, issue of Nature.

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