For Hendrickson, though, the excitement of the work comes not just from the answers it provides but from the new ideas it generates. For example, in many protein-protein interactions, the interface between the molecules tends to be “greasy” and excludes water, but in this case the contact area between the receptor and the hormone was highly charged, full of negative and positive charges attracting each other.

“We knew that charge was important in the binding,” says Dias, “but the new structure showed us that stereochemistry [the spatial arrangement or organization of the molecules] was also important and we couldn’t have gotten that information without the structure.”

The new structure provided by Hendrickson and Fan gives a picture of how the hormone interacts with part of the receptor protein, but it doesn’t show how the receptor becomes activated in response to hormone binding. To observe that phenomenon, the researchers think they need to see the hormone binding to the whole receptor protein, including the membrane-spanning region. This presents a formidable challenge because proteins that are designed to reside in membranes are difficult to purify and crystallize.

Meanwhile, the team is starting to think about how the current structure might be used in medical practice. “Protein-protein interfaces are notoriously difficult to disrupt with small-molecule drugs,” says Hendrickson. “But if we could disrupt the hormone-receptor interaction, we’d instantly have a contraception approach that works for both men and women.” Conversely, better knowledge of how FSH interacts with its receptor might also help researchers develop a new, orally available mimic that could be used to treat infertility by stimulating egg or sperm production.

Photo: Christopher Jones

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