Better Medications for Treating Breast Cancer Could Come from Estrogen Receptor Studies at Yale University 3-D "Snapshot" of Progesterone Receptor Also Captured

Yale University researchers have visualized in atomic detail how two important female sex hormones, progesterone and estrogen, bind to their receptors – an accomplishment that could help scientists design better medications to treat breast cancer, ease the symptoms of menopause and prevent unwanted pregnancies.

Paul B. Sigler, a Howard Hughes Medical Institute investigator at Yale, and his colleagues are the first to solve the structure of progesterone binding with its receptor in humans and to make the data available to the worldwide research community through the Protein Data Bank at Brookhaven National Laboratories on Long Island. The Yale team was not the first to solve the structure of estrogen binding, but was the first to make it available to scientists through the data bank.

Sigler’s detailed atomic comparison of the estrogen and progesterone receptors binding – prepared in collaboration with Yale graduate student David M. Tanenbaum and postdoctoral associates Shawn P. Williams and Yong Wang – was published in the May 26 issue of the Proceedings of the National Academy of Sciences. A separate report by Sigler and Williams on the progesterone receptor alone was published May 28 in the journal Nature.

Drugs such as tamoxifin and raloxifene that bind to the estrogen receptor and block the uptake of estrogen have been shown in recent studies to be effective in treating and even preventing breast cancer. However, even more effective estrogen blockers could be created using the three-dimensional, computerized “snapshot” of the estrogen receptor captured at Yale, Sigler said. Tailor-made medications that improve the uptake of estrogen instead of blocking it could help relieve menopausal symptoms

Knowledge of a receptor’s molecular structure makes it possible to craft medications that bind to it more tightly, like a key fitting snugly in a lock. Such medications are less likely to cause unwanted side-effects, said Sigler, who specializes in molecular studies of a large family of important hormone receptors that includes those for the adrenal and sex steroids, vitamin D, thyroid hormone, and for retinoic acid, a derivative of vitamin A that is crucial for normal development of an embryo.

This family of steroid hormones plays a critical role in shaping the body and its internal organs, and in keeping the body functioning normally. The hormones work by entering the cell, where they are detected by specific receptors that, in turn, trigger gene expression.

“Our work with the progesterone receptor has given us by far the highest resolution, the clearest look we have ever had, of a steroid binding to receptor,” said Sigler, who is professor of molecular biophysics and biochemistry at Yale. Using a technique called X-ray crystallography, the researchers generated an image of progesterone bound snugly in its receptor’s specific binding pocket at a resolution of 1.8 angstroms, which is roughly the distance between two atoms.

Because progesterone is important for supporting gestation, blocking the progesterone receptor with a medication such as the European “morning after” pill RU486 can terminate a pregnancy. In the Yale studies, scientists created a computer model of how RU486 most likely binds to the progesterone receptor and disrupts its function.

The Yale discoveries, in addition to being important for drug design, reveal basic mechanisms of hormone action. “We found that progesterone and estrogen, which are very close to one another in structure at the atomic level, differ primarily in the polarity of one hydrogen bond,” Sigler said. “That distinction places progesterone among 3-keto steroids – a group that includes testosterone, androgens, cortisone and others – while estrogen is a 3-hydroxy steroid.”

Solving the structure of the two key hormone receptors adds to a string of successes in Sigler’s lab in demystifying the role of steroid hormones. Earlier, Sigler and his colleagues viewed for the first time how genes in cells throughout the body are targeted by steroids and related molecules like thyroid hormone. Gene expression is triggered by hormone receptors that reside in every cell, where they remain inactive until they receive a cue from an arriving hormone. Each receptor has three components: a sensor that recognizes an activating hormone, a courier that knows the correct address for the hormone’s target gene, and a gene activator that triggers gene transcription once the correct gene has been located, Sigler explained.

The recent Yale experiments focused on the receptor’s sensor component that recognizes hormones. Previous work focused on the courier component that directs the receptor to the appropriate hormone-responsive gene.

Professor Sigler explained that a steroid hormone diffuses into a cell and is detected by a specific receptor, which then travels to the heart of the cell and invades the nucleus, where genes are stored. Once inside the nucleus, the courier component of the receptor recognizes the target gene and latches onto it, thus triggering only that gene to go into action out of about 60,000 other genes.

“Hormone receptors are large, complicated molecules with domains or substructures responsible for various functions,” Sigler said. “Fortunately, we can crystallize the individual domains and, with X-ray diffraction, directly observe how the atoms are arranged in each domain.” The research was funded by Howard Hughes Medical Institute and the National Institutes of Health.