Nuclear receptors are proteins that directly bind DNA to turn genes on or off in response to outside signals. For some of the 48 members of this protein family, it’s well known what sets them in motion and what genes they activate or inactivate. The estrogen receptor, for example, is a nuclear receptor that receives estrogen, the female hormone, and switches on genes that drive female characteristics. For other nuclear receptors, the orphans, all we really know is that they resemble other family members. Their function and their binding partners remain a mystery.
Enter Dr. Fraydoon Rastinejad, new professor in Sanford-Burnham’s Diabetes and Obesity Research Center in Lake Nona and caretaker of orphan receptors.
“We are interested in how a subset of the nuclear receptor family works – the orphans. Even though some of these receptors have thousands of publications already, there are still dozens that very few people work on,” Dr. Rastinejad explains. “We don’t have a clue what their natural binding partners are or what genes they regulate. But they’re all part of the nuclear receptor family, so there’s a lot of excitement every time a new one is uncovered.”
Dr. Rastinejad recently made the move to Sanford-Burnham at Lake Nona from the University of Virginia, where he spent 15 years studying the structure of nuclear receptors, especially one called PPAR, though it is not an orphan. PPAR is known to regulate how much fat accumulates in fat tissue versus how much ends up in muscle. Drugs that target PPAR to treat type 2 diabetes are currently on the market.
“One of the things I like most about working on this receptor family is that each member already has an internal pocket that you can find or design molecules to fit… making them ready-made drug targets,” he says.
In Lake Nona, the Rastinejad lab is interested in determining the crystal structures of nuclear receptors, especially the orphans. They want to see the actual atoms that comprise them. They want to understand how binding partners fit inside the nuclear receptor pocket. Ultimately they want to use this information to optimize current drugs, as well as design new therapies targeting this family.
That’s a lot of work and Dr. Rastinejad believes that his fellow researchers at Sanford-Burnham will help make it possible. “I enjoy being here because our research is complementary – we all bring different things to the show. This is the perfect place for me. I wish I’d found Sanford-Burnham 15 years ago! I guess I’m still young… better than finding it ten years from now, right?” he says.
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For more info on Dr. Rastinejad’s favorite protein family, see Nuclear Receptors 101.
For more Sanford-Burnham faculty, view all profiles on Beaker.