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Team Receives $2.7 Million to Investigate Major Therapeutic Target

By Eric Sauter

A consortium of scientists from both campuses of The Scripps Research Institute (TSRI) has been awarded $2.7 million from the National Institute of General Medical Sciences of the National Institutes of Health to study the structural rules that govern a large superfamily of proteins that help regulate critical functions such as reproduction, development and metabolism.

The principal investigators for the three-year study will be Kendall Nettles, an associate professor, and Pat Griffin, professor and chair of the Department of Molecular Therapeutics, both on the Florida campus of TSRI. They will work with Professor Ian Wilson and the Joint Center for Structural Genomics on TSRI’s La Jolla campus.

The focus of the new project is nuclear receptors, a superfamily of proteins that mediate hormone, lipid and fatty acid activity inside the cell. Nuclear receptors have been implicated in a number of cancers, including prostate, breast and colon cancers. They also represent excellent targets for drug development, including cancer drugs, birth control and anti-inflammatory agents and treatments for diabetes and metabolic syndrome.

Nuclear receptors are ligand-dependent transcription factors that function as scaffold proteins recruiting enzyme complexes to specifically turn genes on and off. Triggering nuclear receptor activity are molecules that include the sex hormones, vitamins A and D, glucocorticoids (which regulate the body’s response to stress) and many small molecules involved in metabolism, such as fatty acids, lipids and cholesterols. While several structures of the ligand-binding domain of nuclear receptors have been reported, little is known about the structural rules that allow nuclear receptors to control the function of the enzymes that mediate the receptors’ activity. The new study is aimed at filling this gap by obtaining structures of larger domains of nuclear receptors in complex with a subset of interacting proteins.

“We want to look at these proteins—which play key roles in metabolism, cancer, inflammation and bone health and are targets for widely prescribed drugs—and understand their signaling mechanisms through structural biology,” Nettles said.

To conduct this research, the team will use x-ray crystallography and nuclear magnetic resonance (NMR), methods that provide a three-dimensional picture of a molecule’s atomic structure. The team will draw on the high-throughput screening resources at Scripps Florida, as well as the high-throughput structural biology resources of the Joint Center for Structural Genomics based on the La Jolla, California campus.

The National Institutes of Health project number for the grant is 1U01GM102148-01.

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“We want to look at [nuclear receptors]—which play key roles in metabolism, cancer, inflammation and bone health … and understand their signaling mechanisms through structural biology.”
— Kendall Nettles