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NIGMS Gives $2.7M to Scripps Research Institute for Nuclear Receptor Study

NEW YORK (GenomeWeb News) – Scripps Research Institute has received a three-year, $2.7 million grant from the National Institute of General Medical Sciences to study the structural rules governing a class of proteins that help regulate cellular functions, such as reproduction, development, and metabolism.

Scripps will use the grant for research into nuclear receptors, which comprise 48 proteins that "control endocrine and metabolic physiology by regulating gene expression, and control other cellular function such as signal transduction," according to the grant's abstract. Nuclear receptors, Scripps said, also make "excellent" targets for drug development.

They function as "a scaffold to recruit enzymes and other proteins to DNA, regulating the reading of the DNA code in each cell and thus controlling cellular functions," and while several structures of the ligand-binding domains of nuclear receptors have been reported, the structural rules that allow nuclear receptors to control the function of the enzymes mediating receptor activity remains a mystery.

In their work, Scripps researchers will attempt to fill the knowledge gap by "obtaining structures of larger domains of nuclear receptors in complex with a subset of interacting proteins."

The principal investigators on the study are Kendall Nettles, an associate professor, and Pat Griffin, a professor and chair of the Department of Molecular Therapeutics at Scripps' Florida campus. Ian Wilson, a professor at the Joint Center for Structural Genomics at Scripps' La Jolla, Calif., campus is also participating in the study.

"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 in a statement.

As part of their work, the researchers will use X-ray crystallography and nuclear magnetic resonance methods to obtain a three-dimensional image of a molecule's atomic structure, followed by high-throughput screening and high-throughput structural biology methods.

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