Invoking Fitzgerald

Scripps Florida scientists’ structural discoveries could aid in better drug design

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JUPITER, Fla.—Some concepts—the general theory of relativity and aspects of quantum mechanics come to mind—are sufficiently complex that attempts to explain and understand them are elusive. So when The Scripps Research Institute (TSRI) references F. Scott Fitzgerald, who once said that the test of a first-rate intelligence is the ability to hold two opposed ideas in mind at the same time and still retain the ability to function, you can expect to be challenged. “Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have found the biological equivalent of that idea, or something very close,” TSRI said in its release announcing the results of their work.
The abstract of the article titled “Structural mechanism for signal transduction in RXR nuclear receptor heterodimers,” published recently in Nature Communications, explains:
“A subset of nuclear receptors (NRs) function as obligate heterodimers with retinoid X receptor (RXR), allowing integration of ligand-dependent signals across the dimer interface via an unknown structural mechanism. Using nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry, here we show an allosteric mechanism through which RXR cooperates with a permissive dimer partner, peroxisome proliferator-activated receptor (PPAR)-γ, while rendered generally unresponsive by a non-permissive dimer partner, thyroid hormone (TR) receptor. Amino acid residues that mediate this allosteric mechanism comprise an evolutionarily conserved network discovered by statistical coupling analysis (SCA). This SCA network acts as a signaling rheostat to integrate signals between dimer partners, ligands and coregulator-binding sites, thereby affecting signal transmission in RXR heterodimers. These findings define rules guiding how NRs integrate two ligand-dependent signaling pathways into RXR heterodimer-specific responses.”
For the first time, the TSRI team has uncovered the structural details of how some proteins interact to turn two different signals into a single integrated output. These new findings could aid future drug design by giving scientists an edge in fine-tuning the signal between these partnered proteins—and the drug’s course of action.
“Thyroid, vitamin D and retinoid receptors all rely on integrated signals—their own signal plus a partner receptor,” said TSRI Associate Prof. Kendall Nettles, who led the study with TSRI colleague Associate Prof. Douglas Kojetin. “These new findings will have important implications for drug design by clearly defining exactly how these signals become integrated, so we will be able to predict how changes in a drug’s design could affect signaling.”
Using a number of complementary technologies, including nuclear magnetic resonance, X-ray crystallography and hydrogen/deuterium exchange mass spectrometry from the laboratory of Scripps Florida colleague Chair of the Department of Molecular Therapeutics Patrick R. Griffin, the scientists were able to determine the mechanism through which two signaling pathways become integrated.
The study focused on a small subset of nuclear receptors, a large family of proteins that regulate gene expression in response to signals from various binding partners, including steroids and fats. Once receptors sense the presence of these binding partners, they send out new signals that initiate other cellular processes.
“Nuclear receptors bind different types of molecules, and some of these receptors physically interact with each other to integrate different signals,” Kojetin said. “Earlier studies basically accepted this without any structural evidence for communication between receptors. This is the first time that anyone has looked at what’s actually going on at the atomic level.”
In addition to Nettles, Kojetin and Griffin, authors of the study include Edna Matta-Camacho, Travis S. Hughes, Sathish Srinivasan, Jerome C. Nwachukwu, Valerie Cavett, Jason Nowak, Michael J. Chalmers, David P. Marciano and Theodore M. Kamenecka of TSRI; Andrew I. Shulman of the University of California, Irvine; Mark Rance of the University of Cincinnati; and John B. Bruning of The University of Adelaide.
The work was supported by the National Institutes of Health, the Frenchman’s Creek Women for Cancer Research, the James and Esther King Biomedical Research Program, the Florida Department of Health and the State of Florida.
TSRI is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, Calif., and Jupiter, Fla., where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top 10 of its kind in the nation.

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