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In drug design, a loose fit may be best bet

vision of Intramural Research and senior author of the paper.

"At first glance, a cellular process that affects the thyroid gland may not seem especially meaningful to the study of communication disorders," says John Northup, Ph.D., who heads the Section on Signal Transduction of NIDCD's Laboratory of Cellular Biology. "However this research provides information that is fundamental to cellular signaling, a function that is essential to all cells in all systems in the body, including our sensory systems of hearing, balance, taste, and smell."

By tweaking portions of the TRH molecule, the researchers developed six slightly edited versions, while retaining most of the properties of the natural hormone. Measuring the cellular response when hormone meets receptor, they found that the lower the affinity between the two, the stronger the signal that is elicited, with certain analogs performing up to twice as effectively as TRH. As to why this would be the case, the researchers suggest that a loose connection between hormone and GPCR may allow a hormone to repetitively dock to and undock from its associated GPCR, activating a succession of G-proteins, and firing signal after signal. A tight connection, alternatively, may tie up a hormone with its GPCR, activating one G-protein, and limiting its signaling ability.

In future studies, the scientists hope to determine whether their findings are consistent with other hormone-GPCR reactions. Other researchers taking part in the study represent the National Institute of Pharmaceutical Education and Research, Punjab, India.


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Source:NIH/National Institute of Diabetes and Digestive and Kidney Diseases


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