May 19, 2006

In Drug Design, a Loose Fit May Be Best

Hormones bind to receptors on the surface of cells, causing a cascade of chemical reactions inside the cell A hormone molecule fits into a specially shaped site on a receptor protruding from the surface of a cell. This interaction forces the receptor to change shape and splits apart the G-protein to which the receptor is linked. This triggers a cascade of chemical reactions inside the cellNIH's National Institute of General Medical Sciences.

Researchers have long thought that the stronger the association between a hormone and its receptor, the more effective its signaling. In a new study, chemical knockoffs resembling a key thyroid-related hormone are, in certain cases, more effective than the real thing at activating their target receptor. The improved performance is related to how closely the chemical and receptor are coupled. But what's surprising is that the researchers found a loose connection to be more effective than a tight one. If the findings hold true, they could help change the way drug therapies are designed for a host of health problems, from smell and taste disorders to heart disease, asthma, migraine and pain.

The research team, which included researchers at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute on Deafness and Other Communication Disorders (NIDCD), looked at thyrotropin-releasing hormone (TRH). TRH is a hormone released in the brain that kicks off a chain of events throughout the body, including the stimulation of the thyroid gland. As with many of the body's hormones, cells recognize TRH using a receptor from a mega-family of proteins known as G-protein-coupled receptors (GPCRs). GPCRs and G-proteins play crucial roles in cell-to-cell communication. When a hormone binds to its designated GPCR on the outside of a cell, a specific G-protein is activated within the cell, initiating a cascade of chemical reactions that produce the unique cellular effects of that hormone.

In the study, published in the May 12 issue of the Journal of Biological Chemistry, the researchers tweaked portions of the TRH molecule to develop 6 slightly edited variations that retained most of the properties of the natural hormone. Measuring the cellular responses to the hormones, they found that the weaker the connection, the stronger the signal — in fact, up to twice as strong as TRH.

As an explanation, the researchers suggest that a loose connection between hormone and receptor may allow a hormone to repetitively dock and undock from its associated GPCR, activating a succession of G-proteins and thus firing signal after signal. A tighter connection, in contrast, may tie up a hormone with its GPCR, activating fewer G-proteins and resulting in a weaker signal.

"GPCRs are the targets of roughly a third of medicines sold today, so if this finding for TRH holds for other GPCR targets, it could have significant implications for drug development," says Dr. Marvin C. Gershengorn, director of NIDDK's Division of Intramural Research and senior author of the paper.

Related Links