Detailed structure of bitter taste receptor revealed

Taste bud cells in the mouth allow us to detect substances that are bitter, salty, sweet, sour, and savory (or umami). These cells are studded with tiny receptors that bind to molecules in food called tastants. This binding helps to activate nerve cells that send signals to the brain, which then give us the sensation of taste.

But oddly enough, taste receptor genes are also activated in areas outside the mouth. Bitter taste receptors, for instance, have been observed in the intestines, lungs, heart, brain, and other tissues. Taste receptors in non-oral tissues are thought to serve as sensors that can send signals to activate other processes. However, the functions and activities of both oral and non-oral bitter taste receptors remain poorly understood.

To learn more, a research team led by Dr. Bryan L. Roth and Dr. Yoojoong Kim at the University of North Carolina took a closer look at the detailed structure and function of the bitter taste receptor called TAS2R14. Compared to the 25 other known bitter taste receptors, TAS2R14 is found at higher levels in non-oral tissues. It can also recognize over 100 unique tastants. Previous studies had suggested that cholesterol and bile acids, which are produced from cholesterol in the liver, can affect the activation of TAS2R14. But how this might happen was unknown.

The scientists used a high-resolution imaging technique called cryo-electron microscopy (cryo-EM) to uncover the structural details of TAS2R14 at near-atomic resolution (2.7 to 2.9 Å). Results were reported in Nature on April 10, 2024.

Cryo-EM structures revealed unique structural features of the activated TAS2R14 receptor, including two pockets where molecules can bind to activate the receptor. The researchers were surprised to find that the main pocket on the cell surface, called the orthosteric binding site, was occupied by a cholesterol molecule. A second pocket inside the cell, called an allosteric binding site, binds to smaller molecules. This binding was then analyzed in more detail.

Further studies showed that the cholesterol binding at the cell-surface site of the TAS2R14 receptor seems to prime the receptor, putting it into a semi-active state. This priming enables more ready activation of the receptor by small molecules, which then initiates nerve signals to the brain. Cholesterol binding alone does not seem to fully activate the receptor.

The new structural analysis hints that bile acids may bind to the same site as cholesterol. The researchers suggest that in non-oral tissues, the TAS2R14 receptor may serve as a sensor for cholesterol, bile acids, and other metabolites. In future studies, the scientists aim to learn more about taste receptor function in non-oral tissues.

“Scientists know very little about the structural make up of sweet, bitter, and umami taste receptors,” Kim says. “Using a combination of biochemical and computational methods, we now know the structure of the bitter taste receptor TAS2R14 and the mechanisms that initialize the sensation of bitter taste in our tongues.”

—by Vicki Contie