For a new study, researchers from the UNC School of Medicine wanted to explore how people perceive the taste of bitterness.

Understanding the Taste of Bitterness

The new study, entitled "Bitter taste receptor activation by cholesterol and an intracellular tastant," sheds light on the TAS2R14 bitter taste receptor's intricate protein structure. In addition to solving the taste receptor's structure, the scientists were also able to determine where the substances of bitter taste bind to the protein and how they can activate them and enable the bitter taste.

Yoojoong Jum, Ph.D., a postdoctoral researcher from the Roth Lab, explains that very little is known about the structural makeup of the umami, sweet, and bitter taste receptors. Using a mix of computational and biochemical methods, the researchers were able to learn more about the structure of the TAS2R14 bitter taste receptors and the mechanisms that initialize the bitter taste sensation in the tongue.

Such data is crucial for the design and discovery of drug candidates that directly regulate taste receptors. These candidates could potentially treat metabolic conditions such as diabetes and obesity.

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Bitter Taste Receptors

The TAS2R14 receptors belong to the GPCR (G protein-coupled receptor) family of bitter taste receptors. These receptors are linked to a protein called G protein. Compared to other proteins within the family, TAS2R14 stands out due to its capacity to identify over 100 unique substances called bitter substances.

The scientists discovered that when bitter tastants come into contact with TAS2R14s, the chemicals are wedged into a certain receptor spot known as the allosteric site. This prompts the protein to alter its shape and activate the G protein attached to it.

This leads to various biochemical reactions in the taste receptor cell. It further leads to the receptor's activation, which could relay signals to tiny fibers of nerves to a brain region known as the gustatory cortex. This is where the signals are processed and perceived as bitterness. Such a complex system of signals happens nearly instantaneously.

The researchers discovered another distinct feature of the taste receptor. They found that cholesterol was aiding its activation. Kim explains that cholesterol was in a different binding site in the TAS2R14 known as the orthosteric pocket, while the bitter tastants bind with the allosteric site. The researchers discovered through molecular dynamics simulations that cholesterols semi-activate the receptor, enabling it to be easily activated by a bitter tastant.

With their newly discovered structure, the researchers found that bile acids, which are produced in the liver and have chemical structures similar to cholesterol, could bind to the orthosteric pocket, similar to cholesterol. The exact purpose of cholesterol or bile acid in the taste receptor remains a mystery, but it could have a role in the substances' metabolism or relation to metabolic conditions.

The finding regarding the allosteric binding site for substances that taste bitter is unique. Kim explains that in the future, the structure will be pivotal in the design and discovery of drug candidates that may regulate G proteins via allosteric sites.

The scientists are planning further research to elucidate protein function beyond the mouth.

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