Humans can sense five different flavors: sour, sweet, umami, bitter and salty, using specialized sensors on our tongue called taste receptors. In addition to allowing us to enjoy delicious foods, the sensation of taste allows us to determine the chemical composition of food and prevents us from consuming toxic substances.
UNC School of Medicine researchers, including Bryan Roth, MD, PhD, Michael Hooker Distinguished Professor of Pharmacology, and Yoojoong Kim, PhD, postdoctoral researcher in the Roth Laboratory, recently set out to address a very basic question: ” How exactly do we perceive the bitter taste?”
A new study, published in Nature, reveals the detailed protein structure of the bitter taste receptor TAS2R14. In addition to solving the structure of this taste receptor, the researchers were also able to determine where bitter-tasting substances bind to TAS2R14 and how they activate them, allowing us to taste bitter substances.
“Scientists know very little about the structural composition of sweet, bitter and umami taste receptors,” Kim said. “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 bitter taste sensation on our tongues.”
This detailed information is important for discovering and designing drug candidates that can directly regulate taste receptors, with potential to treat metabolic diseases such as obesity and diabetes.
From chemistry to electricity to sensation
TAS2R14 are members of the G protein-coupled receptor (GPCR) family of bitter taste receptors. The receptors are attached to a protein known as the G protein. TAS2R14 stands out from the others in its family because it can identify more than 100 different substances known as bitter tastes.
The researchers found that when bitter tastes come into contact with the TAS2R14 receptors, the chemicals lock into a specific spot on the receptor called the allosteric site, causing the protein to change its shape, activating the attached G protein.
This triggers a series of biochemical reactions within the taste receptor cell, leading to activation of the receptor, which can then send signals down small nerve fibers (via the cranial nerves of the face) to an area of the brain called gustatory cortex. . This is where the brain processes and perceives signals as bitterness. And of course, this complex signaling system occurs almost instantaneously.
The role of cholesterol in the reception of bitter taste
While working to define its structure, the researchers found another unique feature of TAS2R14: that cholesterol aids in its activation.
“Cholesterol resided in another binding site called the orthosteric pocket in TAS2R14, while bitter taste binds to the allosteric site,” Kim said. “Through molecular dynamics simulations, we also discovered that cholesterol puts the receptor in a semi-active state, so it can be easily activated by bitter taste.”
Bile acids, which are created in the liver, have similar chemical structures to cholesterol. Previous studies have suggested that bile acids can bind and activate TAS2R14, but little is known about how and where they bind on the receptor.
Using their new structure, the researchers discovered that bile acids could bind to the same orthosteric pocket as cholesterol. While the exact role of bile acids or cholesterol in TAS2R14 is still unknown, it may play a role in the metabolism of these substances or in relation to metabolic disorders such as obesity or diabetes.
How this can help drug development
The discovery of this new allosteric binding site for bitter-tasting substances is unique.
The allosteric binding region is located between TAS2R14 and its coupled G protein is called G protein alpha. This region is critical for forming a signaling complex, which helps transfer the taste receptor signal to the G protein to taste receptor cells.
“In the future, this structure will be key to discovering and designing drug candidates that can directly regulate G proteins through allosteric sites,” Kim said. “We also have the ability to affect specific G protein subtypes, such as G protein alpha or G protein beta, rather than other G protein pathways that we don’t want to cause other side effects.”
Roth and Kim have made several new discoveries, but some leave more questions than answers. While conducting a genomic study, they discovered that the TAS2R14 protein in complex with GI is expressed outside the tongue, especially in the cerebellum of the brain, thyroid, and pancreas. The researchers are planning future studies to elucidate the function these proteins may have outside the mouth.
This work was supported by the NIH shines a light on drug genome initiative.