Humans can sense five different tastes: sour, sweet, umami, bitter, and salty, using specialized sensors on our tongues known as taste receptors. These receptors not only allow us to enjoy delicious foods but also help us determine the chemical composition of foods and prevent us from consuming toxic substances. Researchers at the UNC School of Medicine recently set out to address how exactly we perceive bitter taste, focusing on the TAS2R14 bitter taste receptor. By solving the structure of this receptor and determining how bitter-tasting substances bind to it and activate it, they were able to gain insight into the mechanisms that initiate the sensation of bitter taste in our tongues.
TAS2R14 is a member of the G protein-coupled receptor (GPCR) family of bitter taste receptors. When bitter tastants come into contact with TAS2R14 receptors, they bind to a specific spot called an allosteric site, causing the protein to change shape and activate the attached G protein. This activation leads to a series of biochemical reactions within the taste receptor cell, ultimately sending signals to the brain’s gustatory cortex to be perceived as bitterness. Cholesterol also plays a role in the activation of TAS2R14 by residing in another binding site and helping to put the receptor in a semi-active state, making it easier to be activated by bitter tastants.
The discovery of the allosteric binding site for bitter tastants on TAS2R14 is significant as it opens up possibilities for the development of drugs that can directly regulate taste receptors. By targeting specific locations on the receptor, researchers may be able to treat metabolic diseases such as obesity and diabetes. The newfound structure of TAS2R14 allows for the discovery and design of drug candidates that can regulate G proteins through allosteric sites, affecting specific G-protein subtypes without causing unwanted side effects. This research also raises questions about the function of TAS2R14 outside of the mouth, as the protein has been found in locations such as the brain, thyroid, and pancreas, sparking further studies into its role in these areas.
The detailed protein structure of TAS2R14 and insights into its activation mechanisms provide a foundation for future drug development targeting taste receptors. By understanding how bitter tastants bind to TAS2R14 and initiate the sensation of bitter taste, researchers hope to develop drugs that can modulate taste perception and potentially treat metabolic disorders. The revelation that cholesterol plays a role in TAS2R14 activation adds to the complexity of taste perception and opens up new avenues for research into the interactions between cholesterol, bile acids, and TAS2R14. The discovery of a novel allosteric binding site for bitter tasting substances on TAS2R14 highlights the intricate mechanisms involved in taste sensation and provides valuable information for drug discovery efforts aimed at targeting taste receptors for therapeutic purposes.
Overall, the study sheds light on the structural makeup of taste receptors, particularly the bitter taste receptor TAS2R14, and the mechanisms by which these receptors initiate the perception of bitter taste. By solving the structure of TAS2R14 and uncovering the role of cholesterol in its activation, researchers have laid the groundwork for developing drugs that can modulate taste receptors and potentially treat metabolic diseases. The newfound knowledge of the allosteric binding site for bitter tastants on TAS2R14 offers promising prospects for drug development that can directly regulate taste receptors, aiming to improve taste perception and potentially address metabolic disorders such as obesity and diabetes.