The protein structure of the bitter taste receptor TAS2R14 has been revealed in a new study. Researchers have also identified the specific location where bitter-tasting substances bind to TAS2R14 and how they activate it. These findings could potentially pave the way for the development of drugs targeting taste receptors. Humans have the ability to perceive five different tastes – sour, sweet, umami, bitter, and salty, which are detected by specialized sensors on our tongues known as taste receptors. In addition to enhancing our enjoyment of food, the sense of taste plays a crucial role in our overall perception of flavor.The chemical makeup of food is determined by researchers at the UNC School of Medicine, such as Bryan Roth, MD, PhD, and Yoojoong Kim, PhD. They wanted to understand how we perceive bitter taste. Their study, published in Nature, revealed the detailed protein structure of the TAS2R14 bitter taste receptor. This allowed them to identify and prevent toxic substances from being consumed.The process involves substances that are bitter-tasting binding to TAS2R14 and activating them, allowing us to perceive bitter tastes. ”There is very limited knowledge among scientists about the structural composition of sweet, bitter, and umami taste receptors,” Kim stated. “With the use of biochemical and computational methods, we now have a better understanding of the structure of the bitter taste receptor TAS2R14 and the mechanisms that initiate the sensation of bitter taste on our tongues.” This in-depth knowledge is crucial for the development and creation of drug candidates that can directly control taste receptors, which has the potential to address metabolic diseases like obesity.and diabetes.
From Chemicals to Electricity to Sensation
TAS2R14s belong to the G protein-coupled receptor (GPCR) family of bitter taste receptors. These receptors are linked to a protein called a G protein. What sets TAS2R14 apart from the others in its family is its ability to detect over 100 different substances known as bitter tastants.
Scientists discovered that when bitter tastants interact with TAS2R14 receptors, the chemicals insert themselves into a specific spot on the receptor known as an allosteric site. This leads to the protein changing its shape, causing a cascade of electrical signals within the cell.The G protein that is connected to the taste receptor is activated, setting off a chain of biochemical reactions within the taste receptor cell. This leads to the activation of the receptor, which then transmits signals to small nerve fibers in the face, through the cranial nerves, and on to the gustatory cortex in the brain. This is where the brain interprets the signals as bitterness. All of this happens almost instantly.
Additionally, as researchers were examining the structure of TAS2R14, they discovered another interesting characteristic related to cholesterol’s role in bitter taste reception.
When cholesterol is present in the orthosteric pocket of TAS2R14, it allows the receptor to be in a semi-active state, making it more easily activated by bitter tastants. Bile acids, which have similar chemical structures to cholesterol, are also known to activate TAS2R14, but the specific binding mechanism is not well understood.
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Researchers have discovered that bile acids may be binding to the same orthosteric pocket as cholesterol. The exact role of bile acid or cholesterol in TAS2R14 is still unknown, but it could be related to the metabolism of these substances or to metabolic disorders such as obesity or diabetes.
Significance for Drug Development
This discovery of a new allosteric binding site for bitter substances is significant.
The allosteric binding site is located between TAS2R14 and its associated G protein, known as G-protein alpha. This site is crucial for the function of the receptor.A call to form a signaling complex helps transfer signals from taste receptors to G-proteins in taste receptor cells. According to Kim, this structure will be crucial for discovering and designing drug candidates that can directly regulate G-proteins through allosteric sites in the future. The ability to affect specific G-protein subtypes, such as G-protein alpha or G-protein beta, rather than unwanted G-protein pathways, is also possible. Although Roth and Kim have made several new discoveries, some raise more questions than answers. While conducting a genomics study, they discovered The TAS2R14 protein, when in complex with the GI, is found to be expressed in areas outside of the tongue, such as the cerebellum, thyroid, and pancreas in the brain. Researchers are looking to conduct further studies to understand the potential functions of these proteins outside of the mouth.
Funding for this work was provided by the NIH Illuminating the Druggable Genome Initiative.
