“Tasting Upside-Down - An Unusual Sensing Mechanism was Found in Human Bitter Sensing” A new study revealed that some bitter molecules target their sensor through binding simultaneously at two distinct locations, one outside the cell, and the other inside it. This discovery is fascinating because bitter taste receptors are expressed in extra-oral tissues and the new study shows the potential of our cells to sense not only external but also internal signals, opening up new possibilities for drug design, including asthma and inflammation.

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A new study, published in Nature Communications, led by Prof. Masha Niv from the Hebrew University of Jerusalem, Dr. Moran Shalev-Benami from the Weizmann Institute, and Dr. Dorothee Weikert from FAU Erlangen, describes an exciting discovery that changes the way we understand human bitter taste receptors. The research has revealed a hidden "pocket" inside one of the body’s bitter taste receptors, called TAS2R14. This breakthrough could help not only understand how our tongue senses bitterness, but also investigate the physiological roles of bitter taste receptors that are expressed extraorally.

There are many chemically different molecules that trigger bitter taste sensations, and the body uses a family of 25 receptors to detect them. Interestingly, many drugs also activate this bitter taste system.

Unlike most other bitter taste receptors, TAS2R14 is highly "promiscuous," meaning it can recognize and respond to a wide variety of bitter substances, from vitamins to certain drugs and even odorants. The receptor’s ability to respond to such a diverse array of compounds makes it a subject of great interest for researchers. Until now, however, how exactly TAS2R14 binds to these compounds and triggers a response in the body was not fully understood.

The scientists used an advanced technology in electron microscopy (EM) that allows to see the three-dimensional architecture of proteins in great detail. This technique, called cryo-EM, enabled to solve the structure of TAS2R14 together with flufenamic acid (FFA)—a bitter anti-inflammatory drug that activates TAS2R14. The structure led to a surprising discovery: the drug binds simultaneously at two distinct positions of the receptor: one copy bound at an extracellular site and the other at the intracellular one. This dual binding, sheds new light on how the receptor interacts with diverse chemical compounds, including those that cause bitterness.

“This discovery gives us a new clue into how TAS2R14 works,” explained Professor Niv. “It’s fascinating because the receptor is not just sensing chemicals from outside the cell, like food or drugs, but also 'tasting' what’s happening inside the cell. This new intracellular pocket could be a game-changer in how we design drugs to interact with these receptors.”

“To provide direct evidence for binding of the molecule at different pockets of the receptor, we have developed a new assay, which enables us to measure the binding specifically at the extracellular and the intracellular binding site, providing a unique tool for site-specific discovery”, says Dr. Dorothee Weikert.

“TAS2R receptors do much more than just help us taste bitterness,” the scientists Lior Peri and Dr. Matzov said. “They are found in many parts of the body and are involved in processes like breathing, digestion, and the immune system. By discovering this new pocket, we’ve opened the door to new ways of designing medications that target these receptors, potentially helping to treat conditions like asthma, obesity, and inflammation.”