Bitter Taste Receptor Engages Compounds Not Just Outside the Cell, but Inside

A bitter taste receptor, TAS2R14, has been shown to respond to both extracellular and intracellular signals. Indeed, it can respond to both signals simultaneously. This finding is especially interesting because bitter taste receptors are expressed not just orally, but extraorally. Also, these receptors respond not just to bitter-tasting substances, but to various kinds of drugs. Consequently, the dual-binding mechanism found for TAS2R14 opens up new possibilities for drug design.

The extracellular/intracellular capabilities of TAS2R14 were uncovered by scientists led by Masha Niv, PhD, from the Hebrew University of Jerusalem; Moran Shalev-Benami, PhD, from the Weizmann Institute; and Dorothée Weikert, PhD, from Friedrich-Alexander-Universität Erlangen-Nürnberg. They presented their work in Nature Communications, in an article titled, “A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR.”

“Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 complexed with its signaling partner gustducin and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug,” the article’s authors wrote. “The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the transmembrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin.”

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

Essentially, the research has revealed a hidden “pocket” inside 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. Interestingly, bitter taste receptors are also activated by many drugs.

The scientists used cryo-EM techniques, which allow the three-dimensional architecture of proteins to be seen in great detail. In the current study, cryo-EM revealed the structure of TAS2R14 together with flufenamic acid—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 mechanism sheds new light on how the receptor interacts with diverse chemical compounds, including those that cause bitterness.

“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,” Weikert added.

“TAS2R receptors do much more than just help us taste bitterness,” noted the study’s lead authors, Hebrew University’s Lior Peri and the Weizmann Institute’s Donna Matzov. “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.”