Regular coffee drinkers know there is a big difference between a brew’s aroma and its taste. A cup may smell warm and full-bodied only to leave you with a lingering bitterness behind the first sip. Researchers have long known a coffee’s potentially acrid flavor profile is dictated at a molecular level thanks to your tongue’s taste receptors, but how that occurs has remained a mystery. Now, a team at the University of North Carolina at Chapel Hill has the answer thanks to precise imaging technology—and their findings may have much wider ramifications beyond the coffee pot.

The details were published in the journal Nature Structure & Molecular Biology, and focuses on TAS2R43, one of our 26 different bitter taste receptors. These mechanisms are expressed throughout the human body, and likely evolved to guard the species against toxic substances as well as helping regulate our metabolisms.

“Bitter taste receptors are thought to be important for detecting toxins, pathogens, and harmful bacteria in the airways, gut, skin, and organs, initiating immune responses, clearing pathogens, regulating immune cells, influencing hormone secretion, and aiding digestion,” explained study co-author and molecular biologist Bryan Roth.

Scientists first determined the microscopic structure of TAS2R43 a few years ago, but until Roth’s team, no one had analyzed how it responds to bitter compounds. To accomplish this, researchers relied on a technique called cryogenic electron microscopy (cryo-EM). This method involves flash-freezing biological molecules, then employing electrons to generate highly detailed 3D images of their overall shape. Roth and his colleagues recorded how TAS2R43 receptors responded to coffee’s bitter elements including caffeine and mozambioside, then compared those to the reaction of other receptors.

“In this work, we solved the structures of TAS2R43 bound to bitter compounds and showed, in molecular detail, how this receptor detects bitter molecules,” said molecular biologist and study co-author Yoojoong Kim.

Researchers now have a molecular framework for creating future compounds that intentionally control how someone experiences bitterness in drugs or foods. Aside from finally understanding how taste receptors like TAS2R43 physically respond to bitter molecules, the discoveries could also help develop new medical treatments. 

“In the long term, this could help guide the development of new therapeutic strategies for diseases involving airway defense, gut function, inflammation, or host responses to microbes,” Kim added.