Cryo-EM Study Explains Why Coffee Tastes Bitter to Humans

Have you ever wondered why freshly brewed coffee smells so delicious, but tastes bitter?

New research from the University of North Carolina School of Medicine has revealed the molecular details responsible for the detection of this bitter taste.

"Before this study, we did not know how coffee bitterness is initiated at the molecular level, because there was no three-dimensional structure showing how the bitter taste receptor TAS2R43 recognizes bitter tastants," said Yoojoong Kim, PhD, a post-doctoral research associate in the laboratory of Bryan Roth, MD, PhD, and first author of the article, which was published recently in Nature Structure & Molecular Biology.

In this work, we solved the structures of TAS2R43 bound to bitter compounds and showed, in molecular detail, how this receptor detects bitter molecules. We also combined these structures with cell-based experiments and computational analyses to understand how TAS2R43 can recognize diverse bitter tastants, including coffee-derived compounds."

Yoojoong Kim, PhD, post-doctoral research associate in the laboratory of Bryan Roth, MD, PhD, and first author of the article

Roth explained that to achieve this result, Kim purified TAS2R43, which is one of 26 bitter taste receptors, and solved its structure using cryogenic electron microscopy (cryo-EM) at the UNC Cryo-EM Core facility. Cryo-EM is a technique that flash-freezes biological molecules and uses electrons to create detailed 3D images of their natural structures. These structures reveal how TAS2R43, which responds to coffee's ingredients including caffeine, mozambioside, and other bitter substituents of coffee, recognizes these and other compounds distinctly from other reported TAS2Rs.

"Bitter taste receptors like Tas2R43 are expressed throughout the body, where they have been proposed to act as both defense mechanisms against potentially toxic substances and for metabolic regulation. 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," Roth said.

"The discovery of the molecular mechanisms responsible for interactions of these compounds with bitter taste receptors could thus provide new therapeutic strategies for a number of diseases, beyond explaining how coffee gets it bitter taste," Roth said.

Kim noted that by revealing how TAS2R43 recognizes bitter molecules, the study provides a molecular framework for designing compounds that can selectively activate or block bitter taste receptors. "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, while also improving our ability to control bitter taste in foods and medicines," Kim said.

Other authors of the study are Ryan H. Gumpper, PhD, from the UNC Eshelman School of Pharmacy; Yuxuan Zhuang, PhD and Ron O. Dror, PhD, of Stanford University; and Roth, who is the senior and corresponding author. Roth is also the Michael Hooker Distinguished Professor in the School of Medicine's Department of Pharmacology, director of the National Institute of Mental Health Psychoactive Drug Screening Program in the UNC Eshelman School of Pharmacy, and a member of the UNC Lineberger Comprehensive Cancer Center.