Scientists Reveal the Full Structure of the Human Sweet Taste Receptor

Sucralose, aspartame, sugar—they all light up the same receptor in your mouth.

But how?

A team of researchers just cracked the structural code of human sweetness, revealing the intricate architecture of the sweet taste receptor that powers our love for all things sugary.

Why sweets are tasted as sweet has long been speculated about biochemically. Until recently, the answer was mostly speculated upon by scientists. But now, the first complete cryo-electron microscopy (cryo-EM) structure of the human sweet taste receptor has been provided by a groundbreaking study that was done by scientists at Columbia University-a scientific milestone by which exactly how sugars and sweeteners are detected by our bodies at the atomic level is uncovered (Juen et al., 2025).

In Cell, the study is published, and it is shown how two specific G protein-coupled receptor (GPCR) proteins, TAS1R2 and TAS1R3, are formed into a heterodimeric complex by which our perception of sweetness is given rise to. In the taste cells of the tongue, this receptor is embedded, and the neural cascade that tells the brain “this tastes sweet” is initiated by it.

A Single Receptor That Senses a Universe of Sweetness

More than 20 years ago, scientists discovered that just one receptor could detect a wide range of sweet compounds—from natural sugars like glucose and sucrose to synthetic sweeteners like aspartame and sucralose. But until now, the actual 3D structure of this receptor remained unknown.

The new study shows that TAS1R2 is the "sensor" subunit that directly binds sweet molecules, while TAS1R3 is a structural partner essential for stabilization and proper function. Both are members of the Class C GPCR family, which includes receptors for umami, glutamate, and calcium.

Using cryo-EM, the researchers resolved the receptor bound to sucralose and aspartame, achieving resolutions between 3.3 and 3.7 angstroms. This level of detail allowed them to visualize every twist and fold of the protein, as well as precisely how sweet molecules nestle into the receptor’s Venus flytrap domain (VFT)—a structural motif resembling the snapping lobes of the insect-eating plant.

ADVERTISEMENTS

ADVERTISEMENTS

The Binding Pocket That Makes Things Sweet

Inside TAS1R2’s VFT lies a common binding pocket where molecules like sucralose and aspartame dock. Six amino acid residues—Y103, D142, N143, S165, Y215, and D278—line this pocket. Through site-directed mutagenesis, the team proved that replacing some of these residues (like Y103A or D142A) severely impaired the receptor’s ability to respond to sweeteners, confirming their crucial role in ligand recognition (Juen et al., 2025).

Interestingly, although the sweeteners sucralose and aspartame differ in structure, they both bind to the same pocket and interact with overlapping residues. Yet, the precise way they engage these residues varies slightly, explaining why each sweetener has unique potency and taste characteristics.

Why Only TAS1R2 Connects to the Brain

Though both TAS1R2 and TAS1R3 form the receptor, only TAS1R2 directly couples to the G protein that relays sweetness signals to the brain. The study pinpointed two intracellular residues—Y756 and F827—as essential for G protein interaction. Mutating either one (especially Y756) broke the signaling pathway, rendering the receptor inactive despite the presence of sweeteners.

TAS1R3, in contrast, appears to facilitate conformational changes, help the receptor fold correctly, and support intracellular signaling by stabilizing the overall structure—but it does not bind sweet molecules or signal directly.

Evolution Favors Weak Binding—and That’s a Good Thing

Unlike high-affinity receptors in the brain or hormones that bind at nanomolar levels, the sweet receptor has low affinity, binding most sugars only at millimolar concentrations. Why? This allows humans and other mammals to differentiate between sources of food based on energy richness. A receptor that saturates too quickly would treat a carrot the same as candy. Evolution preferred one that responds more strongly to sweeter, higher-calorie foods.

Species Differences: Why Your Pet Doesn’t Taste Sweet Like You Do

Although primates like humans and apes can detect aspartame, rodents and New World monkeys cannot. Interestingly, the key binding residues in TAS1R2 are conserved even in these "non-taster" species. This suggests that other subtle structural features prevent binding and activation in those animals. Unlocking this mystery may reveal more about species-specific taste evolution and help design tailored sweeteners in the future.

What This Means for Food, Health, and the Future of Sweeteners

Understanding the full structure of the human sweet receptor opens up new avenues for taste modulation. Food scientists could design next-generation sweeteners that taste better, last longer, and cause fewer side effects. Pharmacologists could create inhibitors to dampen sugar cravings. Even more, personalized nutrition might one day account for genetic differences in TAS1R2 or TAS1R3, explaining why some people are more sensitive to sweetness or have a "sweet tooth."

This achievement also lays the groundwork for future research into apo-state receptors (unbound, inactive states), natural sugar recognition, and receptor evolution across the animal kingdom.

Citation:

Juen, Z., Lu, Z., Yu, R., Chang, A. N., Wang, B., Fitzpatrick, A. W. P., & Zuker, C. S. (2025). The structure of human sweetness. Cell, 188(1), 1–13. https://doi.org/10.1016/j.cell.2025.04.021

JOURNAL SOURCE : CELL

Mind Map

ADVERTISEMENTS

ADVERTISEMENTS

Drop Us a Line

We’d Love to Hear from You

RECENT POSTS