The First Report of The Structure of Human Sweet Receptors
Sweetness is one of the five basic tastes of human beings and a universal and beautiful sensory experience. Whether it is the sweetness of fruits or the fragrance of snacks, sweetness is always closely related to pleasure, happiness and satisfaction.
People's preference for sweetness is an innate instinct. Sugar usually represents an important source of energy, so in the process of evolution, sweetness has become an important signal for us to tend to take food. However, in the modern era of material abundance, human beings' strong love for sugar has caused a series of public health problems, such as obesity, diabetes and cardiovascular disease. In order to reduce sugar intake, people have developed a variety of artificial sweeteners (such as Sucralose and aspartame) to replace sugar, which are widely used in daily food.
Like other tastes, the perception of sweetness begins with specific taste receptor cells in the taste buds of the tongue and the taste receptors they express. Over the past two decades, Charles S. Zuker's team has discovered various taste receptors in mammalian taste receptor cells and explored how neural circuits encode taste signals to produce corresponding behaviors.
As early as 2001, Charles S. Zuker and his colleagues discovered the sweet taste receptor of mammals. It is composed of TAS1R2 and TAS1R3, which can recognize sugar and other sweet substances, trigger a series of signal transductions, and ultimately form a "sweet" perception in the brain. Although related research has been continuously advanced since then, and the structural analysis of other sensory Receptors (such as bitter and olfactory receptors) has also made major breakthroughs, the structure of the sweet taste receptor has never been revealed.
On May 7, 2025, the research group of Charles S. Zuker from Columbia University published an article entitled "The structure of human sweetness" in Cell, reporting the structure of human sweet receptor for the first time, revealing the structural basis of its recognition of sweet molecules.
Sweet receptor is a heterodimer composed of TAS1R2 and TAS1R3 subunits, belonging to the C family of G Protein-coupled Receptor (GPCR). Other members of this family include metabotropic glutamate receptors (mGluRs), gamma-aminobutyric acid receptor B (GABAB) and calcium-sensing receptors (CaSRs). Structurally, it has a Venus flytrap agonist-binding domain (VFT) that binds to the ligand and a seven-transmembrane domain (7TM) characteristic of GPCR, which is connected by a cysteine-rich domain (CR).
After hundreds of repeated attempts and optimization, the researchers successfully prepared a stable protein complex of this receptor and eliminated the interference of homodimers in the sample. Subsequently, cryo-electron microscopy (cryo-EM) was used to analyze the high-resolution structure of the sweet receptor when it was bound to two common sweeteners (sucralose and aspartame, which are 600 times and 200 times sweeter than sucrose, respectively).
Fig. 1 Structure of the human sweet receptor. (Juen, et al., 2025)
Overall, the sweet receptor showed obvious asymmetry. Among them, the VFT of TAS1R3 was in an open state, while the VFT of TAS1R2 was in a closed state, suggesting that only the TAS1R2 subunit bound the ligand molecule. Further analysis of the VFT region also found the electron density of the ligand in the VFT binding pocket of TAS1R2, and thus revealed the key interaction between the ligand and the amino acid residues of the binding pocket.
The researchers then made point mutations at multiple amino acid sites in the binding pocket and detected receptor-mediated downstream calcium signals in cells to evaluate the role of these sites in sweetener binding. The results showed that multiple point mutations can significantly affect receptor function, and the effects on different ligands (sucralose, Aspartame and sucrose) are different, which is consistent with some differences observed in the structure. In summary, different sweet molecules can share the same binding pocket to activate receptors, but their specific interaction mechanisms are different.
This structure also shows some unique features. For example, the CR domain of TAS1R3 has a ring structure composed of five amino acids, which protrudes upward and is embedded between the VFTs of TAS1R2 and TAS1R3. This feature has not been observed in other C-family of GPCRs before.
It is worth mentioning that during the data analysis process, the researchers also obtained a class of protein particles in different states, showing the structure of the transmembrane domain of TAS1R2 and G protein binding. The signal of TAS1R3 in this structure is weak, but the analysis of the relative position of its 7TM suggests that this type of receptor is in an inactive state, which may be a pre-G protein binding state.
In summary, this study revealed the Three-dimensional Structure of human sweet receptor for the first time, providing key information for understanding the molecular mechanism of taste. This discovery is expected to promote the development of new strategies to regulate receptor function, thereby regulating human desire and intake of sugar, and taking an important step towards addressing the public health crisis caused by excessive sugar intake.
Reference
