‘Loose’ state is key to improved sweetness
“Our structural and functional studies suggest that this ‘loose’ state, as we have dubbed it, is the fully activated state,” said Lee. “With this knowledge, we can better understand the activation mechanism of the sweet receptor and infer that molecules that can stabilize this particular loose state should be sweeter.”
The research provided a detailed view of the “loose” state, which refers to the shapes taken by parts of TAS1R2 and TAS1R3, called the Venus flytrap (VFT) domain. The VFT domains (one from each protein) are packed tightly together in the absence of a sweetener.
“In this new structure, when the sweetener binds to TAS1R2, a loop of TAS1R2 inserts into the interface between TAS1R2 and TAS2R3, triggering the separation of VFT domains,” said first author Haolan Wang, PhD, St. Jude Department of Structural Biology. “This is a big difference compared to other class C GPCRs, where the VFT domains stick together in the activated state.”
The research also showed that while mechanistically similar, sucralose and advantame engage with the receptor in different ways. This presents an opportunity to improve on currently available sweeteners.
“We were very curious about why this sweet taste receptor can bind to so many different kinds of sweeteners,” said co-first author Xiao Chen, St. Jude Department of Structural Biology. “By revealing unprecedented snapshots of the sweet taste receptor, our study provides new insights into how we perceive sweetness and helps guide the design of better sweeteners.”
Reference: Wang H, Chen X, Dai Y, et al. Structure and activation mechanism of human sweet taste receptor. Cell Res. 2025. doi: 10.1038/s41422-025-01156-x
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