image: Co-first authors Xiao Chen, PhD, and Haolan Wang, PhD, (pictured) and corresponding author Chia-Hsueh Lee, PhD, St. Jude Department of Structural Biology provide structural and functional insight into the human taste receptor with implications for the design of safer and more effective sweeteners.
Credit: St. Jude Children's Research Hospital
(MEMPHIS, Tenn. – August 4, 2025) Sweet taste receptors are proteins in taste buds that detect sugar and other sweeteners, but the mechanism underlying how they elicit a sweet response has been unclear. Scientists at St. Jude Children’s Research Hospital used cryo-electron microscopy to uncover the sweet taste receptor’s full range of motion as it binds the sweeteners sucralose and advantame, revealing a previously unknown mechanism of activation. This study provides unique insight into how these receptors trigger the sweet sensation and offers guidance to the design of more effective sweeteners. The results were published today in Cell Research.
The human sweet receptor is part of a protein family called the class C G protein–coupled receptors (GPCRs) and comprises two proteins: TAS1R2 and TAS1R3. Scientists did not fully understand how the receptor changes its shape when a sweet molecule binds to it.
“There’s a lot of functional data accumulated in the literature, but without capturing the receptor’s full range of motion, it’s tough to understand the molecular mechanism,” said corresponding author Chia-Hsueh Lee, PhD, St. Jude Department of Structural Biology. “That’s why we decided to use a structural approach to study this receptor.”
Through structural and functional studies, the researchers found a new state for the sweetness taste receptor. The new state complements unbound and bound structures of the receptor and appears to represent the fully activated state of the receptor.
‘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 interfacebetween 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.”
Authors and funding
The study’s other authors are Yiming Niu, The Rockefeller University; Chen Zhao, University of Florida; and Yaxin Dai, Shabareesh Pidathala, Siyu Li and Liang Wang, St. Jude.
The study was supported by the National Institutes of Health (R01GM143282 and R01NS133147) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read Progress: A Digital Magazine and follow St. Jude on social media at @stjuderesearch.