Structural and functional characterization of human sweet taste receptor

• 成果类型: Article
• 署名作者: Shi, Zongjun; Xu, Weixiu; Wu, Lijie; Yue, Xiaolei; Liu, Shenhui; Ding, Wei; Zhang, Jinyi; Meng, Bing; Zhao, Lianghao; Liu, Xiaoyan; Liu, Junlin; Liu, Zhi-Jie; Hua, Tian
• 署名单位: ShanghaiTech University; ShanghaiTech University; Chinese Academy of Sciences; Institute of Physics, CAS
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2245
• DOI: 10.1038/s41586-025-09302-6
• 发表日期: 2025-09-18
• 关键词: molecular-mechanism; mammalian sweet; t1r3; modulators; gustducin; accuracy; SYSTEM; FAMILY; cells; sense

摘要

Sweet taste perception influences dietary choices and metabolic health. The human sweet taste receptor, a class C G-protein-coupled receptor (GPCR) heterodimer composed of TAS1R2 and TAS1R3 (refs. 1,2), senses a wide range of sweet compounds-including natural sugars, artificial sweeteners and sweet proteins-and affects metabolic regulation beyond taste. However, the lack of three-dimensional structures hinders our understanding of its precise working mechanism. Here we present cryo-electron microscopy structures of the full-length human sweet taste receptor in apo and sucralose-bound states. These structures reveal a distinct asymmetric heterodimer architecture, with sucralose binding exclusively to the Venus flytrap domain of TAS1R2. Combining mutagenesis and molecular dynamics simulations, this work delineates the sweetener-recognition modes in TAS1R2. Structural comparisons further uncover conformational changes upon ligand binding and a unique activation mechanism. These findings illuminate the signal transduction mechanisms of chemosensory receptors in the class C GPCR family and provide the molecular basis for the design of a new generation of sweeteners.