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
iHuman Institute, ShanghaiTech University, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Nature. 2025 Jun 24. doi: 10.1038/s41586-025-09302-6.
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. ), 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.
甜味感知会影响饮食选择和代谢健康。人类甜味受体是一种C类G蛋白偶联受体（GPCR）异二聚体，由TAS1R2和TAS1R3组成（参考文献），能感知多种甜味化合物，包括天然糖、人工甜味剂和甜味蛋白，并影响味觉之外的代谢调节。然而，缺乏三维结构阻碍了我们对其精确工作机制的理解。在此，我们展示了全长人类甜味受体在无配体和三氯蔗糖结合状态下的冷冻电镜结构。这些结构揭示了一种独特的不对称异二聚体结构，三氯蔗糖仅与TAS1R2的捕蝇草结构域结合。结合诱变和分子动力学模拟，这项工作描绘了TAS1R2中的甜味剂识别模式。结构比较进一步揭示了配体结合时的构象变化和独特的激活机制。这些发现阐明了C类GPCR家族中化学感应受体的信号转导机制，并为新一代甜味剂的设计提供了分子基础。
