Structure and activation mechanism of human sweet taste receptor
Haolan Wang, Xiao Chen, Yaxin Dai, Shabareesh Pidathala, Yiming Niu, Chen Zhao, Siyu Li, Liang Wang, Chia‐Hsueh Lee
Abstract
Taste perception is initiated in the taste buds by cells that express G protein-coupled receptors (GPCRs) and ion channels tuned to specific modalities — sweet, bitter, umami, salty, and sour. 1 Sugars and other sweet-tasting compounds are detected by the sweet taste receptor, a member of the class C GPCR family. 2 , 3 The sweet receptor system evolved to prioritize energy-dense nutrients, engaging central reward pathways that reinforce sugar cravings and promote excessive calorie intake, contributing to obesity, type 2 diabetes, and other metabolic diseases. Though generally considered safe, use of artificial sweeteners has been associated with altered appetite regulation and increased cardiometabolic risk; moreover, non- or low-caloric sweeteners, such as sucralose, aspartame, and advantame, activate the sweet receptor but may not fully replicate the downstream effects of natural sugars (Supplementary information, Note S1 ). Therefore, elucidating the molecular basis of sweet receptor signaling and understanding how natural and artificial sweeteners engage the receptor may inform the rational design of next-generation sweeteners.