Fig. 1: Ligand recognition and activation of the sweet taste receptor.

a Cryo-EM density (top) and model (bottom) of the receptor in the apo state. b Conformations of the sweet receptor in the presence of sweeteners. Top row, human TAS1R2 and mouse TAS1R3 (hm) in the apo, sucralose- or advantame-bound state. Bottom row, human TAS1R2 and human TAS1R3 (hh) in the advantame-bound state; inset, interface between the inter-subunit VFT cleft and the CRD loops. c Sucralose-binding pocket in the TAS1R2 VFT domain, showing density of sucralose (Suc). Yellow dashed lines indicate polar interactions. d Clamshell closure induced by sucralose binding, illustrated by superimposing TAS1R2 VFT lobes in the apo (gray) and sucralose-bound loose (blue) states, aligned by LB1. Distances between the centers of mass (COMs) of LB1 and LB2: apo, 32 Å; sucralose-bound: 29.4 Å. Bottom, clamshell opening angles. e Advantame-binding pocket in the TAS1R2 VFT domain, showing density of advantame (Adv). Yellow dashed lines indicate polar interactions. f Clamshell closure induced by advantame binding, illustrated by superimposing the TAS1R2 VFT lobes in the apo (gray) and sucralose-bound loose (blue) states, aligned by LB1. Distances between COM of LB1 and LB2: apo, 32 Å; advantame-bound: 29.5 Å. Bottom, clamshell opening angles. g Conformational transitions of TAS1R2 VFT from apo to the sucralose-bound states. Disordered regions are shown as dashed lines. h Sweetener-induced rearrangement of the TAS1R2/TAS1R3 VFT interface in the sucralose-bound loose state. The loop from TAS1R2 is shown in red; TAS1R2 and TAS1R3 are colored blue and yellow, respectively. Inset, superposition of compact (gray) and loose (color) states showing the inter-subunit interface. Cα of selected residues in TAS1R3 shown as spheres. i, j Separation of TAS1R2 and TAS1R3 VFT domains induced by sucralose (i) or advantame (j). TAS1R2 and TAS1R3 in the apo state are colored light gray, and in the sweetener-bound (loose) state in blue and yellow, respectively. The COM of each individual lobe is shown as a filled circle; the distance between the LB1s, shown at the top, remains unchanged. The distances between the LB2s: apo, 33.7 Å; sweetener-bound: ~39 Å. Insets, change in the clamshell opening angle of TAS1R3 VFT. k Responses of human TAS1R2/TAS1R3 mutants measured by cell-based Ca²⁺ assays. Data are shown as mean ± SEM; wild type (WT), n = 29; mutants, n = 3–15. EC₅₀: WT, 1.2 μM; TAS1R2 V49A, 17.1 μM; TAS1R2 V49R, 1.8 μM; TAS1R3 F159A, 4.0 μM. l 7TM domain interfaces of the sweet receptor in the apo state. Insets, residues lining the major interfaces between 7TM of TAS1R2 and TAS1R3. m Receptor activation triggers remodeling of the 7TM interface. TAS1R2 and TAS1R3 are colored in the sucralose-bound (loose) states, or gray in the apo state. n A schematic diagram illustrating the unique activation mechanism of the sweet receptor.