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Structural and functional characterization of human sweet taste receptor

Nature volume 645, pages 801–808 (2025)Cite this article

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Abstract

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.

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Fig. 1: Cryo-EM structures of the human sweet taste receptor.
Fig. 2: Sucralose binding mode in TAS1R2.
Fig. 3: The VFTD and CRD in the TAS1R2–TAS1R3 heterodimer.
Fig. 4: Asymmetric configuration of CRDs and dimerization interface of TMDs in TAS1R2–TAS1R3 heterodimer.
Fig. 5: Schematic comparison of TAS1R2–TAS1R3 with mGlu5 and GABAB receptors.
Fig. 6: Predicted G-protein binding mode in TAS1R2.

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Data availability

The atomic coordinates and cryo-EM density maps for apo-TAS1R2–TAS1R3 heterodimer and sucralose-bound TAS1R2–TAS1R3 heterodimer have been deposited in the Protein Data Bank and Electron Microscopy Data Bank, respectively. The accession codes for TAS1R2–TAS1R3 heterodimer reported in this paper are 9UT8 and EMDB-64484 (apo full-length TAS1R2–TAS1R3); 9UT9 and EMDB-64485 (apo-TAS1R2-VFTD–TAS1R3); 9UTA and EMDB-64486 (apo TMD of TAS1R2–TAS1R3); 9UTB and EMDB-64487 (sucralose-bound full-length TAS1R2–TAS1R3); 9UTC and EMDB-64488 (sucralose-bound TAS1R2-VFTD–TAS1R3). Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China grants 32271262 and 32471267 (T.H.), and 32230026 (Z.-J.L.), ShanghaiTech University School of Life Science Development Fund Project (Z.-J.L.), National Key Research and Development Program of China grant 2022YFA1302903 (T.H.) and 2023YFC2509100 (T.H.), Shanghai’s Top Priority Research Center 2022ZZ01017 (Z.-J.L.), AI4S Program at ShanghaiTech University (Z.-J.L.), Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University. We thank the Shanghai Municipal Government and ShanghaiTech University for financial support. We thank S.-W. Zhao, Y.-R. Wu and F. Zhao for discussions and suggestions for sucralose binding pose modelling; N. Chen, S.-W. Hu and P. Si at cell expression core; and Q.-Y. Shi at protein purification core of iHuman Institute for their support. The cryo-EM data were collected at the Bio-Electron Microscopy Facility of ShanghaiTech University, with the assistance of L. Wang and Q.-Q. Sun.

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Author notes

  1. These authors contributed equally: Zongjun Shi, Weixiu Xu, Lijie Wu, Xiaolei Yue

Authors and Affiliations

  1. iHuman Institute, ShanghaiTech University, Shanghai, China

    Zongjun Shi, Weixiu Xu, Lijie Wu, Xiaolei Yue, Shenhui Liu, Jinyi Zhang, Bing Meng, Lianghao Zhao, Xiaoyan Liu, Junlin Liu, Zhi-Jie Liu & Tian Hua

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Zongjun Shi, Xiaolei Yue, Shenhui Liu, Lianghao Zhao, Zhi-Jie Liu & Tian Hua

  3. Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China

    Wei Ding

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  1. Zongjun Shi
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Contributions

Z.-J.L. and T.H. initiated the project. Z.S., W.X. and X.Y. designed the expression constructs, purified the receptor complexes, prepared the final samples for cryo-EM data collection, participated in the electron microscopy data processing, and participated in the figure and manuscript preparation. L.W. performed the electron microscopy data processing and structure determination. W.X. performed the functional assays. S.L. performed the molecular docking and molecular dynamics simulations. W.D. assisted with the electron microscopy data processing. J.Z. and B.M. performed the initial constructs and sample optimization. L.Z. assisted with the construct design with fluorescent protein. X.L. performed the mammalian cell expression. J.L. performed the insect cell expression. Z.-J.L. and T.H. conceived and supervised the research, analysed the structures and wrote the manuscript with the input from all authors.

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Correspondence to Zhi-Jie Liu or Tian Hua.

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Extended data figures and tables

Extended Data Fig. 1 Construct design and protein property analysis of human TAS1R2-TAS1R3.

a, Schematic diagram of the modified constructs for human TAS1R2 and TAS1R3 used for structure determination. b, The representative SDS-PAGE and western blotting of the TAS1R2-TAS1R3 heterodimer sample (≥ 4 independent experiments). The presence of TAS1R2 and TAS1R3 was confirmed by western blotting with anti-TAS1R2 and anti-TAS1R3 antibody, respectively. c, Analytical size-exclusion chromatograph (aSEC) analysis of the TAS1R2-TAS1R3 heterodimer sample, using UV280 absorbance and fluorescence detection. Left vertical axis: UV280 absorbance values (protein elution profile); Right vertical axis: normalized fluorescence values. Fluorescence detection parameters: TAS1R2-mScarlet3: Excitation 569 nm/ Emission 592 nm; for TAS1R3-mNeonGreen: Excitation 506 nm/ Emission 517 nm. d, Dose-response curves of glycerol on WT human sweet taste receptor measured in calcium mobilization assay. Data are mean ± s.e.m. of three independent experiments performed in triplicate.

Source Data

Extended Data Fig. 2 Structure determination of human TAS1R2-TAS1R3 heterodimer in apo state.

a, Size exclusion chromatogram profile of the apo TAS1R2-TAS1R3 heterodimer. b, Representative cryo-EM micrograph (30,495 micrographs) (scale bars, 50 nm). c, Two-dimensional (2D) class averages of apo TAS1R2-TAS1R3 particles, showing different particle view. d, Data processing pipeline for the apo TAS1R2-TAS1R3 complex, including 2D classification and 3D reconstruction workflow and final 3D density map colored according to local resolution (Å). e, Fourier shell correlation (FSC) curves for the final 3D density maps of the apo TAS1R2-TAS1R3 complex. Also shown are the Euler Angle Distributions of particles used for the final 3D reconstruction.

Extended Data Fig. 3 Structure determination of human TAS1R2-TAS1R3 heterodimer in sucralose bound state.

a, Size exclusion chromatogram profile of the TAS1R2-TAS1R3 in complex with sucralose. b, Representative cryo-EM micrograph (scale bars, 50 nm) (120,009 micrographs). c, Two-dimensional (2D) class averages of TAS1R2-TAS1R3 in complex with sucralose, showing different particle views. d, Data processing pipeline for the sucralose bound TAS1R2-TAS1R3 complex, including 2D classification and 3D reconstruction workflow and final 3D density map colored according to local resolution (Å). e, Fourier shell correlation (FSC) curves for the final 3D density maps of the TAS1R2-TAS1R3 in complex with sucralose. Euler Angle Distributions of the particles used for the final 3D reconstruction are also shown.

Extended Data Fig. 4 Representative density maps for apo- and sucralose-bound TAS1R2-TAS1R3 structures.

a, Cryo-EM density maps of representative regions in VFTD and CRD of apo TAS1R2-TAS1R3 heterodimer structure. b, Glycosylation sites in VFTD and CRD of the apo TAS1R2-TAS1R3 heterodimer, shown in ball sticks representation. Extra EM density around the side chains of these glycosylation sites is displayed. c, Cryo-EM density maps of representative regions in VFTD, CRD, TMD and ECL2 of sucralose-bound TAS1R2-TAS1R3 heterodimer structure. d, Cryo-EM density maps of loops in CRDs that insert into the VFTD dimerization interface in apo TAS1R2-TAS1R3 heterodimer structure. e, Cryo-EM density maps of extracellular regions of TMDs including the conserved disulfide bonds between ECL2 and TM3 in TAS1R2 and TAS1R3, respectively, in apo-state structure. f, Cryo-EM density maps for helices TM1-TM7 of transmembrane domain, ICL2 and ECL2 of TAS1R2 and TAS1R3, respectively, in apo-state structure. g, Structural comparison of TAS1R2 and TAS1R3 in apo state aligned with TMD.

Extended Data Fig. 5 Structure determination of human TAS1R2-TAS1R3 heterodimer in glycerol-free condition and structural comparisons with reported sucralose-bound sweet taste receptor.

a, Size exclusion chromatogram profile of the apo TAS1R2-TAS1R3 heterodimer in the glycerol-free buffer condition. b, Representative cryo-EM micrograph (scale bars, 50 nm) (6,412 micrographs). c, Two-dimensional (2D) class averages of apo TAS1R2-TAS1R3 particles in the glycerol-free buffer condition, showing different particle view. d, The raw map for apo TAS1R2-TAS1R3 in the glycerol-free buffer condition. e, The raw map for apo TAS1R2-TAS1R3 in the glycerol-free buffer condition aligns well with that of apo TAS1R2-TAS1R3 map. f, The apo TAS1R2-TAS1R3 structure fits well into the two raw maps. g, Structural comparisons of reported full-length TAS1R2-TAS1R3 (PDB: 9NOR) with apo TAS1R2-TAS1R3 (left) (RMSD: 2.07 Å) and sucralose-bound TAS1R2-TAS1R3 (right) (RMSD: 0.99 Å), respectively.

Extended Data Fig. 6 Structural features of full-length TAS1R2-TAS1R3 heterodimers.

a, Molecular surface of the apo-state TAS1R2-TAS1R3 complex, showing the plane of heterodimer interfaces for the VFTD and TMD. Structural elements involved in heterodimer formation are highlighted in cartoon representation. b, Structural comparison of TAS1R2 and TAS1R3 in apo- and sucralose-bound states. TAS1R3 is shown as cartoon and TAS1R2 is shown as transparent surface (left). TAS1R2 is shown as cartoon and TAS1R3 is shown as transparent surface (right). c, Conformational changes of VFTDs in apo- and sucralose-bound states viewed from the extracellular top. d, The bending of CRDs in TAS1R2 and TAS1R3 from apo- to sucralose-bound states.

Extended Data Fig. 7 Sequence alignment of human TAS1R2 and TAS1R3.

The secondary structure is shown.

Extended Data Fig. 8 Molecular dynamics simulations of sucralose binding pose in TAS1R2 and the docking poses of sucrose and neotame in sweet taste receptor.

a, Cryo-EM density maps for sucralose and surrounding residues in its binding pocket. b, RMSD of sucralose during 500 ns simulations of sucralose-TAS1R2-TAS1R3 (VFTDs). The colors denote for 3 independent runs. c, Structural comparisons with reported sucralose-bound TAS1R2-TAS1R3 VFTDs (PDB: 9NOV) and sucralose adopts a similar binding pose in TAS1R2-VFTD. d, Comparison of docking poses of sucrose and neotame with the experimental determined sucralose binding pose in TAS1R2-VFTD. e-f, The docking pose of neotame (e) and sucrose (f) in TAS1R2-VFTD. g-h, Dose-response curves of key residues mutations in LB1 and LB2 of TAS1R2-VFTD in response to stimulation with neotame (g) and sucrose (h) in calcium mobilization assay. Data are mean ± s.e.m. of three independent experiments performed in triplicate.

Source Data

Extended Data Fig. 9 Structural comparison of VFTD and TMD in TAS1R2-TAS1R3 structure with other class C GPCRs and AlphaFold 3 predicted model of TAS1R2-TAS1R3 in complex with G protein.

a, Electrostatic potential mapped onto the cleft formed by LB1 and LB2 in the VFTDs of TAS1R2 and TAS1R3. b, The structural comparison of TMD between agonist-bound mGlu5 homodimer and sucralose bound TAS1R2-TAS1R3 heterodimer. c, ICL2 in TAS1R2 and TAS1R3 forms a similar short helix conformation with that in bitter taste receptors TAS2R14 and TAS2R46. d, Conformational changes of VFTDs from apo- to agonist-bound states in TAS1R2, GABAB1, mGlu5 and CaSR. e-f, Structural comparison of VFTDs between L-Gln bound medaka fish TAS1R2-TAS1R3 (PDB: 5X2M) and sucralose bound human TAS1R2-TAS1R3 (e), the ligands binding modes in TAS1R2 (f). g, The overall structure model of TAS1R2-TAS1R3 in complex with Gustducin (Gαgustducin β1γ2) predicted by AlphaFold3. h, AlphaFold3 predicted TAS1R2-Gαgustducin complex model is similar with that of TAS1R2TMD-miniGαs/gust (PDB: 9NOX).

Extended Data Table 1 Cryo-EM data collection, model refinement, and validation statistics of TAS1R2-TAS1R3 heterodimer structures
Full size table
Extended Data Table 2 Sweetener molecules-induced intracellular calcium mobilization of wild-type (WT) and mutants of TAS1R2 or TAS1R3
Full size table
Extended Data Table 3 Relative surface expression of wild-type and mutants
Full size table

Supplementary information

Supplementary Figure

Uncropped SDS–PAGE and western blotting for Extended Data Fig. 1.

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Supplementary Video 1

The conformational changes between full-length apo-TAS1R2–TAS1R3 and sucralose-bound TAS1R2–TAS1R3 structures.

Supplementary Video 2

The binding mode of sucralose in TAS1R2-VFTD and the conformational changes of key residues from apo to sucralose-bound states.

Supplementary Video 3

The conformational changes of VFTDs from apo to sucralose-bound states in sweet taste receptor.

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Shi, Z., Xu, W., Wu, L. et al. Structural and functional characterization of human sweet taste receptor. Nature 645, 801–808 (2025). https://doi.org/10.1038/s41586-025-09302-6

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