Abstract
Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2,3,4,5,6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.
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Data availability
Atomic coordinates and cryo-EM maps have been deposited in the Protein Data Bank and Electron Microscopy Data Bank under the accession codes PDB 8VY7 (EMDB accession EMD-43647 for the globally refined map and EMD-43656 for the locally refined map) and PDB 8VY9 (EMD-43650 for the globally refined map and EMD-43657 for the locally refined map) for the TAS2R14–Gi1–scFv16 and TAS2R14–Ggust–scFv16 complexes, respectively. Source data are provided with this paper.
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Acknowledgements
This work was supported by NIH grant U24DK116195, the NIMH Psychoactive Drug Screening Program, and the Michael Hooker Distinguished Professorship to B.L.R. The authors acknowledge E. Robinson and J. Strauss for technical assistance in this project. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from NIH SIG grants 1S10OD025132 and 1S10OD028504. This work was also supported by NIH grants T32HD040127 and K99GM149931 to D.D.K.
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Contributions
Y.K. designed the experiments, performed cloning of mutagenesis constructs, performed expression and purification of the TAS2R14–Gi1–scFv16 and TAS2R14–Ggust–scFv16 complexes, prepared the cryo-EM grids, processed cryo-EM data, built and refined the models, analysed structural data, performed the BRET2 and cAMP inhibition assays, and prepared the figures, tables and manuscript. R.H.G. helped with cryo-EM data processing, performed the molecular docking and molecular dynamics simulations, edited the manuscript, and prepared the figures and manuscript for the molecular docking and molecular dynamics simulations. Y.L. performed the cloning of the mutagenesis constructs and conducted BRET2 assays. D.D.K. conducted RT–qPCR for TAS2R14 RNA abundance and prepared the figures and manuscript for the RT–qPCR and mRNA analyses. Y.X. and Z.D. synthesized cmpd28.1. C.C. helped with the purification and provided the expression plasmid for TAS2R14 and Gi1. B.E.K. provided the expression plasmid for Ggust. M.K.J. helped with the BRET2 assays. S.Z. helped with the purification. J.J. supervised the synthesis of cmpd28.1. B.L.R. supervised the entire project and edited the manuscript.
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J.J. is a co-founder and equity shareholder in Cullgen Inc., a scientific co-founder and scientific advisory board member of Onsero Therapeutics Inc., and a consultant for Cullgen Inc., EpiCypher Inc., Accent Therapeutics Inc. and TavotekBiotherapeutics Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics Inc., Cullgen Inc. and Cullinan Oncology Inc. B.L.R. is a co-founder of Onsero and Epiodyne and a scientific advisory board member of Escient Pharmaceuticals and Lassogen. University of North Carolina has licensed TRUPATH technology to many pharmaceutical and biotechnology companies.
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Extended data figures and tables
Extended Data Fig. 1 Cryo-EM data processing for the TAS2R14–Gi1–scFv16 complex.
a, Workflow of cryo-EM data processing for TAS2R14–Gi1–scFv16 complex. Masks used for focused classification and local refinement were colored pink and magenta, respectively. The locally refined map is rotated by 90° based on the y-axis from the globally refined map for clarity. b, A representative motion-corrected micrograph imaged at a nominal 81,000 × magnification. The experiment was repeated three times with similar results. c, Representative 2D class averages without alignment. d, Map-to-model FSC curve calculated by mtriage in Phenix software. e-j, Representative local resolution (e), Gold-standard Fourier shell correlation (GSFSC) curves adopted from cryoSPARCv4 (f), and particle angular distributions (g) for globally refined map (e-g) and locally refined map (h-j).
Extended Data Fig. 2 Cryo-EM data processing for the TAS2R14–Ggust–scFv16 complex.
a, Workflow of cryo-EM data processing for TAS2R14–Ggust–scFv16 complex. Masks used for focused classification and local refinement were colored pink and magenta, respectively. The locally refined map is rotated by 90° based on the y-axis from the globally refined map for clarity. b, A representative motion-corrected micrograph imaged at a nominal 81,000 × magnification. The experiment was repeated three times with similar results. c, Representative 2D class averages without alignment. d, Map-to-model FSC curve calculated by mtriage in Phenix software. e-j, Representative local resolution (e), Gold-standard Fourier shell correlation (GSFSC) curves adopted from cryoSPARCv4 (f), and particle angular distributions (g) for globally refined map (e-g) and locally refined map (h-j).
Extended Data Fig. 3 Structural features of TAS2R14 coupled with Gi1 and Ggust.
a-j, Representative atomic model-fitted EM map for the structure of TAS2R14–Gi1–scFv16 (a-e), and TAS2R14–Ggust–scFv16 (f-j), respectively. Cholesterol and cmpd28.1 which are shown as model-fitted EM maps were observed in the orthosteric pocket and allosteric site, respectively (b,g). Cmpd28.1 in the allosteric site interacts with Hα5 of Gαi1 (c) and Gαgust (h). No interactions were observed between ICL1 and Gβ1 in both complexes (d,i). e, W124 of ICL2 forms a hydrogen bond with R32 of αN of Gα in TAS2R14–Gi1–scFv16. The distances between R125 of ICL2 and E28 of αN of Gα in TAS2R14–Ggust–scFv16 is 9 Å indicated by a red arrow. j, E28 of αN of Gαgust forms a hydrogen bond and an ionic interaction with W124 and R125 of ICL2, respectively. k, Two orthogonal views aligned onto the receptors between TAS2R14–Ggust–scFv16 and TAS2R14–Gi1–scFv16. Black dashed lines indicate two HαN helices distant by 8.5 Å. Models are presented as cylinders for clarity. l-n, Structural comparison of TAS2R14–Ggust with reported structure TAS2R46-miniGs/gust (PDB 7XP6). This comparison highlights TMs 4, 5, and 7 (l), as well as 6 (m). n, Conserved residue W3.32 (red circle) of TAS2R14 in the orthosteric pocket is located in the same position as TAS2R46. Cholesterol and strychnine are shown as yellow and purple sticks, respectively. o-r, Structural comparison between TAS2R14–Gi1 and class A GPCR β2AR–Gs (PDB 3SN6) to highlight the conserved motifs in class A GPCRs which are CWxP (o), PIF (p), DRY (q), and NPxxY (r) motif. A large movement of TMs of TAS2R14–Gi1 is shown in the black arrows. A yellow dashed line indicates an interaction between H2767.49 of TAS2R14–Gi1 and cmpd28.1 (r). s,t Interactions formed between the residues N241.50 and S2777.50 (s) as well as W983.41 and P1905.50 (t).
Extended Data Fig. 4 Sequence alignment of TAS2R family and Gα proteins.
a, The residues of TAS2R14 mentioned throughout the text are labeled as generic residue numbering. The black squares, stars, and circles indicate the residues involved in the interactions with cholesterol, cmpd28.1, and the α5 helices of Gαi1 and Gαgust. b, Sequence alignment of α5 helix of Gα subunits. Labeled residues interact with TAS2R14. The sequence was aligned using GPCR generic residue numbers based on GPCRdb (https://gpcrdb.org) (a,b).
Extended Data Fig. 5 Computational analyses for TAS2R14.
a,b, EMERALD docking based on our cryo-EM map and model. a, The top-scoring pose for the cholesterol can recapitulate the modeled binding pose off of the map. b, The cmpd28.1 binding pose can also be recapitulated with EMERALD and the top scoring pose. c,d, Docking of bile acids to our TAS2R14 structure. The following bile acids were docked using Glide (Maestro v13.3): Cholate, Chendeoxycholate, Deoxycholate, Glycocholate, Lithocholate, Taurocholate, Taurolithocholate, and Ursodeoxycholate to orthosteric pocket occupied by cholesterol. The top score was taken from each docking run and visualized in ChimeraX. e-g, PCA of Simulations Reveal Conformational Change. The first two principal components for each simulation of the receptor alone state with CLR and cmpd28.1 (e), just CLR (f), or just cmpd28.1 (g). Circled is the conformational change seen in TM5/TM6 when traversing PC1. TM6 swings much further out only in the presence of CLR and cmpd28.1, not in the other simulations.
Extended Data Fig. 6 Activation of TAS2R14 by cholesterol and cmpd28.1.
a,b, Basal activities of TAS2R14 coupled with Ggust (a) and Gi1 (b) measured by BRET2 assays. Data represent mean ± s.e.m. of n = 3 biological replicates. The activation levels according to the increase of relative amounts of transfection of TAS2R14 were normalized by BRET ratio from the pcDNA3.1-transfected conditions. c-g, Split luciferase biosensor cAMP inhibition assay upon cholesterol depletion and replenishment. The values represent the mean ± s.e.m. of n = 3–6 biologically independent experiments. Significant differences were determined by ordinary one-way ANOVA with Dunnett’s test for multiple comparison analysis with reference to the pcDNA3.1 (c,d) and WT (e-g). h-j, BRET2 assays for TAS2R14 mutations at the orthosteric binding pocket in the absence/presence of cmpd28.1. Data represent mean ± s.e.m. of n = 3 biological replicates. h,i, All values are subtracted by net BRET of pcDNA3.1 in each of the six cellular conditions, separately. j, The net BRET values were subtracted by the net BRET of WT in the absence of cmpd28.1. Statistical differences were determined by ordinary two-way ANOVA with Dunnett’s test for multiple comparison analysis with reference to each of WT with either 0 μM or 10 μM cmpd28.1, separately. k-n, Agonist-stimulated TAS2R14 (k) and TAS2R46 (m) activation upon conditions of cholesterol depletion and replenishment. Representative column graphs for TAS2R14 (l) and TAS2R46 (n) adopted from the values at 100 μM agonists in a dose-response curve for TAS2R14 (k) and TAS2R46 (m), respectively. Data represent mean ± s.e.m. of n = 6 (k, l) and 3 (m, n). Statistical differences were determined by ordinary one-way ANOVA with Dunnett’s test for multiple comparison analysis with reference to the no-treatment condition (l, n). o-q, BRET2 assays with a dose-response of cmpd28.1 under the conditions of no treatment (o), depletion (p), and replenishment (q). All the significant differences were indicated by ****P < 0.0001, ***P < 0.001, **P < 0.01, and *P < 0.05, and ns (not significantly different) (c-g, j,l,n).
Extended Data Fig. 7 TAS2R14 activation by intracellular cmpd28.1.
a, Close-up view of structures of cmpd28.1 in the allosteric site by aligning between TAS2R14–Gi1 and TAS2R14–Ggust. The ligands and interacting residues are shown as sticks. Hydrogen bonds are indicated as yellow dashed lines. b, Close-up view of the intracellular allosteric site of structures aligned between TAS2R14-Gi1 and TAS2R46-mGs/gust (PDB 7XP6). The labeling of the conserved residues of TAS2R46 compared to TAS2R14 was omitted for clarity. c, d, Structural superposition of TAS2R14-Gi1 with either NTSR1-Go (c) or PTH1R-Gs (d). The ligands bound to the intracellular allosteric sites were shown as sticks. e-g, Representative agonist-stimulated BRET2 assays upon no treatment (e), cholesterol depletion (f), and replenishment (g) using mutations at the allosteric site. h-j, Split luciferase biosensor cAMP inhibition assays for mutations of TAS2R14 at the allosteric site with a dose-response of cmpd28.1 (h), flufenamic acid (i), and aristolochic acid I (j). k-n, Substitution of L353 of Gα which interacts with cmpd28.1 with Alanine affects the coupling of TAS2R14 to Gαi1 (k) and Gαgust (l) as well as NTSR1 to Gαi1 (m) and Gαgust (n). Data represent mean ± s.e.m. of n = 3 biological replicates (e-n).
Extended Data Fig. 8 MD Simulations confirm cholesterol and cmpd28.1 pockets.
a, Overall simulation results for cmpd28.1 and cholesterol (CLR). Representative average RMSD with the top and bottom part of the box plot showing the 75th percentile and 25th percentile, respectively. The simulations were independently repeated three times. b-f, Average RMSD plot by frame shown in solid blue (cmpd28.1) and teal (CLR). The grey shaded area is the calculated standard deviation across each frame across each simulation. Cartoon representations are shown on the right-hand side of each panel of selected frames from the MD simulation. Each one has either circled cmpd28.1 (blue) or CLR in (teal). Particularly focus on panels (d,e) which show cmpd28.1 occupying other sites than the intracellular pocket of the receptor. TAS2R14 are labeled as red stars.
Extended Data Fig. 9 Models for representative cavity between the orthosteric pocket and allosteric site in TAS2R14.
a, Representative orthosteric and allosteric site of TAS2R14. The pockets are occupied by cholesterol and cmpd28.1 shown as spheres. b, A model for electrostatic potential surface showing the orthosteric binding pocket engaged by cholesterol of TAS2R14. Red, negative (−5 kT e−1); blue, positive (+5 kT e−1). c, Extensive aromatic residues which are abundant in TM5 and TM6 form a hydrophobic network along with the cavity. The network interacts with cholesterol and cmpd28.1. d, A representative model for TAS2R14-Gi1 with the deep and elongated cavity which was predicted using Caver 3.0.3 software63. The cavity was colored orange. Four predicted tunnels for the entrance of cholesterol are indicated by black squares (e-h). e-h, Close-up views of the predicted entrance from d. Surrounding residues are shown as sticks. i-k, Cavities predicted by Caver 3.0.363 in SMO receptor (PDB 6O3C) (i), GPBAR (PDB 7CFN) (j), and TAS2R46 (PDB 7XP6) (k). The calculated cavities were colored green (i-k).
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Kim, Y., Gumpper, R.H., Liu, Y. et al. Bitter taste receptor activation by cholesterol and an intracellular tastant. Nature 628, 664–671 (2024). https://doi.org/10.1038/s41586-024-07253-y
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DOI: https://doi.org/10.1038/s41586-024-07253-y
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