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Basic information

Entry
Database: EMDB / ID: EMD-19445
TitleGPCR - G-protein complex
Map dataCryo-EM map of TAS2R14 in complex with G-proteins
Sample
  • Complex: Human Taste receptor type 2 member 14 in complex with G-proteins
    • Complex: Human Taste receptor type 2 member 14 in complex with G-proteins
      • Protein or peptide: Taste receptor type 2 member 14
      • Protein or peptide: Guanine nucleotide-binding protein G(t) subunit alpha-3
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: scFv16 (antibody)
      • Protein or peptide: scFv16
  • Ligand: 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID
KeywordsSingle particle cryo-EM / GPCR / G-protein / STRUCTURAL PROTEIN
Function / homology
Function and homology information


bitter taste receptor activity / taste receptor activity / sensory perception of umami taste / sensory perception of sweet taste / detection of chemical stimulus involved in sensory perception of bitter taste / Class C/3 (Metabotropic glutamate/pheromone receptors) / axoneme / photoreceptor outer segment / Adenylate cyclase inhibitory pathway / photoreceptor inner segment ...bitter taste receptor activity / taste receptor activity / sensory perception of umami taste / sensory perception of sweet taste / detection of chemical stimulus involved in sensory perception of bitter taste / Class C/3 (Metabotropic glutamate/pheromone receptors) / axoneme / photoreceptor outer segment / Adenylate cyclase inhibitory pathway / photoreceptor inner segment / acrosomal vesicle / response to nicotine / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / apical plasma membrane / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / protein-containing complex / extracellular exosome / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Taste receptor type 2 / Taste receptor protein (TAS2R) / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...Taste receptor type 2 / Taste receptor protein (TAS2R) / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(t) subunit alpha-3 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Taste receptor type 2 member 14
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculoides (Temminck's mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsMatzov D / Peri L / Niv M / Shalev Benami M
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)949364European Union
CitationJournal: Nat Commun / Year: 2024
Title: A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR.
Authors: Lior Peri / Donna Matzov / Dominic R Huxley / Alon Rainish / Fabrizio Fierro / Liel Sapir / Tara Pfeiffer / Lukas Waterloo / Harald Hübner / Yoav Peleg / Peter Gmeiner / Peter J McCormick / ...Authors: Lior Peri / Donna Matzov / Dominic R Huxley / Alon Rainish / Fabrizio Fierro / Liel Sapir / Tara Pfeiffer / Lukas Waterloo / Harald Hübner / Yoav Peleg / Peter Gmeiner / Peter J McCormick / Dorothee Weikert / Masha Y Niv / Moran Shalev-Benami /
Abstract: Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional ...Bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs) expressed orally and extraorally, elicit signaling in response to a large set of tastants. Among 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse ligands. Here we present the cryo-electron microscopy (cryo-EM) structure of the human TAS2R14 in complex with its signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode, where two copies of FFA are bound at distinct pockets: one at the canonical receptor site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Together with a pocket-specific BRET-based ligand binding assay, these results illuminate bitter taste signaling and provide tools for a site-targeted compound design.
History
DepositionJan 18, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateJan 22, 2025-
Current statusJan 22, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19445.png

Downloads & links

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Map

FileDownload / File: emd_19445.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM map of TAS2R14 in complex with G-proteins
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 297.36 Å		0.83 Å/pix.
x 360 pix.
= 297.36 Å		0.83 Å/pix.
x 360 pix.
= 297.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.306
Minimum - Maximum-2.4695551 - 1.5733217
Average (Standard dev.)-0.00062009523 (±0.03262641)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 297.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: cryo-EM map of TAS2R14 in complex with G-proteins - unsharpened

Fileemd_19445_additional_1.map
Annotationcryo-EM map of TAS2R14 in complex with G-proteins - unsharpened
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human Taste receptor type 2 member 14 in complex with G-proteins

EntireName: Human Taste receptor type 2 member 14 in complex with G-proteins
Components
  • Complex: Human Taste receptor type 2 member 14 in complex with G-proteins
    • Complex: Human Taste receptor type 2 member 14 in complex with G-proteins
      • Protein or peptide: Taste receptor type 2 member 14
      • Protein or peptide: Guanine nucleotide-binding protein G(t) subunit alpha-3
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: scFv16 (antibody)
      • Protein or peptide: scFv16
  • Ligand: 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID

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Supramolecule #1: Human Taste receptor type 2 member 14 in complex with G-proteins

SupramoleculeName: Human Taste receptor type 2 member 14 in complex with G-proteins
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Molecular weightTheoretical: 118.3 kDa/nm

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Supramolecule #2: Human Taste receptor type 2 member 14 in complex with G-proteins

SupramoleculeName: Human Taste receptor type 2 member 14 in complex with G-proteins
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: scFv16 (antibody)

SupramoleculeName: scFv16 (antibody) / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Mus musculoides (Temminck's mouse)

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Macromolecule #1: Taste receptor type 2 member 14

MacromoleculeName: Taste receptor type 2 member 14 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.20007 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGGVIKSIFT FVLIVEFIIG NLGNSFIALV NCIDWVKGRK ISSVDRILTA LAISRISLVW LIFGSWCVSV FFPALFATEK MFRMLTNIW TVINHFSVWL ATGLGTFYFL KIANFSNSIF LYLKWRVKKV VLVLLLVTSV FLFLNIALIN IHINASINGY R RNKTCSSD ...String:
MGGVIKSIFT FVLIVEFIIG NLGNSFIALV NCIDWVKGRK ISSVDRILTA LAISRISLVW LIFGSWCVSV FFPALFATEK MFRMLTNIW TVINHFSVWL ATGLGTFYFL KIANFSNSIF LYLKWRVKKV VLVLLLVTSV FLFLNIALIN IHINASINGY R RNKTCSSD SSNFTRFSSL IVLTSTVFIF IPFTLSLAMF LLLIFSMWKH RKKMQHTVKI SGDASTKAHR GVKSVITFFL LY AIFSLSF FISVWTSERL EENLIILSQV MGMAYPSCHS CVLILGNKKL RQASLSVLLW LRYMFKDGEP SGHKEFRESS

UniProtKB: Taste receptor type 2 member 14

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Macromolecule #2: Guanine nucleotide-binding protein G(t) subunit alpha-3

MacromoleculeName: Guanine nucleotide-binding protein G(t) subunit alpha-3
type: protein_or_peptide / ID: 2
Details: Mini G alpha gustducin protein,Mini G alpha gustducin protein
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.983604 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKELE KKLQEDAERD ARTVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGII ETQFSFKDLH FRMFDVGGQ RSERKKWIHC FEDVTCIIFC ADLSDYNRMH ESLHLFNSIC NHKYFSTTSI VLFLNKKDIF QEKVTKVHLS I CFPEYTGP ...String:
MGSTVSAEDK AAAERSKELE KKLQEDAERD ARTVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGII ETQFSFKDLH FRMFDVGGQ RSERKKWIHC FEDVTCIIFC ADLSDYNRMH ESLHLFNSIC NHKYFSTTSI VLFLNKKDIF QEKVTKVHLS I CFPEYTGP NTFEDAGNYI KNQFLDLNLK KEDKEIYSHM TCATDTQNAK FIFDAVTDII IKENLKDCGL F

UniProtKB: Guanine nucleotide-binding protein G(t) subunit alpha-3, Guanine nucleotide-binding protein G(t) subunit alpha-3

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculoides (Temminck's mouse)
Molecular weightTheoretical: 27.340482 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KGSLEVLFQ

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Macromolecule #6: 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID

MacromoleculeName: 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / type: ligand / ID: 6 / Number of copies: 2 / Formula: FLF
Molecular weightTheoretical: 281.23 Da
Chemical component information

ChemComp-FLF:
2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / antiinflammatory, inhibitor*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 38.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 20.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 127503
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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