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- PDB-8rql: TAS2R14 receptor bound to flufenamic acid and gustducin -

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Entry
Database: PDB / ID: 8rql
TitleTAS2R14 receptor bound to flufenamic acid and gustducin
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Taste receptor type 2 member 14
  • scFv16
KeywordsSTRUCTURAL PROTEIN / Single particle cryo-EM / GPCR / G-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
2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsMatzov, D. / Peri, L. / Niv, M. / Shalev Benami, M.
Funding supportEuropean Union, 1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Data collection / Structure summary / Category: em_admin / struct / Item: _em_admin.last_update / _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Taste receptor type 2 member 14
A: Guanine nucleotide-binding protein G(t) subunit alpha-3
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,3667
Polymers136,8035
Non-polymers5622
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#2: Protein Guanine nucleotide-binding protein G(t) subunit alpha-3 / Gustducin alpha-3 chain


Mass: 25983.604 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Mini G alpha gustducin protein,Mini G alpha gustducin protein
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAT3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A8MTJ3
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Antibody / Non-polymers , 3 types, 4 molecules RS

#1: Protein Taste receptor type 2 member 14 / T2R14 / Taste receptor family B member 1 / TRB1


Mass: 36200.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TAS2R14 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9NYV8
#5: Antibody scFv16


Mass: 27340.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Production host: Trichoplusia ni (cabbage looper)
#6: Chemical ChemComp-FLF / 2-[[3-(TRIFLUOROMETHYL)PHENYL]AMINO] BENZOIC ACID / FLUFENAMIC ACID


Mass: 281.230 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10F3NO2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antiinflammatory, inhibitor*YM

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Human Taste receptor type 2 member 14 in complex with G-proteinsCOMPLEX#1-#50MULTIPLE SOURCES
2Human Taste receptor type 2 member 14 in complex with G-proteinsCOMPLEX#1-#41RECOMBINANT
3scFv16 (antibody)COMPLEX#51RECOMBINANT
Molecular weightValue: 118.3 kDa/nm / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculoides (Temminck's mouse)60742
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 20000 nm / Nominal defocus min: 8000 nm / Cs: 2.7 mm
Image recordingElectron dose: 38.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127503 / Symmetry type: POINT
RefinementCross valid method: NONE

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