Cardiac human bitter taste receptors contain naturally occurring variants that alter function

Bloxham, Conor J.; Hulme, Katina D.; Fierro, Fabrizio; Fercher, Christian; Pegg, Cassandra L.; O'Brien, Shannon L.; Foster, Simon R.; Short, Kirsty R.; Furness, Sebastian G.B.; Reichelt, Melissa E.; Niv, Masha Y.; Thomas, Walter G.

doi:10.1016/j.bcp.2023.115932

Cited by 6 publications

(4 citation statements)

References 80 publications

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“…3F-G ), and performed BRET assays to test the receptor susceptibility to FFA. The first two mutations, F198L 5.58 (rs202123922) and L201F 5.61 (rs35804287) are natural variants in human, where L201F 5.61 was reported to reduce the receptor’s sensitivity to agonists ( 13 ). The corresponding positions in TAS2Rs are mostly conserved.…”

Section: Resultsmentioning

confidence: 99%

“…Those include S220 6.27 in TAS2R46 that interacts with D341 gus-H5. 13 and K345 gus-H5.17 and V223 6.30 that interacts with F354 gus-H5. 26 .…”

Section: Comparison Of Tas2r14 With Other Taste Receptorsmentioning

confidence: 99%

“…TAS2R14 is abundant in the taste buds but is also expressed in extraoral tissues such as the respiratory (10,11), cardiovascular (12,13) and digestive (14) systems. Polymorphisms in the TAS2R14 gene were associated with cardiac physiology (13) and male infertility (15). TAS2R14 overexpression was also documented in several types of cancer (12,16), and its stimulation was shown to elicit anti-proliferative and proapoptotic effects in multiple cancer cell lines (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…TAS2R14 is a notable taste receptor that responds to the largest number of agonists, including vitamins ( 5 ), flavonoids ( 6 ), pharmaceuticals ( 7, 8 ) and odorants ( 9 ). TAS2R14 is abundant in the taste buds but is also expressed in extraoral tissues such as the respiratory ( 10, 11 ), cardiovascular ( 12, 13 ) and digestive ( 14 ) systems. Polymorphisms in the TAS2R14 gene were associated with cardiac physiology ( 13 ) and male infertility ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Intracellular binding pocket revealed in the human bitter taste receptor TAS2R14

Peri,

Matzov,

Huxley

et al. 2024

Preprint

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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 ligands. Among the 25 functional TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of chemically diverse agonists. Here, we present the cryo–electron microscopy (cryo-EM) structure of the human TAS2R14 (hTAS2R14) in complex with its cognate signaling partner gustducin, and bound to flufenamic acid (FFA), a clinically approved nonsteroidal anti-inflammatory drug. The structure reveals an unusual binding mode for FFA, where two copies are bound at distinct binding pockets: one at the canonical GPCR site within the trans-membrane bundle, and the other in the intracellular facet, bridging the receptor with gustducin. Combined with site-directed mutagenesis and the design of a fluorescent FFA derivative for pocket-specific ligand binding BRET assays, our studies support a dual binding mode for FFA in TAS2R14. These results fill a gap in the understanding of bitter taste signaling and provide tools for guided design of TAS2R-targeted compounds.

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Section: Resultsmentioning

confidence: 99%

“…Those include S220 6.27 in TAS2R46 that interacts with D341 gus-H5. 13 and K345 gus-H5.17 and V223 6.30 that interacts with F354 gus-H5. 26 .…”

Section: Comparison Of Tas2r14 With Other Taste Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intracellular binding pocket revealed in the human bitter taste receptor TAS2R14

Peri,

Matzov,

Huxley

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Bitter taste receptor T2R14-Gαi coupling mediates innate immune responses to microbial quorum sensing molecules in cystic fibrosis

Singh,

Cunnington,

Bhagirath

et al. 2024

iScience

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A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR

Peri,

Matzov,

Huxley

et al. 2024

Nat Commun

View full text Add to dashboard Cite

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.

show abstract

Cardiac human bitter taste receptors contain naturally occurring variants that alter function

Cited by 6 publications

References 80 publications

Intracellular binding pocket revealed in the human bitter taste receptor TAS2R14

Intracellular binding pocket revealed in the human bitter taste receptor TAS2R14

Bitter taste receptor T2R14-Gαi coupling mediates innate immune responses to microbial quorum sensing molecules in cystic fibrosis

A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR

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