A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR
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 TAS2Rs encoded in the human genome, TAS2R14 is the most promiscuous, and responds to hundreds of...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54157-6 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lior Peri |
| collection | DOAJ |
| description | 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 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. |
| format | Article |
| id | doaj-art-ffe236aefc0341b29447e20725da57e1 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ffe236aefc0341b29447e20725da57e12024-11-24T12:32:38ZengNature PortfolioNature Communications2041-17232024-11-0115111510.1038/s41467-024-54157-6A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCRLior Peri0Donna Matzov1Dominic R. Huxley2Alon Rainish3Fabrizio Fierro4Liel Sapir5Tara Pfeiffer6Lukas Waterloo7Harald Hübner8Yoav Peleg9Peter Gmeiner10Peter J. McCormick11Dorothee Weikert12Masha Y. Niv13Moran Shalev-Benami14The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of JerusalemDepartment of Chemical and Structural Biology, Weizmann Institute of ScienceCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, Charterhouse SquareThe Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of JerusalemThe Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of JerusalemThe Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of JerusalemDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-NürnbergDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-NürnbergDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-NürnbergStructural Proteomics Unit (SPU), Life Sciences Core Facilities (LSCF), Weizmann Institute of ScienceDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-NürnbergCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, Charterhouse SquareDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-NürnbergThe Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of JerusalemDepartment of Chemical and Structural Biology, Weizmann Institute of ScienceAbstract 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.https://doi.org/10.1038/s41467-024-54157-6 |
| spellingShingle | 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 A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR Nature Communications |
| title | A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR |
| title_full | A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR |
| title_fullStr | A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR |
| title_full_unstemmed | A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR |
| title_short | A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR |
| title_sort | bitter anti inflammatory drug binds at two distinct sites of a human bitter taste gpcr |
| url | https://doi.org/10.1038/s41467-024-54157-6 |
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