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

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

doi:10.1038/s41467-024-54157-6

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	9991
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-54157-6
Publication status	Published - 18 Nov 2024

Funding

This work was funded by the European Union\u2019s Horizon 2020 research and innovation program under the European Research Council (ERC; grant no. 949364) to M.S.-B, the German Research Foundation Grants Gm 13/12 to P.G. and M.Y.N, the Israel Science Foundation grant 1129/19 to M.Y.N and Pancreatic Cancer Research Fund, the UKRI BBSRC, UUKi and the Weizmann Institute - UK joint research program to P.J.M and M.S.-B. M.S.-B. holds the Tauro Career Development Chair in Biomedical Research. M.S.-B. is supported by the Zuckerman STEM Leadership Program, the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research, the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly, the Joseph and Wolf Lebovic Lab, the Dov and Ziva Rabinovich Endowed Fund for Structural Biology, the Harmstieg New Scientist Fund, and the Pearl Welinsky Merlo Foundation and by P. and T. Gardner. L.P. was partially supported by Excellence Fellowship from the Hebrew University Center for Nanoscience and Nanotechnology and COST Action 18133-ERNEST STSM grant. D.R.H. was supported by a British Heart Foundation project grant and fellowship. We thank Khajidmaa Flad for the cloning of the secNLuc-TAS2R14 construct, and Michael Naim, Asa Tirosh, Evgenii Ziaikin, and George Chalhoub for helpful discussions. We thank Nadav Elad for technical support with microscope operation.

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Peri, L., Matzov, D., Huxley, D. R., Rainish, A., Fierro, F., Sapir, L., Pfeiffer, T., Waterloo, L., Hübner, H., Peleg, Y., Gmeiner, P., McCormick, P. J., Weikert, D., Niv, M. Y., & Shalev-Benami, M. (2024). A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR. Nature Communications, 15, Article 9991. https://doi.org/10.1038/s41467-024-54157-6

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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.",

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AU - Gmeiner, Peter

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AU - Niv, Masha Y.

AU - Shalev-Benami, Moran

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

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