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

Peri L, Matzov D, Huxley DR, Rainish A, Fierro F, Sapir L, Pfeiffer T, Waterloo L, Hübner H, Peleg Y, Gmeiner P, McCormick PJ, Weikert D, Niv MY, Shalev-Benami M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 15

Article Number: 9991

Journal Issue: 1

DOI: 10.1038/s41467-024-54157-6

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.

Authors with CRIS profile

Tara Pfeiffer Lehrstuhl für Pharmazeutische Chemie Lukas Waterloo Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie Dorothée Weikert Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

FAU Forschungszentrum Neue Wirkstoffe (FAU NeW)

Involved external institutions

Hebrew University of Jerusalem IL Israel (IL) Weizmann Institute of Science IL Israel (IL) Queen Mary University of London GB United Kingdom (GB)

How to cite

APA:

Peri, L., Matzov, D., Huxley, D.R., Rainish, A., Fierro, F., Sapir, L.,... Shalev-Benami, M. (2024). A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-54157-6

MLA:

Peri, Lior, et al. "A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR." Nature Communications 15.1 (2024).

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