8RQL

TAS2R14 receptor bound to flufenamic acid and gustducin

Summary for 8RQL

• Entry DOI: 10.2210/pdb8rql/pdb
• EMDB information: 19445
• Descriptor: Taste receptor type 2 member 14, Guanine nucleotide-binding protein G(t) subunit alpha-3, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: single particle cryo-em, gpcr, g-protein, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 137365.85

Authors

Matzov, D.,Peri, L.,Niv, M.,Shalev Benami, M. (deposition date: 2024-01-18, release date: 2024-11-27, Last modification date: 2025-01-22)

Primary citation

Peri, L.,Matzov, D.,Huxley, D.R.,Rainish, A.,Fierro, F.,Sapir, L.,Pfeiffer, T.,Waterloo, L.,Hubner, H.,Peleg, Y.,Gmeiner, P.,McCormick, P.J.,Weikert, D.,Niv, M.Y.,Shalev-Benami, M.
A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR.
Nat Commun, 15:9991-9991, 2024

PubMed 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.

PubMed: 39557861
DOI: 10.1038/s41467-024-54157-6

Experimental method

ELECTRON MICROSCOPY (3.03 Å)