The Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
The Fritz Haber Research Center, and the Harvey M. Kruger Center for Nanoscience & Nanotechnology, Institute of Chemistry, The Hebrew University, Jerusalem, Israel.
Nat Commun. 2024 Nov 18;15(1):9991. doi: 10.1038/s41467-024-54157-6.
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.
苦味受体（TAS2Rs）是 G 蛋白偶联受体（GPCR）的一个亚家族，在口腔内外表达，可对一大组味觉物质产生信号。在人类基因组中编码的 25 个功能性 TAS2R 中，TAS2R14 最为混杂，可响应数百种化学上不同的配体。在这里，我们展示了与人 TAS2R14 与其信号伙伴 gustducin 复合物以及与氟芬那酸（FFA）结合的冷冻电镜（cryo-EM）结构，FFA 是一种临床批准的非甾体抗炎药。该结构揭示了一种不寻常的结合模式，其中两个 FFA 分子结合在不同的口袋中：一个位于跨膜束内的经典受体部位，另一个位于细胞内表面，将受体与 gustducin 桥接。结合特定于口袋的 BRET 基于配体结合测定，这些结果阐明了苦味信号转导，并为靶向特定部位的化合物设计提供了工具。
