Structural basis of β-glucopyranoside salicin recognition by a human bitter taste GPCR

Cell Rep. 2025 May 27;44(5):115604. doi: 10.1016/j.celrep.2025.115604. Epub 2025 Apr 21.

Abstract

The human perception of bitterness is mediated by type 2 taste receptors (TAS2Rs), which recognize a broad array of bitter substances with distinct chemical properties. TAS2R16 exhibits a pronounced selectivity for β-glucoside-moiety-containing compounds, such as salicin from willow bark. However, the molecular mechanism of moiety-specific recognition and receptor activation in TAS2R16 remains unclear. Here, we present cryoelectron microscopy structures of the salicin-activated human TAS2R16 complexed with gustducin and Gi1 and Gi2 proteins. The binding mode of salicin with TAS2R16 and the specific interactions of the β-D-glucopyranoside moiety are detailed. Together with molecular docking and mutagenesis data, this study uncovers the structural underpinnings of TAS2R16's group-specific recognition, receptor activation, and subsequent gustducin and Gi protein coupling. These findings advance our understanding of human bitter taste receptors and provide a foundation for structural modifications of bitter glycosides, opening potential therapeutic applications.

Keywords: CP: Molecular biology; GPCR; TAS2R16; bitter taste receptor; salicin; β-glucopyranoside.

MeSH terms

  • Benzyl Alcohols* / chemistry
  • Benzyl Alcohols* / metabolism
  • Cryoelectron Microscopy
  • Glucosides* / chemistry
  • Glucosides* / metabolism
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Taste Receptors, Type 2
  • Taste*
  • Transducin / chemistry
  • Transducin / metabolism

Substances

  • salicin
  • Glucosides
  • Receptors, G-Protein-Coupled
  • Benzyl Alcohols
  • Taste Receptors, Type 2
  • Transducin
  • gustducin