Unsaturated bond recognition leads to biased signal in a fatty acid receptor

Science. 2023 Apr 7;380(6640):eadd6220. doi: 10.1126/science.add6220. Epub 2023 Apr 7.


Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.

MeSH terms

  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Cryoelectron Microscopy
  • Drug Design*
  • Eicosapentaenoic Acid / chemistry
  • Eicosapentaenoic Acid / metabolism
  • Fatty Acids, Omega-3* / chemistry
  • Fatty Acids, Omega-3* / metabolism
  • Humans
  • Ligands
  • Mutation, Missense
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Receptors, G-Protein-Coupled* / agonists
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / genetics


  • Ligands
  • Receptors, G-Protein-Coupled
  • Fatty Acids, Omega-3
  • FFAR4 protein, human
  • 3-(4-((4-fluoro-4'-methyl-(1,1'-biphenyl)-2-yl)methoxy)phenyl)propanoic acid
  • Biphenyl Compounds
  • Phenylpropionates
  • Eicosapentaenoic Acid