Molecular Basis of NPY Recognition and Ligand Selectivity at the Neuropeptide Y₅ Receptor

Neuropeptide Y receptors (YRs) have been demonstrated to mediate physiological functions such as food intake, energy expenditure and mood regulation. Despite the low sequence identity exhibited by the four YR subtypes, Y₁R, Y₂R, Y₄R, and Y₅R, all of them recognize the endogenous ligand neuropeptide Y (NPY), which demonstrates their complex ligand recognition and activation mechanisms. The Y₅R is regarded as a promising drug target for cachexia and cancer, but drug development has been hampered by the lack of structural information on ligand-Y₅R interactions. We report the cryo-electron microscopy structure of Y₅R in complex with NPY and the G_i1 protein, revealing unique features of the Y₅R extracellular regions that participate in ligand recognition and illustrating the specific binding mode of the NPY C-terminus to Y₅R. The structural information is supported by mutagenesis studies investigating ligand binding and receptor activation with the endogenous ligand NPY and the selective Y₅R agonist sY₅ago. Structural analysis provides valuable insights into the factors driving receptor subtype selectivity, thus offering an opportunity for drug discovery of Y₅R.