Molecular Basis of NPY Recognition and Ligand Selectivity at the Neuropeptide Y 5 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, Y 1 R, Y 2 R, Y 4 R, and Y 5 R, all of them recognize the endogenous ligand neuropeptide Y (NPY), which demonstrates their complex ligand recognition and activation mechanisms. The Y 5 R 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‐Y 5 R interactions. We report the cryo‐electron microscopy structure of Y 5 R in complex with NPY and the G i1 protein, revealing unique features of the Y 5 R extracellular regions that participate in ligand recognition and illustrating the specific binding mode of the NPY C‐terminus to Y 5 R. The structural information is supported by mutagenesis studies investigating ligand binding and receptor activation with the endogenous ligand NPY and the selective Y 5 R agonist sY 5 ago. Structural analysis provides valuable insights into the factors driving receptor subtype selectivity, thus offering an opportunity for drug discovery of Y 5 R.