Structural basis for Y2 receptor-mediated neuropeptide Y and peptide YY signaling

Neuropeptide Y (NPY) and its receptors are expressed in various human tissues including the brain where they regulate appetite and emotion. Upon NPY stimulation, the neuropeptide Y1 and Y2 receptors (Y₁R and Y₂R, respectively) activate G_I signaling, but their physiological responses to food intake are different. In addition, deletion of the two N-terminal amino acids of peptide YY (PYY(3-36)), the endogenous form found in circulation, can stimulate Y₂R but not Y₁R, suggesting that Y₁R and Y₂R may have distinct ligand-binding modes. Here, we report the cryo-electron microscopy structures of the PYY(3-36)‒Y₂R‒G_i and NPY‒Y₂R‒G_i complexes. Using cell-based assays, molecular dynamics simulations, and structural analysis, we revealed the molecular basis of the exclusive binding of PYY(3-36) to Y₂R. Furthermore, we demonstrated that Y₂R favors G protein signaling over β-arrestin signaling upon activation, whereas Y₁R does not show a preference between these two pathways.