Structural basis of neuropeptide Y signaling through Y1 receptor

Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (Y(1)R) in complex with G(i1) protein. The NPY C-terminal segment forming the extended conformation binds deep into the Y(1)R transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with Y(1)R extracellular loops, contributing to the high affinity of NPY for Y(1)R. The structural analysis of NPY-bound Y(1)R and mutagenesis studies provide molecular insights into the activation mechanism of Y(1)R upon NPY binding.