Binding of Natural Peptide Ligands to the Neuropeptide Y5 Receptor

The binding mode of natural peptide ligands to the Y5 G protein-coupled receptor (Y5R), an attractive therapeutic target for treatment obesity, is largely unknown. Here, we apply complementary biochemical and computational approaches, including scanning surface with a genetically encoded crosslinker, Ala-scanning ligand double-cycle mutagenesis, map interactions in ligand-receptor interface build structural model NPY-Y5R complex guided by experimental data. In model, carboxyl (C)-terminus bound NPY placed close extracellular loop (ECL) 3, whereas characteristic α-helical segment drapes over ECL1 tethered towards ECL2 hydrophobic cluster. We further show that other two Y5R, YY (PYY) pancreatic polypeptide (PP) dock similar pose.