Molecular recognition of the NPY hormone family by their receptors

Many G-protein-coupled receptors belong to families of different receptor subtypes, which are recognized by a variety of distinct ligands. We summarize the current state of the art of the multireceptor/multiligand system of the so-called Y-receptor family. This family consists of four G-protein-coupled Y receptors in humans (hY1, hY2, hY4, and hY5) and is activated by the so-called neuropeptide Y hormone family, which consists of three native peptide ligands named neuropeptide Y, pancreatic polypeptide, and peptide YY. We recently reported that one conserved aspartate residue in the third extracellular loop is essential for ligand binding in all four Y receptors, but binds the endogenous ligands in a different mode by interacting with different ligand arginine residues. By combining peptide synthesis to obtain chemically modified neuropeptide Y, peptide YY, and pancreatic polypeptide analogs, receptor mutagenesis, and receptor chimeras, we could trace binding and signaling to a molecular level. The data on the variation of the ligands and an overview of the currently known mutagenesis data are summarized and specific models for the binding mode of the three ligands in all four receptors are provided.