Structural basis of ligand binding modes at the neuropeptide Y Y(1) receptor

Neuropeptide Y (NPY) receptors belong to the G protein-coupled receptor (GPCR) superfamily and play important roles in food intake, anxiety and cancer regulation(1,2). The NPY/Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in mammals, namely Y(1), Y(2), Y(4) and Y(5) receptors, with different affinity and selectivity(3). NPY is the most powerful stimulant of food intake and this effect is primarily mediated by Y(1) receptor (Y(1)R)(4). A number of peptides and small-molecule compounds have been characterized as Y(1)R antagonists and have shown clinical potential in the treatment of obesity(4), tumor(1) and bone loss(5). However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability(6). Here we report crystal structures of the human Y(1)R bound to two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal binding modes of Y(1)R to several structurally diverse antagonists and determinants of ligand selectivity. The Y(1)R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance (NMR), photo-crosslinking and functional studies, provide insights into the binding behavior of the agonist and for the first time determine the interaction of its N terminus with the receptor. These insights into Y(1)R can enable structure-based drug discovery targeting NPY receptors.