Structural basis of ligand binding modes at the neuropeptide Y Y₁ receptor

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology ^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 most mammals, namely the Y₁, Y₂, Y₄ and Y₅ receptors, with different affinity and selectivity ³ . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y₁ receptor (Y₁R) ⁴ . A number of peptides and small-molecule compounds have been characterized as Y₁R antagonists and have shown clinical potential in the treatment of obesity ⁴ , tumour 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 Y₁R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y₁R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y₁R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y₁R can enable structure-based drug discovery that targets NPY receptors.