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

Nature. 2018 Apr;556(7702):520-524. doi: 10.1038/s41586-018-0046-x. Epub 2018 Apr 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Arginine / analogs & derivatives*
  • Arginine / chemistry
  • Arginine / metabolism
  • Arginine / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Dihydropyridines / chemistry*
  • Dihydropyridines / metabolism*
  • Dihydropyridines / pharmacology
  • Diphenylacetic Acids / chemistry*
  • Diphenylacetic Acids / metabolism*
  • Diphenylacetic Acids / pharmacology
  • Humans
  • Inositol Phosphates / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Mutation
  • Neuropeptide Y / chemistry
  • Neuropeptide Y / metabolism*
  • Neuropeptide Y / pharmacology
  • Nuclear Magnetic Resonance, Biomolecular
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / metabolism*
  • Phenylurea Compounds / pharmacology
  • Protein Binding
  • Receptors, Neuropeptide Y / agonists
  • Receptors, Neuropeptide Y / antagonists & inhibitors*
  • Receptors, Neuropeptide Y / chemistry*
  • Receptors, Neuropeptide Y / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity


  • BMS 193885
  • Dihydropyridines
  • Diphenylacetic Acids
  • Inositol Phosphates
  • Ligands
  • Mutant Proteins
  • Nalpha-diphenylacetyl-Nomega-(propionylaminoethyl)aminocarbonyl-(4-hydroxybenzyl)argininamide
  • Neuropeptide Y
  • Phenylurea Compounds
  • Receptors, Neuropeptide Y
  • neuropeptide Y-Y1 receptor
  • Arginine