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

Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B
Nature. 2018 556 (7702): 520-524

PMID: 29670288 · PMCID: PMC5920736 · DOI:10.1038/s41586-018-0046-x

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . 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 Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) . A number of peptides and small-molecule compounds have been characterized as YR antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human YR 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 YR to several structurally diverse antagonists and the determinants of ligand selectivity. The YR 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 YR can enable structure-based drug discovery that targets NPY receptors.

MeSH Terms (18)

Arginine Binding Sites Crystallography, X-Ray Dihydropyridines Diphenylacetic Acids Humans Inositol Phosphates Ligands Molecular Docking Simulation Mutant Proteins Mutation Neuropeptide Y Nuclear Magnetic Resonance, Biomolecular Phenylurea Compounds Protein Binding Receptors, Neuropeptide Y Structure-Activity Relationship Substrate Specificity

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