Yang, Zhenlin and Han, Shuo and Keller, Max and Kaiser, Anette and Bender, Brian J. and Bosse, Mathias and Burkert, Kerstin and Koegler, Lisa M. and Wifling, David and Bernhardt, Guenther and Plank, Nicole and Littmann, Timo and Schmidt, Peter and Yi, Cuiying and Li, Beibei and Ye, Sheng and Zhang, Rongguang and Xu, Bo and Larhammar, Dan and Stevens, Raymond C. and Huster, Daniel and Meiler, Jens and Zhao, Qiang and Beck-Sickinger, Annette G. and Buschauer, Armin and Wu, Beili (2018) Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor. NATURE, 556 (7702). 520-+. ISSN 0028-0836, 1476-4687
Full text not available from this repository. (Request a copy)Abstract
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 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 the Y-1 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 angstrom 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTORS; PANCREATIC-POLYPEPTIDE; NEUROTENSIN RECEPTOR; PEPTIDE YY; ANTAGONISTS; MUTAGENESIS; AFFINITY; TOOL; ACTIVATION; REFINEMENT; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2020 08:14 |
| Last Modified: | 24 Mar 2020 08:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14705 |
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