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

Zhenlin Yang, Shuo Han, Max Keller (), Anette Kaiser, Brian J. Bender, Mathias Bosse, Kerstin Burkert, Lisa M. Kögler, David Wifling, Guenther Bernhardt, Nicole Plank, Timo Littmann, Peter Schmidt, Cuiying Yi, Beibei Li, Sheng Ye, Rongguang Zhang, Bo Xu, Dan Larhammar, Raymond C. Stevens, Daniel Huster, Jens Meiler, Qiang Zhao, Annette G. Beck-Sickinger (), Armin Buschauer and Beili Wu ()
Additional contact information
Shuo Han: Chinese Academy of Sciences
Max Keller: University of Regensburg
Anette Kaiser: Leipzig University
Brian J. Bender: Vanderbilt University
Mathias Bosse: Leipzig University
Kerstin Burkert: Leipzig University
Lisa M. Kögler: Leipzig University
David Wifling: University of Regensburg
Guenther Bernhardt: University of Regensburg
Nicole Plank: University of Regensburg
Timo Littmann: University of Regensburg
Peter Schmidt: Leipzig University
Cuiying Yi: Chinese Academy of Sciences
Beibei Li: Chinese Academy of Sciences
Sheng Ye: Chinese Academy of Sciences
Rongguang Zhang: Chinese Academy of Sciences
Bo Xu: Uppsala University
Dan Larhammar: Uppsala University
Raymond C. Stevens: ShanghaiTech University
Daniel Huster: Leipzig University
Jens Meiler: Vanderbilt University
Qiang Zhao: Chinese Academy of Sciences
Annette G. Beck-Sickinger: Leipzig University
Armin Buschauer: University of Regensburg
Beili Wu: Chinese Academy of Sciences

Nature, 2018, vol. 556, issue 7702, 520-524

Abstract: Abstract Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology1,2. 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 selectivity3. 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 obesity4, tumour1 and bone loss5. However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability6. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0046-x

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