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

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

Author information

1
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
4
Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany. max.keller@chemie.uni-regensburg.de.
5
Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany.
6
Department of Pharmacology, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
7
Institute for Medical Physics and Biophysics, Leipzig University, Leipzig, Germany.
8
Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
9
University of Chinese Academy of Sciences, Beijing, China.
10
National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
11
Department of Neuroscience, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
12
iHuman Institute, ShanghaiTech University, Shanghai, China.
13
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
14
Departments of Chemistry and Bioinformatics, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
15
Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China.
16
Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany. abeck-sickinger@uni-leipzig.de.
17
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
18
University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
19
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.
20
Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.

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 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.

PMID:
29670288
PMCID:
PMC5920736
DOI:
10.1038/s41586-018-0046-x
[Indexed for MEDLINE]
Free PMC Article

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