Structural basis of ligand binding modes at the neuropeptide Y Y 1 receptor.

Autor: Yang Z; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Han S; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Keller M; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany. max.keller@chemie.uni-regensburg.de., Kaiser A; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany., Bender BJ; Department of Pharmacology, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA., Bosse M; Institute for Medical Physics and Biophysics, Leipzig University, Leipzig, Germany., Burkert K; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany., Kögler LM; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany., Wifling D; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany., Bernhardt G; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany., Plank N; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany., Littmann T; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany., Schmidt P; Institute for Medical Physics and Biophysics, Leipzig University, Leipzig, Germany., Yi C; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Li B; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China., Ye S; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Zhang R; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.; National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China., Xu B; Department of Neuroscience, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Larhammar D; Department of Neuroscience, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Stevens RC; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Huster D; Institute for Medical Physics and Biophysics, Leipzig University, Leipzig, Germany., Meiler J; Department of Pharmacology, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.; Departments of Chemistry and Bioinformatics, Center for Structural Biology, Vanderbilt University, Nashville, TN, USA., Zhao Q; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; University of Chinese Academy of Sciences, Beijing, China.; Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China., Beck-Sickinger AG; Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany. abeck-sickinger@uni-leipzig.de., Buschauer A; Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany., Wu B; Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.; Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 Apr; Vol. 556 (7702), pp. 520-524. Date of Electronic Publication: 2018 Apr 18.
DOI: 10.1038/s41586-018-0046-x
Abstrakt: 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 (Y 1 R) 4 . A number of peptides and small-molecule compounds have been characterized as Y 1 R 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 Y 1 R 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 Y 1 R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y 1 R 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 Y 1 R can enable structure-based drug discovery that targets NPY receptors.
Databáze: MEDLINE
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