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  • Yang, ZhenlinChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China (author)

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

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • 2018-04-18
  • Springer Science and Business Media LLC,2018
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-354947
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-354947URI
  • https://doi.org/10.1038/s41586-018-0046-xDOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Han, ShuoChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China (author)
  • Keller, MaxUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Kaiser, Anette (author)
  • Bender, Brian J.Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA (author)
  • Bosse, MathiasUniv Leipzig, Inst Med Phys & Biophys, Leipzig, Germany (author)
  • Burkert, KerstinUniv Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany (author)
  • Koegler, Lisa M.Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany (author)
  • Wifling, DavidUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Bernhardt, GuentherUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Plank, NicoleUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Littmann, TimoUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Schmidt, PeterUniv Leipzig, Inst Med Phys & Biophys, Leipzig, Germany (author)
  • Yi, CuiyingChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China (author)
  • Li, BeibeiChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China (author)
  • Ye, ShengChinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China (author)
  • Zhang, RongguangChinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China;Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai, Peoples R China (author)
  • Xu, Bo,1980-Uppsala universitet,Farmakologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)boaxu109 (author)
  • Larhammar, Dan,1956-Uppsala universitet,Farmakologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)dla05000 (author)
  • Stevens, Raymond C.ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China (author)
  • Huster, DanielUniv Leipzig, Inst Med Phys & Biophys, Leipzig, Germany (author)
  • Meiler, JensVanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA;Vanderbilt Univ, Struct Biol Ctr, Dept Chem, 221 Kirkland Hall, Nashville, TN 37235 USA;Vanderbilt Univ, Dept Bioinformat, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA (author)
  • Zhao, QiangChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China (author)
  • Beck-Sickinger, Annette G.Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany (author)
  • Buschauer, ArminUniv Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany (author)
  • Wu, BeiliChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China (author)
  • Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China (creator_code:org_t)

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  • In:Nature: Springer Science and Business Media LLC556:7702, s. 520-5240028-08361476-4687

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