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Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor
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 China.
Chinese 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.
Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
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2018 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 556, no 7702, p. 520-524Article in journal, Letter (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 556, no 7702, p. 520-524
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-354947DOI: 10.1038/s41586-018-0046-xISI: 000430793000051PubMedID: 29670288OAI: oai:DiVA.org:uu-354947DiVA, id: diva2:1223545
Funder
German Research Foundation (DFG), Be1264-16German Research Foundation (DFG), SFB 1052/A3German Research Foundation (DFG), KE 1857/1-1German Research Foundation (DFG), GRK 1910Available from: 2018-06-25 Created: 2018-06-25 Last updated: 2019-01-03Bibliographically approved

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Xu, BoLarhammar, Dan

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