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Structural basis of...
Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor
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- Yang, Zhenlin (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 China
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- Han, Shuo (author)
- 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
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- Keller, Max (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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Kaiser, Anette (author)
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- Bender, Brian J. (author)
- Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA
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- Bosse, Mathias (author)
- Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany
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- Burkert, Kerstin (author)
- Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany
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- Koegler, Lisa M. (author)
- Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany
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- Wifling, David (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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- Bernhardt, Guenther (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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- Plank, Nicole (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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- Littmann, Timo (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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- Schmidt, Peter (author)
- Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany
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- Yi, Cuiying (author)
- Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China
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- Li, Beibei (author)
- Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China
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- Ye, Sheng (author)
- Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China
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- Zhang, Rongguang (author)
- Chinese 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
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- Xu, Bo, 1980- (author)
- Uppsala universitet,Farmakologi,Science for Life Laboratory, SciLifeLab
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- Larhammar, Dan, 1956- (author)
- Uppsala universitet,Farmakologi,Science for Life Laboratory, SciLifeLab
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- Stevens, Raymond C. (author)
- ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
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- Huster, Daniel (author)
- Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany
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- Meiler, Jens (author)
- Vanderbilt 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
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- Zhao, Qiang (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 China;Univ Chinese Acad Sci, Beijing, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China
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- Beck-Sickinger, Annette G. (author)
- Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany
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- Buschauer, Armin (author)
- Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany
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- Wu, Beili (author)
- Chinese 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
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(creator_code:org_t)
- 2018-04-18
- 2018
- English.
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 556:7702, s. 520-524
- Related links:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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Nature
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- By the author/editor
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Yang, Zhenlin
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Han, Shuo
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Keller, Max
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Kaiser, Anette
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Bender, Brian J.
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Bosse, Mathias
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show more...
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Burkert, Kerstin
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Koegler, Lisa M.
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Wifling, David
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Bernhardt, Guent ...
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Plank, Nicole
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Littmann, Timo
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Schmidt, Peter
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Yi, Cuiying
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Li, Beibei
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Ye, Sheng
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Zhang, Rongguang
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Xu, Bo, 1980-
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Larhammar, Dan, ...
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Stevens, Raymond ...
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Huster, Daniel
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Meiler, Jens
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Zhao, Qiang
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Beck-Sickinger, ...
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Buschauer, Armin
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Wu, Beili
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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Nature
- By the university
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Uppsala University