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

doi:10.1038/s41586-018-0046-x

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	Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor
	Yang, Zhenlin 14,15; Han, Shuo 13,15; Keller, Max 12; Kaiser, Anette ; Bender, Brian J.10; Bosse, Mathias 9; Burkert, Kerstin 11; Koegler, Lisa M.11; Wifling, David 12; Bernhardt, Guenther 12
刊名	NATURE
	2018-04-26
卷号	556 期号:7702 页码:520-+
ISSN号	0028-0836
DOI	10.1038/s41586-018-0046-x
文献子类	Article
英文摘要	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.
资助项目	CAS Strategic Priority Research Programs[XDB08020000] ; CAS Strategic Priority Research Programs[XDB08030102] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-SMC024] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-SMC054] ; National Science Foundation of China[31570739] ; National Science Foundation of China[81525024] ; National Science Foundation of China[3170040264] ; National Science Foundation of China[31470792] ; Program of Shanghai Academic/Technology Research Leader[18XD1404800] ; European Community[00000000] ; Free State of Saxony[SAB 100148835] ; Free State of Saxony[100881433] ; Deutsche Forschungsgemeinschaft (DFG)[Be1264-16] ; Deutsche Forschungsgemeinschaft (DFG)[SFB 1052/A3] ; Deutsche Forschungsgemeinschaft (DFG)[KE 1857/1-1] ; Deutsche Forschungsgemeinschaft (DFG)[GRK 1910] ; NIH[R01 GM080403] ; NIH[R01 DK097376] ; NIH[R01 HL122010] ; NSF[CHE 1305874] ; Japan Synchrotron Radiation Research Institute[2015B2026] ; Japan Synchrotron Radiation Research Institute[2015B2027] ; Japan Synchrotron Radiation Research Institute[2016A2517] ; Japan Synchrotron Radiation Research Institute[2016A2518] ; Japan Synchrotron Radiation Research Institute[2016B2517] ; Japan Synchrotron Radiation Research Institute[2016B2518]
WOS关键词	PROTEIN-COUPLED RECEPTORS ; PANCREATIC-POLYPEPTIDE ; NEUROTENSIN RECEPTOR ; PEPTIDE YY ; ANTAGONISTS ; MUTAGENESIS ; AFFINITY ; TOOL ; ACTIVATION ; REFINEMENT
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000430793000051
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279792]
专题	药物靶标结构与功能中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Keller, Max; Beck-Sickinger, Annette G.; Wu, Beili
作者单位	1.Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China 2.Vanderbilt Univ, Dept Bioinformat, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA; 3.Vanderbilt Univ, Struct Biol Ctr, Dept Chem, 221 Kirkland Hall, Nashville, TN 37235 USA; 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 5.ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China; 6.Uppsala Univ, Sci Life Lab, Dept Neurosci, Uppsala, Sweden; 7.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai, Peoples R China; 8.Univ Chinese Acad Sci, Beijing, Peoples R China; 9.Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany; 10.Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA;
推荐引用方式 GB/T 7714	Yang, Zhenlin,Han, Shuo,Keller, Max,et al. Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor[J]. NATURE,2018,556(7702):520-+.
APA	Yang, Zhenlin.,Han, Shuo.,Keller, Max.,Kaiser, Anette.,Bender, Brian J..,...&Wu, Beili.(2018).Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor.NATURE,556(7702),520-+.
MLA	Yang, Zhenlin,et al."Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor".NATURE 556.7702(2018):520-+.