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

doi:10.1038/s41586-018-0046-x

KMS > iHuman研究所

	Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor
	Yang, Zhenlin 1,2; Han, Shuo 1,3; Keller, Max 4; Kaiser, Anette ; Bender, Brian J.6; Bosse, Mathias 7; Burkert, Kerstin 5; Koegler, Lisa M.5; Wifling, David 4; Bernhardt, Guenther 4; Plank, Nicole 4; Littmann, Timo 4; Schmidt, Peter 7; Yi, Cuiying 1; Li, Beibei 1,8; Ye, Sheng 3; Zhang, Rongguang 3,9; Xu, Bo 10; Larhammar, Dan 10; Stevens, Raymond C.11,12 ; Huster, Daniel 7; Meiler, Jens 6,13,14; Zhao, Qiang 1,2,8,15; Beck-Sickinger, Annette G.5; Buschauer, Armin 4; Wu, Beili1,8,12,15
	2018-04-26
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	556 期号:7702 页码:520-+
发表状态	已发表
DOI	10.1038/s41586-018-0046-x
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.
收录类别	SCI ; SCIE
语种	英语
资助项目	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研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000430793000051
出版者	NATURE PUBLISHING GROUP
WOS关键词	PROTEIN-COUPLED RECEPTORS ; PANCREATIC-POLYPEPTIDE ; NEUROTENSIN RECEPTOR ; PEPTIDE YY ; ANTAGONISTS ; MUTAGENESIS ; AFFINITY ; TOOL ; ACTIVATION ; REFINEMENT
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/20822
专题	iHuman研究所 iHuman研究所_特聘教授组_Raymond Stevens组生命科学与技术学院_特聘教授组_吴蓓丽组
通讯作者	Keller, Max; Beck-Sickinger, Annette G.; Wu, Beili
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 3.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China 4.Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany 5.Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany 6.Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA 7.Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany 8.Univ Chinese Acad Sci, Beijing, Peoples R China 9.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai, Peoples R China 10.Uppsala Univ, Sci Life Lab, Dept Neurosci, Uppsala, Sweden 11.ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China 12.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 13.Vanderbilt Univ, Struct Biol Ctr, Dept Chem, 221 Kirkland Hall, Nashville, TN 37235 USA 14.Vanderbilt Univ, Dept Bioinformat, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA 15.Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China
通讯作者单位	生命科学与技术学院
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-+.