Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)

doi:10.1074/jbc.M116.721977

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	Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)
	Yang, Dehua8,9 ; de Graaf, Chris 10; Yang, Linlin 1; Song, Gaojie 2; Dai, Antao 8,9; Cai, Xiaoqing 8,9; Feng, Yang 8,9; Reedtz-Runge, Steffen 3; Hanson, Michael A.4; Yang, Huaiyu 1
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2016-06-17
卷号	291 期号:25 页码:12991-13004
ISSN号	0021-9258
DOI	10.1074/jbc.M116.721977
文献子类	Article
英文摘要	The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members of the class B family are distinguished by their large extracellular domain, which works cooperatively with the canonical seven-transmembrane (7TM) helical domain to signal in response to binding of various peptide hormones. We have combined structure-based site-specific mutational studies with molecular dynamics simulations of a full-length model of GLP-1R bound to multiple peptide ligand variants. Despite the high sequence similarity between GLP-1R and its closest structural homologue, the glucagon receptor (GCGR), nearly half of the 62 stably expressed mutants affected GLP-1R in a different manner than the corresponding mutants in GCGR. The molecular dynamics simulations of wild-type and mutant GLP-1R center dot ligand complexes provided molecular insights into GLP-1R-specific recognition mechanisms for the N terminus of GLP-1 by residues in the 7TM pocket and explained how glucagon-mimicking GLP-1 mutants restored binding affinity for (GCGR-mimicking) GLP-1R mutants. Structural analysis of the simulations suggested that peptide ligand binding mode variations in the 7TM binding pocket are facilitated by movement of the extracellular domain relative to the 7TM bundle. These differences in binding modes may account for the pharmacological differences between GLP-1 peptide variants.
资助项目	Ministry of Science and Technology of China[2012CB518005] ; Ministry of Science and Technology of China[2012AA020302] ; Ministry of Science and Technology of China[2013ZX09507001] ; Ministry of Science and Technology of China[91313000] ; National Natural Science Foundation of China[81573479] ; National Natural Science Foundation of China[81373463] ; National Natural Science Foundation of China[21422208] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21210003] ; National Health and Family Planning Commission of China[2013ZX09507001] ; National Health and Family Planning Commission of China[2012ZX09304-011] ; National Health and Family Planning Commission of China[2013ZX09401003-005] ; National Health and Family Planning Commission of China[2013ZX09507-002] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Development Fund[14431901200] ; National Institutes of Health[U54 GM094618] ; European Cooperation in Science and Technology Action[CM1207] ; Netherlands eScience Center (NLeSC)/Netherlands Organisation for Scientific Research (NWO) Enabling Technologies Project, 3D-e-Chem[027.014.201] ; CAS-Novo Nordisk Research Fund[00000000] ; SA-SIBS Scholarship Program[00000000] ; Thousand Talents Program in China (Chinese Academy of Sciences)[00000000]
WOS关键词	PROTEIN-COUPLED-RECEPTOR ; CORTICOTROPIN-RELEASING-FACTOR ; TERMINAL EXTRACELLULAR DOMAIN ; 2ND TRANSMEMBRANE HELIX ; CLASS-B GPCRS ; AMINO-TERMINUS ; LIGAND-BINDING ; SPATIAL APPROXIMATIONS ; BIOLOGICAL-ACTIVITY ; MOLECULAR-DYNAMICS
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000379770500009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275995]
专题	国家新药筛选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	Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 2.ShanghaiTech Univ, iHuman Inst, 99 Haike Rd, Shanghai 201203, Peoples R China; 3.Novo Nordisk, Dept Prot Struct, Novo Nordisk Pk, DK-2760 Malov, Denmark; 4.GPCR Consortium, San Marcos, CA 92078 USA; 5.Univ Southern Calif, Dept Biol Sci, Bridge Inst, Los Angeles, CA 90089 USA; 6.Fudan Univ, Sch Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China 7.Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA; 8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 9.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 10.Vrije Univ Amsterdam, AIMMS, Div Med Chem, Fac Sci, De Boelelaan 1083, NL-1081 HV Amsterdam, Netherlands;
推荐引用方式 GB/T 7714	Yang, Dehua,de Graaf, Chris,Yang, Linlin,et al. Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(25):12991-13004.
APA	Yang, Dehua.,de Graaf, Chris.,Yang, Linlin.,Song, Gaojie.,Dai, Antao.,...&Wang, Ming-Wei.(2016).Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R).JOURNAL OF BIOLOGICAL CHEMISTRY,291(25),12991-13004.
MLA	Yang, Dehua,et al."Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)".JOURNAL OF BIOLOGICAL CHEMISTRY 291.25(2016):12991-13004.