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, Dehua 1,2; de Graaf, Chris 3; Yang, Linlin 4; Song, Gaojie5 ; Dai, Antao 1,2; Cai, Xiaoqing 1,2; Feng, Yang 1,2; Reedtz-Runge, Steffen 6; Hanson, Michael A.7; Yang, Huaiyu 4; Jiang, Hualiang 4; Stevens, Raymond C.5,8,9 ; Wang, Ming-Wei1,2,10
	2016-06-17
发表期刊	JOURNAL OF BIOLOGICAL CHEMISTRY (IF:4.0[JCR-2023],4.4[5-Year])
ISSN	1083351X
卷号	291 期号:25 页码:12991-13004
发表状态	已发表
DOI	10.1074/jbc.M116.721977
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.
收录类别	SCI ; EI
语种	英语
资助项目	Netherlands eScience Center (NLeSC)/Netherlands Organisation for Scientific Research (NWO) Enabling Technologies Project, 3D-e-Chem[027.014.201]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000379770500009
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
EI入藏号	20162502528308
EI主题词	Binding energy ; Bins ; Biological membranes ; Complexation ; Hormones ; Ligands ; Molecular dynamics
EI分类号	Biological Materials and Tissue Engineering:461.2 ; Biology:461.9 ; Storage:694.4 ; Physical Chemistry:801.4 ; Chemical Reactions:802.2
WOS关键词	CORTICOTROPIN-RELEASING-FACTOR ; 2ND TRANSMEMBRANE HELIX ; LIGAND-BINDING ; AMINO-TERMINUS ; SPATIAL APPROXIMATIONS ; EXTRACELLULAR DOMAIN ; CRYSTAL-STRUCTURE ; DRUG TARGETS ; RESIDUES ; ACTIVATION
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/1802
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_王明伟组 iHuman研究所_PI研究组_刘志杰组
通讯作者	Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 3.Vrije Univ Amsterdam, AIMMS, Div Med Chem, Fac Sci, De Boelelaan 1083, NL-1081 HV Amsterdam, Netherlands 4.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 5.ShanghaiTech Univ, iHuman Inst, 99 Haike Rd, Shanghai 201203, Peoples R China 6.Novo Nordisk, Dept Prot Struct, Novo Nordisk Pk, DK-2760 Malov, Denmark 7.GPCR Consortium, San Marcos, CA 92078 USA 8.Univ Southern Calif, Dept Biol Sci, Bridge Inst, Los Angeles, CA 90089 USA 9.Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA 10.Fudan Univ, Sch Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China
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.