Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors

doi:10.1074/jbc.M117.782987

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	Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors
	Yin, Yanting 2,3,4,5; de Waal, Parker W.3,4; He, Yuanzheng 3,4; Zhao, Li-Hua 2; Yang, Dehua6,7 ; Cai, Xiaoqing 6,7; Jiang, Yi2 ; Melcher, Karsten 3,4; Wang, Ming-Wei1,6,7 ; Xu, H. Eric2,3,4,5
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2017-06-16
卷号	292 期号:24 页码:9865-9881
ISSN号	0021-9258
DOI	10.1074/jbc.M117.782987
文献子类	Article
英文摘要	The glucagon receptor (GCGR) belongs to the secretin-like (class B) family of G protein-coupled receptors (GPCRs) and is activated by the peptide hormone glucagon. The structures of an activated class B GPCR have remained unsolved, preventing a mechanistic understanding of how these receptors are activated. Using a combination of structural modeling and mutagenesis studies, we present here two modes of ligand-independent activation of GCGR. First, we identified a GCGR-specific hydrophobic lock comprising Met-338 and Phe-345 within the IC3 loop and transmembrane helix 6 (TM6) and found that this lock stabilizes the TM6 helix in the inactive conformation. Disruption of this hydrophobic lock led to constitutive G protein and arrestin signaling. Second, we discovered a polar core comprising conserved residues in TM2, TM3, TM6, and TM7, and mutations that disrupt this polar core led to constitutive GCGR activity. On the basis of these results, we propose a mechanistic model of GCGR activation in which TM6 is held in an inactive conformation by the conserved polar core and the hydrophobic lock. Mutations that disrupt these inhibitory elements allow TM6 to swing outward to adopt an active TM6 conformation similar to that of the canonical beta(2)-adrenergic receptor complexed with G protein and to that of rhodopsin complexed with arrestin. Importantly, mutations in the corresponding polar core of several other members of class B GPCRs, including PTH1R, PAC1R, VIP1R, and CRFR1, also induce constitutive G protein signaling, suggesting that the rearrangement of the polar core is a conserved mechanism for class B GPCR activation.
资助项目	National Natural Science Foundation of China[31300245] ; Jay and Betty Van Andel Foundation, Ministry of Science and Technology of China[2012ZX09301001] ; Jay and Betty Van Andel Foundation, Ministry of Science and Technology of China[2012CB910403] ; Jay and Betty Van Andel Foundation, Ministry of Science and Technology of China[2013CB910600] ; Jay and Betty Van Andel Foundation, Ministry of Science and Technology of China[XDB08020303] ; Jay and Betty Van Andel Foundation, Ministry of Science and Technology of China[2013ZX09507001] ; Amway (China)[00000000] ; National Institutes of Health[DK071662] ; National Institutes of Health[GM102545] ; National Institutes of Health[GM104212] ; Outstanding Young Scientist Foundation of CAS[00000000] ; Youth Innovation Promotion Association of CAS[00000000] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Development Fund[14431901200] ; National Natural Science Foundation[81373463] ; CAS[00000000]
WOS关键词	MUSCARINIC ACETYLCHOLINE-RECEPTOR ; BETA(2) ADRENERGIC-RECEPTOR ; CROSS-LINKING STRATEGY ; GLUCAGON RECEPTOR ; METAPHYSEAL CHONDRODYSPLASIA ; BETA(2)-ADRENERGIC RECEPTOR ; CRYSTAL-STRUCTURE ; LIGAND-BINDING ; IONIC LOCK ; PEPTIDE
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:000403580600002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272606]
专题	国家新药筛选中心药物靶标结构与功能中心
通讯作者	Wang, Ming-Wei; Xu, H. Eric
作者单位	1.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Van Andel Res Inst, Shanghai Inst Mat Med VARI SIMM Ctr,Shanghai Inst, Ctr Struct & Funct Drug Targets,CAS Key Lab Recep, Shanghai 201203, Peoples R China; 3.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 4.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA; 5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 6.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 7.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Yin, Yanting,de Waal, Parker W.,He, Yuanzheng,et al. Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292(24):9865-9881.
APA	Yin, Yanting.,de Waal, Parker W..,He, Yuanzheng.,Zhao, Li-Hua.,Yang, Dehua.,...&Xu, H. Eric.(2017).Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors.JOURNAL OF BIOLOGICAL CHEMISTRY,292(24),9865-9881.
MLA	Yin, Yanting,et al."Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors".JOURNAL OF BIOLOGICAL CHEMISTRY 292.24(2017):9865-9881.