Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors
文献类型：期刊论文
| 作者 | Zhao, Li-Hua2,3,4,5; Yin, Yanting3,4,7; Yang, Dehua8,9 ; Liu, Bo3,4; Hou, Li3,4; Wang, Xiaoxi3,4; Pal, Kuntal7; Jiang, Yi3,4; Feng, Yang8,9; Cai, Xiaoqing8,9
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| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2016-07-15 |
| 卷号 | 291期号:29页码:15119-15130 |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.M116.726620 |
| 文献子类 | Article |
| 英文摘要 | G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extra cellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the LCD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its LCD, suggesting a direct role of the ECD in GLP-1R activation. |
| WOS关键词 | CORTICOTROPIN-RELEASING-FACTOR ; SMALL-MOLECULE AGONISTS ; PEPTIDE-1 RECEPTOR ; GLUCAGON RECEPTOR ; PARATHYROID-HORMONE ; DRUG DISCOVERY ; GLP-1 RECEPTOR ; RECOGNITION ; LIGANDS ; BINDING |
| 资助项目 | National Institutes of Health[DK071662] ; National Institutes of Health[GM102545] ; National Institutes of Health[GM104212] ; National Natural Science Foundation of China[31300245] ; National Natural Science Foundation of China[31300607] ; Van Andel Research Institute, Ministry of Science and Technology of China[2012ZX09301001] ; Van Andel Research Institute, Ministry of Science and Technology of China[2012CB910403] ; Van Andel Research Institute, Ministry of Science and Technology of China[2013CB910600] ; Van Andel Research Institute, Ministry of Science and Technology of China[XDB08020303] ; Van Andel Research Institute, Ministry of Science and Technology of China[2013ZX09507001] ; Amway (China)[00000000] ; National Health and Family Planning Commission[2012ZX09304-011] ; National Health and Family Planning Commission[2013ZX09401003-005] ; National Health and Family Planning Commission[2013ZX 09507001] ; National Health and Family Planning Commission[2013ZX09507-002] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Committee[13ZR1447600] ; Shanghai Rising-Star Program[14QA1404300] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000380583200022 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275955]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Melcher, Karsten; Xu, H. Eric |
| 作者单位 | 1.Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Houston, TX 77030 USA; 2.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 5.East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China; 6.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 7.Van Andel Res Inst, Ctr Struct Biol & Drug Discovery, Lab Struct Sci, Grand Rapids, MI 49503 USA; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 9.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhao, Li-Hua,Yin, Yanting,Yang, Dehua,et al. Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(29):15119-15130. |
| APA | Zhao, Li-Hua.,Yin, Yanting.,Yang, Dehua.,Liu, Bo.,Hou, Li.,...&Xu, H. Eric.(2016).Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors.JOURNAL OF BIOLOGICAL CHEMISTRY,291(29),15119-15130. |
| MLA | Zhao, Li-Hua,et al."Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors".JOURNAL OF BIOLOGICAL CHEMISTRY 291.29(2016):15119-15130. |
入库方式： OAI收割
来源：上海药物研究所
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