Common activation mechanism of class A GPCRs

doi:10.7554/eLife.50279

	Common activation mechanism of class A GPCRs
	Zhou, Qingtong1 ; Yang, Dehua 2,3,4; Wu, Meng1,3,5 ; Guo, Yu1,3,5 ; Guo, Wangjing 2,3,4; Zhong, Li 2,3,4; Cai, Xiaoqing 2,4; Dai, Antao 2,4; Jang, Wonjo 6; Shakhnovich, Eugene I.7; Liu, Zhi-Jie1,5 ; Stevens, Raymond C.1,5 ; Lambert, Nevin A.6; Babu, M. Madan 8; Wang, Ming-Wei2,3,4,5,9 ; Zhao, Suwen1,5
	2019-12-19
发表期刊	ELIFE (IF:6.4[JCR-2023],7.2[5-Year])
ISSN	2050-084X
卷号	8
发表状态	已发表
DOI	10.7554/eLife.50279
摘要	Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.
收录类别	SCI ; SCIE
语种	英语
资助项目	National Institute of General Medical Sciences[GM130142]
WOS研究方向	Life Sciences & Biomedicine - Other Topics
WOS类目	Biology
WOS记录号	WOS:000506841000001
出版者	ELIFE SCIENCES PUBLICATIONS LTD
WOS关键词	PROTEIN-COUPLED RECEPTOR ; SERIAL FEMTOSECOND CRYSTALLOGRAPHY ; STABILIZED ACTIVE STATE ; CRYO-EM STRUCTURE ; STRUCTURAL INSIGHTS ; CRYSTAL-STRUCTURE ; OPIOID RECEPTOR ; ALLOSTERIC COMMUNICATION ; CONFORMATIONAL-CHANGES ; OLFACTORY RECEPTORS
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/105289
专题	生命科学与技术学院_博士生 iHuman研究所_特聘教授组_Andrej Sali组 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 iHuman研究所_PI研究组_赵素文组生命科学与技术学院_硕士生
通讯作者	Babu, M. Madan; Wang, Ming-Wei; Zhao, Suwen
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 6.Augusta Univ, Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA USA 7.Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA 8.MRC Lab Mol Biol, Cambridge, England 9.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
第一作者单位	iHuman研究所
通讯作者单位	生命科学与技术学院; iHuman研究所
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Zhou, Qingtong,Yang, Dehua,Wu, Meng,et al. Common activation mechanism of class A GPCRs[J]. ELIFE,2019,8.
APA	Zhou, Qingtong.,Yang, Dehua.,Wu, Meng.,Guo, Yu.,Guo, Wangjing.,...&Zhao, Suwen.(2019).Common activation mechanism of class A GPCRs.ELIFE,8.
MLA	Zhou, Qingtong,et al."Common activation mechanism of class A GPCRs".ELIFE 8(2019).