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Common activation mechanism of class A GPCRs

文献类型：期刊论文

作者Zhou, Qingtong5; Yang, Dehua4,6,7; Wu, Meng5,6,8; Guo, Yu5,6,8; Guo, Wangjing4,6,7; Zhong, Li4,6,7; Cai, Xiaoqing4,7; Dai, Antao4,7; Jang, Wonjo1; Shakhnovich, Eugene I.9
刊名ELIFE
出版日期2019-12-19
卷号8页码:31
ISSN号2050-084X
DOI10.7554/eLife.50279
通讯作者Babu, M. Madan(madanm@mrc-lmb.cam.ac.uk) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Zhao, Suwen(zhaosw@shanghaitech.edu.cn)
英文摘要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.
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
资助项目Medical Research Council[MC_U105185859] ; Novo Nordisk-CAS Research[NNCAS-2017-1-CC] ; Young Talent Program of Shanghai ; Shanghai Science and Technology Development Fund[16ZR1448500] ; Shanghai Science and Technology Development Fund[16ZR1407100] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[81573479] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[31971178] ; National Natural Science Foundation of China[81872915] ; National Mega R&D Program for Drug Discovery[2018ZX09735-001] ; National Mega R&D Program for Drug Discovery[2018ZX09711002-002-005] ; National Key R&D Program of China[2016YFC0905900] ; National Key R&D Program of China[2018YFA0507000] ; National Institute of General Medical Sciences[GM130142]
WOS研究方向Life Sciences & Biomedicine - Other Topics
语种英语
WOS记录号WOS:000506841000001
出版者ELIFE SCIENCES PUBLICATIONS LTD
源URL[http://119.78.100.183/handle/2S10ELR8/282481]  
专题中国科学院上海药物研究所
通讯作者Babu, M. Madan; Wang, Ming-Wei; Zhao, Suwen
作者单位1.Augusta Univ, Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA USA
2.MRC Lab Mol Biol, Cambridge, England
3.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
5.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Beijing, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
8.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
9.Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA
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,2019,8:31.
APA Zhou, Qingtong.,Yang, Dehua.,Wu, Meng.,Guo, Yu.,Guo, Wangjing.,...&Zhao, Suwen.(2019).Common activation mechanism of class A GPCRs.ELIFE,8,31.
MLA Zhou, Qingtong,et al."Common activation mechanism of class A GPCRs".ELIFE 8(2019):31.

入库方式： OAI收割

来源：上海药物研究所

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