单颗粒冷冻电镜揭开G蛋白偶联受体结构生物学研究的新篇章
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摘要
G蛋白偶联受体(GPCR)是生物体内一类庞大而又多样的细胞膜蛋白。GPCR可以应细胞外信号发生构象变化,进而结合不同效应蛋白激活下游多种信号转导通路,调控众多生命活动过程,参与几乎所有病理过程的发生和发展。近年来,冷冻电镜技术在研究生物大分子结构方面取得了突飞猛进的发展,基于冷冻电镜的GPCR信号转导复合物的高分辨率三维结构不断出现。本文阐述了GPCR和G蛋白复合物相互作用的共性结构特征——受体第六个跨膜螺旋的构象变化,也展示了GPCR识别不同G蛋白亚型选择性的结构基础。单颗粒冷冻电镜提供了更加高效地鉴定受体与配体相互作用分子机制的方法,为GPCR信号通路的机制研究以及基于结构的药物理性设计提供了重要信息。
G protein-coupled receptors (GPCRs) represent the largest class of cell surface receptors,mediating wide range of cellular and physiological processes through their transducers,G proteins and the-arrestins participate in almost all pathological processes. Recent technological advances are revolutionizing the utility of cryo-electron microscopy(cryo-EM),leading to a tremendous progress in the structural studies of biological macromolecules and cryo-EM has played a leading role in the structural biology of GPCR signaling complex. New discoveries of high-resolution threedimensional structures of GPCR signaling complexes based on cryo-EM have emerged vigorously, which depict the common structural characteristics of intermolecular interaction between GPCR and G protein complex-the conformational changes of the transmembrane helix 6 of receptors,and also demonstrate the structural basis of G protein subtype selectivity. Single-particle cryo-EM becomes an efficient tool for identifying the molecular mechanism of receptor-ligand interaction,providing important information for understanding GPCR signaling and the structure-based drug design.
G protein-coupled receptors (GPCRs) represent the largest class of cell surface receptors,mediating wide range of cellular and physiological processes through their transducers,G proteins and the-arrestins participate in almost all pathological processes. Recent technological advances are revolutionizing the utility of cryo-electron microscopy(cryo-EM),leading to a tremendous progress in the structural studies of biological macromolecules and cryo-EM has played a leading role in the structural biology of GPCR signaling complex. New discoveries of high-resolution threedimensional structures of GPCR signaling complexes based on cryo-EM have emerged vigorously, which depict the common structural characteristics of intermolecular interaction between GPCR and G protein complex-the conformational changes of the transmembrane helix 6 of receptors,and also demonstrate the structural basis of G protein subtype selectivity. Single-particle cryo-EM becomes an efficient tool for identifying the molecular mechanism of receptor-ligand interaction,providing important information for understanding GPCR signaling and the structure-based drug design.
引文
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[4]GHOSH E,KUMARI P,JAIMAN D,et al.Methodological advances:the unsung heroes of the GPCR structural revolution[J].Nat Rev Mol Cell Biol,2015,16(2):69-81.
[5]RASMUSSEN S G,DEVREE B T,ZOU Y,et al.Crystal structure of theβ2adrenergic receptor-Gs protein complex[J].Nature,2011,477(7366),549-555.
[6]CARPENTER B,NEHMéR,WARNE T,et al.Structure of the adenosine A(2A)receptor bound to an engineered G protein[J].Nature,2016,536(7614):104-107.
[7]LIANG Y L,KHOSHOUEI M,RADJAINIA M,et al.Phase-plate cryo-EM structure of a class B GPCR-G-protein complex[J].Nature,2017,546(7656):118-123.
[8]ZHANG Y,SUN B,FENG D,et al.Cryo-EM structure of the activated GLP-1 receptor in complex with a Gprotein[J].Nature,2017,546(7657):248-253.
[9]LIANG Y L,KHOSHOUEI M,GLUKHOVA A,et al.Phase-plate cryo-EM structure of a biased agonistbound human GLP-1 receptor-Gs complex[J].Nature,2018,555(7694):121-125.
[10]GARCíA-NAFRíA J,LEE Y,BAI X,et al.Cryo-EMstructure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein[J/OL].Elife,2018,7:e35946.
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[12]KANG Y,KUYBEDA O,DE WAAL P W,et al.Publisher correction:cryo-EM structure of human rhodopsin bound to an inhibitory G protein[J/OL].Nature,2018,561(7724):E44.
[13]KOEHL A,HU H,MAEDA S,et al.Structure of theμ-opioid receptor-Gi protein complex[J].Nature,2018,558(7711):547-552.
[14]DRAPER-JOYCE C J,KHOSHOUEI M,THAL D M,et al.Structure of the adenosine-bound human adenosine A1 receptor-Gi complex[J].Nature,2018,558(7711):559-563.
[15]GARCíA-NAFRíA J,NEHMéR,EDWARDS P C,et al.Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go[J].Nature,2018,558(7711):620-623.
[16]KUMARI P,SRIVASTAVA A,BANERJEE R,et al.Functional competence of a partially engaged GPCR-beta-arrestin complex[J].Nat Commun,2016,7:13416.
[17]THOMSEN A R B,PLOUFFE B,CAHILL T J 3RD,et al.GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling[J].Cell,2016,166(4):907-919.
[18]CAHILL T J 3RD,THOMSEN A R,TARRASCH J T,et al.Distinct conformations of GPCR-beta-arrestin complexes mediate desensitization,signaling,and endocytosis[J].Proc Natl Acad Sci U S A,2017,114(10):2562-2567.
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