Different conformational responses of the beta(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline

doi:10.1093/nsr/nwaa284

	Different conformational responses of the beta(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline
	Yang, Fan 1,3; Ling, Shenglong 1,3; Zhou, Yingxin 1,3; Zhang, Yanan 1,3; Lv, Pei 1,3; Liu, Sanling 1,3; Fang, Wei 1,3; Sun, Wenjing 1,3; Hu, Liaoyuan A.4; Zhang, Longhua 1,3
刊名	NATIONAL SCIENCE REVIEW
	2021-09-01
卷号	8
关键词	cryo-EM structure G protein-coupled receptor (GPCR) partial and full agonists conformational change desensitization
ISSN号	2095-5138
DOI	10.1093/nsr/nwaa284
通讯作者	Shi, Pan(shipan@ustc.edu.cn) ; Tian, Changlin(cltian@ustc.edu.cn)
英文摘要	G protein-coupled receptors (GPCRs) are responsible for most cytoplasmic signaling in response to extracellular ligands with different efficacy profiles. Various spectroscopic techniques have identified that agonists exhibiting varying efficacies can selectively stabilize a specific conformation of the receptor. However, the structural basis for activation of the GPCR-G protein complex by ligands with different efficacies is incompletely understood. To better understand the structural basis underlying the mechanisms by which ligands with varying efficacies differentially regulate the conformations of receptors and G proteins, we determined the structures of beta(2)AR-G alpha(s)beta gamma bound with partial agonist salbutamol or bound with full agonist isoprenaline using single-particle cryo-electron microscopy at resolutions of 3.26 angstrom and 3.80 angstrom, respectively. Structural comparisons between the beta(2)AR-Gs-salbutamol and beta(2)AR-Gs-isoprenaline complexes demonstrated that the decreased binding affinity and efficacy of salbutamol compared with those of isoprenaline might be attributed to weakened hydrogen bonding interactions, attenuated hydrophobic interactions in the orthosteric binding pocket and different conformational changes in the rotamer toggle switch in TM6. Moreover, the observed stronger interactions between the intracellular loop 2 or 3 (ICL2 or ICL3) of beta(2)AR and G alpha(s) with binding of salbutamol versus isoprenaline might decrease phosphorylation in the salbutamol-activated beta(2)AR-Gs complex. From the observed structural differences between these complexes of beta(2)AR, a mechanism of beta(2)AR activation by partial and full agonists is proposed to provide structural insights into beta(2)AR desensitization.
资助项目	National Key Research and Development Project of China[2016YFA0400903] ; National Key Research and Development Project of China[2017YFA0505400] ; National Natural Science Foundation of China[21825703] ; National Natural Science Foundation of China[31971152] ; Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology[2018CXFX004] ; Amgen Postdoc Fellowship (China)
WOS关键词	PROTEIN-COUPLED RECEPTOR ; STRUCTURAL INSIGHTS ; CRYSTAL-STRUCTURE ; BETA(2) ; PHOSPHORYLATION ; EFFICACY ; BIAS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	OXFORD UNIV PRESS
WOS记录号	WOS:000701659300006
资助机构	National Key Research and Development Project of China ; National Natural Science Foundation of China ; Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology ; Amgen Postdoc Fellowship (China)
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/124897]
专题	中国科学院合肥物质科学研究院
通讯作者	Shi, Pan; Tian, Changlin
作者单位	1.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China 2.Chinese Acad Sci, High Magnet Field Lab, Hefei 230030, Peoples R China 3.Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Peoples R China 4.Amgen Res, Amgen Asia R&D Ctr, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Yang, Fan,Ling, Shenglong,Zhou, Yingxin,et al. Different conformational responses of the beta(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline[J]. NATIONAL SCIENCE REVIEW,2021,8.
APA	Yang, Fan.,Ling, Shenglong.,Zhou, Yingxin.,Zhang, Yanan.,Lv, Pei.,...&Tian, Changlin.(2021).Different conformational responses of the beta(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline.NATIONAL SCIENCE REVIEW,8.
MLA	Yang, Fan,et al."Different conformational responses of the beta(2)-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline".NATIONAL SCIENCE REVIEW 8(2021).