Molecular mechanism of GPCR-mediated arrestin activation

doi:10.1038/s41586-018-0077-3

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	Molecular mechanism of GPCR-mediated arrestin activation
	Latorraca, Naomi R.2,3,4,5,7; Wang, Jason K.3; Bauer, Brian 6; Townshend, Raphael J. L.3; Hollingsworth, Scott A.2,3,5,7; Olivieri, Julia E.4; Xu, H. Eric1,8 ; Sommer, Martha E.6; Dror, Ron O.2,3,4,5,7
刊名	NATURE
	2018-05-17
卷号	557 期号:7705 页码:452-+
ISSN号	0028-0836
DOI	10.1038/s41586-018-0077-3
文献子类	Article
英文摘要	Despite intense interest in discovering drugs that cause G-protein coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear(1,2). Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail which bind distinct surfaces on arrestin can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective ('biased') GPCR-targeted ligands with desired effects on arrestin signalling.
资助项目	National Institutes of Health (NIH)[R01GM127359] ; Deutsche Forschungsgemeinschaft[S01037/1-2] ; Berlin Institute of Health[BIH_PRO_314] ; NIH[T15-LM007033-33] ; NIH[R01GM116961] ; Stanford Terman Faculty Fellowship[00000000] ; NSF[00000000]
WOS关键词	PROTEIN-COUPLED RECEPTORS ; GENERAL FORCE-FIELD ; BETA-ARRESTIN ; CRYSTAL-STRUCTURE ; VISUAL ARRESTIN ; PHOSPHORYLATED RHODOPSIN ; STRUCTURAL BASIS ; ERK ACTIVATION ; BIASED LIGANDS ; SPLICE VARIANT
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000432242000065
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279755]
专题	药物靶标结构与功能中心
通讯作者	Sommer, Martha E.; Dror, Ron O.
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai, Peoples R China; 2.Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA; 3.Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA; 4.Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA; 5.Stanford Univ, Biophys Program, Stanford, CA 94305 USA; 6.Charite Univ Med Berlin, Inst Med Physi & Biophys CC2, Berlin, Germany; 7.Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA; 8.Van Andel Res Inst, Lab Struct Sci, Ctr Struct Biol & Drug Discovery, Grand Rapids, MI USA
推荐引用方式 GB/T 7714	Latorraca, Naomi R.,Wang, Jason K.,Bauer, Brian,et al. Molecular mechanism of GPCR-mediated arrestin activation[J]. NATURE,2018,557(7705):452-+.
APA	Latorraca, Naomi R..,Wang, Jason K..,Bauer, Brian.,Townshend, Raphael J. L..,Hollingsworth, Scott A..,...&Dror, Ron O..(2018).Molecular mechanism of GPCR-mediated arrestin activation.NATURE,557(7705),452-+.
MLA	Latorraca, Naomi R.,et al."Molecular mechanism of GPCR-mediated arrestin activation".NATURE 557.7705(2018):452-+.