Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor

doi:10.1016/j.bcp.2021.114715

	Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor
	Yuliantie, Elita 1,2,3; van der Velden, Wijnand J. C.4; Labroska, Viktorija 1,2,3; Dai, Antao 1,2; Zhao, Fenghui 5; Darbalaei, Sanaz 1,2,3; Deganutti, Giuseppe 6; Xu, Tongyang 5; Zhou, Qingtong 7; Yang, Dehua 1,2,3
刊名	BIOCHEMICAL PHARMACOLOGY
	2021-10-01
卷号	192 页码:16
关键词	Glucose-dependent insulinotropic polypeptide receptor G protein-coupled receptor GPCR structure-function relationship ERK cAMP Arrestin
ISSN号	0006-2952
DOI	10.1016/j.bcp.2021.114715
通讯作者	Rosenkilde, Mette M.(rosenkilde@sund.ku.dk) ; Sexton, Patrick M.(patrick.sexton@monash.edu) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Wootten, Denise(denise.wootten@monash.edu)
英文摘要	Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are part of the incretin system that regulates glucose homeostasis. A series of GIPR residues putatively important for ligand binding and receptor activation were mutated and pharmacologically evaluated using GIPR selective agonists in cAMP accumulation, ERK1/2 phosphorylation (pERK1/2) and beta-arrestin 2 recruitment assays. The impact of mutation on ligand efficacy was determined by operational modelling of experimental data for each mutant, with results mapped onto the full-length, active-state GIPR structure. Two interaction networks, comprising transmembrane helix (TM) 7, TM1 and TM2, and extracellular loop (ECL) 2, TM5 and ECL3 were revealed, respectively. Both networks were critical for G(alpha s)-mediated cAMP accumulation and the recruitment of beta-arrestin 2, however, cAMP response was more sensitive to alanine substitution, with most mutated residues displaying reduced signaling. Unlike the other two assays, activation of ERK1/2 was largely independent of the network involving ECL2, TM5 and ECL3, indicating that pERK1/2 is at least partially distinct from Gas or beta-arrestin pathways and this network is also crucial for potential biased agonism at GIPR. Collectively, our work advances understanding of the structure-function relationship of GIPR and provides a framework for the design and/or interpretation of GIP analogues with unique signaling profiles.
资助项目	National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[81773792] ; National Science and Technology Major Project of China -Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China -Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; SA-SIBS Scholarship Program ; Australian National Health and Medical Research Council (NHMRC)[1126857] ; Australian National Health and Medical Research Council (NHMRC)[1184726] ; Australian National Health and Medical Research Council (NHMRC)[1150083] ; CAS-TWAS President's Fellowship for International Doctoral Students ; The Belt and Road Master Fellowship program ; UCAS Scholarship for International Students ; NHMRC[1154434] ; NHMRC[1155302] ; NIH[P41-GM103311]
WOS关键词	CRYO-EM STRUCTURE ; GLP-1 RECEPTOR ; GIP RECEPTOR ; PEPTIDE-1 RECEPTOR ; BINDING ; GIP(3-30)NH2 ; CELLS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000701938400003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297481]
专题	中国科学院上海药物研究所
通讯作者	Rosenkilde, Mette M.; Sexton, Patrick M.; Wang, Ming-Wei; Wootten, Denise
作者单位	1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Medial, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark 5.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 6.Coventry Univ, Fac Hlth & Life Sci, Ctr Sport Exercise & Life Sci, Alison Gingell Bldg, Coventry CV1 2DS, W Midlands, England 7.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 8.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol Theme, Parkville, Vic 3052, Australia 9.Monash Univ, Monash Inst Pharmaceut Sci, ARC Ctr Cryoelectron Microscopy Membrane Prot, Parkville, Vic 3052, Australia
推荐引用方式 GB/T 7714	Yuliantie, Elita,van der Velden, Wijnand J. C.,Labroska, Viktorija,et al. Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor[J]. BIOCHEMICAL PHARMACOLOGY,2021,192:16.
APA	Yuliantie, Elita.,van der Velden, Wijnand J. C..,Labroska, Viktorija.,Dai, Antao.,Zhao, Fenghui.,...&Wootten, Denise.(2021).Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor.BIOCHEMICAL PHARMACOLOGY,192,16.
MLA	Yuliantie, Elita,et al."Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor".BIOCHEMICAL PHARMACOLOGY 192(2021):16.