Cryo-EM structures of orphan GPR21 signaling complexes

doi:10.1038/s41467-023-35882-w

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	Cryo-EM structures of orphan GPR21 signaling complexes
	Lin, Xi1 ; Chen, Bo1 ; Wu, Yiran1 ; Han, Yingqi 2; Qi, Ao 2,3; Wang, Junyan 4,5; Yang, Zhao 4,5; Wei, Xiaohu6 ; Zhao, Tingting 7,8; Wu, Lijie1 ; Xie, Xin2,3,6 ; Sun, Jinpeng 4,5; Zheng, Jie 2,3; Zhao, Suwen1,6 ; Xu, Fei1,6
	2023-12-01
发表期刊	NATURE COMMUNICATIONS;
ISSN	2041-1723
EISSN	2041-1723
卷号	14 期号:1
发表状态	已发表
DOI	10.1038/s41467-023-35882-w
摘要	GPR21 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for type 2 diabetes and other metabolic disorders. This receptor shows high basal activity in coupling to multiple G proteins in the absence of any known endogenous agonist or synthetic ligand. Here, we present the structures of ligand-free human GPR21 bound to heterotrimeric miniGs and miniG15 proteins, respectively. We identified an agonist-like motif in extracellular loop 2 (ECL2) that occupies the orthosteric pocket and promotes receptor activation. A side pocket that may be employed as a new ligand binding site was also uncovered. Remarkably, G protein binding is accommodated by a flexible cytoplasmic portion of transmembrane helix 6 (TM6) which adopts little or undetectable outward movement. These findings will enable the design of modulators for GPR21 for understanding its signal transduction and exploring opportunity for deorphanization.
学科门类	Chemistry (all) ; Biochemistry, Genetics and Molecular Biology (all) ; Multidisciplinary ; Physics and Astronomy (all)
URL	查看原文
收录类别	SCOPUS ; SCI
语种	英语
资助项目	Ministry of Science and Technology of China[2018YFA0507000] ; National Natural Science Foundation of China["32071194","32122024","31971178","22107072"] ; China Postdoctoral Science Foundation[BX20200349]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000955813400018
出版者	NATURE PORTFOLIO
原始文献类型	Article
Scopus 记录号	2-s2.0-85146258429
来源库	SCOPUS
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/286537
专题	iHuman研究所生命科学与技术学院生命科学与技术学院_特聘教授组_谢欣组 iHuman研究所_PI研究组_徐菲组 iHuman研究所_PI研究组_赵素文组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_博士生 iHuman研究所_特聘教授组_Wolfgang Baumeister组
通讯作者	Zheng, Jie; Zhao, Suwen; Xu, Fei
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China 4.Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Key Lab Expt Teratol,Minist Educ, Jinan, Shandong, Peoples R China 5.Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Biochem & Mol Biol, Jinan, Shandong, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai, Peoples R China
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Lin, Xi,Chen, Bo,Wu, Yiran,et al. Cryo-EM structures of orphan GPR21 signaling complexes[J]. NATURE COMMUNICATIONS;,2023,14(1).
APA	Lin, Xi.,Chen, Bo.,Wu, Yiran.,Han, Yingqi.,Qi, Ao.,...&Xu, Fei.(2023).Cryo-EM structures of orphan GPR21 signaling complexes.NATURE COMMUNICATIONS;,14(1).
MLA	Lin, Xi,et al."Cryo-EM structures of orphan GPR21 signaling complexes".NATURE COMMUNICATIONS; 14.1(2023).