Cryo-EM structures of adenosine receptor A<sub>3</sub>AR bound to selective agonists

doi:10.1038/s41467-024-47207-6

	Cryo-EM structures of adenosine receptor A₃AR bound to selective agonists
	Cai, Hongmin 1; Guo, Shimeng 1; Xu, Youwei 1; Sun, Jun 1,2; Li, Junrui 1; Xia, Zhikan 1; Jiang, Yi 3; Xie, Xin1,2,4,5,6 ; Xu, H. Eric1,2,5
	2024-04-16
发表期刊	NATURE COMMUNICATIONS (IF:14.7[JCR-2023],16.1[5-Year])
EISSN	2041-1723
卷号	15 期号:1
发表状态	已发表
DOI	10.1038/s41467-024-47207-6
摘要	The adenosine A(3) receptor (A(3)AR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective A(3)AR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human A(3)AR bound to CF101 and CF102 with heterotrimeric G(i) protein in complex at 3.3-3.2 & Aring; resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in A(3)AR's ligand selectivity and receptor activation. Key mutations, including His(3.37), Ser(5.42), and Ser(6.52), in a unique sub-pocket of A(3)AR, significantly impact receptor activation. Comparative analysis with the inactive A(2A)AR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of A(3)AR, paving the way for designing subtype-selective adenosine receptor ligands.
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收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China (National Science Foundation of China)[XDB37030103] ; CAS Strategic Priority Research Program["32301004","82121005","32130022","82330113","82304579","32171187"] ; National Natural Science Foundation of China[LG-GG-202204-01] ; Shanghai Municipal Science and Technology Major Project[2022YFC2703105] ; National Key R&D Program of China["2021M703341","2023T160662"] ; China Postdoctoral Science Foundation[2021423]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001220478200032
出版者	NATURE PORTFOLIO
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/378320
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_徐华强组生命科学与技术学院_特聘教授组_谢欣组
通讯作者	Cai, Hongmin; Xie, Xin; Xu, H. Eric
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Lingang Lab, Shanghai, Peoples R China 4.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 6.Inst Drug Discovery, Bohai Rim Adv Res, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Cai, Hongmin,Guo, Shimeng,Xu, Youwei,et al. Cryo-EM structures of adenosine receptor A₃AR bound to selective agonists[J]. NATURE COMMUNICATIONS,2024,15(1).
APA	Cai, Hongmin.,Guo, Shimeng.,Xu, Youwei.,Sun, Jun.,Li, Junrui.,...&Xu, H. Eric.(2024).Cryo-EM structures of adenosine receptor A₃AR bound to selective agonists.NATURE COMMUNICATIONS,15(1).
MLA	Cai, Hongmin,et al."Cryo-EM structures of adenosine receptor A₃AR bound to selective agonists".NATURE COMMUNICATIONS 15.1(2024).