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Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84

文献类型：期刊论文

作者Liu, Heng1; Zhang, Qing1,2,3,4; He, Xinheng1,5; Jiang, Mengting6; Wang, Siwei1,4,5; Yan, Xiaoci1,2,5; Cheng, Xi1,5; Liu, Yang1,4; Nan, Fa-Jun1,2,3,4; Xu, H. Eric1,5,6,7
刊名NATURE COMMUNICATIONS
出版日期2023-06-06
卷号14期号:1页码:14
DOI10.1038/s41467-023-38985-6
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Yin, Wanchao(wcyin@simm.ac.cn)
英文摘要GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of G alpha(i) protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and G alpha(i)-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84. The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.
WOS关键词PROTEIN-COUPLED-RECEPTOR ; CRYO-EM STRUCTURE ; MODEL ; SOFTWARE
资助项目CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[LG202103-03-05] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[32171189] ; National Key R&D Program of China[2018YFA0507002] ; Youth Innovation Promotion Association of CAS[2020283] ; Youth Innovation Promotion Association of CAS[2021278] ; National Science Fund for Excellent Young Scholars[82122067] ; High-level new R&D institute from Department of Science and Technology of Guangdong Province[2021B0909050003] ; High-level Innovative Research Institute from Department of Science and Technology of Guangdong Province[2019SHZDZX02] ; Key tasks of the Lingang Laboratory ; Sanofi Scholarship Program ; [2019B090904008]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:001002604900001
源URL[http://119.78.100.183/handle/2S10ELR8/306668]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Xie, Xin; Yin, Wanchao
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
8.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangdong 528400, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Heng,Zhang, Qing,He, Xinheng,et al. Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84[J]. NATURE COMMUNICATIONS,2023,14(1):14.
APA Liu, Heng.,Zhang, Qing.,He, Xinheng.,Jiang, Mengting.,Wang, Siwei.,...&Yin, Wanchao.(2023).Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84.NATURE COMMUNICATIONS,14(1),14.
MLA Liu, Heng,et al."Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84".NATURE COMMUNICATIONS 14.1(2023):14.

入库方式： OAI收割

来源：上海药物研究所

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