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  2. 上海药物研究所
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  4. 新药研究国家重点实验室
Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

文献类型：期刊论文

作者Guo, Lulu14,15; Zhang, Yumu12,13; Fang, Guoxing10,11; Tie, Lu8,9; Zhuang, Yuming10,11; Xue, Chenyang7; Liu, Qi15; Zhang, Minghui14; Zhu, Kongkai14; You, Chongzhao13
刊名NATURE COMMUNICATIONS
出版日期2023-08-17
卷号14期号:1页码:12
DOI10.1038/s41467-023-40705-z
通讯作者Zhou, Jiuyao(zhoujiuyao@tom.com) ; Liu, Zhongmin(liuzm@sustech.edu.cn) ; Yang, Fan(yangfan1357@163.com) ; Eric Xu, H.(eric.xu@simm.ac.cn) ; Sun, Jin-Peng(sunjinpeng@sdu.edu.cn)
英文摘要MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal "RF/RY" motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the G6.48XP6.50F6.51G6.52X(2)F/W6.55 motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling. MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.
WOS关键词MAS ; FAMILY ; VALIDATION ; ACTIVATION ; X1
资助项目We acknowledge support from the National Key Ramp;D Program of China (2019YFA0904200 to J.-P.S., 2022YFC2702603 to F.Y.), the National Science Fund for Distinguished Young Scholars Grant (81825022 to J.-P.S.), the National Science Fund for Excellent Young[2019YFA0904200] ; We acknowledge support from the National Key Ramp;D Program of China (2019YFA0904200 to J.-P.S., 2022YFC2702603 to F.Y.), the National Science Fund for Distinguished Young Scholars Grant (81825022 to J.-P.S.), the National Science Fund for Excellent Young[2022YFC2702603] ; National Key Ramp;D Program of China[81825022] ; National Science Fund for Distinguished Young Scholars Grant[82122070] ; National Science Fund for Excellent Young Scholars[91939301] ; National Science Fund for Excellent Young Scholars[92057121] ; National Science Fund for Excellent Young Scholars[92168120] ; National Natural Science Foundation of China[ZR2020ZD39] ; Major Basic Research Project of Shandong Natural Science Foundation[Z200019] ; Beijing Natural Science Foundation[32171187] ; Beijing Natural Science Foundation[82121005] ; Beijing Natural Science Foundation[32130022] ; National Natural Science Foundation[2018YFA0507002] ; Ministry of Science and Technology (China) ; Shanghai Municipal Science and Technology Major Project[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[LG202101-01-03] ; CAS Strategic Priority Research Program
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:001097141200029
源URL[http://119.78.100.183/handle/2S10ELR8/308170]  
专题新药研究国家重点实验室
通讯作者Zhou, Jiuyao; Liu, Zhongmin; Yang, Fan; Eric Xu, H.; Sun, Jin-Peng
作者单位1.Guangzhou Univ Chinese Med, Sch Pharmaceut Sci, Dept Pharmacol, Guangzhou, Peoples R China
2.Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA
3.Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD USA
4.Lingang Lab, Shanghai, Peoples R China
5.Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Key Lab Chem Biol,Minist Educ, Jinan, Peoples R China
6.Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Jinan, Shandong, Peoples R China
7.Southern Univ Sci & Technol, Dept Immunol & Microbiol, Shenzhen, Guangdong, Peoples R China
8.Peking Univ, Beijing Key Lab Tumor Syst Biol, Beijing, Peoples R China
9.Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing, Peoples R China
10.Shandong Univ, Sch Basic Med Sci, Dept Physiol, Jinan, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Lulu,Zhang, Yumu,Fang, Guoxing,et al. Ligand recognition and G protein coupling of the human itch receptor MRGPRX1[J]. NATURE COMMUNICATIONS,2023,14(1):12.
APA Guo, Lulu.,Zhang, Yumu.,Fang, Guoxing.,Tie, Lu.,Zhuang, Yuming.,...&Sun, Jin-Peng.(2023).Ligand recognition and G protein coupling of the human itch receptor MRGPRX1.NATURE COMMUNICATIONS,14(1),12.
MLA Guo, Lulu,et al."Ligand recognition and G protein coupling of the human itch receptor MRGPRX1".NATURE COMMUNICATIONS 14.1(2023):12.

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来源：上海药物研究所

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