中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

文献类型:期刊论文

AuthorGuo, Lulu14,15; Zhang, Yumu12,13; Fang, Guoxing10,11; Tie, Lu8,9; Zhuang, Yuming10,11; Xue, Chenyang7; Liu, Qi15; Zhang, Minghui14; Zhu, Kongkai14; You, Chongzhao13
SourceNATURE COMMUNICATIONS
Issued Date2023-08-17
Volume14Issue:1Pages:12
DOI10.1038/s41467-023-40705-z
Corresponding AuthorZhou, 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)
English AbstractMRGPRX1, 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 KeywordMAS ; FAMILY ; VALIDATION ; ACTIVATION ; X1
Funding ProjectWe 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 Research AreaScience & Technology - Other Topics
Language英语
WOS IDWOS:001097141200029
PublisherNATURE PORTFOLIO