Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

Lulu Guo, Yumu Zhang, Guoxing Fang, Lu Tie, Yuming Zhuang, Chenyang Xue, Qi Liu, Minghui Zhang, Kongkai Zhu, Chongzhao You, Peiyu Xu, Qingning Yuan, Chao Zhang, Lei Liu, Naikang Rong, Shengxuan Peng, Yuan Liu, Chuanzheng Wang, Xin Luo, Zongyao Lv, Dongwei Kang, Xiao Yu, Cheng Zhang, Yi Jiang, Xinzhong Dong, Jiuyao Zhou (), Zhongmin Liu (), Fan Yang (), H. Eric Xu () and Jin-Peng Sun ()
Additional contact information
Lulu Guo: Shandong University
Yumu Zhang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Guoxing Fang: Shandong University
Lu Tie: Peking University
Yuming Zhuang: Shandong University
Chenyang Xue: Southern University of Science and Technology
Qi Liu: Shandong University
Minghui Zhang: Shandong University School of Medicine
Kongkai Zhu: Shandong University School of Medicine
Chongzhao You: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Peiyu Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Qingning Yuan: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Chao Zhang: Shandong University School of Medicine
Lei Liu: Shandong University
Naikang Rong: Shandong University School of Medicine
Shengxuan Peng: Shandong University
Yuan Liu: Shandong University
Chuanzheng Wang: Shandong University
Xin Luo: Shandong University
Zongyao Lv: Shandong University
Dongwei Kang: Shandong University
Xiao Yu: Shandong University
Cheng Zhang: Shandong University
Yi Jiang: Lingang Laboratory
Xinzhong Dong: Johns Hopkins University School of Medicine
Jiuyao Zhou: Guangzhou University of Chinese Medicine
Zhongmin Liu: Southern University of Science and Technology
Fan Yang: Shandong University
H. Eric Xu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Jin-Peng Sun: Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40705-z

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