Nature Communications (Aug 2023)
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,
- Jin-Peng Sun
Affiliations
- Lulu Guo
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Yumu Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Guoxing Fang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University
- Lu Tie
- Department of Pharmacology, School of Basic Medical Sciences, Peking University and Beijing Key Laboratory of Tumor Systems Biology, Peking University
- Yuming Zhuang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University
- Chenyang Xue
- Department of Immunology and Microbiology, Southern University of Science and Technology
- Qi Liu
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Minghui Zhang
- Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine
- Kongkai Zhu
- Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine
- Chongzhao You
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Peiyu Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Qingning Yuan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Chao Zhang
- Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine
- Lei Liu
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Naikang Rong
- Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine
- Shengxuan Peng
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Yuan Liu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University
- Chuanzheng Wang
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Xin Luo
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Zongyao Lv
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- Dongwei Kang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University
- Xiao Yu
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University
- Cheng Zhang
- Qilu Hospital, Cheeloo College of Medicine, Shandong University
- Yi Jiang
- Lingang Laboratory
- Xinzhong Dong
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
- Jiuyao Zhou
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine
- Zhongmin Liu
- Department of Immunology and Microbiology, Southern University of Science and Technology
- Fan Yang
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- H. Eric Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Jin-Peng Sun
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University
- DOI
- https://doi.org/10.1038/s41467-023-40705-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
