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

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机构: [1]Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China [2]Key Laboratory of Experimental Teratology of theMinistry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China [3]State Key Laboratory ofDrug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China [4]School of Life Science and Technology, ShanghaiTechUniversity, Shanghai 201210, China [5]Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of BasicMedical Sciences, Shandong University, Jinan, Shandong, China [6]Department of Pharmacology, School of Basic Medical Sciences, Peking University andBeijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China [7]Department of Immunology and Microbiology, Southern University ofScience and Technology, Shenzhen, Guangdong, China [8]Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China [9]Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University,Jinan, China [10]Lingang Laboratory, Shanghai, China [11]The Solomon H.Snyder Department of Neuroscience, Johns Hopkins University School of Medicine,Baltimore, MD, USA [12]Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA [13]Department of Pharmacology,School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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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.© 2023. Springer Nature Limited.

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大类 | 1 区 综合性期刊
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第一作者机构: [1]Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China [2]Key Laboratory of Experimental Teratology of theMinistry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China
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通讯机构: [1]Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China [2]Key Laboratory of Experimental Teratology of theMinistry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China [5]Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of BasicMedical Sciences, Shandong University, Jinan, Shandong, China [6]Department of Pharmacology, School of Basic Medical Sciences, Peking University andBeijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China
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