Structure, function and pharmacology of human itch receptor complexes.

Autor: Yang F; Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Ministry of Education, Beijing, China.; State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, Shandong University School of Medicine, Jinan, China.; Advanced Medical Research Institute, Shandong University, Jinan, China., Guo L; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Li Y; Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Ministry of Education, Beijing, China.; State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China., Wang G; State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.; Cryo-EM platform, School of Life Sciences, Peking University, Beijing, China., Wang J; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Zhang C; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Fang GX; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China.; Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China., Chen X; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, Shandong University School of Medicine, Jinan, China., Liu L; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Yan X; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, Shandong University School of Medicine, Jinan, China., Liu Q; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Qu C; Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Ministry of Education, Beijing, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Xu Y; Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China., Xiao P; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China., Zhu Z; School of Life Sciences, University of Science and Technology of China, Hefei, China., Li Z; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Research, Beijing, China., Zhou J; Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China., Yu X; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, Shandong University School of Medicine, Jinan, China., Gao N; State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China. gaon@pku.edu.cn., Sun JP; Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Ministry of Education, Beijing, China. sunjinpeng@sdu.edu.cn.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China. sunjinpeng@sdu.edu.cn.; Advanced Medical Research Institute, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Dec; Vol. 600 (7887), pp. 164-169. Date of Electronic Publication: 2021 Nov 17.
DOI: 10.1038/s41586-021-04077-y
Abstrakt: In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals 1,2 . As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions 3-6 . MRGPRX2 has been targeted by drug development efforts to prevent the side effects induced by certain drugs or to treat allergic diseases. Here we report a set of cryo-electron microscopy structures of the MRGPRX2-G i1 trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2-G i1 complex exhibited shallow, solvent-exposed ligand-binding pockets. We identified key common structural features of MRGPRX2 and describe a consensus motif for peptidic allergens. Beneath the ligand-binding pocket, the unusual kink formation at transmembrane domain 6 (TM6) and the replacement of the general toggle switch from Trp 6.48 to Gly 6.48 (superscript annotations as per Ballesteros-Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the G i trimer, and mapped the residues associated with key single-nucleotide polymorphisms on both the ligand and G-protein interfaces of MRGPRX2. Collectively, our results provide a structural basis for the sensing of cationic allergens by MRGPRX2, potentially facilitating the rational design of therapies to prevent unwanted pseudoallergic reactions.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: