Structure, function and pharmacology of human itch receptor complexes

Fan Yang, Lulu Guo, Yu Li, Guopeng Wang, Jia Wang, Chao Zhang, Guo-Xing Fang, Xu Chen, Lei Liu, Xu Yan, Qun Liu, Changxiu Qu, Yunfei Xu, Peng Xiao, Zhongliang Zhu, Zijian Li, Jiuyao Zhou, Xiao Yu, Ning Gao () and Jin-Peng Sun ()
Additional contact information
Fan Yang: Peking University, Ministry of Education
Lulu Guo: Shandong University School of Medicine
Yu Li: Peking University, Ministry of Education
Guopeng Wang: Peking University
Jia Wang: Shandong University School of Medicine
Chao Zhang: Shandong University School of Medicine
Guo-Xing Fang: Shandong University School of Medicine
Xu Chen: Shandong University School of Medicine
Lei Liu: Shandong University School of Medicine
Xu Yan: Shandong University School of Medicine
Qun Liu: Shandong University School of Medicine
Changxiu Qu: Peking University, Ministry of Education
Yunfei Xu: Qilu Hospital of Shandong University
Peng Xiao: Shandong University School of Medicine
Zhongliang Zhu: University of Science and Technology of China
Zijian Li: Peking University Third Hospital, Research
Jiuyao Zhou: Guangzhou University of Chinese Medicine
Xiao Yu: Shandong University School of Medicine
Ning Gao: Peking University
Jin-Peng Sun: Peking University, Ministry of Education

Nature, 2021, vol. 600, issue 7887, 164-169

Abstract: Abstract 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 signals1,2. As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions3–6. 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–Gi1 trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2–Gi1 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 Trp6.48 to Gly6.48 (superscript annotations as per Ballesteros–Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the Gi 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.

Date: 2021
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DOI: 10.1038/s41586-021-04077-y

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