Structure, function and pharmacology of human itch receptor complexes

• Published in: Nature (London) Vol. 600; no. 7887; pp. 164 - 169
• Main Authors: Yang, Fan, Guo, Lulu, Li, Yu, Wang, Guopeng, Wang, Jia, Zhang, Chao, Fang, Guo-Xing, Chen, Xu, Liu, Lei, Yan, Xu, Liu, Qun, Qu, Changxiu, Xu, Yunfei, Xiao, Peng, Zhu, Zhongliang, Li, Zijian, Zhou, Jiuyao, Yu, Xiao, Gao, Ning, Sun, Jin-Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.12.2021; Nature Publishing Group
• Subjects: 101/28; 631/154/436/2387; 631/45/535/1258/1259; 82; 82/83; 96; 96/95; Allergens; Allergens - immunology; Allergic diseases; Allergies; Amino Acid Motifs; Amino Acid Sequence; Annotations; Binding Sites; Compound 48/80; Consensus Sequence; Cryoelectron Microscopy; Drug development; Electron microscopy; G protein-coupled receptors; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Humanities and Social Sciences; Humans; Inflammation; Interfaces; Ligands; Microscopy; Models, Molecular; multidisciplinary; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - ultrastructure; Nucleotides; Peptides; Pharmacology; Proteins; Pruritus - metabolism; Receptors; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - immunology; Receptors, G-Protein-Coupled - metabolism; Receptors, G-Protein-Coupled - ultrastructure; Receptors, Neuropeptide - chemistry; Receptors, Neuropeptide - immunology; Receptors, Neuropeptide - metabolism; Receptors, Neuropeptide - ultrastructure; Science; Science (multidisciplinary); Side effects; Single-nucleotide polymorphism; Solvents; Structure-function relationships; Trimers
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-021-04077-y

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. Cryo-electron microscopy structures of the MRGPRX2–G i1 trimer in complex with polycationic compound 48/80 or inflammatory peptides provide insights into the sensing of cationic allergens by MRGPRX2, potentially facilitating the design of therapies to prevent unwanted pseudoallergic reactions.