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^3,4,5,6. 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.

在与硬骨鱼不同的动物进化枝中，进化出一组与 Mas 相关的 G 蛋白偶联受体 (MRGPR)，它们在瘙痒和过敏信号^1,2中发挥着积极作用。作为 MRGPR，MRGPRX2 可以感知基本促分泌剂（促进分泌的物质），并参与瘙痒信号和引发假性过敏反应^3,4,5,6。MRGPRX2已成为药物开发工作的目标，以防止某些药物引起的副作用或治疗过敏性疾病。在这里，我们报告了一组与聚阳离子化合物 48/80 或炎症肽复合的 MRGPRX2-G _{i1三聚体的低温电子显微镜结构。}MRGPRX2-G _i1的结构复合物表现出浅的、溶剂暴露的配体结合口袋。我们确定了 MRGPRX2 的关键共同结构特征，并描述了肽过敏原的共有基序。在配体结合口袋下方，跨膜结构域 6 (TM6) 处的不寻常扭结形成以及从 Trp ^6.48到 Gly ^6.48的一般切换开关的替换（根据 Ballesteros-Weinstein 命名法的上标注释）表明了一个独特的激活过程。我们描述了 MRGPRX2 和 G _i的接口三聚体，并在 MRGPRX2 的配体和 G 蛋白界面上绘制了与关键单核苷酸多态性相关的残基。总的来说，我们的结果为 MRGPRX2 检测阳离子过敏原提供了结构基础，可能有助于合理设计治疗方法以防止不必要的假性过敏反应。