Structure, function and pharmacology of human itch receptor complexes
Structure, function and pharmacology of human itch receptor complexes
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人类瘙痒受体复合物的结构、功能和药理学
DOI：
10.1038/s41586-021-04077-y
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发表时间：
2021-11-17
期刊：
影响因子：
64.8
通讯作者：
Sun, Jin-Peng
中科院分区：
文献类型：
--
作者：
Yang, Fan;Guo, Lulu;Sun, Jin-Peng
在从硬骨鱼分化出来的动物分支中，进化出了一组Mas-related G蛋白偶联受体（MRGPRs），它们在瘙痒和过敏信号中起着积极的作用。作为一种MRGPR，已知MRGPRX 2可感知基本促分泌素（促进分泌的物质），并参与瘙痒信号和引发假性过敏反应。MRGPRX 2已成为药物开发的目标，以防止某些药物引起的副作用或治疗过敏性疾病。在这里，我们报告了一组冷冻电子显微镜结构的MRGPRX 2-Gil三聚体与聚阳离子化合物48/80或炎症肽的复合物。MRGPRX 2-Gi 1复合物的结构表现出浅的、溶剂暴露的配体结合口袋。我们确定了MRGPRX 2的关键共同结构特征，并描述了肽过敏原的一致基序。在配体结合口袋下面，跨膜结构域6（TM 6）处不寻常的扭结形成和一般的切换开关从Trp6.48到Gly6.48的替换（上标注释根据Ballesteros-Weinstein命名法）表明了独特的激活过程。我们表征了MRGPRX 2和Gitrimer的界面，并绘制了与MRGPRX 2的配体和G蛋白界面上的关键单核苷酸多态性相关的残基。总的来说，我们的研究结果为MRGPRX 2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预防不必要的假性过敏反应。
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,. As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions, , –. 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–Gi1trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2–Gi1complex 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 Trp6.48to Gly6.48(superscript annotations as per Ballesteros–Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the Gitrimer, 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.