Laboratory of Receptor Structure and Signaling, The HIT Center for Life Sciences, Harbin Institute of Technology, Harbin, China.
The HIT cryo-EM facility, Harbin Institute of Technology, Harbin, China.
Nat Commun. 2021 Apr 7;12(1):2086. doi: 10.1038/s41467-021-22427-2.
Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human HR in complex with a G protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for G engagement in a model of "squash to activate and expand to deactivate". The structure also reveals features for G coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of G protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.
组胺受体在各种病理生理条件中发挥重要作用，是抗过敏治疗的有效靶点，但其受体激活机制仍不清楚。在这里，我们通过 NanoBiT 连接策略展示了与人 HR 复合物的冷冻电镜（cryo-EM）结构，该复合物与处于活性构象的 G 蛋白复合。该结构表明，组胺通过与跨膜域 3（TM3）和 TM6 的关键残基相互作用激活受体，从而压缩细胞外结合口袋，并打开细胞内腔以与 G 结合，该模型为“压缩以激活，扩展以失活”。该结构还揭示了 G 偶联的特征，包括细胞内环 2（ICL2）与 G 蛋白αN-β 连接的相互作用。我们结构的详细分析将为理解 G 蛋白偶联选择性提供框架，并为设计新型抗组胺药提供线索。
