Structural basis of ligand recognition and activation of the histamine receptor family
Xuan Zhang, Guibing Liu, Ya-Ni Zhong, Ru Zhang, Chuan-Cheng Yang, Canyang Niu, Xuanyu Pu, Jingjing Sun, Tianyao Zhang, Lejin Yang, Chao Zhang, Xiu Li, Xinyuan Shen, Peng Xiao, Jin‐Peng Sun, Weimin Gong, Jin‐Peng Sun, Weimin Gong
Abstract
Histamine is a biogenic amine that is critical in various physiological and pathophysiological processes, including but not limited to allergic reactions, wakefulness, gastric acid secretion and neurotransmission. Here, we determine 9 cryo-electron microscopy (cryo-EM) structures of the 4 histamine receptors in complex with four different G protein subtypes, with endogenous or synthetic agonists bound. Inside the ligand pocket, we identify key motifs for the recognition of histamine, the distinct binding orientations of histamine and three subpockets that facilitate the design of specific ligands. In addition, we also identify key residues responsible for the selectivity of immethridine. Moreover, we reveal distinct structural features as determinants of Gq vs. Gs or Gs vs. Gi coupling differences among the histamine receptors. Our study provides a structural framework for understanding the ligand recognition and G protein coupling of all 4 histamine receptors, which may facilitate the rational design of ligands targeting these receptors. Histamine mediates allergic reactions, inflammation, wakefulness, gastric acid secretion and neurotransmission, among others. Here, the authors determine 9 cryo-EM structures of the 4 histamine receptors in complexes with four different G protein subtypes, with endogenous or synthetic agonists bound, revealing their distinct features.