EMD-39416
Cryo-EM structure of histamine H3 receptor in complex with imetit and Gi
EMD-39416
Single-particle2.77 Å
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Map released: 09/10/2024
Last modified: 27/11/2024
Sample Organism:
Homo sapiens,
synthetic construct
Sample: Imetit-H3R-Gi-scFv16 complex
Fitted models: 8yn6 (Avg. Q-score: 0.546)
Deposition Authors: Zhang X
,
Liu G
,
Li X
,
Gong W
Sample: Imetit-H3R-Gi-scFv16 complex
Fitted models: 8yn6 (Avg. Q-score: 0.546)
Deposition Authors: Zhang X
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Structural basis of ligand recognition and activation of the histamine receptor family.
Zhang X
,
Liu G
,
Zhong YN,
Zhang R,
Yang CC,
Niu C,
Pu X,
Sun J,
Zhang T,
Yang L
,
Zhang C,
Li X
,
Shen X,
Xiao P
,
Sun JP
,
Gong W
(2024) Nat Commun , 15 , 8296 - 8296
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(2024) Nat Commun , 15 , 8296 - 8296
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 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.