8YN5

Cryo-EM structure of histamine H3 receptor in complex with histamine and Gi

Summary for 8YN5

• Entry DOI: 10.2210/pdb8yn5/pdb
• EMDB information: 39415
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 191048.29

Authors

Zhang, X.,Liu, G.,Li, X.,Gong, W. (deposition date: 2024-03-10, release date: 2024-10-09, Last modification date: 2024-11-13)

Primary citation

Zhang, X.,Liu, G.,Zhong, Y.N.,Zhang, R.,Yang, C.C.,Niu, C.,Pu, X.,Sun, J.,Zhang, T.,Yang, L.,Zhang, C.,Li, X.,Shen, X.,Xiao, P.,Sun, J.P.,Gong, W.
Structural basis of ligand recognition and activation of the histamine receptor family.
Nat Commun, 15:8296-8296, 2024

PubMed 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.

PubMed: 39333117
DOI: 10.1038/s41467-024-52585-y

Experimental method

ELECTRON MICROSCOPY (2.7 Å)