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Structure paper

TitleStructural basis of ligand recognition and activation of the histamine receptor family.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 8296, Year 2024
Publish dateSep 27, 2024
AuthorsXuan 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 /
PubMed AbstractHistamine 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 ...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.
External linksNat Commun / PubMed:39333117 / PubMed Central
MethodsEM (single particle)
Resolution2.3 - 2.97 Å
Structure data

EMDB-39412, PDB-8yn2:
Cryo-EM structure of histamine H1 receptor in complex with histamine and miniGq
Method: EM (single particle) / Resolution: 2.66 Å

EMDB-39413, PDB-8yn3:
Cryo-EM structure of histamine H2 receptor in complex with histamine and miniGs
Method: EM (single particle) / Resolution: 2.56 Å

EMDB-39414, PDB-8yn4:
Cryo-EM structure of histamine H2 receptor in complex with histamine and miniGq
Method: EM (single particle) / Resolution: 2.97 Å

EMDB-39415, PDB-8yn5:
Cryo-EM structure of histamine H3 receptor in complex with histamine and Gi
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-39416, PDB-8yn6:
Cryo-EM structure of histamine H3 receptor in complex with imetit and Gi
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-39417, PDB-8yn7:
Cryo-EM structure of histamine H3 receptor in complex with immethridine and miniGo
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-39418, PDB-8yn8:
Cryo-EM structure of histamine H3 receptor in complex with proxyfan and miniGo
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-39419, PDB-8yn9:
Cryo-EM structure of histamine H4 receptor in complex with histamine and Gi
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-39420, PDB-8yna:
Cryo-EM structure of histamine H4 receptor in complex with immepip and Gi
Method: EM (single particle) / Resolution: 2.63 Å

Chemicals

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-ITF:
2-(1~{H}-imidazol-5-yl)ethyl carbamimidothioate

PDB-1ly2:
Crystal structure of unliganded human CD21 SCR1-SCR2 (Complement receptor type 2)

PDB-1ly3:
ANALYSIS OF QUINAZOLINE AND PYRIDOPYRIMIDINE N9-C10 REVERSED BRIDGE ANTIFOLATES IN COMPLEX WITH NADP+ AND PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE

ChemComp-HOH:
WATER

PDB-1ly4:
Analysis of quinazoline and PYRIDO[2,3D]PYRIMIDINE N9-C10 reversed bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN / GPCR

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