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TitleStructural insights into ligand recognition and G protein preferences across histamine receptors.
Journal, issue, pagesCommun Biol, Vol. 8, Issue 1, Page 957, Year 2025
Publish dateJun 27, 2025
AuthorsYuma Matsuzaki / Fumiya K Sano / Hidetaka S Oshima / Hiroaki Akasaka / Kazuhiro Kobayashi / Tatsuki Tanaka / Yuzuru Itoh / Wataru Shihoya / Yoshiaki Kise / Tsukasa Kusakizako / Asuka Inoue / Osamu Nureki /
PubMed AbstractHistamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H receptor (HR) modulates chemotaxis ...Histamine exerts critical physiological roles by activating four receptor subtypes, each exhibiting a specific G protein preference. Among these, the histamine H receptor (HR) modulates chemotaxis and interferon production through G protein activation, suggesting its therapeutic potential. Despite its physiological significance, the mechanisms underlying HR signalling and G protein preference across histamine receptors remain poorly understood. Here, we present the cryo-electron microscopy structure of the HR-G complex, revealing unique mechanisms of histamine recognition and receptor activation. We further solved the structures of the histamine H receptor (HR) bound to the non-canonical G proteins G and G. Through a combination of functional and computational analyses, we identified the intracellular loop 2 as a critical determinant of G protein preference in HR and HR. Collectively, our comprehensive study revealed the structural basis for distinct mechanisms of ligand recognition and receptor activation, offering a profound insight into G protein preference across receptor subtypes.
External linksCommun Biol / PubMed:40579541 / PubMed Central
MethodsEM (single particle)
Resolution2.77 - 3.23 Å
Structure data

EMDB-63324, PDB-9lrb:
Cryo-EM structure of the histamine H1 receptor-Gs protein complex
Method: EM (single particle) / Resolution: 2.77 Å

EMDB-63325, PDB-9lrc:
Cryo-EM structure of the histamine H4 receptor-Gi protein complex (Receptor focused)
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-63326, PDB-9lrd:
Cryo-EM structure of the histamine H1 receptor-Gi protein complex
Method: EM (single particle) / Resolution: 3.23 Å

EMDB-63327, PDB-9lre:
Cryo-EM structure of the histamine H4 receptor-Gi protein complex (Overall)
Method: EM (single particle) / Resolution: 2.84 Å

Chemicals

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • bos taurus (domestic cattle)
  • unidentified (others)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Class A GPCR / Histamine / G protein / Complex / Receptor

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