Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor

Dohyun Im, Jun-ichi Kishikawa, Yuki Shiimura, Hiromi Hisano, Akane Ito, Yoko Fujita-Fujiharu, Yukihiko Sugita, Takeshi Noda, Takayuki Kato (), Hidetsugu Asada () and So Iwata ()
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Dohyun Im: Kyoto University
Jun-ichi Kishikawa: Osaka University
Yuki Shiimura: Kyoto University
Hiromi Hisano: Kyoto University
Akane Ito: Kyoto University
Yoko Fujita-Fujiharu: Kyoto University
Yukihiko Sugita: Kyoto University
Takeshi Noda: Kyoto University
Takayuki Kato: Osaka University
Hidetsugu Asada: Kyoto University
So Iwata: Kyoto University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H4 receptor (H4R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H4R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe3447.39, which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H4R and subtype selectivity of histamine receptors, and show that the H4R structures may be valuable in rational drug design of drugs targeting the H4R.

Date: 2023
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DOI: 10.1038/s41467-023-42260-z

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