2. Academic Validation
  3. Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor

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

  • Nat Commun. 2023 Oct 20;14(1):6538. doi: 10.1038/s41467-023-42260-z.
Dohyun Im # 1,  Jun-Ichi Kishikawa # 2,  Yuki Shiimura 1 3,  Hiromi Hisano 1,  Akane Ito 1,  Yoko Fujita-Fujiharu 4 5 6,  Yukihiko Sugita 4 5 7,  Takeshi Noda 4 5 6,  Takayuki Kato 8,  Hidetsugu Asada 9,  So Iwata 10 11
Affiliations

Affiliations

  • 1 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
  • 2 Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
  • 3 Institute of Life Science, Kurume University, Kurume, Fukuoka, 830-0011, Japan.
  • 4 Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
  • 5 Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
  • 6 CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
  • 7 Hakubi Center for Advanced Research, Kyoto University, Kyoto, 606-8501, Japan.
  • 8 Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. [email protected].
  • 9 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan. [email protected].
  • 10 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan. [email protected].
  • 11 RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-5148, Japan. [email protected].
  • # Contributed equally.
PMID: 37863901 DOI: 10.1038/s41467-023-42260-z
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.

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