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

Im, Dohyun Kishikawa, Jun-ichi Shiimura, Yuki Hisano, Hiromi Ito, Akane Fujita-Fujiharu, Yoko Sugita, Yukihiko Noda, Takeshi Kato, Takayuki Asada, Hidetsugu Iwata, So 京都大学 DOI:10.1038/s41467-023-42260-z

2023.10.20

概要

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 Phe344[7.39], 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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Acknowledgements

This work was supported by a Grant-in-Aid from the Japanese Ministry of

Education, Culture, Sports, Science and Technology (19H00923 (S.I.)

and 23K06357 (D.I.)) and the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug

Discovery and Life Science Research (BINDS)) from Japan Agency for

Medical Research and Development (AMED) under the grant number

JP21am0101079 and JP23ama121007 (S.I.). This study was also supported by the Takeda Science Foundation and the Mochida Memorial

Foundation for Medical and Pharmaceutical Research (D.I.). This work

was performed in part under the Collaborative Research Program as the

Visiting Fellow of Institute for Protein Research, Osaka University,

VFCR–23-02 (S.I.) and in part using the cryo-electron microscope under

Nature Communications | (2023)14:6538

https://doi.org/10.1038/s41467-023-42260-z

the Collaborative Research Program of Institute for Protein Research,

Osaka University, CEMCR-23-02 (H.A.).

Author contributions

D.I., H.A., and S.I. designed the experiments. D.I. prepared the cryo-EM

samples, and Y. Shiimura helped with the construction of Gq-heterotrimer expression. D.I., J.K., Y.F.F., Y. Sugita, T.N., T.K., and H.A. performed the cryo-EM analysis. H.H., A.I., and H.A. performed the TGFα

shedding assay. D.I., H.A., and S.I. wrote the paper with assistance from

all of the authors. T.K., H.A., and S.I. supervised the project. All authors

have read and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Additional information

Supplementary information The online version contains

supplementary material available at

https://doi.org/10.1038/s41467-023-42260-z.

Correspondence and requests for materials should be addressed to

Takayuki Kato, Hidetsugu Asada or So Iwata.

Peer review information Nature Communications thanks Javier GarciaNafria and the other, anonymous, reviewer(s) for their contribution to the

peer review of this work. A peer review file is available.

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