Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor
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-electro...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42260-z |
| _version_ | 1797388221450027008 |
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| author | Dohyun Im Jun-ichi Kishikawa Yuki Shiimura Hiromi Hisano Akane Ito Yoko Fujita-Fujiharu Yukihiko Sugita Takeshi Noda Takayuki Kato Hidetsugu Asada So Iwata |
| author_facet | Dohyun Im Jun-ichi Kishikawa Yuki Shiimura Hiromi Hisano Akane Ito Yoko Fujita-Fujiharu Yukihiko Sugita Takeshi Noda Takayuki Kato Hidetsugu Asada So Iwata |
| author_sort | Dohyun Im |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T22:37:39Z |
| format | Article |
| id | doaj.art-aecb7ce92dad48079fb1d6b2c25e5659 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:39Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-aecb7ce92dad48079fb1d6b2c25e56592023-12-17T12:23:37ZengNature PortfolioNature Communications2041-17232023-10-0114111110.1038/s41467-023-42260-zStructural insights into the agonists binding and receptor selectivity of human histamine H4 receptorDohyun Im0Jun-ichi Kishikawa1Yuki Shiimura2Hiromi Hisano3Akane Ito4Yoko Fujita-Fujiharu5Yukihiko Sugita6Takeshi Noda7Takayuki Kato8Hidetsugu Asada9So Iwata10Department of Cell Biology, Graduate School of Medicine, Kyoto UniversityInstitute for Protein Research, Osaka UniversityDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityLaboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto UniversityLaboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto UniversityLaboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto UniversityInstitute for Protein Research, Osaka UniversityDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityDepartment of Cell Biology, Graduate School of Medicine, Kyoto UniversityAbstract 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.https://doi.org/10.1038/s41467-023-42260-z |
| spellingShingle | Dohyun Im Jun-ichi Kishikawa Yuki Shiimura Hiromi Hisano Akane Ito Yoko Fujita-Fujiharu Yukihiko Sugita Takeshi Noda Takayuki Kato Hidetsugu Asada So Iwata Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor Nature Communications |
| title | Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor |
| title_full | Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor |
| title_fullStr | Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor |
| title_full_unstemmed | Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor |
| title_short | Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor |
| title_sort | structural insights into the agonists binding and receptor selectivity of human histamine h4 receptor |
| url | https://doi.org/10.1038/s41467-023-42260-z |
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