Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor

Ruixue Xia, Shuang Shi, Zhenmei Xu, Henry F. Vischer, Albert D. Windhorst, Yu Qian, Yaning Duan, Jiale Liang, Kai Chen, Anqi Zhang, Changyou Guo, Rob Leurs () and Yuanzheng He ()
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Ruixue Xia: Harbin Institute of Technology
Shuang Shi: Vrije Universiteit Amsterdam
Zhenmei Xu: Harbin Institute of Technology
Henry F. Vischer: Vrije Universiteit Amsterdam
Albert D. Windhorst: VU University Medical Center Amsterdam
Yu Qian: Harbin Institute of Technology
Yaning Duan: Harbin Institute of Technology
Jiale Liang: Harbin Institute of Technology
Kai Chen: Harbin Institute of Technology
Anqi Zhang: Harbin Institute of Technology
Changyou Guo: Harbin Institute of Technology
Rob Leurs: Vrije Universiteit Amsterdam
Yuanzheng He: Harbin Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

Date: 2024
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DOI: 10.1038/s41467-024-46840-5

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