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

Author

Listed:
  • 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
    Harbin Institute of Technology)

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.

Suggested Citation

  • 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 & Yuanzheng He, 2024. "Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46840-5
    DOI: 10.1038/s41467-024-46840-5
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