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TitleStructural basis of ligand recognition and design of antihistamines targeting histamine H receptor.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 2493, Year 2024
Publish dateMar 20, 2024
AuthorsRuixue 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 /
PubMed AbstractThe histamine H receptor (HR) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of HR remains ...The histamine H receptor (HR) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of HR remains elusive. Here, we report four cryo-EM structures of HR/G 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 D94 and a π-π network determine the orientation of the positively charged group of ligands, while E182, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into HR ligand binding allows us to identify mutants at E182 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 G engagement, we establish a framework for understanding HR signaling and provide a rational basis for designing novel antihistamines targeting HR.
External linksNat Commun / PubMed:38509098 / PubMed Central
MethodsEM (single particle)
Resolution3.01 - 3.21 Å
Structure data

36712

8jxt

EMDB-36712, PDB-8jxt:
Histamine-bound H4R/Gi complex
Method: EM (single particle) / Resolution: 3.07 Å

36714

8jxv

EMDB-36714, PDB-8jxv:
Clozapine-bound H4R/Gi complex
Method: EM (single particle) / Resolution: 3.21 Å

36715

8jxw

EMDB-36715, PDB-8jxw:
VUF6884-bound H4R/Gi complex
Method: EM (single particle) / Resolution: 3.01 Å

36716

8jxx

EMDB-36716, PDB-8jxx:
Clobenpropit-bound H4R/Gi complex
Method: EM (single particle) / Resolution: 3.06 Å

Chemicals

ChemComp-HSM:
HISTAMINE / neurotransmitter, hormone*YM

ChemComp-PO4:
PHOSPHATE ION


ChemComp, No image

ChemComp-VBU:
Unknown entry


ChemComp, No image

ChemComp-VCF:
Unknown entry


ChemComp, No image

ChemComp-VCL:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR-G-protein complex

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