8JXV

Clozapine-bound H4R/Gi complex

Summary for 8JXV

• Entry DOI: 10.2210/pdb8jxv/pdb
• EMDB information: 36714
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr-g-protein complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 157369.59

Authors

He, Y.,Xia, R. (deposition date: 2023-07-01, release date: 2024-03-20, Last modification date: 2024-04-03)

Primary citation

Xia, R.,Shi, S.,Xu, Z.,Vischer, H.F.,Windhorst, A.D.,Qian, Y.,Duan, Y.,Liang, J.,Chen, K.,Zhang, A.,Guo, C.,Leurs, R.,He, Y.
Structural basis of ligand recognition and design of antihistamines targeting histamine H 4 receptor.
Nat Commun, 15:2493-2493, 2024

PubMed Abstract: 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.

PubMed: 38509098
DOI: 10.1038/s41467-024-46840-5

Experimental method

ELECTRON MICROSCOPY (3.21 Å)