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VUF6884-bound H4R/Gi complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedThe histamine H(4) receptor (H(4)R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H(4)R remains elusive. Here, we report four cryo-EM structures of H(4)R/G(i) 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(3.32) and a pi-pi network determine the orientation of the positively charged group of ligands, while E182(5.46), located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H(4)R ligand binding allows us to identify mutants at E182(5.46) 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 G(i) engagement, we establish a framework for understanding H(4)R signaling and provide a rational basis for designing novel antihistamines targeting H(4)R. Structural basis of ligand recognition and design of antihistamines targeting histamine H(4) receptor.,Xia R, Shi S, Xu Z, Vischer HF, Windhorst AD, Qian Y, Duan Y, Liang J, Chen K, Zhang A, Guo C, Leurs R, He Y Nat Commun. 2024 Mar 20;15(1):2493. doi: 10.1038/s41467-024-46840-5. PMID:38509098[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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