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Publication Abstract from PubMed

Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H(1) receptor (H(1)R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H(1)R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H(1)R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H(1)R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W428(6.48). Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Molecular mechanism of antihistamines recognition and regulation of the histamine H(1) receptor.,Wang D, Guo Q, Wu Z, Li M, He B, Du Y, Zhang K, Tao Y Nat Commun. 2024 Jan 2;15(1):84. doi: 10.1038/s41467-023-44477-4. PMID:38167898^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.