Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor

Dandan Wang, Qiong Guo, Zhangsong Wu, Ming Li, Binbin He, Yang Du, Kaiming Zhang () and Yuyong Tao ()
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Dandan Wang: University of Science and Technology of China
Qiong Guo: University of Science and Technology of China
Zhangsong Wu: The Chinese University of Hong Kong
Ming Li: University of Science and Technology of China
Binbin He: University of Science and Technology of China
Yang Du: The Chinese University of Hong Kong
Kaiming Zhang: University of Science and Technology of China
Yuyong Tao: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract 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 H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, 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 W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Date: 2024
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DOI: 10.1038/s41467-023-44477-4

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