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

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 W428^6.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

SUBMITTER: Wang D

PROVIDER: S-EPMC10762250 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Wang Dandan D Guo Qiong Q Wu Zhangsong Z Li Ming M He Binbin B Du Yang Y Zhang Kaiming K Tao Yuyong Y

Nature communications 20240102 1

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 ...[more]

PMID: 38167898

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Dataset Information

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

Publications

Molecular mechanism of antihistamines recognition and regulation of the histamine H<sub>1</sub> receptor.

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