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.

组胺受体是一组 G 蛋白偶联受体 (GPCR)，在各种生理和病理生理条件下发挥重要作用。针对组胺 H ₁受体 (H ₁ R) 的抗组胺药已广泛用于缓解过敏和炎症症状。在这里，为了揭示已知的第二代抗组胺药对 H ₁ R 的调节细节，从而为新型抗组胺药的合理设计提供线索，我们确定了 apo 形式的 H ₁ R 的冷冻电镜结构，并与不同的抗组胺药。除了深层疏水腔外，我们还确定了 H ₁ R 中的第二配体结合位点，该位点可能支持引入新的衍生基团以产生更新的抗组胺药。此外，这些结构表明抗组胺药通过利用共享的苯基插入深腔并阻止拨动开关残基W428 ^6.48的运动来发挥反向调节作用。总之，这些结果丰富了我们对 GPCR 调节的理解，并促进了新型抗组胺药的基于结构的设计。