Department of Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan.
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Nat Commun. 2023 Oct 20;14(1):6538. doi: 10.1038/s41467-023-42260-z.
Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the HR-G complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of HR and subtype selectivity of histamine receptors, and show that the HR structures may be valuable in rational drug design of drugs targeting the HR.
组胺是一种生物胺，通过刺激组胺受体参与过敏和炎症过程。组胺 H 受体 (HR) 是哮喘和特应性皮炎等慢性炎症性疾病的潜在治疗靶点。在这里，我们展示了与内源性激动剂组胺或选择性激动剂依替唑结合在正位结合口袋中的 HR-G 复合物的冷冻电子显微镜结构。这些结构表明了组胺激动剂的结合模式，并且亚型选择性激动剂的结合导致 Phe344 的构象变化，进而形成“芳香槽”。研究结果为 HR 的激动作用和组胺受体的亚型选择性的分子基础提供了深入了解，并表明 HR 结构可能对针对 HR 的药物的合理药物设计具有重要价值。
