PDF(Pubmed)
Abstract：
The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.
摘要：
组胺H4受体（H4R）在免疫细胞功能中起关键作用，是治疗过敏性和炎症性疾病的重要靶标。然而,H4R的结构信息仍然难以捉摸。这里,我们报道了H4R/Gi复合物的四种低温EM结构，用组胺或合成激动剂Clobenpropit，VUF6884和氯氮平结合。结合诱变，配体结合和功能测定，结构数据揭示了一种独特的配体结合模式，其中D943.32和π-π网络确定了带正电荷的配体基团的方向，而E1825.46位于配体结合袋的另一端，在调节受体活性中起关键作用。对H4R配体结合的结构见解使我们能够鉴定E1825.46的突变体，其中激动剂clobenpropit充当反向激动剂，并正确预测具有纳摩尔效力的密切相关类似物的反向激动作用。连同关于受体激活和Gi参与的发现，我们建立了理解H4R信号传导的框架,并为设计靶向H4R的新型抗组胺药提供了合理的基础.
