TMDU Advanced Research Institute, Tokyo Medical and Dental University Bunkyo-ku, Tokyo, Japan.
Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Nagoya, Japan.
Nat Commun. 2023 Sep 22;14(1):5899. doi: 10.1038/s41467-023-41650-7.
Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.
羟羧酸受体 (HCA) 在各种组织和免疫细胞中表达。因此，HCA2 及其激动剂是治疗炎症和代谢紊乱的重要靶点。然而，关于 HCA 与激动剂的活性结合状态的信息有限。在这里，我们展示了与人 HCA2-Gi 和 HCA3-Gi 信号复合物结合的多个结合化合物的冷冻电镜结构。激动剂与精氨酸形成盐桥，精氨酸在 HCA 家族中保守，从而激活这些受体。受体的细胞外区域形成一个类似盖子的结构，覆盖配体结合口袋。尽管 HCA 中的跨膜 (TM) 6 经历动态构象变化，但配体不会直接与 TM6 中的氨基酸相互作用，这表明间接信号转导导致 TM6 发生微小位移以激活 Gi 蛋白。激动剂结合的 HCA2 和 HCA3 的结构分析以及突变和分子动力学模拟为 HCA 配体识别和激活机制提供了分子见解。
