Ionotropic orphan delta (GluD) receptors are not gated by glutamate or any other endogenous ligand but are grouped with ionotropic glutamate receptors (iGluRs) based on sequence similarity. GluD1 receptors play critical roles in synaptogenesis and synapse maintenance and have been implicated in neuronal disorders, including schizophrenia, cognitive deficits, and cerebral ataxia. Here we report cryo-EM structures of the rat GluD1 receptor complexed with calcium and the ligand 7-chlorokynurenic acid (7-CKA), elucidating molecular architecture and principles of receptor assembly. The structures reveal a non-swapped architecture at the interface of the extracellular amino-terminal domain (ATD) and the ligand-binding domain (LBD). This finding is in contrast with structures of other families of iGluRs, where the dimer partners between the ATD and LBD layers are swapped. Our results demonstrate that principles of architecture and symmetry are not conserved between delta receptors and other iGluRs and provide a molecular blueprint for understanding the functions of the ‘orphan’ class of iGluRs.

离子型孤儿三角洲 (GluD) 受体不受谷氨酸或任何其他内源性配体的控制，而是根据序列相似性与离子型谷氨酸受体 (iGluR) 分组。GluD1 受体在突触发生和突触维持中起关键作用，并与神经元疾病有关，包括精神分裂症、认知缺陷和脑共济失调。在这里，我们报告了与钙和配体 7-氯犬尿酸 (7-CKA) 复合的大鼠 GluD1 受体的冷冻电镜结构，阐明了受体组装的分子结构和原理。这些结构揭示了在细胞外氨基末端结构域 (ATD) 和配体结合结构域 (LBD) 的界面处的非交换结构。这一发现与其他 iGluR 家族的结构形成对比，ATD 和 LBD 层之间的二聚体伙伴被交换。我们的研究结果表明，delta 受体和其他 iGluR 之间的结构和对称性原则并不保守，并为理解“孤儿”类 iGluR 的功能提供了分子蓝图。