Cryo-EM structures of the ionotropic glutamate receptor GluD1 reveal a non-swapped architecture.

Abstract

Ionotropic orphan delta receptors (GluD) are not gated by glutamate or any other endogenous ligand but are grouped with ionotropic glutamate receptors based on sequence similarity. GluD1 receptors play critical roles in synaptogenesis, synapse maintenance and have been implicated in neuronal disorders including schizophrenia, cognitive deficits, and cerebral ataxia. Here we report cryo-electron microscopy structures of the rat GluD1 receptor complexed with calcium and the ligand 7-chlorokynurenic acid, elucidating molecular architecture and principles of receptor assembly. The structures reveal a non-swapped architecture at the extracellular amino-terminal (ATD) and ligand-binding domain (LBD) interface. This is in contrast to other families of ionotropic glutamate receptors (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.