Ionotropic Glutamate Receptors (iGluRs): Overview of iGluR2 ligand binding domain in complex with agonists and antagonists

Ionotropic glutamate receptors (iGluRs) constitute a family of ligand gated ion channels subdivided in three classes, NMDA, AMPA (iGluA1-4) and KA (1-5) according to the agonists that selectively activate them. iGluRs are tetrameric assemblies of highly homologous receptor subunits. They are critically important for normal brain function and are considered to be involved on neurological disorders and degenerative diseases such as schizophrenia, Alzheimer’s disease, brain damage following stroke and epilepsy. Since the first publication of the structure of recombinant soluble protein of ligand binding domain of GluA2 extensive studies on this group of receptors were performed and many crystal structures as complexes of GluA2-LBD with agonists, partial agonists and antagonists were obtained. The structural information in combination with functional data makes good platform for consecutive investigation and design of new selective drugs which will be used in treatment of neurodegerative diseases

Structures of the ligand-binding core of iGluR2 in complex with the agonists (R)- and (S)-2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)propionic acid explain their unusual equipotency

AMPA type ionotropic glutamate receptors generally display high stereoselectivity in agonist binding. However, the stereoisomers of 2 amino 3 4 hydroxy 1,2,5 thiadiazol 3 yl propionic acid TDPA have similar enantiopharmacology. To understand this observation, we have determined the X ray structures of R TDPA and S TDPA in complex with the ligand binding core of iGluR2 and investigated the binding pharmacology at AMPA and kainate receptors. Both enantiomers induce full domain closure in iGluR2 but adopt different conformations when binding to the receptor, which may explain the similar enantiopharmacolog