Modeling of Glutamate GluR6 Receptor and Its Interactions with Novel Noncompetitive Antagonists

The study proposes the first complete model of an ionotropic glutamate receptor (GluR6). The model is in accordance with available experimental data from single-particle electron microscopy images and exhibits correct shape and dimensions and the appropriate symmetry: 2-fold in the N-terminal domain (NTD), ligand-binding domain (LBD), and external part of the transmembrane region, whereas it is 4-fold deeper in the channel. The methodology applied for GluR6 receptor model building was validated in the docking procedure of competitive and uncompetitive antagonists. The constructed model was used to study molecular interactions of novel noncompetitive GluR6 antagonists with their molecular target. A new binding site in the GluR6 receptor transduction domain has been identified. It is situated between two subunits in the receptor dimer. The following residues were recognized as crucial for interactions: Arg663A, Arg663B (M3-S2 linker), Ser809B (S2-M4 linker), and Phe553A (S1-M1 linker).