Theoretical studies on the structure and symmetry of the transmembrane region of glutamatergic GluR5 receptor.

There is numerous experimental and conceptual proof that the extracellular portion of ionotropic glutamate receptors (iGluRs), i.e., N-terminal domain (NTD) and ligand-binding core (LBD), exhibits 2-fold rotational symmetry and thus dimer of dimers architecture. However, the problem of the structure and symmetry of the transmembrane channel forming region of iGluRs has not been solved yet. According to the most common approach, glutamate ion channels possess 4-fold symmetry, similar to homologous potassium channels. This results in a symmetry mismatch between the extracellular fragment of the receptor and its transmembrane domain. To overcome the above discrepancies in iGluR symmetry, homology modeling was applied to propose an alternative model of GluR5 channel transmembrane region. Because of modification of M3 helix structure, as indicated by experimental results, the obtained model is generally characterized by 2-fold rotational symmetry. As a validation of the applied methodology, IEM-1754 was docked to the obtained GluR5 receptor transmembrane fragment model. However, because there are no affinity values available for IEM-1754, the applied methodology was additionally validated by building of NMDA receptor transmembrane region model and its evaluation in the docking of dextrorphan, (+)-MK-801, and IEM-1925. Moreover, the NMDA and GluR5 channel models are consistent with all available experimental data, including the latest single-particle electron microscopy images of iGluRs.