The structural basis for kainoid selectivity at AMPA receptors revealed by low-mode docking calculations

The kainoids are a class of excitatory and excitotoxic pyrrolidine dicarboxylates that act at ionotropic glutamate receptors. The kainoids bind kainate receptors with high affinity and, while binding affinity is lower at AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, they are active in functional assays at this receptor subtype as well. However, kainoids are only partial agonists at AMPA receptors. Currents evoked by kainoids have been described as either slowly desensitizing, partially desensitizing, or non-desensitizing. Recently acquired X-ray crystal structures of the ligand binding domain of the iGluR2, AMPA sensitive receptor suggest that differences in ligand-receptor interactions may influence functional properties of an agonist. In an effort to identify important ligand-receptor interactions of various kainoids, we have conducted a series of low-mode docking searches of AMPA agonists in the iGluR2 binding domain. Kainic acid exhibited alternate low-lying geometries, with loss of hydrogen bonds to domain 2, which may represent a dissociation route not available to other kainoids. The most potent of the kainoids are capable of forming hydrogen bonding interactions that span the two domains of the receptor. In particular, a hydrogen bond between the domoic acid C6' carboxylic acid and Ser652 may prevent a peptide bond rotation that is associated with the desensitized state of the receptor.