Dysiherbaine (DH) and its congener neodysiherbaine A (NDH) are naturally occurring excitatory amino acids with high-affinity and subunit-selectivity for kainate type ionotropic glutamate receptors, especially GluR5 and GluR6 subunits. To elucidate why DH and NDH bind selectively to GluR5, we have determined the crystal structures of human GluR5 ligand-binding core in complexes with DH and NDH, in addition to the glutamate-complex. DH and NDH form unique hydrogen-bonding and hydrophobic interactions with the amino acid residues in the binding-cleft by excluding the water molecules, which mediate hydrogen bonding interactions with glutamate. The domain openings upon binding DH and NDH are much smaller than that found in the structures of partial-agonist- or antagonist-bound forms of GluR5. Here, we propose that the efficacy and ability of an agonist are not simply in inverse proportion to the extent of domain separation, but appear to be related to the stability of the "closed" conformation of the ligand-binding core. This structural information provides the basis for rational development of a series of novel synthetic analogues as useful probes for studying iGluRs in central nervous system and as potential therapeutic leads.
