Mechanisms for activation and antagonism of an AMPA-Sensitive glutamate receptor: Crystal structures of the GluR2 ligand binding core

Crystal structures of the GluR2 ligand binding core (S1S2) have been determ ined in the apo state and in the presence of the antagonist DNQX, the parti al agonist kainate, and the full agonists AMPA and glutamate. The domains o f the S1S2 ligand binding core are expanded in the apo state and contract u pon ligand binding with the extent of domain separation decreasing in the o rder of apo > DNQX > kainate > glutamate congruent to AMPA. These results s uggest that agonist-induced domain closure gates the transmembrane channel and the extent of receptor activation depends upon the degree of domain clo sure. AMPA and glutamate also promote a 180 degrees flip of a trans peptide bond in the ligand binding site. The crystal packing of the ligand binding cores suggests modes for subunit-subunit contact in the intact receptor an d mechanisms by which allosteric effecters modulate receptor activity.