Molecular mechanism of agonist recognition by the ligand‐binding core of the ionotropic glutamate receptor 4

The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) class of ionotropic glutamate receptors comprises four different subunits: iGluR1/iGluR2 and iGluR3/iGluR4 forming two subgroups. Three‐dimensional structures have been reported only of the ligand‐binding core of iGluR2. Here, we present two X‐ray structures of a soluble construct of the R/G unedited flip splice variant of the ligand‐binding core of iGluR4 (iGluR4 i (R)‐S1S2) in complex with glutamate or AMPA. Subtle, but important differences are found in the ligand‐binding cavity between the two AMPA receptor subgroups at position 724 (Tyr in iGluR1/iGluR2 and Phe in iGluR3/iGluR4), which in iGluR4 may lead to displacement of a water molecule and hence points to the possibility to make subgroup specific ligands.