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

FEBS Lett. 2008 Dec 10;582(29):4089-94. doi: 10.1016/j.febslet.2008.11.005. Epub 2008 Nov 18.


The alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Glutamic Acid / chemistry*
  • Ligands
  • Protein Conformation
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / chemistry*
  • Receptors, AMPA / genetics
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry*


  • Ligands
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 4
  • Glutamic Acid
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid