High Conformational Variability in the GluK2 Kainate Receptor Ligand-Binding Domain

Structure. 2019 Jan 2;27(1):189-195.e2. doi: 10.1016/j.str.2018.09.008. Epub 2018 Oct 25.


The kainate family of ionotropic glutamate receptors (iGluRs) mediates pre- and postsynaptic neurotransmission. Previously computed conformational potentials of mean force (PMFs) for iGluR ligand-binding domains (LBDs) revealed subtype-dependent conformational differences between α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) iGluR subfamilies. Here we report PMFs for the kainate receptor GluK2 in apo and glutamate-bound states. Apo and glutamate-bound GluK2 LBDs preferentially access closed-cleft conformations. Apo GluK2 exhibits a surprisingly high degree of conformational flexibility, accessing open and closed states. Comparing across iGluR subtypes, these results are similar to glycine-binding GluN1 and GluN3A NMDA subunits and differ from glutamate-binding GluA2 and GluN2A subunits. To test the contribution of cross-lobe interactions on closed-cleft LBD stability, we computed PMFs for two GluK2 mutants, D462A and D656S. D462A, but not D656S, weakens closed-cleft conformations of the glutamate-bound LBD. Theoretical Boltzmann-weighted small-angle X-ray scattering profiles improve agreement with experimental results compared with calculations from the LBD crystal structure alone.

Keywords: free energy calculations; glutamate receptors; kainate receptors; ligand binding; molecular dynamics simulations; small-angle X-ray scattering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Glutamates / chemistry
  • Glutamates / metabolism
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Receptors, Kainic Acid / chemistry*
  • Receptors, Kainic Acid / metabolism


  • Gluk2 kainate receptor
  • Glutamates
  • Receptors, Kainic Acid