High Conformational Variability in the GluK2 Kainate Receptor Ligand-Binding Domain.
| Publication Type | Academic Article |
| Authors | Wied T, Chin A, Lau A |
| Journal | Structure |
| Volume | 27 |
| Issue | 1 |
| Pagination | 189-195.e2 |
| Date Published | 10/25/2018 |
| ISSN | 1878-4186 |
| Keywords | Molecular Dynamics Simulation, Receptors, Kainic Acid |
| Abstract | 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. |
| DOI | 10.1016/j.str.2018.09.008 |
| PubMed ID | 30482727 |
| PubMed Central ID | PMC6363114 |