Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Feb;82(2):676–683. doi: 10.1016/S0006-3495(02)75430-1

Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.

Yalini Arinaminpathy 1, Mark S P Sansom 1, Philip C Biggin 1
PMCID: PMC1301877  PMID: 11806910

Abstract

Ionotropic glutamate receptors are essential for fast synaptic nerve transmission. Recent x-ray structures for the ligand-binding (S1S2) region of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive receptor have suggested how differences in protein/ligand interactions may determine whether a ligand will behave as a full agonist. We have used multiple molecular dynamics simulations of 2-5 ns duration to explore the structural dynamics of GluR2 S1S2 in the presence and absence of glutamate and in a complex with kainate. Our studies indicate that not only is the degree of domain closure dependent upon interactions with the ligand, but also that protein/ligand interactions influence the motion of the S2 domain with respect to S1. Differences in domain mobility between the three states (apo-S1S2, glutamate-bound, and kainate-bound) are surprisingly clear-cut. We discuss how these changes in dynamics may provide an explanation relating the mechanism of transmission of the agonist-binding event to channel opening. We also show here how the glutamate may adopt an alternative mode of binding not seen in the x-ray structure, which involves a key threonine (T480) side chain flipping into a new conformation. This new conformation results in an altered pattern of hydrogen bonding at the agonist-binding site.

Full Text

The Full Text of this article is available as a PDF (222.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adcock C., Smith G. R., Sansom M. S. Electrostatics and the ion selectivity of ligand-gated channels. Biophys J. 1998 Sep;75(3):1211–1222. doi: 10.1016/S0006-3495(98)74040-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armstrong N., Gouaux E. Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron. 2000 Oct;28(1):165–181. doi: 10.1016/s0896-6273(00)00094-5. [DOI] [PubMed] [Google Scholar]
  3. Armstrong N., Sun Y., Chen G. Q., Gouaux E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature. 1998 Oct 29;395(6705):913–917. doi: 10.1038/27692. [DOI] [PubMed] [Google Scholar]
  4. Borges K., Dingledine R. AMPA receptors: molecular and functional diversity. Prog Brain Res. 1998;116:153–170. doi: 10.1016/s0079-6123(08)60436-7. [DOI] [PubMed] [Google Scholar]
  5. Chen G. Q., Gouaux E. Overexpression of a glutamate receptor (GluR2) ligand binding domain in Escherichia coli: application of a novel protein folding screen. Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13431–13436. doi: 10.1073/pnas.94.25.13431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chittajallu R., Braithwaite S. P., Clarke V. R., Henley J. M. Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol Sci. 1999 Jan;20(1):26–35. doi: 10.1016/s0165-6147(98)01286-3. [DOI] [PubMed] [Google Scholar]
  7. Dingledine R., Borges K., Bowie D., Traynelis S. F. The glutamate receptor ion channels. Pharmacol Rev. 1999 Mar;51(1):7–61. [PubMed] [Google Scholar]
  8. Hayward S., Berendsen H. J. Systematic analysis of domain motions in proteins from conformational change: new results on citrate synthase and T4 lysozyme. Proteins. 1998 Feb 1;30(2):144–154. [PubMed] [Google Scholar]
  9. Hollmann M., Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31–108. doi: 10.1146/annurev.ne.17.030194.000335. [DOI] [PubMed] [Google Scholar]
  10. Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996 Feb;14(1):33-8, 27-8. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  11. Kawamoto S., Uchino S., Xin K. Q., Hattori S., Hamajima K., Fukushima J., Mishina M., Okuda K. Arginine-481 mutation abolishes ligand-binding of the AMPA-selective glutamate receptor channel alpha1-subunit. Brain Res Mol Brain Res. 1997 Jul;47(1-2):339–344. doi: 10.1016/s0169-328x(97)00103-4. [DOI] [PubMed] [Google Scholar]
  12. Keinänen K., Wisden W., Sommer B., Werner P., Herb A., Verdoorn T. A., Sakmann B., Seeburg P. H. A family of AMPA-selective glutamate receptors. Science. 1990 Aug 3;249(4968):556–560. doi: 10.1126/science.2166337. [DOI] [PubMed] [Google Scholar]
  13. Lerma J., Morales M., Vicente M. A., Herreras O. Glutamate receptors of the kainate type and synaptic transmission. Trends Neurosci. 1997 Jan;20(1):9–12. doi: 10.1016/S0166-2236(96)20055-4. [DOI] [PubMed] [Google Scholar]
  14. Leuschner W. D., Hoch W. Subtype-specific assembly of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits is mediated by their n-terminal domains. J Biol Chem. 1999 Jun 11;274(24):16907–16916. doi: 10.1074/jbc.274.24.16907. [DOI] [PubMed] [Google Scholar]
  15. Panchenko V. A., Glasser C. R., Mayer M. L. Structural similarities between glutamate receptor channels and K(+) channels examined by scanning mutagenesis. J Gen Physiol. 2001 Apr;117(4):345–360. doi: 10.1085/jgp.117.4.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Roccatano D., Mark A. E., Hayward S. Investigation of the mechanism of domain closure in citrate synthase by molecular dynamics simulation. J Mol Biol. 2001 Jul 27;310(5):1039–1053. doi: 10.1006/jmbi.2001.4808. [DOI] [PubMed] [Google Scholar]
  17. Smith T. C., Wang L. Y., Howe J. R. Heterogeneous conductance levels of native AMPA receptors. J Neurosci. 2000 Mar 15;20(6):2073–2085. doi: 10.1523/JNEUROSCI.20-06-02073.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sprengel R., Aronoff R., Völkner M., Schmitt B., Mosbach R., Kuner T. Glutamate receptor channel signatures. Trends Pharmacol Sci. 2001 Jan;22(1):7–10. doi: 10.1016/s0165-6147(00)01588-1. [DOI] [PubMed] [Google Scholar]
  19. Tai K., Shen T., Börjesson U., Philippopoulos M., McCammon J. A. Analysis of a 10-ns molecular dynamics simulation of mouse acetylcholinesterase. Biophys J. 2001 Aug;81(2):715–724. doi: 10.1016/S0006-3495(01)75736-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Uchino S., Sakimura K., Nagahari K., Mishina M. Mutations in a putative agonist binding region of the AMPA-selective glutamate receptor channel. FEBS Lett. 1992 Aug 24;308(3):253–257. doi: 10.1016/0014-5793(92)81286-u. [DOI] [PubMed] [Google Scholar]
  21. Wafford K. A., Kathoria M., Bain C. J., Marshall G., Le Bourdellès B., Kemp J. A., Whiting P. J. Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site. Mol Pharmacol. 1995 Feb;47(2):374–380. [PubMed] [Google Scholar]
  22. Wallace A. C., Laskowski R. A., Thornton J. M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995 Feb;8(2):127–134. doi: 10.1093/protein/8.2.127. [DOI] [PubMed] [Google Scholar]
  23. Wriggers W., Schulten K. Protein domain movements: detection of rigid domains and visualization of hinges in comparisons of atomic coordinates. Proteins. 1997 Sep;29(1):1–14. [PubMed] [Google Scholar]
  24. Yamakura T., Shimoji K. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol. 1999 Oct;59(3):279–298. doi: 10.1016/s0301-0082(99)00007-6. [DOI] [PubMed] [Google Scholar]
  25. Young M. A., Gonfloni S., Superti-Furga G., Roux B., Kuriyan J. Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation. Cell. 2001 Apr 6;105(1):115–126. doi: 10.1016/s0092-8674(01)00301-4. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES