Journal of Molecular Modeling

, Volume 10, Issue 5–6, pp 305–316 | Cite as

Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits

  • Mathias-Costa Blaise
  • Ramanathan Sowdhamini
  • Metpally Raghu Prasad Rao
  • Nithyananda PradhanEmail author
Original Paper


The ionotropic N-methyl-d-aspartate (NMDA) receptor is of importance in neuronal development, functioning, and degeneration in the mammalian central nervous system. The functional NMDA receptor is a heterotetramer comprising two NR1 and two NR2 or NR3 subunits. We have carried out evolutionary trace (ET) analysis of forty ionotropic glutamate receptor (IGRs) sequences to identify and characterize the residues forming the binding socket. We have also modeled the ligand binding core (S1S2) of NMDA receptor subunits using the recently available crystal structure of NR1 subunit ligand binding core which shares ~40% homology with other NMDA receptor subunits. A short molecular dynamics simulation of the glycine-bound form of wild-type and double-mutated (D481N; K483Q) NR1 subunit structure shows considerable RMSD at the hinge region of S1S2 segment, where pore forming transmembrane helices are located in the native receptor. It is suggested that the disruption of domain closure could affect ion-channel activation and thereby lead to perturbations in normal animal behavior. In conclusion, we identified the amino acids that form the ligand-binding pocket in many ionotropic glutamate receptors and studied their hydrogen bonded and nonbonded interaction patterns. Finally, the disruption in the S1S2 domain conformation (of NR1 subunit- crystal structure) has been studied with a short molecular dynamics simulation and correlated with some experimental observations.

Figure The figure shows the binding mechanism of glutamate with NR2B subunit of the NMDA receptor. Glutamate is shown in cpk, hydrogen bonds in dotted lines and amino acids in blue. The amino acids shown here are within a 4-Å radius of the ligand (glutamate)


NMDA Ligand binding core S1S2 segment ET analysis Homology modeling Hydrogen bonding 



We thank Dr. Chittaranjan Andrade and Dr. Innis Axel for language correction of the manuscript.


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mathias-Costa Blaise
    • 1
  • Ramanathan Sowdhamini
    • 2
  • Metpally Raghu Prasad Rao
    • 2
  • Nithyananda Pradhan
    • 1
    Email author
  1. 1.Department of PsychopharmacologyNational Institute of Mental Health and Neuro Sciences (NIMHANS)BangaloreIndia
  2. 2.National Centre for Biological Sciences (NCBS)TIFRBangaloreIndia

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