Journal of Molecular Modeling

, Volume 11, Issue 6, pp 489–502

Comparative analysis of different competitive antagonists interaction with NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor

  • Mathias-Costa Blaise
  • Ramanathan Sowdhamini
  • Nithyananda Pradhan
Original Paper

DOI: 10.1007/s00894-005-0258-5

Cite this article as:
Blaise, MC., Sowdhamini, R. & Pradhan, N. J Mol Model (2005) 11: 489. doi:10.1007/s00894-005-0258-5

Abstract

The antagonist-bound conformation of the NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor are modeled using the crystal structure of the DCKA (5,7-dichloro-kynurenic acid)-bound form of the NR1 subunit ligand-binding core (S1S2). Five different competitive NMDA receptor antagonists [(1) DL-AP5; (2) DL-AP7; (3) CGP-37847; (4) CGP 39551; (5) (RS)-CPP] have been docked into both NR2A and NR2B subunits. Experimental studies report NR2A and NR2B subunits having dissimilar interactions and affinities towards the antagonists. However, the molecular mechanism of this difference remains unexplored. The distinctive features in the antagonist’s interaction with these two different but closely related (~80% sequence identity at this region) subunits are analyzed from the patterns of their hydrogen bonding. The regions directly involved in the antagonist binding have been classified into seven different interaction sites. Two conserved hydrophilic pockets located at both the S1 and S2 domains are found to be crucial for antagonist binding. The positively charged (Lys) residues present at the second interaction site and the invariant residue (Arg) located at the fourth interaction site are seen to influence ligand binding. The geometry of the binding pockets of NR2A and NR2B subunits have been determined from the distance between the C-α atoms in the residues interacting with the ligands. The binding pockets are found to be different for NR2A and NR2B. There are gross dissimilarities in competitive antagonist binding between these two subunits. The binding pocket geometry identified in this study may have the potential for future development of selective antagonists for the NR2A or NR2B subunit.

Figure The figure shows the interactions of Drug-E with the NR2A subunit of the NMDA receptor. The amino acids shown here are within 4Å radius of drug. Hydrogen bonds between the drug and receptor are marked in green dotted lines. Drugs are rendered in cpk (ball and stick) and amino acids are shown in blue color (lines).

Keywords

NMDA receptor Homology modeling Docking NR2A NR2B Competitive antagonist Binding pocket 

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Mathias-Costa Blaise
    • 1
  • Ramanathan Sowdhamini
    • 2
  • Nithyananda Pradhan
    • 1
  1. 1.Department of PsychopharmacologyNational Institute of Mental Health and Neuro Sciences (NIMHANS)BangaloreIndia
  2. 2.National Centre for Biological Sciences (NCBS), TIFRUAS-GKVK CampusBangaloreIndia

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