Evolutionary trace analysis of ionotropic glutamat

Authors: MathiasCosta Blaise Ramanathan Sowdhamini Metpally Raghu Prasad Rao Nithyananda Pradhan

Publish Date: 2004/10/22

Volume: 10, Issue: 5-6, Pages: 305-316

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Abstract

The ionotropic Nmethyldaspartate 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 glycinebound form of wildtype and doublemutated 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 ionchannel activation and thereby lead to perturbations in normal animal behavior In conclusion we identified the amino acids that form the ligandbinding 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 observationsFigure 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 4Å radius of the ligand glutamate

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