Structural consequences of D481N/K483Q mutation at glycine binding site of NMDA ionotropic glutamate receptors: a molecular dynamics study.
N-Methyl-D-Aspartate (NMDA) receptors are the ligand gated as well as voltage sensitive ionotropic glutamate receptors, widely distributed in the vertebrate central nervous system and they play critical role in the pathogenesis of schizophrenia. Molecular dynamics simulations have been carried out on high resolution crystal structure of NR1 subunit of NMDA receptor ligand binding core (S1S2) in four different conformations. We have investigated consequence of D481N/K483Q double mutation of NR1 subunit from simulation results of (a) glycine bound form (WG), (b) unbound (closed-apo) form (WOG), (c) a double mutated form (DM), and (d) the antagonist (5,7-dichlorokynuric acid) bound form (DCKA). The MD simulations and simulated annealing for 4ns show a distinct conformation for the double mutated conformation that neither follows the antagonist nor apo conformation. There are two distinct sites, loop1 and loop2 where the double mutated structure in its glycine bound form shows significant RMSD deviations as compared to the wild-type. The interactions of glycine with the receptor remain theoretically unchanged in the double mutated structure and there is no detachment of S1S2 domains. The results suggest that separation of S1 and S2 domains may not be essential for channel inactivation. Therefore, it is hypothesized that hypoactivation of NMDA receptor channels may arise out of the conformational changes at non-conserved Loop1 and Loop2 regions observed in the mutated structure. The Loop1 and Loop2 regions responsible for inter-subunit interactions in a functional NMDA receptor, may therefore, render the ligand bound form defunct. This may account for behavioral anomalies due to receptor inactivation seen in grin1 mutated mice.
Blaise
Mathias-Costa
MC
Department of Psychopharmacology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore-560029, India.
Bhattacharyya
Dananjay
D
Sowdhamini
Ramanathan
R
Pradhan
Nityananda
N
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D007736:Kynurenic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014867:Water / Q000737:chemistry
D016194:Receptors, N-Methyl-D-Aspartate; D014867:Water; D016202:N-Methylaspartate; D007736:Kynurenic Acid; D005998:Glycine