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

@article{Blaise2004EvolutionaryTA,
  title={Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits},
  author={Mathias-Costa Blaise and Ramanathan Sowdhamini and Metpally Raghu Prasad Rao and Nithyananda Pradhan},
  journal={Journal of Molecular Modeling},
  year={2004},
  volume={10},
  pages={305-316}
}
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… Expand
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References

SHOWING 1-10 OF 48 REFERENCES
Molecular Determinants of Agonist Discrimination by NMDA Receptor Subunits: Analysis of the Glutamate Binding Site on the NR2B Subunit
TLDR
Homology-based molecular modeling of the glutamate and glycine binding domains indicates that the NR2 and NR1 subunits use similar residues to ligate the agonists' alpha-aminocarboxylic acid groups, whereas differences in side chain interactions and size of aromatic residues determine ligand selectivity. Expand
Identification of a new site in the S1 ligand binding region of the NMDA receptor NR2A subunit involved in receptor activation by glutamate
TLDR
The results extend the knowledge base of residues involved in NMDA receptor function and identifies a new site in S1, in the region of A508, that has a role in receptor activation by glutamate. Expand
Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.
TLDR
Differences in domain mobility between the three states (apo-S1S2, glutamate-bound, and kainate-bound) are surprisingly clear-cut and this work discusses how changes in dynamics may provide an explanation relating the mechanism of transmission of the agonist-binding event to channel opening. Expand
Identification of Amino Acid Residues of the NR2A Subunit That Control Glutamate Potency in Recombinant NR1/NR2A NMDA Receptors
TLDR
It is shown that residues on the NR2A subunit control glutamate potency in recombinant NR1/NR2A receptors, without affecting glycine potency, and proposed that the glutamate binding site is located on NR2 subunits and (taking the data together with previous work) implies that each NMDA receptor subunit possesses a binding site for an agonist. Expand
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand‐binding core
TLDR
The cocrystal structures of the NR1 S1S2 ligand‐binding core with the agonists glycine and D‐serine (DS), the partial agonist D‐cycloserine (DCS) and the antagonist 5,7‐dichlorokynurenic acid (DCKA) are described. Expand
Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins
TLDR
The two discontinuous segments of approximately 150 amino acid residues each that control the agonist pharmacology of these glutamate receptors are identified and a model for the glutamate-binding site of ionotropic glutamate receptors is proposed. Expand
Molecular dissection of the agonist binding site of an AMPA receptor.
TLDR
It is reported that an extracellularly expressed fusion protein consisting of the S1 and S2 domains of alpha‐amino‐5‐methyl‐3‐hydroxyisoxazolone‐4‐propionate (AMPA)‐selective glutamate receptor GluR‐D joined together via a hydrophilic linker peptide specifically reproduces the AMPA‐binding properties of GluD, whereas the separately expressed segments do not bind ligand. Expand
Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes
TLDR
Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% ientical in sequence, and these are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor sub Units. Expand
Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits
TLDR
The cloning and characterization of the final member of the NMDAR family, NR3B, is reported, which shares high sequence homology with NR3A and is expressed predominantly in motor neurons, whereasNR3A is more widely distributed. Expand
Expression and Initial Characterization of a Soluble Glycine Binding Domain of the N-Methyl-d-aspartate Receptor NR1 Subunit*
TLDR
The formation of the S1 and S2 domains of the NR1 subunit are sufficient for the formation of a glycine binding site that displays pharmacological properties similar to those of the NMDA receptorin vivo. Expand
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5
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