Structural Features of the Glutamate Binding Site in Recombinant NR1/NR2A N-Methyl-d-aspartate Receptors Determined by Site-Directed Mutagenesis and Molecular Modeling

@article{Chen2005StructuralFO,
  title={Structural Features of the Glutamate Binding Site in Recombinant NR1/NR2A N-Methyl-d-aspartate Receptors Determined by Site-Directed Mutagenesis and Molecular Modeling},
  author={Philip E. Chen and Matthew T. Geballe and Phillip J. Stansfeld and Alexander R. Johnston and Hongjie Yuan and Amanda L. Jacob and James P. Snyder and Stephen F. Traynelis and David J. A. Wyllie},
  journal={Molecular Pharmacology},
  year={2005},
  volume={67},
  pages={1470 - 1484}
}
We have used site-directed mutagenesis of amino acids located within the S1 and S2 ligand binding domains of the NR2A N-methyl-d-aspartate (NMDA) receptor subunit to explore the nature of ligand binding. Wild-type or mutated NR1/NR2A NMDA receptors were expressed in Xenopus laevis oocytes and studied using two electrode voltage clamp. We investigated the effects of mutations in the S1 and S2 regions on the potencies of the agonists l-glutamate, l-aspartate, (R,S)-tetrazol-5yl-glycine, and NMDA… Expand
Tweaking Agonist Efficacy at N-Methyl-d-aspartate Receptors by Site-Directed Mutagenesis
TLDR
The data indicate that agonist efficacy at the NR2B subunit can be controlled by the extent of steric clashes between the agonist and the ligand binding domains and by ligand-dependent arrangements of residues within the binding pocket. Expand
The Integrity of the Glycine Co-agonist Binding Site of N-Methyl-d-aspartate Receptors Is a Functional Quality Control Checkpoint for Cell Surface Delivery*
TLDR
Findings demonstrate that integrity of the glycine co-agonist binding site is a functional checkpoint requisite for efficient cell surface trafficking of assembled NMDA receptors. Expand
Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of N-Methyl-d-Aspartate Receptors
TLDR
Variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits are proposed. Expand
The NR1 M3 Domain Mediates Allosteric Coupling in the N-Methyl-D-aspartate Receptor
TLDR
The data demonstrate that theNR1 M3 segment is functionally coupled to key structural domains in both the NR1 and NR2 subunits, and suggests that perturbation of M3 can stabilize the ligand binding domain in a closed cleft conformation, even in the absence of agonist. Expand
The NR 1 M 3 Domain Mediates Allosteric Coupling in the N-Methyl-D-aspartate Receptor
N-Methyl-D-aspartate (NMDA) receptors play a critical role in both development of the central nervous system and adult neuroplasticity. However, although the NMDA receptor presents a valuableExpand
Single-channel properties of N-methyl-D-aspartate receptors containing chimaeric GluN2A/GluN2D subunits.
TLDR
The results show that the identity of the GluN2 LBD not only controls glutamate potency, but also influences the potency of the NMDAR co-agonist glycine, whereas the single-channel conductance and the duration of single activations of ion channels can be predicted by the identities of the M1-M3 regions and the LBD. Expand
Single‐channel analysis of a point mutation of a conserved serine residue in the S2 ligand‐binding domain of the NR2A NMDA receptor subunit
TLDR
The authors' single‐channel data, together with modelling using a kinetic scheme to describe channel activations, support the hypothesis that the S670G point mutation reduces the dwell time of glutamate in its binding site. Expand
Constitutive Activation of the N-Methyl-d-aspartate Receptor via Cleft-spanning Disulfide Bonds*
TLDR
Dual cysteine point mutations spanning the NR1 and NR2 ligand-binding clefts are designed, providing compelling evidence for the Venus flytrap mechanism of glutamate receptor domain closure. Expand
Subunit-Specific Agonist Activity at NR2A-, NR2B-, NR2C-, and NR2D-Containing N-Methyl-d-aspartate Glutamate Receptors
TLDR
Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists. Expand
Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes
TLDR
It is concluded that the variation in glycine potency is caused by interactions between the NR1 and NR2 ligand‐binding domains that occur following agonist binding and which may be involved in the initial conformation changes that determine channel gating. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 44 REFERENCES
Molecular determinants of ligand discrimination in the glutamate-binding pocket of the NMDA receptor
TLDR
Specific side chain interactions that determine ligand efficacy and pharmacology at the glutamate site of the NMDA receptor are described. Expand
Mutational analysis of the glycine-binding site of the NMDA receptor: Structural similarity with bacterial amino acid-binding proteins
TLDR
A common amino acid-binding fold appears to be conserved from prokaryotic periplasmic proteins to glutamate receptors in the mammalian brain, as shown in the NMDA subtype of ionotropic glutamate receptors. Expand
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 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
Activation of N-methyl-D-aspartate receptors by glycine: role of an aspartate residue in the M3-M4 loop of the NR1 subunit.
Glutamate and glycine are coagonists that act at distinct sites to activate N-methyl-D-aspartate (NMDA) receptors. In the NR1 subunit of the NMDA receptor, mutation of D732 to glutamate (D732E),Expand
Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core.
TLDR
An excellent correlation between domain closure and efficacy has been obtained from electrophysiology experiments undertaken on non-desensitising GluR2i(Q)-L483Y receptors expressed in oocytes, providing strong evidence that receptor activation occurs as a result of domain closure. Expand
Influence of a threonine residue in the S2 ligand binding domain in determining agonist potency and deactivation rate of recombinant NR1a/NR2D NMDA receptors
TLDR
The results suggest that this conserved threonine residue plays a crucial role in ligand binding to NMDA NR2 receptor subunits and supports the idea that the slow decay kinetics associated with NR1a/NR2D NMDA receptors can be explained by the slow dissociation of glutamate from this NMDA receptor subtype. Expand
Cysteine Mutagenesis and Homology Modeling of the Ligand-binding Site of a Kainate-binding Protein*
TLDR
The results are consistent with the proposal that the energy driving kainate binding is contributed both from residues within the binding site and from interactions between two regions of the protein that are brought into contact upon ligand binding in a manner analogous to that seen in bacterial amino acid-binding proteins. 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
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
...
1
2
3
4
5
...