Stereochemistry of Quinoxaline Antagonist Binding to a Glutamate Receptor Investigated by Fourier Transform Infrared Spectroscopy

Madden, Dean R.; Thiran, Shalita; Zimmermann, Herbert; Romm, Jonathan; Jayaraman, Vasanthi

doi:10.1074/jbc.m106171200

Cited by 21 publications

(7 citation statements)

References 11 publications

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“…Activation of the GluA2 system is associated with the ion channel opening, which in turn is related to a high degree of ligand binding domain closure by action of an agonist . On the other hand, an antagonist such as DNQX does not exhibit any considerable conformation changes in the binding domain in relation to the apo state. , From previous experimental and theoretical reports, one of the main interaction sites in the binding of DNQX to GluA2 involves the interaction of carbonyl oxygens and the Arg485 residue. , From our results, DNQXA1 species bind more strongly to the GluA2 binding pocket than DNQX, which is consistent with the fact that the Arg485 side chain must be protonated in physiological conditions. Another important finding from the MD study consists of the hydrogen bonding interaction between oxygen of the anionic DNQX nitro group and Tyr220, which could contribute as a restriction to the conformational changes required by the ion channel activation.…”

Section: Results and Discussionsupporting

confidence: 60%

“…The compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX) is well-established as a potent antagonist at the ionotropic glutamate (Glu) receptors, which are directly related to learning and memory processes. Thus, DNQX has been extensively reported in biochemical studies, including experimental and theoretical works evaluating specific interactions with its natural receptor, as well as a model for developing bioactive species. − Although structural aspects of DNQX inside the biological environment have been richly reported in literature, to the best of our knowledge, there are only two reports focusing on their primary structural aspects. Yu et al reported DNQX proving to be a chemosensor for anionic species in DMSO because of its H-donor ability .…”

Section: Introductionmentioning

confidence: 99%

“…Yu et al reported DNQX proving to be a chemosensor for anionic species in DMSO because of its H-donor ability . Kubicki and co-authors reported X-ray crystallographic data of DNQX, and Madden and co-authors reported an infrared spectroscopy-based study focused on dissociation of DNQX in aqueous medium in an attempt to improve the understating of its binding mechanism to the glutamate receptor . In fact, this latter work proved to be interesting due to some additional information about electronic configurations that are not possible to be extracted from X-ray crystallographic data alone.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding

et al. 2017

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The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pK values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pK of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by H NMR analysis. Five computational methods were applied for estimating the theoretical pK values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pK associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1' binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2.

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Section: Results and Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding

et al. 2017

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“…ATPO and DNQX have been investigated with the aim of gaining a better understanding of which factors play a role in determining AMPA receptor antagonist affinity. ATPO and DNQX are tri-ionized and neutral, respectively, in water at physiological pH, 24,25 and our analysis suggests that these forms are also present in the polar binding site. ATPO is a comparatively weak AMPA antagonist; the IC 50 of DNQX is 1 µM 5 while it is 12.2 µM for ATPO, i.e.…”

Section: Resultsmentioning

confidence: 55%

Competitive Antagonism of AMPA Receptors by Ligands of Different Classes: Crystal Structure of ATPO Bound to the GluR2 Ligand-Binding Core, in Comparison with DNQX

et al. 2002

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Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.

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“…Using vibrational and fluorescence techniques, we have been able to identify a panel of signals that distinguish between the partial agonist kainate and the full agonist glutamate. Some of these signals reflect the stereochemical environment of the ligand, whereas others reflect the overall conformation of the domain ( − ).…”

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confidence: 99%

Stereochemistry of Glutamate Receptor Agonist Efficacy: Engineering a Dual-Specificity AMPA/Kainate Receptor

et al. 2004

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Upon agonist binding, the bilobate ligand-binding domains of the ionotropic glutamate receptors (iGluR) undergo a cleft closure whose magnitude correlates broadly with the efficacy of the agonist. AMPA (alpha-amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid) and kainate are nonphysiological agonists that distinguish between subsets of iGluR. Kainate acts with low efficacy at AMPA receptors. Here we report that the structure-based mutation L651V converts the GluR4 AMPA receptor into a dual-specificity AMPA/kainate receptor fully activated by both agonists. To probe the stereochemical basis of partial agonism, we have also investigated the correlation between agonist efficacy and a series of vibrational and fluorescence spectroscopic signals of agonist binding to the corresponding wild-type and mutant GluR4 ligand-binding domains. Two signals track the extent of channel activation: the maximal change in intrinsic tryptophan fluorescence and the environment of the single non-disulfide bonded C426, which appears to probe the strength of interactions with the ligand alpha-amino group. Both of these signals arise from functional groups that are poised to detect changes in the extent of channel cleft closure and thus provide additional information about the coupling between conformational changes in the ligand-binding domain and activation of the intact receptor.

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Stereochemistry of Quinoxaline Antagonist Binding to a Glutamate Receptor Investigated by Fourier Transform Infrared Spectroscopy

Abstract: This is an Open Access article under the CC BY license.

Cited by 21 publications

References 11 publications

Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding

Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding

Competitive Antagonism of AMPA Receptors by Ligands of Different Classes: Crystal Structure of ATPO Bound to the GluR2 Ligand-Binding Core, in Comparison with DNQX

Stereochemistry of Glutamate Receptor Agonist Efficacy: Engineering a Dual-Specificity AMPA/Kainate Receptor

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