Model structures of the N-methyl-d-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands

Moretti, Loris; Pentikäinen, Olli T.; Settimo, Luca; Johnson, Mark S.

doi:10.1016/j.jsb.2003.10.016

Cited by 11 publications

(8 citation statements)

References 55 publications

(59 reference statements)

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“…This imbalance reflects the greater difficulty of crystallizing antagonist-bound forms of iGluRs. Although the available agonist and antagonist structures provided a starting point for modeling additional receptor subtypes and ligand complexes (Foucaud et al, 2003;Pentikainen et al, 2003;Moretti et al, 2004), they are limited in their usefulness by the conformational flexibility of iGluR ligand binding cores, for which domain closure varies with both ligand and iGluR subtype (Mayer, 2005b), and also by the complex network of solvent molecules that plays a key role in ligand binding but that it is difficult to model without previous structural knowledge (Armstrong and Gouaux, 2000).…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Mayer¹,

Ghosal²,

Dolman³

et al. 2006

J. Neurosci.

107

131

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Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 Å extension of the ion channel linkers in the transition from antagonist-to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.

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Section: Introductionmentioning

confidence: 99%

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Mayer¹,

Ghosal²,

Dolman³

et al. 2006

J. Neurosci.

107

131

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“…1) (Yamakura and Shimoh 1999;Cull-Candy et al 2001;Moretti et al 2004). Despite their physical separation, glutamate and Glycine B binding sites functionally interact (Danysz and Parsons 1998).…”

Section: Introduction: Glutamatergic Transmission and Schizophreniamentioning

confidence: 99%

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

2005

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Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine(B) sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine(B) sites alone improves psychotic states.

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“…Numerous docking studies have been previously performed based on a single (crystal or homology) protein structure1920212223242526. Nevertheless, NMDARs are highly flexible per se as illustrated by published crystal structures, namely GluN1 in co-complexes with glycine (PDB code: 1PB7), 5,7-dichlorokynurenic acid (DCKA) (PDB code: 1PBQ), and cycloleucine (PDB code: 1Y1M)2728.…”

mentioning

confidence: 99%

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

Leong

Syu

Ding

et al. 2017

Sci Rep

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The glycine-binding site of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN1 is a potential pharmacological target for neurodegenerative disorders. A novel combinatorial ensemble docking scheme using ligand and protein conformation ensembles and customized support vector machine (SVM)-based models to select the docked pose and to predict the docking score was generated for predicting the NMDAR GluN1-ligand binding affinity. The predicted root mean square deviation (RMSD) values in pose by SVM-Pose models were found to be in good agreement with the observed values (n = 30, r2 = 0.928–0.988, = 0.894–0.954, RMSE = 0.002–0.412, s = 0.001–0.214), and the predicted pKi values by SVM-Score were found to be in good agreement with the observed values for the training samples (n = 24, r2 = 0.967, = 0.899, RMSE = 0.295, s = 0.170) and test samples (n = 13, q2 = 0.894, RMSE = 0.437, s = 0.202). When subjected to various statistical validations, the developed SVM-Pose and SVM-Score models consistently met the most stringent criteria. A mock test asserted the predictivity of this novel docking scheme. Collectively, this accurate novel combinatorial ensemble docking scheme can be used to predict the NMDAR GluN1-ligand binding affinity for facilitating drug discovery.

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Model structures of the N-methyl-d-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands

Cited by 11 publications

References 55 publications

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

Crystal Structures of the Kainate Receptor GluR5 Ligand Binding Core Dimer with Novel GluR5-Selective Antagonists

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

Prediction of N-Methyl-D-Aspartate Receptor GluN1-Ligand Binding Affinity by a Novel SVM-Pose/SVM-Score Combinatorial Ensemble Docking Scheme

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