Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2017 Feb 14;932:141-156. doi: 10.1124/mol.117.110940.
Show Gene links
Show Anatomy links
The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor.
Kaiser TM
,
Kell SA
,
Kusumoto H
,
Shaulsky G
,
Bhattacharya S
,
Epplin MP
,
Strong KL
,
Miller EJ
,
Cox BD
,
Menaldino DS
,
Liotta DC
,
Traynelis SF
,
Burger PB
.
???displayArticle.abstract???
N-methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors.
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011, Pubmed
Acker,
Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators.
2011,
Pubmed
Akazawa,
Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats.
1994,
Pubmed
Bettini,
Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors.
2010,
Pubmed
Burger,
A novel inhibitor of Plasmodium falciparum spermidine synthase: a twist in the tail.
2015,
Pubmed
Carvill,
GRIN2A mutations cause epilepsy-aphasia spectrum disorders.
2013,
Pubmed
Chen,
GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.
2017,
Pubmed
Choi,
Excitotoxic cell death.
1992,
Pubmed
Clark,
Prediction of Protein-Ligand Binding Poses via a Combination of Induced Fit Docking and Metadynamics Simulations.
2016,
Pubmed
Collingridge,
The NMDA receptor as a target for cognitive enhancement.
2013,
Pubmed
Costa,
N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild traumatic brain injury in mice.
2010,
Pubmed
Coyle,
NMDA receptor and schizophrenia: a brief history.
2012,
Pubmed
Danelius,
Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins.
2016,
Pubmed
da Silva,
LMProt: an efficient algorithm for Monte Carlo sampling of protein conformational space.
2004,
Pubmed
Dravid,
Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors.
2010,
Pubmed
,
Xenbase
Edgar,
MUSCLE: multiple sequence alignment with high accuracy and high throughput.
2004,
Pubmed
Friesner,
Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.
2004,
Pubmed
Friesner,
Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.
2006,
Pubmed
Gielen,
Mechanism of differential control of NMDA receptor activity by NR2 subunits.
2009,
Pubmed
Hackos,
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
2016,
Pubmed
Hackos,
Diverse modes of NMDA receptor positive allosteric modulation: Mechanisms and consequences.
2017,
Pubmed
Halgren,
Identifying and characterizing binding sites and assessing druggability.
2009,
Pubmed
Hansen,
Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.
2014,
Pubmed
,
Xenbase
Hansen,
Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase
Hansen,
Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors.
2011,
Pubmed
,
Xenbase
Hansen,
Subunit-selective allosteric inhibition of glycine binding to NMDA receptors.
2012,
Pubmed
Harder,
OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.
2016,
Pubmed
Hawkins,
Conformer generation with OMEGA: learning from the data set and the analysis of failures.
2012,
Pubmed
Hawkins,
Comparison of shape-matching and docking as virtual screening tools.
2007,
Pubmed
Hillisch,
Utility of homology models in the drug discovery process.
2004,
Pubmed
Hu,
Human GRIN2B variants in neurodevelopmental disorders.
2016,
Pubmed
Irwin,
ZINC--a free database of commercially available compounds for virtual screening.
2005,
Pubmed
Jackson,
NMDA antagonists make learning and recall state-dependent.
1992,
Pubmed
Kalas,
Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions.
2017,
Pubmed
Karakas,
Crystal structure of a heterotetrameric NMDA receptor ion channel.
2014,
Pubmed
Karakas,
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
2011,
Pubmed
,
Xenbase
Karavanova,
Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-beta-galactosidase knock-in mice.
2007,
Pubmed
Khatri,
Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.
2014,
Pubmed
,
Xenbase
Lakhan,
NMDA Receptor Activity in Neuropsychiatric Disorders.
2013,
Pubmed
Laskowski,
PDBsum new things.
2009,
Pubmed
Lee,
NMDA receptor structures reveal subunit arrangement and pore architecture.
2014,
Pubmed
,
Xenbase
Lemke,
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
2013,
Pubmed
,
Xenbase
Lesca,
GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.
2013,
Pubmed
Maolanon,
Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites.
2017,
Pubmed
,
Xenbase
McCloskey,
New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine.
2009,
Pubmed
Menniti,
CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents.
2000,
Pubmed
Mosley,
Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase
Mullasseril,
A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
2010,
Pubmed
Nicola,
Connecting proteins with drug-like compounds: Open source drug discovery workflows with BindingDB and KNIME.
2015,
Pubmed
Ogden,
Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.
2014,
Pubmed
,
Xenbase
Ogden,
New advances in NMDA receptor pharmacology.
2011,
Pubmed
Preskorn,
An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder.
2008,
Pubmed
Sali,
Derivation of rules for comparative protein modeling from a database of protein structure alignments.
1994,
Pubmed
Santangelo Freel,
Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors.
2013,
Pubmed
,
Xenbase
Seeliger,
Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
2010,
Pubmed
Shan,
How does a drug molecule find its target binding site?
2011,
Pubmed
Sheinin,
Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine.
2001,
Pubmed
,
Xenbase
Shelley,
Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.
2007,
Pubmed
Söderhjelm,
Locating binding poses in protein-ligand systems using reconnaissance metadynamics.
2012,
Pubmed
Stern,
Single-channel conductances of NMDA receptors expressed from cloned cDNAs: comparison with native receptors.
1992,
Pubmed
,
Xenbase
Stroebel,
Controlling NMDA receptor subunit composition using ectopic retention signals.
2014,
Pubmed
,
Xenbase
Strong,
NMDA receptor modulators: an updated patent review (2013-2014).
2014,
Pubmed
Strong,
The Structure-Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl-d-Aspartate Receptor Modulators that Potentiates GluN2B-Containing N-Methyl-d-Aspartate Receptors.
2017,
Pubmed
Sun,
Allosteric Interactions between NMDA Receptor Subunits Shape the Developmental Shift in Channel Properties.
2017,
Pubmed
,
Xenbase
Swanger,
A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons.
2018,
Pubmed
,
Xenbase
Tajima,
Activation of NMDA receptors and the mechanism of inhibition by ifenprodil.
2016,
Pubmed
Thepchatri,
Conformations of laulimalide in DMSO-d6.
2005,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Vance,
GluN1 splice variant control of GluN1/GluN2D NMDA receptors.
2012,
Pubmed
,
Xenbase
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Williams,
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
1993,
Pubmed
,
Xenbase
Wyllie,
Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors.
1998,
Pubmed
,
Xenbase
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
Yuan,
Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy.
2014,
Pubmed
Zerangue,
Analysis of endoplasmic reticulum trafficking signals by combinatorial screening in mammalian cells.
2001,
Pubmed
Zhu,
Mechanism of NMDA Receptor Inhibition and Activation.
2016,
Pubmed
,
Xenbase
Zimmerman,
Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.
2014,
Pubmed
,
Xenbase
