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.
Proc Natl Acad Sci U S A
2017 Aug 15;11433:E6942-E6951. doi: 10.1073/pnas.1707752114.
Show Gene links
Show Anatomy links
Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits.
Lind GE
,
Mou TC
,
Tamborini L
,
Pomper MG
,
De Micheli C
,
Conti P
,
Pinto A
,
Hansen KB
.
???displayArticle.abstract???
NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A-D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010, Pubmed
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010,
Pubmed
ARUNLAKSHANA,
Some quantitative uses of drug antagonists.
1959,
Pubmed
Auberson,
5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.
2002,
Pubmed
Benveniste,
Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Two binding sites each for glutamate and glycine.
1991,
Pubmed
Benveniste,
Structure-activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction.
1991,
Pubmed
Benveniste,
Concentration-jump experiments with NMDA antagonists in mouse cultured hippocampal neurons.
1990,
Pubmed
Bissantz,
A medicinal chemist's guide to molecular interactions.
2010,
Pubmed
Carter,
The use of double mutants to detect structural changes in the active site of the tyrosyl-tRNA synthetase (Bacillus stearothermophilus).
1984,
Pubmed
Chen,
MolProbity: all-atom structure validation for macromolecular crystallography.
2010,
Pubmed
Chen,
Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes.
2008,
Pubmed
,
Xenbase
Cheng,
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.
1973,
Pubmed
Chovancova,
CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures.
2012,
Pubmed
Clements,
The time course of glutamate in the synaptic cleft.
1992,
Pubmed
Conti,
Novel 3-carboxy- and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: design, synthesis, and pharmacological characterization.
2010,
Pubmed
Costa,
A novel family of negative and positive allosteric modulators of NMDA receptors.
2010,
Pubmed
,
Xenbase
Costa,
N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives: preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse.
2009,
Pubmed
,
Xenbase
Emsley,
Features and development of Coot.
2010,
Pubmed
Erreger,
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles.
2005,
Pubmed
Evans,
The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.
1982,
Pubmed
Feng,
The effect of competitive antagonist chain length on NMDA receptor subunit selectivity.
2005,
Pubmed
,
Xenbase
Frizelle,
Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission.
2006,
Pubmed
,
Xenbase
Furukawa,
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core.
2003,
Pubmed
Goldschen-Ohm,
A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors.
2014,
Pubmed
Hackos,
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.
2016,
Pubmed
Hansen,
Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.
2014,
Pubmed
,
Xenbase
Hansen,
Structural determinants of agonist efficacy at the glutamate binding site of N-methyl-D-aspartate receptors.
2013,
Pubmed
,
Xenbase
Hansen,
Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors.
2011,
Pubmed
,
Xenbase
Hedegaard,
Molecular pharmacology of human NMDA receptors.
2012,
Pubmed
Horovitz,
Strategy for analysing the co-operativity of intramolecular interactions in peptides and proteins.
1990,
Pubmed
Inanobe,
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
2005,
Pubmed
,
Xenbase
Jespersen,
Structural insights into competitive antagonism in NMDA receptors.
2014,
Pubmed
,
Xenbase
Karakas,
Crystal structure of a heterotetrameric NMDA receptor ion channel.
2014,
Pubmed
Khatri,
Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator.
2014,
Pubmed
,
Xenbase
Kinarsky,
Identification of subunit- and antagonist-specific amino acid residues in the N-Methyl-D-aspartate receptor glutamate-binding pocket.
2005,
Pubmed
,
Xenbase
Kvist,
Crystal structure and pharmacological characterization of a novel N-methyl-D-aspartate (NMDA) receptor antagonist at the GluN1 glycine binding site.
2013,
Pubmed
,
Xenbase
Lee,
NMDA receptor structures reveal subunit arrangement and pore architecture.
2014,
Pubmed
,
Xenbase
Lew,
Analysis of competitive agonist-antagonist interactions by nonlinear regression.
1995,
Pubmed
Luo,
The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B).
1997,
Pubmed
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Monaghan,
Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.
2012,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed
Moreau,
Optimized N-phenyl-N'-(2-chloroethyl)ureas as potential antineoplastic agents: synthesis and growth inhibition activity.
2005,
Pubmed
Ogden,
New advances in NMDA receptor pharmacology.
2011,
Pubmed
Otwinowski,
Processing of X-ray diffraction data collected in oscillation mode.
1997,
Pubmed
Otwinowski,
[20] Processing of X-ray diffraction data collected in oscillation mode.
2018,
Pubmed
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Pfefferkorn,
Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: discovery of (3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxyheptanoic acid (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
2008,
Pubmed
Ranganathan,
Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis.
1996,
Pubmed
Rauner,
Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses.
2011,
Pubmed
Romero-Hernandez,
Novel Mode of Antagonist Binding in NMDA Receptors Revealed by the Crystal Structure of the GluN1-GluN2A Ligand-Binding Domain Complexed to NVP-AAM077.
2017,
Pubmed
,
Xenbase
Sheng,
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.
1994,
Pubmed
Sheng,
The selectivity of conantokin-G for ion channel inhibition of NR2B subunit-containing NMDA receptors is regulated by amino acid residues in the S2 region of NR2B.
2009,
Pubmed
Strong,
NMDA receptor modulators: an updated patent review (2013-2014).
2014,
Pubmed
Sun,
Allosteric Interactions between NMDA Receptor Subunits Shape the Developmental Shift in Channel Properties.
2017,
Pubmed
,
Xenbase
Tamborini,
Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain.
2016,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Volkmann,
MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit.
2016,
Pubmed
,
Xenbase
Williams,
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
1993,
Pubmed
,
Xenbase
Wyllie,
Taking the time to study competitive antagonism.
2007,
Pubmed
Yi,
Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors.
2016,
Pubmed
,
Xenbase
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
