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.
Neuron
2014 Jan 22;812:366-78. doi: 10.1016/j.neuron.2013.11.033.
Show Gene links
Show Anatomy links
Structural insights into competitive antagonism in NMDA receptors.
Jespersen A
,
Tajima N
,
Fernandez-Cuervo G
,
Garnier-Amblard EC
,
Furukawa H
.
???displayArticle.abstract???
There has been a great level of enthusiasm to downregulate overactive N-methyl-D-aspartate (NMDA) receptors to protect neurons from excitotoxicity. NMDA receptors play pivotal roles in basic brain development and functions as well as in neurological disorders and diseases. However, mechanistic understanding of antagonism in NMDA receptors is limited due to complete lack of antagonist-bound structures for the L-glutamate-binding GluN2 subunits. Here, we report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting antagonists. The crystal structures reveal that the antagonists, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and 1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have discrete binding modes and mechanisms for opening of the bilobed architecture of GluN2A LBD compared to the agonist-bound form. The current study shows distinct ways by which the conformations of NMDA receptor LBDs may be controlled and coupled to receptor inhibition and provides possible strategies to develop therapeutic compounds with higher subtype-specificity.
Acker,
Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
2013, Pubmed
Acker,
Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
2013,
Pubmed
Adams,
PHENIX: building new software for automated crystallographic structure determination.
2002,
Pubmed
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed
Benveniste,
Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Two binding sites each for glutamate and glycine.
1991,
Pubmed
Bettini,
Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors.
2010,
Pubmed
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
Clements,
Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor.
1991,
Pubmed
Davies,
Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord.
1982,
Pubmed
Dawe,
Defining the structural relationship between kainate-receptor deactivation and desensitization.
2013,
Pubmed
Dyson,
The role of hydrophobic interactions in initiation and propagation of protein folding.
2006,
Pubmed
Emsley,
Coot: model-building tools for molecular graphics.
2004,
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
Farina,
Separation of domain contacts is required for heterotetrameric assembly of functional NMDA receptors.
2011,
Pubmed
Feng,
Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid.
2004,
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
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Gallagher,
Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor.
1996,
Pubmed
Hansen,
Subunit-selective allosteric inhibition of glycine binding to NMDA receptors.
2012,
Pubmed
Hayward,
Improvements in the analysis of domain motions in proteins from conformational change: DynDom version 1.50.
2002,
Pubmed
Inanobe,
Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
2005,
Pubmed
,
Xenbase
Irvine,
Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors.
2012,
Pubmed
,
Xenbase
Johnson,
Glycine potentiates the NMDA response in cultured mouse brain neurons.
,
Pubmed
Karakas,
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
2011,
Pubmed
,
Xenbase
Karakas,
Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit.
2009,
Pubmed
,
Xenbase
Kazi,
Asynchronous movements prior to pore opening in NMDA receptors.
2013,
Pubmed
Mayer,
Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.
2005,
Pubmed
Mayer,
Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists.
2006,
Pubmed
,
Xenbase
Mayer,
Regulation of NMDA receptor desensitization in mouse hippocampal neurons by glycine.
1989,
Pubmed
Mayer,
Emerging models of glutamate receptor ion channel structure and function.
2011,
Pubmed
,
Xenbase
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
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
Otwinowski,
Processing of X-ray diffraction data collected in oscillation mode.
1997,
Pubmed
Paoletti,
Molecular basis of NMDA receptor functional diversity.
2011,
Pubmed
Regalado,
Intersubunit cooperativity in the NMDA receptor.
2001,
Pubmed
Riou,
An alternating GluN1-2-1-2 subunit arrangement in mature NMDA receptors.
2012,
Pubmed
,
Xenbase
Schauder,
Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain.
2013,
Pubmed
Sobolevsky,
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
2009,
Pubmed
Stern-Bach,
A point mutation in the glutamate binding site blocks desensitization of AMPA receptors.
1998,
Pubmed
Sun,
Mechanism of glutamate receptor desensitization.
2002,
Pubmed
Talukder,
Local constraints in either the GluN1 or GluN2 subunit equally impair NMDA receptor pore opening.
2011,
Pubmed
,
Xenbase
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Urwyler,
Biphenyl-derivatives of 2-amino-7-phosphono-heptanoic acid, a novel class of potent competitive N-methyl-D-aspartate receptor antagonists--II. Pharmacological characterization in vivo.
1996,
Pubmed
Vance,
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors.
2011,
Pubmed
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Wallace,
LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions.
1995,
Pubmed
Watkins,
Excitatory amino acid transmitters.
1981,
Pubmed
Weston,
Conformational restriction blocks glutamate receptor desensitization.
2006,
Pubmed
Yao,
Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors.
2008,
Pubmed
Yao,
Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics.
2013,
Pubmed
Zauhar,
Evidence for a strong sulfur-aromatic interaction derived from crystallographic data.
2000,
Pubmed
