RGD Reference Report - Structural insights into competitive antagonism in NMDA receptors. - Rat Genome Database

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Structural insights into competitive antagonism in NMDA receptors.

Authors: Jespersen, Annie  Tajima, Nami  Fernandez-Cuervo, Gabriela  Garnier-Amblard, Ethel C  Furukawa, Hiro 
Citation: Jespersen A, etal., Neuron. 2014 Jan 22;81(2):366-78. doi: 10.1016/j.neuron.2013.11.033.
RGD ID: 150521652
Pubmed: PMID:24462099   (View Abstract at PubMed)
PMCID: PMC3997178   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuron.2013.11.033   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Grin1RatNMDA selective glutamate receptor complex part_ofIPI PMID:24462099ComplexPortal 
Grin2aRatNMDA selective glutamate receptor complex part_ofIPI PMID:24462099ComplexPortal 
Grin1Ratplasma membrane located_inIDA PMID:24462099ComplexPortal 
Grin2aRatplasma membrane located_inIDA PMID:24462099ComplexPortal 

Objects Annotated

Genes (Rattus norvegicus)
Grin1  (glutamate ionotropic receptor NMDA type subunit 1)
Grin2a  (glutamate ionotropic receptor NMDA type subunit 2A)


Additional Information