Structural Insights into Competitive Antagonism in NMDA Receptors

Jespersen, A., Tajima, N., Fernandez-Cuervo, G., Garnier-Amblard, E. C., Furukawa, H. (2014) Structural Insights into Competitive Antagonism in NMDA Receptors. Neuron, 81 (2). pp. 366-78. ISSN 0896-6273

URL: http://www.ncbi.nlm.nih.gov/pubmed/24462099
DOI: 10.1016/j.neuron.2013.11.033

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Stanley Institute for Cognitive Genomics
Depositing User: Matt Covey
Date Deposited: 04 Feb 2014 15:10
Last Modified: 08 Sep 2017 15:11
PMCID: PMC3997178
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/29471

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