4NF5

Crystal structure of GluN1/GluN2A ligand-binding domain in complex with glycine and D-AP5

Summary for 4NF5

• Entry DOI: 10.2210/pdb4nf5/pdb
• Related: 4NF4 4NF6 4NF8
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A, GLYCINE, ... (6 entities in total)
• Functional Keywords: receptor, glycine and d-ap5, transport protein
• Biological source: Rattus norvegicus (rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P35439 Q00959
• Total number of polymer chains: 2
• Total formula weight: 65673.81

Authors

Jespersen, A.,Tajima, N.,Furukawa, H. (deposition date: 2013-10-30, release date: 2014-03-12, Last modification date: 2024-10-30)

Primary citation

Jespersen, A.,Tajima, N.,Fernandez-Cuervo, G.,Garnier-Amblard, E.C.,Furukawa, H.
Structural Insights into Competitive Antagonism in NMDA Receptors.
Neuron, 81:366-378, 2014

PubMed 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.

PubMed: 24462099
DOI: 10.1016/j.neuron.2013.11.033

Experimental method

X-RAY DIFFRACTION (1.903 Å)