4nf4

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Crystal structure of GluN1/GluN2A ligand-binding domain in complex with DCKA and glutamate

Structural highlights

4nf4 is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NMDZ1_RAT NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. Plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors.^[1]

Publication Abstract from PubMed

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.

Structural insights into competitive antagonism in NMDA receptors.,Jespersen A, Tajima N, Fernandez-Cuervo G, Garnier-Amblard EC, Furukawa H Neuron. 2014 Jan 22;81(2):366-78. doi: 10.1016/j.neuron.2013.11.033. PMID:24462099^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Inanobe A, Furukawa H, Gouaux E. Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron. 2005 Jul 7;47(1):71-84. PMID:15996549 doi:10.1016/j.neuron.2005.05.022
↑ Jespersen A, Tajima N, Fernandez-Cuervo G, Garnier-Amblard EC, Furukawa H. Structural insights into competitive antagonism in NMDA receptors. Neuron. 2014 Jan 22;81(2):366-78. doi: 10.1016/j.neuron.2013.11.033. PMID:24462099 doi:http://dx.doi.org/10.1016/j.neuron.2013.11.033