4NF8: Crystal Structure of Glun1/glun2a Ligand-binding Domain in Complex With Glycine and Glutamate in Peg2000mme

Citation:
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.
PDB ID: 4NF8Download
MMDB ID: 118282
PDB Deposition Date: 2013/10/30
Updated in MMDB: 2017/08
Experimental Method:
x-ray diffraction
Resolution: 1.86  Å
Source Organism:
Similar Structures:
Biological Unit for 4NF8: dimeric; determined by author and by software (PISA)
Molecular Components in 4NF8
Label Count Molecule
Proteins (2 molecules)
1
Glutamate Receptor Ionotropic, Nmda 1(Gene symbol: Grin1)
Molecule annotation
1
Glutamate Receptor Ionotropic, Nmda 2A(Gene symbol: Grin2a)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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