5u8c

CRYSTAL STRUCTURE OF GLUN1/GLUN2A LIGAND-BINDING DOMAIN IN COMPLEX WITH GLYCINE AND NVP-AAM077

spinqualitylabelsall models 5u8c, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5u8c 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. Method: X-ray diffraction, Resolution 1.598Å Ligands: 84J, GLY, GOL 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. Publication Abstract from PubMed Competitive antagonists against N-methyl-D-aspartate (NMDA) receptors have played critical roles throughout the history of neuropharmacology and basic neuroscience. There are currently numerous NMDA receptor antagonists containing a variety of chemical groups. Among those compounds, a GluN2-specific antagonist, (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5 -yl)-methyl]-phosphonic acid (NVP-AAM077), contains a unique combination of a dioxoquinoxalinyl ring, a bromophenyl group, and a phosphono group. Here, we present the crystal structure of the isolated ligand-binding domain (LBD) of the GluN1-GluN2A NMDA receptor in complex with the GluN1 agonist glycine and the GluN2A antagonist NVP-AAM077. The structure shows placement of the dioxoquinoxalinyl ring and the phosphono group of NVP-AAM077 in the glutamate binding pocket in GluN2A and the novel interaction between the bromophenyl group and GluN1-Glu781 at the GluN1-GluN2A subunit interface. Site-directed mutagenesis of GluN1-Glu781 reduced the potency of inhibition by NVP-AAM077, thus confirming the involvement of the GluN1 subunit for binding of NVP-AAM077. The unique antagonist binding pattern shown in this study provides a novel dimension to design and create antagonists with potential therapeutic values. Novel mode of antagonist binding in NMDA receptors revealed by the crystal structure of the GluN1-GluN2A ligand-binding domain complexed to NVP-AAM077.,Romero-Hernandez A, Furukawa H Mol Pharmacol. 2017 May 3. pii: mol.116.107912. doi: 10.1124/mol.116.107912. PMID:28468946 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutamate receptor 3D structures

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