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5u8c

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

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:	, ,
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

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^[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
↑ Romero-Hernandez A, Furukawa H. Novel mode of antagonist binding in NMDA receptors revealed by the crystal structure of the GluN1-GluN2A ligand-binding domain complexed to NVP-AAM077. Mol Pharmacol. 2017 May 3. pii: mol.116.107912. doi: 10.1124/mol.116.107912. PMID:28468946 doi:http://dx.doi.org/10.1124/mol.116.107912

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5u8c"

Categories: Large Structures | Rattus norvegicus | Furukawa H | Romero-Hernandez A

@@ Line 3: / Line 3: @@
 <StructureSection load='5u8c' size='340' side='right'caption='[[5u8c]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5u8c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U8C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5u8c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U8C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=84J:[(R)-{[(1S)-1-(4-BROMOPHENYL)ETHYL]AMINO}(2,3-DIHYDROXYQUINOXALIN-5-YL)METHYL]PHOSPHONIC+ACID'>84J</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.598&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Grin1, Nmdar1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=84J:[(R)-{[(1S)-1-(4-BROMOPHENYL)ETHYL]AMINO}(2,3-DIHYDROXYQUINOXALIN-5-YL)METHYL]PHOSPHONIC+ACID'>84J</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5u8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u8c OCA], [http://pdbe.org/5u8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u8c RCSB], [http://www.ebi.ac.uk/pdbsum/5u8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u8c ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5u8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u8c OCA], [https://pdbe.org/5u8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u8c RCSB], [https://www.ebi.ac.uk/pdbsum/5u8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u8c ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/NMDZ1_RAT 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.<ref>PMID:15996549</ref>
+[https://www.uniprot.org/uniprot/NMDZ1_RAT 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.<ref>PMID:15996549</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Buffalo rat]]
 [[Category: Large Structures]]
-[[Category: Furukawa, H]]
+[[Category: Rattus norvegicus]]
-[[Category: Romero-Hernandez, A]]
+[[Category: Furukawa H]]
-[[Category: Glycine and nvp-aam077]]
+[[Category: Romero-Hernandez A]]
-[[Category: Receptor]]
-[[Category: Transport protein]]

5u8c

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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