View source for 6uzw


==Crystal structure of GLUN1/GLUN2A ligand-binding domain in complex with glycine and UBP791==
<StructureSection load='6uzw' size='340' side='right'caption='[[6uzw]], [[Resolution|resolution]] 2.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6uzw]] 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=6UZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UZW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=QM4:(2S,3R)-1-[7-(2-carboxyethyl)phenanthrene-2-carbonyl]piperazine-2,3-dicarboxylic+acid'>QM4</scene></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=6uzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uzw OCA], [https://pdbe.org/6uzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uzw RCSB], [https://www.ebi.ac.uk/pdbsum/6uzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uzw ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxyl ic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxyl ic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.

Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.,Wang JX, Irvine MW, Burnell ES, Sapkota K, Thatcher RJ, Li M, Simorowski N, Volianskis A, Collingridge GL, Monaghan DT, Jane DE, Furukawa H Nat Commun. 2020 Jan 22;11(1):423. doi: 10.1038/s41467-020-14321-0. PMID:31969570<ref>PMID:31969570</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6uzw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Furukawa H]]
[[Category: Wang JX]]