View source for 5kdt


==Structure of the human GluN1/GluN2A LBD in complex with GNE0723==
<StructureSection load='5kdt' size='340' side='right'caption='[[5kdt]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5kdt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5i2j 5i2j]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KDT 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]] 2.44&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6RV:(1~{R},2~{R})-2-[7-[[5-CHLORANYL-3-(TRIFLUOROMETHYL)PYRAZOL-1-YL]METHYL]-5-OXIDANYLIDENE-2-(TRIFLUOROMETHYL)-[1,3]THIAZOLO[3,2-A]PYRIMIDIN-3-YL]CYCLOPROPANE-1-CARBONITRILE'>6RV</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</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=5kdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kdt OCA], [https://pdbe.org/5kdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kdt RCSB], [https://www.ebi.ac.uk/pdbsum/5kdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kdt ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN] Landau-Kleffner syndrome;Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation;Continuous spikes and waves during sleep;Rolandic epilepsy;Rolandic epilepsy - speech dyspraxia. The disease is caused by mutations affecting the gene represented in this entry.  A chromosomal aberration involving GRIN2A has been found in a family with epilepsy and neurodevelopmental defects. Translocation t(16;17)(p13.2;q11.2).  GRIN2A somatic mutations have been frequently found in cutaneous malignant melanoma, suggesting that the glutamate signaling pathway may play a role in the pathogenesis of melanoma.<ref>PMID:21499247</ref> <ref>PMID:24455489</ref> 
== Function ==
[https://www.uniprot.org/uniprot/NMDE1_HUMAN NMDE1_HUMAN] NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The N-methyl-d-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.

Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.,Volgraf M, Sellers BD, Jiang Y, Wu G, Ly CQ, Villemure E, Pastor RM, Yuen PW, Lu A, Luo X, Liu M, Zhang S, Sun L, Fu Y, Lupardus PJ, Wallweber HJ, Liederer BM, Deshmukh G, Plise E, Tay S, Reynen P, Herrington J, Gustafson A, Liu Y, Dirksen A, Dietz MG, Liu Y, Wang TM, Hanson JE, Hackos D, Scearce-Levie K, Schwarz JB J Med Chem. 2016 Mar 24;59(6):2760-79. doi: 10.1021/acs.jmedchem.5b02010. Epub, 2016 Mar 8. PMID:26919761<ref>PMID:26919761</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5kdt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lupardus PJ]]
[[Category: Wallweber HJA]]