5tpa: Difference between revisions

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New page: '''Unreleased structure''' The entry 5tpa is ON HOLD Authors: Wallweber, H.J.A., Lupardus, P.J. Description: Structure of the human GluN1/GluN2A LBD in complex with compound 9 (GNE3500...
 
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'''Unreleased structure'''


The entry 5tpa is ON HOLD
==Structure of the human GluN1/GluN2A LBD in complex with compound 9 (GNE3500)==
<StructureSection load='5tpa' size='340' side='right'caption='[[5tpa]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5tpa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TPA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TPA 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]] 2.48&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H2:(1R,2R)-2-(2-{[5-CHLORO-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL]METHYL}-7-METHYL-4-OXO-4H-PYRIDO[1,2-A]PYRIMIDIN-6-YL)CYCLOPROPANE-1-CARBONITRILE'>7H2</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=5tpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpa OCA], [https://pdbe.org/5tpa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tpa RCSB], [https://www.ebi.ac.uk/pdbsum/5tpa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpa 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 an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (13), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.


Authors: Wallweber, H.J.A., Lupardus, P.J.
GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile.,Villemure E, Volgraf M, Jiang Y, Wu G, Ly CQ, Yuen PW, Lu A, Luo X, Liu M, Zhang S, Lupardus PJ, Wallweber HJ, Liederer BM, Deshmukh G, Plise E, Tay S, Wang TM, Hanson JE, Hackos DH, Scearce-Levie K, Schwarz JB, Sellers BD ACS Med Chem Lett. 2016 Oct 31;8(1):84-89. doi: 10.1021/acsmedchemlett.6b00388., eCollection 2017 Jan 12. PMID:28105280<ref>PMID:28105280</ref>


Description: Structure of the human GluN1/GluN2A LBD in complex with compound 9 (GNE3500)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Wallweber, H.J.A]]
<div class="pdbe-citations 5tpa" style="background-color:#fffaf0;"></div>
[[Category: Lupardus, P.J]]
 
==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]]
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