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| | ==Structure of the human GluN1/GluN2A LBD in complex with compound 2 (GNE9178)== | | ==Structure of the human GluN1/GluN2A LBD in complex with compound 2 (GNE9178)== |
| - | <StructureSection load='5tp9' size='340' side='right' caption='[[5tp9]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='5tp9' size='340' side='right'caption='[[5tp9]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tp9]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TP9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TP9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tp9]] 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=5TP9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TP9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7H0:7-{[5-CHLORO-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL]METHYL}-N-ETHYL-2-METHYL-5-OXO-5H-[1,3]THIAZOLO[3,2-A]PYRIMIDINE-3-CARBOXAMIDE'>7H0</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tpa|5tpa]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H0:7-{[5-CHLORO-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL]METHYL}-N-ETHYL-2-METHYL-5-OXO-5H-[1,3]THIAZOLO[3,2-A]PYRIMIDINE-3-CARBOXAMIDE'>7H0</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5tp9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tp9 OCA], [http://pdbe.org/5tp9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tp9 RCSB], [http://www.ebi.ac.uk/pdbsum/5tp9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tp9 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=5tp9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tp9 OCA], [https://pdbe.org/5tp9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tp9 RCSB], [https://www.ebi.ac.uk/pdbsum/5tp9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tp9 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://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> [[http://www.uniprot.org/uniprot/NMDZ1_HUMAN NMDZ1_HUMAN]] Defects in GRIN1 are the cause of mental retardation autosomal dominant type 8 (MRD8) [MIM:[http://omim.org/entry/614254 614254]]. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21376300</ref> | + | [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 == | | == Function == |
| - | [[http://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. [[http://www.uniprot.org/uniprot/NMDZ1_HUMAN NMDZ1_HUMAN]] NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein 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 (By similarity). | + | [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. |
| | + | |
| | + | 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> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5tp9" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lupardus, P J]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Wallweber, H J.A]] | + | [[Category: Large Structures]] |
| - | [[Category: Calcium channel]] | + | [[Category: Lupardus PJ]] |
| - | [[Category: Glutamate]] | + | [[Category: Wallweber HJA]] |
| - | [[Category: Glycine]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Nmda receptor]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
5tp9 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.4Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
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.[1] [2]
Function
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.
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.
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15. PMID:21499247 doi:http://dx.doi.org/10.1038/ng.810
- ↑ D'mello SA, Flanagan JU, Green TN, Leung EY, Askarian-Amiri ME, Joseph WR, McCrystal MR, Isaacs RJ, Shaw JH, Furneaux CE, During MJ, Finlay GJ, Baguley BC, Kalev-Zylinska ML. Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival. Front Oncol. 2014 Jan 13;3:333. doi: 10.3389/fonc.2013.00333. eCollection 2014, Jan 13. PMID:24455489 doi:http://dx.doi.org/10.3389/fonc.2013.00333
- ↑ 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. GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile. ACS Med Chem Lett. 2016 Oct 31;8(1):84-89. doi: 10.1021/acsmedchemlett.6b00388., eCollection 2017 Jan 12. PMID:28105280 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00388
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