5i2n

From Proteopedia

(Difference between revisions)

Current revision

Structure of the human GluN1/GluN2A LBD in complex with N-ethyl-7-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide (compound 29)

Structural highlights

5i2n 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 2.12Å
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 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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ 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. Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design. J Med Chem. 2016 Mar 24;59(6):2760-79. doi: 10.1021/acs.jmedchem.5b02010. Epub, 2016 Mar 8. PMID:26919761 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b02010

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5i2n"

Categories: Homo sapiens | Large Structures | Lupardus PJ | Wallweber HJA

@@ Line 3: / Line 3: @@
 <StructureSection load='5i2n' size='340' side='right'caption='[[5i2n]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5i2n]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I2N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5I2N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5i2n]] 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=5I2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I2N FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=67J:N-ETHYL-7-{[2-FLUORO-3-(TRIFLUOROMETHYL)PHENYL]METHYL}-2-METHYL-5-OXO-5H-[1,3]THIAZOLO[3,2-A]PYRIMIDINE-3-CARBOXAMIDE'>67J</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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]] 2.12&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5i2j|5i2j]], [[5i2k|5i2k]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=67J:N-ETHYL-7-{[2-FLUORO-3-(TRIFLUOROMETHYL)PHENYL]METHYL}-2-METHYL-5-OXO-5H-[1,3]THIAZOLO[3,2-A]PYRIMIDINE-3-CARBOXAMIDE'>67J</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRIN2A, NMDAR2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GRIN1, NMDAR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5i2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2n OCA], [https://pdbe.org/5i2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i2n RCSB], [https://www.ebi.ac.uk/pdbsum/5i2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2n ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5i2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i2n OCA], [http://pdbe.org/5i2n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i2n RCSB], [http://www.ebi.ac.uk/pdbsum/5i2n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i2n ProSAT]</span></td></tr>
 </table>
 == 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 ==
-[[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 ==
@@ Line 29: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Lupardus, P J]]
+[[Category: Lupardus PJ]]
-[[Category: Wallweber, H J.A]]
+[[Category: Wallweber HJA]]
-[[Category: Channel]]
-[[Category: Glutamate]]
-[[Category: Nmda]]
-[[Category: Receptor]]
-[[Category: Transport protein]]

5i2n

From Proteopedia

Current revision

Structure of the human GluN1/GluN2A LBD in complex with N-ethyl-7-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide (compound 29)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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