3qel: Difference between revisions

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<StructureSection load='3qel' size='340' side='right'caption='[[3qel]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
<StructureSection load='3qel' size='340' side='right'caption='[[3qel]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3qel]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/African_clawed_frog African clawed frog] and [https://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QEL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QEL FirstGlance]. <br>
<table><tr><td colspan='2'>[[3qel]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QEL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QEL FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QEL:4-[(1R,2S)-2-(4-BENZYLPIPERIDIN-1-YL)-1-HYDROXYPROPYL]PHENOL'>QEL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</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]] 2.6&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3jpw|3jpw]], [[3qek|3qek]], [[3qem|3qem]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=QEL:4-[(1R,2S)-2-(4-BENZYLPIPERIDIN-1-YL)-1-HYDROXYPROPYL]PHENOL'>QEL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">grin1, NR1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=8355 African clawed frog]), Grin2b ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=3qel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qel OCA], [https://pdbe.org/3qel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qel RCSB], [https://www.ebi.ac.uk/pdbsum/3qel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qel 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=3qel FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qel OCA], [https://pdbe.org/3qel PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qel RCSB], [https://www.ebi.ac.uk/pdbsum/3qel PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qel ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/NMDE2_RAT NMDE2_RAT]] NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. In concert with DAPK1 at extrasynaptic sites, acts as a central mediator for stroke damage. Its phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity inducing injurious Ca2+ influx through them, resulting in an irreversible neuronal death (By similarity).
[https://www.uniprot.org/uniprot/NMDZ1_XENLA NMDZ1_XENLA] Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:16214956, PubMed:19524674, PubMed:21677647, PubMed:25008524, PubMed:26912815, PubMed:27135925, Ref.11, PubMed:28232581). Sensitivity to glutamate and channel kinetics depend on the subunit composition (Probable).<ref>PMID:16214956</ref> <ref>PMID:19524674</ref> <ref>PMID:21677647</ref> <ref>PMID:25008524</ref> <ref>PMID:26912815</ref> <ref>PMID:27135925</ref> <ref>PMID:28232581</ref> [PDB:5IOV]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlying the recognition of phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.
 
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.,Karakas E, Simorowski N, Furukawa H Nature. 2011 Jun 15;475(7355):249-53. doi: 10.1038/nature10180. PMID:21677647<ref>PMID:21677647</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3qel" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: African clawed frog]]
[[Category: Buffalo rat]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Furukawa, H]]
[[Category: Rattus norvegicus]]
[[Category: Karakas, E]]
[[Category: Xenopus laevis]]
[[Category: Simorowski, N]]
[[Category: Furukawa H]]
[[Category: Allosteric modulation]]
[[Category: Karakas E]]
[[Category: Extracellular]]
[[Category: Simorowski N]]
[[Category: Ion channel]]
[[Category: N-glycosylation]]
[[Category: Nmda receptor]]
[[Category: Phenylethanolamine]]
[[Category: Transmembrane]]
[[Category: Transport protein]]

Revision as of 11:43, 14 March 2024

Crystal structure of amino terminal domains of the NMDA receptor subunit GluN1 and GluN2B in complex with ifenprodil

3qel, resolution 2.60Å

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