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| | ==Crystal structure of amino terminal domains of the NMDA receptor subunit GluN1 and GluN2B in apo closed state== | | ==Crystal structure of amino terminal domains of the NMDA receptor subunit GluN1 and GluN2B in apo closed state== |
| - | <StructureSection load='5tpz' size='340' side='right' caption='[[5tpz]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <StructureSection load='5tpz' size='340' side='right'caption='[[5tpz]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tpz]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/African_clawed_frog African clawed frog] and [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TPZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TPZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tpz]] is a 2 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=5TPZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TPZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 3.095Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">grin1, NR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=8355 African clawed frog]), Grin2b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=5tpz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpz OCA], [http://pdbe.org/5tpz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tpz RCSB], [http://www.ebi.ac.uk/pdbsum/5tpz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpz 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=5tpz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tpz OCA], [https://pdbe.org/5tpz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tpz RCSB], [https://www.ebi.ac.uk/pdbsum/5tpz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tpz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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 == |
| | + | Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors. |
| | + | |
| | + | Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain.,Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H Neuron. 2016 Dec 21;92(6):1324-1336. doi: 10.1016/j.neuron.2016.11.006. Epub 2016, Dec 1. PMID:27916457<ref>PMID:27916457</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 5tpz" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: African clawed frog]] | + | [[Category: Large Structures]] |
| - | [[Category: Buffalo rat]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Furukawa, H]] | + | [[Category: Xenopus laevis]] |
| - | [[Category: Karakas, E]] | + | [[Category: Furukawa H]] |
| - | [[Category: Romero-Hernandez, A]] | + | [[Category: Karakas E]] |
| - | [[Category: Simorwski, N]] | + | [[Category: Romero-Hernandez A]] |
| - | [[Category: Allosteric modulation]]
| + | [[Category: Simorwski N]] |
| - | [[Category: Ion channel]]
| + | |
| - | [[Category: Nmda receptor]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
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).[1] [2] [3] [4] [5] [6] [7] [PDB:5IOV]
Publication Abstract from PubMed
Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.
Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain.,Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H Neuron. 2016 Dec 21;92(6):1324-1336. doi: 10.1016/j.neuron.2016.11.006. Epub 2016, Dec 1. PMID:27916457[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schmidt C, Werner M, Hollmann M. Revisiting the postulated "unitary glutamate receptor": electrophysiological and pharmacological analysis in two heterologous expression systems fails to detect evidence for its existence. Mol Pharmacol. 2006 Jan;69(1):119-29. doi: 10.1124/mol.105.016840. Epub 2005 Oct , 7. PMID:16214956 doi:http://dx.doi.org/10.1124/mol.105.016840
- ↑ Schmidt C, Hollmann M. Molecular and functional characterization of Xenopus laevis N-methyl-d-aspartate receptors. Mol Cell Neurosci. 2009 Oct;42(2):116-27. doi: 10.1016/j.mcn.2009.06.004. Epub, 2009 Jun 12. PMID:19524674 doi:http://dx.doi.org/10.1016/j.mcn.2009.06.004
- ↑ Karakas E, Simorowski N, Furukawa H. Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature. 2011 Jun 15;475(7355):249-53. doi: 10.1038/nature10180. PMID:21677647 doi:10.1038/nature10180
- ↑ Lee CH, Lu W, Michel JC, Goehring A, Du J, Song X, Gouaux E. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature. 2014 Jul 10;511(7508):191-7. doi: 10.1038/nature13548. Epub 2014 Jun 22. PMID:25008524 doi:http://dx.doi.org/10.1038/nature13548
- ↑ Stroebel D, Buhl DL, Knafels JD, Chanda PK, Green M, Sciabola S, Mony L, Paoletti P, Pandit J. A novel binding mode reveals two distinct classes of NMDA receptor GluN2B-selective antagonists. Mol Pharmacol. 2016 Feb 24. pii: mol.115.103036. PMID:26912815 doi:http://dx.doi.org/10.1124/mol.115.103036
- ↑ Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R, Grigorieff N, Furukawa H. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature. 2016 May 2. doi: 10.1038/nature17679. PMID:27135925 doi:http://dx.doi.org/10.1038/nature17679
- ↑ Lu W, Du J, Goehring A, Gouaux E. Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. Science. 2017 Feb 23. pii: eaal3729. doi: 10.1126/science.aal3729. PMID:28232581 doi:http://dx.doi.org/10.1126/science.aal3729
- ↑ Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H. Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain. Neuron. 2016 Dec 21;92(6):1324-1336. doi: 10.1016/j.neuron.2016.11.006. Epub 2016, Dec 1. PMID:27916457 doi:http://dx.doi.org/10.1016/j.neuron.2016.11.006
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