5ipr: Difference between revisions

Revision as of 17:05, 30 August 2023

Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3

5ipr, resolution 14.10Å

Structural highlights

5ipr is a 4 chain structure with sequence from Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 14.1Å
Experimental data:	Check
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.

Mechanism of NMDA Receptor Inhibition and Activation.,Zhu S, Stein RA, Yoshioka C, Lee CH, Goehring A, Mchaourab HS, Gouaux E Cell. 2016 Apr 21;165(3):704-14. doi: 10.1016/j.cell.2016.03.028. Epub 2016 Apr, 7. PMID:27062927^[8]

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

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
↑ Zhu S, Stein RA, Yoshioka C, Lee CH, Goehring A, Mchaourab HS, Gouaux E. Mechanism of NMDA Receptor Inhibition and Activation. Cell. 2016 Apr 21;165(3):704-14. doi: 10.1016/j.cell.2016.03.028. Epub 2016 Apr, 7. PMID:27062927 doi:http://dx.doi.org/10.1016/j.cell.2016.03.028

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] Zhu S, Stein RA, Yoshioka C, Lee CH, Goehring A, Mchaourab HS, Gouaux E. Mechanism of NMDA Receptor Inhibition and Activation. Cell. 2016 Apr 21;165(3):704-14. doi: 10.1016/j.cell.2016.03.028. Epub 2016 Apr, 7. PMID:27062927 doi:http://dx.doi.org/10.1016/j.cell.2016.03.028

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@@ Line 3: / Line 3: @@
 <SX load='5ipr' size='340' side='right' viewer='molstar' caption='[[5ipr]], [[Resolution|resolution]] 14.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ipr]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/African_clawed_frog African clawed frog]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IPR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5IPR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ipr]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IPR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IPR FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5iou|5iou]], [[5iov|5iov]], [[5ipq|5ipq]], [[5ips|5ips]], [[5ipt|5ipt]], [[5ipu|5ipu]], [[5ipv|5ipv]]</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 14.1&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR2B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=8355 African clawed frog])</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=5ipr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ipr OCA], [https://pdbe.org/5ipr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ipr RCSB], [https://www.ebi.ac.uk/pdbsum/5ipr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ipr 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=5ipr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ipr OCA], [http://pdbe.org/5ipr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ipr RCSB], [http://www.ebi.ac.uk/pdbsum/5ipr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ipr ProSAT]</span></td></tr>
 </table>
+== Function ==
+[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 ==
@@ Line 24: / Line 25: @@
 __TOC__
 </SX>
-[[Category: African clawed frog]]
 [[Category: Large Structures]]
-[[Category: Goehring, A]]
+[[Category: Xenopus laevis]]
-[[Category: Gouaux, E]]
+[[Category: Goehring A]]
-[[Category: Lee, C H]]
+[[Category: Gouaux E]]
-[[Category: Mchaourab, S H]]
+[[Category: Lee CH]]
-[[Category: Stein, A R]]
+[[Category: Mchaourab SH]]
-[[Category: Yoshioka, C]]
+[[Category: Stein AR]]
-[[Category: Zhu, S]]
+[[Category: Yoshioka C]]
-[[Category: Ligand-gated ion channel]]
+[[Category: Zhu S]]
-[[Category: Signaling protein]]
-[[Category: Synaptic transmission]]

5ipr: Difference between revisions

Revision as of 17:05, 30 August 2023

Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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5ipr: Difference between revisions

Revision as of 17:05, 30 August 2023

Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3Cryo-EM structure of GluN1/GluN2B NMDA receptor in the DCKA/D-APV-bound conformation, state 3

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

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