4tlm

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Crystal structure of GluN1/GluN2B NMDA receptor, structure 2

Structural highlights

4tlm 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:	X-ray diffraction, Resolution 3.77Å
Ligands:	, , ,
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 (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a approximately twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

NMDA receptor structures reveal subunit arrangement and pore architecture.,Lee CH, Lu W, Michel JC, Goehring A, Du J, Song X, Gouaux E Nature. 2014 Jul 10;511(7508):191-7. doi: 10.1038/nature13548. Epub 2014 Jun 22. PMID:25008524^[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
↑ 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