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7yfl

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Structure of GluN1a-GluN2D NMDA receptor in complex with agonists glycine and glutamate.

Structural highlights

7yfl is a 4 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:	Electron Microscopy, Resolution 3.9Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NMDE4_HUMAN Non-specific early-onset epileptic encephalopathy. The disease is caused by variants affecting the gene represented in this entry.

Function

NMDE4_HUMAN 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:9489750, PubMed:27616483, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:9489750).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits. Here we report full-length cryo-EM structures of the human N1-N2D di-heterotetramer (di-receptor), rat N1-N2C di-receptor and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a best resolution of 3.0 A. The bilobate N-terminal domain (NTD) in N2D intrinsically adopts a closed conformation, leading to a compact NTD tetramer in the N1-N2D receptor. Additionally, crosslinking the ligand-binding domain (LBD) of two N1 protomers significantly elevated the channel open probability (Po) in N1-N2D di-receptors. Surprisingly, the N1-N2C di-receptor adopted both symmetric (minor) and asymmetric (major) conformations, the latter further locked by an allosteric potentiator, PYD-106, binding to a pocket between the NTD and LBD in only one N2C protomer. Finally, the N2A and N2C subunits in the N1-N2A-N2C tri-receptor display a conformation close to one protomer in the N1-N2A and N1-N2C di-receptors, respectively. These findings provide a comprehensive structural understanding of diverse function in major NMDA receptor subtypes.

Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits.,Zhang J, Zhang M, Wang Q, Wen H, Liu Z, Wang F, Wang Y, Yao F, Song N, Kou Z, Li Y, Guo F, Zhu S Nat Struct Mol Biol. 2023 Mar 23. doi: 10.1038/s41594-023-00959-z. PMID:36959261^[6]

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

References

↑ Hackos DH, Lupardus PJ, Grand T, Chen Y, Wang TM, Reynen P, Gustafson A, Wallweber HJ, Volgraf M, Sellers BD, Schwarz JB, Paoletti P, Sheng M, Zhou Q, Hanson JE. Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function. Neuron. 2016 Mar 2;89(5):983-99. doi: 10.1016/j.neuron.2016.01.016. Epub 2016 Feb, 11. PMID:26875626 doi:http://dx.doi.org/10.1016/j.neuron.2016.01.016
↑ Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, Kosobucki GJ, Chen W, Schulien AJ, Chiavacci R, Tankovic A, Naase C, Brueckner F, von Stülpnagel-Steinbeis C, Hu C, Kusumoto H, Hedrich UB, Elsen G, Hörtnagel K, Aizenman E, Lemke JR, Hakonarson H, Traynelis SF, Falk MJ. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet. 2016 Oct 6;99(4):802-816. PMID:27616483 doi:10.1016/j.ajhg.2016.07.013
↑ Ogden KK, Chen W, Swanger SA, McDaniel MJ, Fan LZ, Hu C, Tankovic A, Kusumoto H, Kosobucki GJ, Schulien AJ, Su Z, Pecha J, Bhattacharya S, Petrovski S, Cohen AE, Aizenman E, Traynelis SF, Yuan H. Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. PLoS Genet. 2017 Jan 17;13(1):e1006536. PMID:28095420 doi:10.1371/journal.pgen.1006536
↑ Chen W, Tankovic A, Burger PB, Kusumoto H, Traynelis SF, Yuan H. Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy. Mol Pharmacol. 2017 Apr;91(4):317-330. PMID:28126851 doi:10.1124/mol.116.106781
↑ Hess SD, Daggett LP, Deal C, Lu CC, Johnson EC, Veliçelebi G. Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors. J Neurochem. 1998 Mar;70(3):1269-79. PMID:9489750 doi:10.1046/j.1471-4159.1998.70031269.x
↑ Zhang J, Zhang M, Wang Q, Wen H, Liu Z, Wang F, Wang Y, Yao F, Song N, Kou Z, Li Y, Guo F, Zhu S. Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits. Nat Struct Mol Biol. 2023 Mar 23. PMID:36959261 doi:10.1038/s41594-023-00959-z