6IRH

Structure of the human GluN1/GluN2A NMDA receptor in the glutamate/glycine-bound state at pH 6.3, Class III

Summary for 6IRH

• Entry DOI: 10.2210/pdb6irh/pdb
• Related: 6IRA 6IRF 6IRG
• EMDB information: 9714 9715 9716 9717
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A (2 entities in total)
• Functional Keywords: ionotropic glutamate receptors, nmda receptors, synaptic protein, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 379056.78

Authors

Zhang, J.,Chang, S.,Zhang, X.,Zhu, S. (deposition date: 2018-11-12, release date: 2019-01-16, Last modification date: 2019-06-05)

Primary citation

Zhang, J.B.,Chang, S.,Xu, P.,Miao, M.,Wu, H.,Zhang, Y.,Zhang, T.,Wang, H.,Zhang, J.,Xie, C.,Song, N.,Luo, C.,Zhang, X.,Zhu, S.
Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors
Cell Rep, 25:3582-3590.e4, 2018

PubMed Abstract: N-methyl-D-aspartate (NMDA) receptors are critical for synaptic development and plasticity. While glutamate is the primary agonist, protons can modulate NMDA receptor activity at synapses during vesicle exocytosis by mechanisms that are unknown. We used cryo-electron microscopy to solve the structures of the human GluN1-GluN2A NMDA receptor at pH 7.8 and pH 6.3. Our structures demonstrate that the proton sensor predominantly resides in the N-terminal domain (NTD) of the GluN2A subunit and reveal the allosteric coupling mechanism between the proton sensor and the channel gate. Under high-pH conditions, the GluN2A-NTD adopts an "open-and-twisted" conformation. However, upon protonation at the lower pH, the GluN2A-NTD transits from an open- to closed-cleft conformation, causing rearrangements between the tetrameric NTDs and agonist-binding domains. The conformational mobility observed in our structures (presumably from protonation) is supported by molecular dynamics simulation. Our findings reveal the structural mechanisms by which protons allosterically inhibit human GluN1-GluN2A receptor activity.

PubMed: 30590034
DOI: 10.1016/j.celrep.2018.11.071

Experimental method

ELECTRON MICROSCOPY (7.8 Å)