Molecular mechanism of ligand gating and opening of NMDA receptor

Chou, Tsung-Han, Epstein, Max, Fritzemeier, Russell G, Akins, Nicholas S, Paladugu, Srinu, Ullman, Elijah Z, Liotta, Dennis C, Traynelis, Stephen F, Furukawa, Hiro (August 2024) Molecular mechanism of ligand gating and opening of NMDA receptor. Nature, 632 (8023). pp. 209-217. ISSN 0028-0836 (Public Dataset)

PDF 10.1038.s41586-024-07742-0.pdf - Published Version Download (16MB)

Abstract

Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands-glutamate and glycine-for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1-GluN2B (GluN1-2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1-2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1-2B dimer arrangements but insufficient tension in the LBD-TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > small molecules > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organism description > animal > mammal bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > small molecules
CSHL Authors:	Epstein, Max Furukawa, Hiro Chou, Tsung-Han
Communities:	CSHL labs > Furukawa lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 August 2024
Date Deposited:	06 Aug 2024 14:34
Last Modified:	06 Aug 2024 14:34
Related URLs:	Publisher
Dataset ID:	EMDB: EMD-43779 EMDB: EMD-44586 EMDB: EMD-43780 EMDB: EMD-43781 EMDB: EMD-43782 EMDB: EMD-43783 PDB: 9ARE PDB: 9BIB PDB: 9ARF PDB: 9ARG PDB: 9ARH PDB: 9ARI PDB: 6WI1 PDB: 4U5C PDB: 5WEO PDB: 7RZA
URI:	https://repository.cshl.edu/id/eprint/41629

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