Structural Basis of Functional Transitions in Mammalian NMDA Receptors.

Chou, Tsung-Han, Tajima, Nami, Romero-Hernandez, Annabel, Furukawa, Hiro (July 2020) Structural Basis of Functional Transitions in Mammalian NMDA Receptors. Cell, 182 (2). 357-371.e13. ISSN 0092-8674

DOI: 10.1016/j.cell.2020.05.052


Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.

Item Type: Paper
Subjects: Investigative techniques and equipment > microscopy > Cryo-electron microscopy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Furukawa lab
School of Biological Sciences > Publications
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 23 July 2020
Date Deposited: 06 May 2021 13:40
Last Modified: 03 Jun 2022 14:03
PMCID: PMC8278726
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