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
Abstract
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: | bioinformatics Investigative techniques and equipment > microscopy > Cryo-electron microscopy bioinformatics > genomics and proteomics Investigative techniques and equipment bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > small molecules > cofactors bioinformatics > genomics and proteomics > small molecules > cofactors > ligands Investigative techniques and equipment > microscopy bioinformatics > genomics and proteomics > small molecules 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: | 29 Jan 2024 20:48 |
| PMCID: | PMC8278726 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/39997 |
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