Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Chou, Tsung-Han; Tajima, Nami; Romero-Hernandez, Annabel; Furukawa, Hiro

doi:10.1016/j.cell.2020.05.052

Structural Basis of Functional Transitions in Mammalian NMDA Receptors

Journal Article · Tue Jun 30 00:00:00 EDT 2020 · Cell

DOI:https://doi.org/10.1016/j.cell.2020.05.052· OSTI ID:1834851

Chou, Tsung-Han ^[1]; Tajima, Nami ^[1]; Romero-Hernandez, Annabel ^[2]; Furukawa, Hiro ^[2]

Cold Spring Harbor Laboratory Cold Spring Harbor, NY (United States). WM Keck Structural Biology Lab.
Cold Spring Harbor Laboratory Cold Spring Harbor, NY (United States). WM Keck Structural Biology Lab. Watson School of Biological Sciences

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1834851

Journal Information:: Cell, Journal Name: Cell Journal Issue: 2 Vol. 182; ISSN 0092-8674

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
N-methyl-D-aspartate receptors
NMDAR antagonists
NMDARs
X-ray crystallography
channel activation and inhibition mechanisms
cryo-EM
electron cryo-microscopy
ligand-gated ion channels

Structural Basis of Functional Transitions in Mammalian NMDA Receptors

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