Structural insights into binding of therapeutic channel blockers in NMDA receptors

Chou, Tsung-Han, Epstein, Max, Michalski, Kevin, Fine, Eve, Biggin, Philip C, Furukawa, Hiro (May 2022) Structural insights into binding of therapeutic channel blockers in NMDA receptors. Nature Structural and Molecular Biology. ISSN 1545-9993

DOI: 10.1038/s41594-022-00772-0


Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
structural biology
CSHL Authors:
Communities: CSHL labs > Furukawa lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 30 May 2022
Date Deposited: 02 Jun 2022 17:19
Last Modified: 02 Jun 2022 17:19

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