7SAB

Phencyclidine-bound GluN1a-GluN2B NMDA receptors

Summary for 7SAB

• Entry DOI: 10.2210/pdb7sab/pdb
• Related: 7SAA 7SAC 7SAD
• EMDB information: 24946 24947 24948 24949
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ligand-gated ion channel, ionotropic glutamate receptor, synaptic protein, voltage-gated ion channel, transport protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 4
• Total formula weight: 391091.51

Authors

Chou, T.-H.,Furukawa, H. (deposition date: 2021-09-22, release date: 2022-07-20, Last modification date: 2025-06-04)

Primary citation

Chou, T.H.,Epstein, M.,Michalski, K.,Fine, E.,Biggin, P.C.,Furukawa, H.
Structural insights into binding of therapeutic channel blockers in NMDA receptors.
Nat.Struct.Mol.Biol., 29:507-518, 2022

PubMed Abstract: 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.

PubMed: 35637422
DOI: 10.1038/s41594-022-00772-0

Experimental method

ELECTRON MICROSCOPY (4.3 Å)