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Nat Commun. 2019 Jan 18;10(1):321. doi: 10.1038/s41467-019-08291-1.

Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors.

Author information

1
WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
2
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
3
Department of Neonatology, First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
4
Department of Chemistry, Emory University, Atlanta, GA, 30322, USA.
5
WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA. furukawa@cshl.edu.

Abstract

Context-dependent inhibition of N-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases.

PMID:
30659174
PMCID:
PMC6338780
DOI:
10.1038/s41467-019-08291-1
[Indexed for MEDLINE]
Free PMC Article

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