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

Regan, M. C., Zhu, Z., Yuan, H., Myers, S. J., Menaldino, D. S., Tahirovic, Y. A., Liotta, D. C., Traynelis, S. F., Furukawa, H. (January 2019) Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors. Nat Commun, 10 (1). p. 321. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing 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 > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organism description > animal > mammal bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations > mutagenesis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent Investigative techniques and equipment > x ray crystallography
CSHL Authors:	Furukawa, Hiro Regan, Michael
Communities:	CSHL labs > Furukawa lab
Depositing User:	Matthew Dunn
Date:	18 January 2019
Date Deposited:	28 Jan 2019 20:36
Last Modified:	02 Feb 2024 20:22
PMCID:	PMC6338780
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/37667

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