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

Michael C. Regan, Zongjian Zhu, Hongjie Yuan, Scott J. Myers, Dave S. Menaldino, Yesim A. Tahirovic, Dennis C. Liotta, Stephen F. Traynelis and Hiro Furukawa ()
Additional contact information
Michael C. Regan: Cold Spring Harbor Laboratory
Zongjian Zhu: Emory University School of Medicine
Hongjie Yuan: Emory University School of Medicine
Scott J. Myers: Emory University School of Medicine
Dave S. Menaldino: Emory University
Yesim A. Tahirovic: Emory University
Dennis C. Liotta: Emory University
Stephen F. Traynelis: Emory University School of Medicine
Hiro Furukawa: Cold Spring Harbor Laboratory

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-08291-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08291-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-08291-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().