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

Regan, Michael C.; Zhu, Zongjian; Yuan, Hongjie; Myers, Scott J.; Menaldino, Dave S.; Tahirovic, Yesim A.; Liotta, Dennis C.; Traynelis, Stephen F.; Furukawa, Hiro

doi:10.1038/s41467-019-08291-1

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

Journal Article · 17 January 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-08291-1 · OSTI ID:1497175

Regan, Michael C. ^[1]; Zhu, Zongjian ^[2]; Yuan, Hongjie ^[3]; Myers, Scott J. ^[3]; Menaldino, Dave S. ^[4]; Tahirovic, Yesim A. ^[4]; Liotta, Dennis C. ^[4]; Traynelis, Stephen F. ^[3]; Furukawa, Hiro ^[1]

Cold Spring Harbor Lab., NY (United States)
Emory Univ. School of Medicine, Atlanta, GA (United States); First Affiliated Hospital of Xi’an Jiaotong Univ., Xi’an, Shaanxi (China)
Emory Univ. School of Medicine, Atlanta, GA (United States)
Emory Univ., Atlanta, GA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1497175

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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