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

Author

Listed:
  • Michael C. Regan

    (Cold Spring Harbor Laboratory)

  • Zongjian Zhu

    (Emory University School of Medicine
    First Affiliated Hospital of Xi’an Jiaotong University)

  • 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)

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.

Suggested Citation

  • Michael C. Regan & Zongjian Zhu & Hongjie Yuan & Scott J. Myers & Dave S. Menaldino & Yesim A. Tahirovic & Dennis C. Liotta & Stephen F. Traynelis & Hiro Furukawa, 2019. "Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08291-1
    DOI: 10.1038/s41467-019-08291-1
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    Cited by:

    1. Nami Tajima & Noriko Simorowski & Remy A. Yovanno & Michael C. Regan & Kevin Michalski & Ricardo Gómez & Albert Y. Lau & Hiro Furukawa, 2022. "Development and characterization of functional antibodies targeting NMDA receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Madeleine R. Wilcox & Aparna Nigam & Nathan G. Glasgow & Chamali Narangoda & Matthew B. Phillips & Dhilon S. Patel & Samaneh Mesbahi-Vasey & Andreea L. Turcu & Santiago Vázquez & Maria G. Kurnikova & , 2022. "Inhibition of NMDA receptors through a membrane-to-channel path," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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