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Author Notes:

Correspondence and requests for materials should be addressed to H.F. (email: furukawa@cshl.edu)

M.C.R., D.C.L., D.S.M., S.J.M., H.Y., Z.Z., Y.A.T., S.F.T. and H.F. designed experiments.

M.C.R. expressed, purified, and crystallized proteins, collected and processed X-ray diffraction data, and performed and processed ITC experiments.

Y.A.T., D.S.M. and D.C.L. synthesized and purified compounds.

H.Y., Z.Z., S.J.M. and S.F.T. performed TEVC experiments and analyzed electrophysiology data.

All authors wrote the manuscript.

We would like to thank the staff at the National Synchrotron Light Source II, Beam Line 17-ID-1 at Brookhaven National Laboratory, and the Advanced Photon Source, Beam Line 23-ID-B at Argonne National Laboratory for assistance in X-ray crystallographic data collection.

We would also like to thank Noriko Simorowski, Sukhan Kim, Jing Zhang, and Phuong Le for excellent technical assistance.

Darryl Pappin is thanked for insightful discussions on structure-based mechanisms.

We thank Janssen Research and Development, LLC, for providing pKa analysis for 93-31.

S.F.T. is a co-founder of NeurOp Inc., a member of the scientific advisory board of Sage Therapeutics, a paid consultant for Janssen, and the Principal Investigator on a research grant from Janssen to Emory. S.F.T receives royalties for software licensing.

D.C.L. is a member of the Board of Directors for NeurOp Inc.

S.F.T., D.C.L., Y.A.T., and D.S.M. are co-inventors on Emory-owned intellectual property.

H.Y. is PI on a research grant from Sage Therapeutics to Emory University School of Medicine.

The remaining authors declare no competing interests.

Subjects:

Research Funding:

This work was supported by grants from the National Institutes of Health to M.C.R. (NS093753), H.Y. (HD082373), S.F.T. (NS036654 and NS065371), and H.F. (MH085926 and GM105730), Robertson funds at Cold Spring Harbor Laboratory, Austin’s purpose, and Stanley Institute of cognitive genomics (all to H.F.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • SUBUNIT ARRANGEMENT
  • CRYSTAL-STRUCTURE
  • SCHIZOPHRENIA
  • ANTAGONIST
  • MECHANISM
  • MODE

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

Journal Title:

Nature Communications

Volume:

Volume 10, Number 1

Publisher:

, Pages 321-321

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2019, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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