Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors

Wang, J. X., Irvine, M. W., Burnell, E. S., Sapkota, K., Thatcher, R. J., Li, M., Simorowski, N., Volianskis, A., Collingridge, G. L., Monaghan, D. T., Jane, D. E., Furukawa, H. (January 2020) Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors. Nat Commun, 11 (1). p. 423. ISSN 2041-1723 (Public Dataset)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/31969570
DOI: 10.1038/s41467-020-14321-0

Abstract

N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxyl ic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxyl ic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
Investigative techniques and equipment > electrophysiology
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Watson School
Watson School > Publications
Depositing User: Adrian Gomez
Date: 22 January 2020
Date Deposited: 24 Jan 2020 19:37
Last Modified: 05 Feb 2020 18:56
PMCID: PMC6976569
Related URLs:
Dataset ID:
  • Atomic coordinates and structure factors for the GluN1/GluN2A LBDs with glycine and homoquinolinic acid, and with glycine and UBP791 are deposited to the Protein Data Bank under the accession codes, 6UZR and 6UZW, respectively.
  • The coordinates for GluN1/GluN2A-4m LBDs with glycine and glutamate, with glycine and homoquinolinic acid, and with glycine and UBP791 are deposited under the accession codes 6UZ6, 6UZG, and 6UZX, respectively.
URI: https://repository.cshl.edu/id/eprint/38927

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