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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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 |
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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: |
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URI: | https://repository.cshl.edu/id/eprint/38927 |
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