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

Wang, Jue Xiang, Irvine, Mark W., Burnell, Erica S., Sapkota, Kiran, Thatcher, Robert J., Li, Minjun, Simorowski, Noriko, Volianskis, Arturas, Collingridge, Graham L., Monaghan, Daniel T., Jane, David E. and Furukawa, Hiro 2020. Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors. Nature Communications 11 , 423. 10.1038/s41467-020-14321-0

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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-dicarboxylic 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-dicarboxylic 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:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	13 January 2022
Date of Acceptance:	18 December 2019
Last Modified:	02 May 2023 22:33
URI:	https://orca.cardiff.ac.uk/id/eprint/146661

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