Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 01 2020
22 01 2020
Historique:
received:
07
10
2019
accepted:
18
12
2019
entrez:
24
1
2020
pubmed:
24
1
2020
medline:
14
4
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31969570
doi: 10.1038/s41467-020-14321-0
pii: 10.1038/s41467-020-14321-0
pmc: PMC6976569
doi:
Substances chimiques
NR2C NMDA receptor
0
NR2D NMDA receptor
0
Receptors, N-Methyl-D-Aspartate
0
Glutamic Acid
3KX376GY7L
N-methyl D-aspartate receptor subtype 2A
VH92ICR8HX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
423Subventions
Organisme : NIMH NIH HHS
ID : R01 MH085926
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS111745
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L001977/1
Pays : United Kingdom
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