6UZX

Crystal structure of GLUN1/GLUN2A-4M mutant ligand-binding domain in complex with glycine and UBP791

Summary for 6UZX

• Entry DOI: 10.2210/pdb6uzx/pdb
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A, GLYCEROL, ... (6 entities in total)
• Functional Keywords: nmdar, ligand-binding domain, antagonist, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 65908.21

Authors

Wang, J.X.,Furukawa, H. (deposition date: 2019-11-15, release date: 2020-01-29, Last modification date: 2024-10-09)

Primary citation

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.
Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors.
Nat Commun, 11:423-423, 2020

PubMed 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.

PubMed: 31969570
DOI: 10.1038/s41467-020-14321-0

Experimental method

X-RAY DIFFRACTION (2.41 Å)