6UZW

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

6UZW の概要

• エントリーDOI: 10.2210/pdb6uzw/pdb
• 分子名称: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A, GLYCINE, ... (5 entities in total)
• 機能のキーワード: nmdar, ligand-binding domain, antagonist, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65563.76

構造登録者

Wang, J.X.,Furukawa, H. (登録日: 2019-11-15, 公開日: 2020-01-29, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.13 Å)