<br>含 GluN2C/2D 的 NMDA 受体亚型选择性竞争性拮抗的结构基础。,Nature Communications

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含 GluN2C/2D 的 NMDA 受体亚型选择性竞争性拮抗的结构基础。
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-22 , DOI: 10.1038/s41467-020-14321-0
Jue Xiang Wang _{1,

2} , Mark W Irvine ₃ , Erica S Burnell _{3,

4} , Kiran Sapkota ₅ , Robert J Thatcher ₃ , Minjun Li ₁ , Noriko Simorowski ₁ , Arturas Volianskis ₆ , Graham L Collingridge _{3,

7,

8} , Daniel T Monaghan ₅ , David E Jane ₃ , Hiro Furukawa _{1,

2}

Affiliation

N-甲基-D-天冬氨酸受体 (NMDAR) 在中枢神经系统中发挥着关键作用。它们的异四聚体组成产生了具有不同功能特性和大脑时空分布的亚型，提高了通过药理学手段针对亚型特异性靶向治疗神经系统疾病的可能性。虽然针对含有 GluN2A 和 GluN2B 的 NMDAR 的特定化合物已经很成熟，但那些针对 GluN2C 和 GluN2D 的化合物目前尚未开发出来，且结合模式低效且未表征。在这里，利用电生理学和 X 射线晶体学，我们表明 UBP791 ((2S*,3R*)-1-(7-(2-carboxy乙基)phenanthrene-2-carbonyl)piperazine-2,3-diacid) 抑制 GluN2C /2D 的选择性比含 GluN2A 的受体高 40 倍，并且配体结合口袋中的蛋氨酸和赖氨酸残基（GluN2D-Met763/Lys766、GluN2C-Met736/Lys739）是亚型特异性结合的关键分子元件。这些发现导致 UBP1700 ((2S*,3R*)-1-(7-(2-羧乙烯基)菲-2-羰基)哌嗪-2,3-二甲酸) 的开发，其显示出超过 50 倍的 GluN2C/2D - 选择性优于 GluN2A，效力在低纳摩尔范围内。我们的研究表明，L-谷氨酸结合位点可以针对 GluN2C/2D 特异性抑制。

"点击查看英文标题和摘要"

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

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.

更新日期：2020-01-23

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