4ISU

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (2R)-IKM-159 at 2.3A resolution.

4ISU の概要

• エントリーDOI: 10.2210/pdb4isu/pdb
• 分子名称: Glutamate receptor 2, (4aS,5aR,6R,8aS,8bS)-5a-(carboxymethyl)-8-oxo-2,4a,5a,6,7,8,8a,8b-octahydro-1H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6-carboxylic acid, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: ampa receptor ligand-binding domain, glur2-s1s2j, antagonist, membrane protein, membrane protein-antagonist complex, membrane protein/antagonist
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: P19491
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118311.23

構造登録者

Juknaite, L.,Frydenvang, K.,Kastrup, J.S. (登録日: 2013-01-17, 公開日: 2013-03-20, 最終更新日: 2024-10-30)

主引用文献

Juknaite, L.,Sugamata, Y.,Tokiwa, K.,Ishikawa, Y.,Takamizawa, S.,Eng, A.,Sakai, R.,Pickering, D.S.,Frydenvang, K.,Swanson, G.T.,Kastrup, J.S.,Oikawa, M.
Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.
J.Med.Chem., 56:2283-2293, 2013

PubMed Abstract: IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.

PubMed: 23432124
DOI: 10.1021/jm301590z

実験手法

X-RAY DIFFRACTION (2.3 Å)