5CBS

Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (R)-2-amino-3-(3'-hydroxybiphenyl-3-yl)propanoic acid at 1.8A resolution

5CBS の概要

• エントリーDOI: 10.2210/pdb5cbs/pdb
• 分子名称: Glutamate receptor 2,Glutamate receptor 2, (R)-2-amino-3-(3'-hydroxybiphenyl-3-yl)propanoic acid, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: ampa receptor ligand-binding domain, glua2-s1s2j, antagonist, membrane protein, signaling protein
• 由来する生物種: Rattus norvegicus (Rat); 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: 120377.48

構造登録者

Frydenvang, K.,Kastrup, J.S. (登録日: 2015-07-01, 公開日: 2015-12-30, 最終更新日: 2024-10-09)

主引用文献

Szymanska, E.,Frydenvang, K.,Pickering, D.S.,Krintel, C.,Nielsen, B.,Kooshki, A.,Zachariassen, L.G.,Olsen, L.,Kastrup, J.S.,Johansen, T.N.
Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors.
J.Med.Chem., 59:448-461, 2016

PubMed Abstract: A series of racemic aryl-substituted phenylalanines was synthesized and evaluated in vitro at recombinant rat GluA1-3, at GluK1-3, and at native AMPA receptors. The individual enantiomers of two target compounds, (RS)-2-amino-3-(3,4-dichloro-5-(5-hydroxypyridin-3-yl)phenyl)propanoic acid 37 and (RS)-2-amino-3-(3'-hydroxybiphenyl-3-yl)propanoic acid 38, were characterized. (S)-37 and (R)-38 were identified as the only biologically active isomers, both being antagonists at GluA2 receptors with Kb of 1.80 and 3.90 μM, respectively. To address this difference in enantiopharmacology, not previously seen for amino acid-based AMPA receptor antagonists, X-ray crystal structures of both eutomers in complex with the GluA2 ligand binding domain were solved. The cocrystal structures of (S)-37 and (R)-38 showed similar interactions of the amino acid parts but unexpected and different orientations and interactions of the biaromatic parts of the ligands inside the binding site, with (R)-38 having a binding mode not previously identified for amino acid-based antagonists.

PubMed: 26653877
DOI: 10.1021/acs.jmedchem.5b01666

実験手法

X-RAY DIFFRACTION (1.801 Å)