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

Summary for 5CBS

• Entry DOI: 10.2210/pdb5cbs/pdb
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, (R)-2-amino-3-(3'-hydroxybiphenyl-3-yl)propanoic acid, SULFATE ION, ... (7 entities in total)
• Functional Keywords: ampa receptor ligand-binding domain, glua2-s1s2j, antagonist, membrane protein, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P19491
• Total number of polymer chains: 4
• Total formula weight: 120377.48

Authors

Frydenvang, K.,Kastrup, J.S. (deposition date: 2015-07-01, release date: 2015-12-30, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.801 Å)