PDBsum entry 5cbs

Membrane protein

PDB id: 5cbs

Contents

Protein chains

260 a.a.

Ligands

E42 ×4

SO4 ×10

EDO ×14

GOL ×4

Metals

_CL

Waters ×1406

PDB id:

5cbs

Name:

Membrane protein

Title:

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

Structure:

Glutamate receptor 2,glutamate receptor 2. Chain: a, b, c, d. Fragment: unp residues 413-527,unp residues 653-797. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2,glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2,glutamate receptor ionotropic, ampa 2,glua2. Engineered: yes

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: origami b.

Resolution:

1.80Å R-factor: 0.170 R-free: 0.219

Authors:

K.Frydenvang,J.S.Kastrup

Key ref:

E.Szymanska et al. (2016). Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors. J Med Chem, 59, 448-461. PubMed id: 26653877 DOI: 10.1021/acs.jmedchem.5b01666

Date:

01-Jul-15 Release date: 30-Dec-15

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 260 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.5b01666

J Med Chem 59:448-461 (2016)

PubMed id: 26653877

Studies on Aryl-Substituted Phenylalanines: Synthesis, Activity, and Different Binding Modes at AMPA Receptors.

E.Szymanska, K.Frydenvang, D.S.Pickering, C.Krintel, B.Nielsen, A.Kooshki, L.G.Zachariassen, L.Olsen, J.S.Kastrup, T.N.Johansen.

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.