3TZA
Crystal structure of the GluA2 ligand-binding domain (S1S2J) in complex with the antagonist (S)-2-amino-3-(2-(2-carboxyethyl)-5-chloro-4-nitrophenyl)propionic acid at 1.9A resolution
Summary for 3TZA
| Entry DOI | 10.2210/pdb3tza/pdb |
| Related | 1FTL 1N0T |
| Descriptor | Glutamate receptor 2,Glutamate receptor 2, (S)-2-amino-3-(2-(2-carboxyethyl)-5-chloro-4-nitrophenyl)propionic acid, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | ampa receptor ligand-binding domain, glua2-s1s2j, antagonist, membrane protein |
| Biological source | Rattus norvegicus (Rat) More |
| Cellular location | Cell membrane; Multi-pass membrane protein: P19491 |
| Total number of polymer chains | 2 |
| Total formula weight | 59461.00 |
| Authors | Frydenvang, K.,Kastrup, J.S. (deposition date: 2011-09-27, release date: 2011-10-26, Last modification date: 2024-11-13) |
| Primary citation | Szymanska, E.,Frydenvang, K.,Contreras-Sanz, A.,Pickering, D.S.,Frola, E.,Serafimoska, Z.,Nielsen, B.,Kastrup, J.S.,Johansen, T.N. A new phenylalanine derivative acts as an antagonist at the AMPA receptor GluA2 and introduces partial domain closure: synthesis, resolution, pharmacology, and crystal structure J.Med.Chem., 54:7289-7298, 2011 Cited by PubMed Abstract: In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o) and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8°. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands. PubMed: 21923187DOI: 10.1021/jm200862h PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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