1N0T

X-ray structure of the GluR2 ligand-binding core (S1S2J) in complex with the antagonist (S)-ATPO at 2.1 A resolution.

Summary for 1N0T

• Entry DOI: 10.2210/pdb1n0t/pdb
• Related: 1FTJ 1FTK 1FTL 1FTM 1FTO 1FWO 1GR2 1LB8 1LB9 1LBB 1LBC 1M5B 1M5C 1M5D 1M5E 1M5F 1MM6 1MM7
• Descriptor: Glutamate receptor 2, (S)-2-AMINO-3-(5-TERT-BUTYL-3-(PHOSPHONOMETHOXY)-4-ISOXAZOLYL)PROPIONIC ACID, SULFATE ION, ... (5 entities in total)
• Functional Keywords: ionotropic glutamate receptor glur2, ligand-binding core, antagonist complex, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 4
• Total formula weight: 118619.03

Authors

Hogner, A.,Greenwood, J.R.,Liljefors, T.,Lunn, M.-L.,Egebjerg, J.,Larsen, I.K.,Gouaux, E.,Kastrup, J.S. (deposition date: 2002-10-15, release date: 2003-03-04, Last modification date: 2024-10-30)

Primary citation

Hogner, A.,Greenwood, J.R.,Liljefors, T.,Lunn, M.L.,Egebjerg, J.,Larsen, I.K.,Gouaux, E.,Kastrup, J.S.
Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX.
J.Med.Chem., 46:214-221, 2003

PubMed Abstract: Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.

PubMed: 12519060
DOI: 10.1021/jm020989v

Experimental method

X-RAY DIFFRACTION (2.1 Å)