Abstract
Crystal structures of the GluR2 ligand binding core (S1S2) have been determined in the apo state and in the presence of the antagonist DNQX, the partial agonist kainate, and the full agonists AMPA and glutamate. The domains of the S1S2 ligand binding core are expanded in the apo state and contract upon ligand binding with the extent of domain separation decreasing in the order of apo > DNQX > kainate > glutamate approximately equal to AMPA. These results suggest that agonist-induced domain closure gates the transmembrane channel and the extent of receptor activation depends upon the degree of domain closure. AMPA and glutamate also promote a 180 degrees flip of a trans peptide bond in the ligand binding site. The crystal packing of the ligand binding cores suggests modes for subunit-subunit contact in the intact receptor and mechanisms by which allosteric effectors modulate receptor activity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Binding Sites / genetics
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Binding Sites / physiology
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Crystallography, X-Ray
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Dimerization
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Excitatory Amino Acid Agonists / chemistry
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Excitatory Amino Acid Antagonists / chemistry
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Glutamic Acid / chemistry
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Kainic Acid / chemistry
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Ligands
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Magnetic Resonance Spectroscopy
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Models, Molecular*
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Mutagenesis, Site-Directed
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Protein Conformation*
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Protein Structure, Tertiary / genetics
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Quinoxalines / chemistry
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Receptors, AMPA / agonists
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / chemistry*
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Structure-Activity Relationship
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Zinc / chemistry
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry
Substances
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Ligands
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Quinoxalines
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Receptors, AMPA
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Glutamic Acid
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FG 9041
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Zinc
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glutamate receptor ionotropic, AMPA 2
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Kainic Acid
Associated data
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PDB/1FTJ
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PDB/1FTK
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PDB/1FTL
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PDB/1FTM
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PDB/1FTO
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PDB/1FWO