Molecular mechanism of agonist recognition by the ligand-binding core of the ionotropic glutamate receptor 4 |
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Authors: | Christina Kasper Peter Naur Darryl S. Pickering |
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Affiliation: | a Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark b Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark |
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Abstract: | The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) class of ionotropic glutamate receptors comprises four different subunits: iGluR1/iGluR2 and iGluR3/iGluR4 forming two subgroups. Three-dimensional structures have been reported only of the ligand-binding core of iGluR2. Here, we present two X-ray structures of a soluble construct of the R/G unedited flip splice variant of the ligand-binding core of iGluR4 (iGluR4i(R)-S1S2) in complex with glutamate or AMPA. Subtle, but important differences are found in the ligand-binding cavity between the two AMPA receptor subgroups at position 724 (Tyr in iGluR1/iGluR2 and Phe in iGluR3/iGluR4), which in iGluR4 may lead to displacement of a water molecule and hence points to the possibility to make subgroup specific ligands. |
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Keywords: | AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Br-HIBO, (S)-α-amino-4-bromo-3-hydroxy-5-isoxazolepropionic acid Cl-HIBO, (S)-α-amino-4-chloro-3-hydroxy-5-isoxazolepropionic acid CPW399, (S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl)propanoic acid iGluR, ionotropic glutamate receptor iGluR2i(R)-S1S2J, ligand-binding core of the R/G unedited flip splice variant of iGluR2 iGluR2o(G)-S1S2J, ligand-binding core of the R/G edited flop splice variant of iGluR2 iGluR4i(R)-S1S2, ligand-binding core of the R/G unedited flip splice variant of iGluR4 |
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