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- W2091293054 abstract "Ionotropic glutamate receptors couple free energy of agonist binding to opening and desensitization of a transmembrane ion channel. Central to their function is a structural unit formed by a dimer assembly of the ligand binding domains. The rates of transitions between resting, conducting, and desensitized states is controlled by conformational changes in the dimer. The serendipitous discovery that the GluR2 L483Y mutant blocks desensitization by stabilizing dimer assembly has profoundly influenced understanding of AMPA receptor gating. Paradoxically, GluR5-GluR7 subtype kainate receptors have an aromatic amino acid at the equivalent position, but desensitize rapidly and completely. Using a library of GluR6 dimer interface mutants, we used analytical ultracentrifugation to show that for kainate receptors there is a direct correlation between the rate of onset of desensitization and the stability of dimers formed by ligand binding cores, establishing that the gating mechanisms of AMPA and kainate receptors are conserved. Crystal structures for a series of 5 mutants were solved to reveal the underlying molecular mechanisms. Visualized in the crystal structures is a rich complexity of interactions across the dimer interface, illuminating how small sequence differences within the ligand binding domain function to diversify receptor properties. Our results indicate that even following extensive engineering, the stability of kainate receptor dimers is at most half of that of their AMPA counterparts, and that even if it were possible to generate dimers as stable as those for GluR2 L483Y, these would be insufficient to block kainate receptor desensitization. We show this is because the desensitized state in kainate receptors acts as a deep energy well offsetting the stabilizing effects of dimer interface mutants. Our results reveal how receptors with similar structures and gating mechanisms can exhibit strikingly different functional properties." @default.
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- W2091293054 date "2009-02-01" @default.
- W2091293054 modified "2023-09-28" @default.
- W2091293054 title "Structure And Stability Of Ligand Binding Core Dimer Assembly Controls Desensitization In A Kainate Receptor" @default.
- W2091293054 doi "https://doi.org/10.1016/j.bpj.2008.12.2537" @default.
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