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Stereochemistry of quinoxaline antagonist binding to a glutamate receptor investigated by fourier transform infrared spectroscopy

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Madden,  Dean R.
Max Planck Research Group Ion Channel Structure (Dean R. Madden), Max Planck Institute for Medical Research, Max Planck Society;

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Zimmermann,  Herbert
Department of Molecular Physics, Max Planck Institute for Medical Research, Max Planck Society;
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Madden, D. R., Thiran, S., Zimmermann, H., Romm, J., & Jayaraman, V. (2001). Stereochemistry of quinoxaline antagonist binding to a glutamate receptor investigated by fourier transform infrared spectroscopy. The Journal of Biological Chemistry, 276(41), 37821-37826. doi:10.1074/jbc.M106171200.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-F8B3-F
Abstract
The stereochemistry of the interactions between quinoxaline antagonists and the ligand-binding domain of the glutamate receptor 4 (GluR4) have been investigated by probing their vibrational modes using Fourier transform infrared spectroscopy. In solution, the electron-withdrawing nitro groups of both compounds establish a resonance equilibrium that appears to stabilize the keto form of one of the cyclic amide carbonyl bonds. Changes in the 6,7-dinitro-2,3-dihydroxyquinoxaline vibrational spectra on binding to the glutamate receptor, interpreted within the framework of a published crystal structure, illuminate the stereochemistry of the interaction and suggest that the binding site imposes a more polarized electronic bonding configuration on this antagonist. Similar spectral changes are observed for 6-cyano-7-dinitro-2,3-dihydroxyquinoxaline, confirming that its interactions with the binding site are highly similar to those of 6,7-dinitro-2,3-dihydroxyquinoxaline and leading to a model of the 6-cyano-7-dinitro-2,3-dihydroxyquinoxaline-S1S2 complex, for which no crystal structure is available. Conformational changes within the GluR ligand binding domain were also monitored. Compared with the previously reported spectral changes seen on binding of the agonist glutamate, only a relatively small change is detected on antagonist binding. This correlation between the functional effects of different classes of ligand and the magnitude of the spectroscopic changes they induce suggests that the spectral data reflect physiologically relevant conformational processes.