Binding Modes of Noncompetitive GABA-Channel Blockers Revisited Using Engineered Affinity-Labeling Reactions Combined with New Docking Studies

• Published in: Journal of agricultural and food chemistry Vol. 59; no. 7; pp. 2803 - 2807
• Main Authors: Charon, Sébastien, Taly, Antoine, Rodrigo, Jordi, Perret, Philippe, Goeldner, Maurice
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.04.2011
• Subjects: Affinity Labels; Amino Acid Sequence; Animals; Binding Sites; fipronil; GABA-A Receptor Antagonists - chemistry; GABA-A Receptor Antagonists - metabolism; gamma-aminobutyric acid; insecticides; Insecticides - chemistry; Insecticides - metabolism; insects; ion channels; mammals; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Binding; Protein Engineering; Pyrazoles - metabolism; Rats; Receptors, GABA-A - chemistry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; GABAA receptor models; fipronil binding site
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/jf102468n

The binding modes of noncompetitive GABAA-channel blockers were re-examined taking into account the recent description of the 3D structure of prokaryotic pentameric ligand-gated ion channels, which provided access to new mammalian or insect GABA receptor models, emphasizing their transmembrane portion. Two putative binding modes were deciphered for this class of compounds, including the insecticide fipronil, located nearby either the intra- or the extracellular part of the membrane, respectively. These results are in full agreement with previously described affinity-labeling reactions performed with GABAA noncompetitive blockers (Perret et al. J. Biol. Chem. 1999, 274, 25350−25354).