Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor.

Journal article

We present two comparative models of the GABA(A) receptor. Model 1 is based on the 4-A resolution structure of the nicotinic acetylcholine receptor from Torpedo marmorata and represents the unliganded receptor. Two agonists, GABA and muscimol, two benzodiazepines, flunitrazepam and alprazolam, together with the general anaesthetic halothane, have been docked to this model. The ion flow is also explored in model 1 by evaluating the interaction energy of a chloride ion as it traverses the extracellular, transmembrane and intracellular domains of the protein. Model 2 differs from model 1 only in the extracellular domain and represents the liganded receptor. Comparison between the two models not only allows us to explore commonalities and differences with comparative models of the nicotinic acetylcholine receptor, but also suggests possible protein sub-domain interactions with the GABA(A) receptor not previously addressed.

Authors: Mokrab, Y; Bavro, V; Mizuguchi, K; Todorov, N; Martin, I

• Publication status: Published
• Journal: Journal of molecular graphics and modelling
• Volume: 26
• Issue: 4
• Pages: 760-774
• Publication date: 2007-11-01
• DOI: 10.1016/j.jmgm.2007.04.012
• EISSN: 1873-4243
• ISSN: 1093-3263
• Language: English
• Keywords: Muscimol; Humans; gamma-Aminobutyric Acid; Models, Molecular; Amino Acid Sequence; Computer Simulation; Sequence Homology, Amino Acid; Protein Structure, Tertiary; Ligands; Ion Channel Gating; Benzodiazepines; Molecular Sequence Data; Protein Structure, Secondary; Binding Sites; Flunitrazepam; Receptors, GABA-A