Molecular modelling of the GABAA ion channel protein

The GABA(A) ion channel protein is central to the mechanism of action of general anaesthetics and thus to the phenomenon of human consciousness. A molecular model of the alpha B-1(2)gamma(2) gamma-aminobutyric acid type-A (GABA(A)) ligand-gated ion channel protein has been constructed. The cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAM) from Torpedo marmorata and the X-ray crystal structure of the acetylcholine binding protein (AMP) from Lymnaea stagnalis were used as starting templates for comparative modelling. Features of the modelling approach used in the development of this GABA(A) model include: (1) multiple sequence alignment of members of the Cys-loop superfamily; (2) the design and implementation of a quasi-ab initio loop modelling algorithm; (3) expansion of the transmembrane domain (TMD) ion pore to model the open-state of the GABA(A) channel; (4) hydrophobicity analysis of the TMD to refine the structure in regions involved in general anaesthetic binding. The final model of the alpha(1)beta(2)gamma(2) GABA(A) protein agrees with available experimental data concerning general anaesthetics. (c) 2006 Elsevier Inc. All rights reserved.