THE TRANSMEMBRANE REGION OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR - ISIT AN ALL-HELIX BUNDLE

The nicotinic acetylcholine receptor is the best characterised member of the Ligand-Gated-Ion-Channel family of receptors. In spite of a wea lth of data from molecular cloning studies these receptors have so far eluded all attempts at crystallisation; quantitative structural data are few and are at relatively low resolution. The widely accepted curr ent model for the topology of the receptors is that of a pentameric cy lindrical bundle that spans the membrane. The disposition of the trans membrane region of the individual subunits is based on hydropathy prof iles calculated from sequence data which are interpreted as indicating a common structural motif of four antiparallel alpha-helices, M1 to M 4. Until very recently this model has been unquestioned even though th ere are few direct experimental data to support it. We have constructe d models of this key functional region for the nicotinic acetylcholine receptor, building out from the ion-channel. The model of the basic i on-channel comprises a five helical M2 bundle with a left-handed twist . The remainder of the region (M1, M3, M4) was homology modelled, toge ther with M2, as a four helix antiparallel bundle per subunit, using t he crystal structure of myohaemerythrin as a template. The models stro ngly suggest that the four helix bundle model is inappropriate and tha t recent suggestions of a mixed motif of helix and sheet may better ac comodate the existing data.