Mo. Ortells et Gg. Lunt, THE TRANSMEMBRANE REGION OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR - ISIT AN ALL-HELIX BUNDLE, Receptors & channels, 2(1), 1994, pp. 53-59
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.