Modelling of binding sites of the nicotinic acetylcholine receptor and their relation to models of the whole receptor.
Models for the acetylcholine (ACh)-binding site of the nicotinic acetylcholine receptor (nAChR) are proposed. These models have been developed by using the concept of the ligand-gated ion-channel (LGIC) superfamily of receptors that have evolved from a common ancestor. An initial component of the binding site was identified as a highly conserved 15-residue stretch of primary structure in the N-terminal extracellular region of all known LGIC subunits, based on aligned sequence data of LGICs. This subregion, termed the Cys-loop, was modelled as an amphiphilic beta-hairpin and we propose that it forms a major determinant of the binding cleft for agonists. This initial, partial binding-site model has been extended to include residues biochemically identified as spatially adjacent to the binding cleft. A recently developed technique for rapidly scanning the known protein structural database for 'non-homologous similarity' using just sequence information identified the known structure of the enzyme pyrophosphatase (PPase) as a candidate scaffold for the N-terminal domain of the nAChR. This similarity was investigated further using sequence alignments. A framework model of the full N-terminal domain in which the position of the Cys-loop and other binding-site determinants, as well as the main immunogenic region (MIR), have been mapped on to the PPase structure.
Cockcroft
V B
VB
Molecular Graphics Unit, University of Bath, U.K.
Lunt
G G
GG
Osguthorpe
D J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D011978:Receptors, Nicotinic