title: Determinants of alpha-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit.
abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) are pentamers composed of alpha and beta subunits. Different molecular compositions of these subunits constitute various receptor subtypes that are implicated in the pathophysiology and/or treatment of several disease states but are difficult to distinguish pharmacologically. Alpha-conotoxins are a group of small, structurally defined peptides that may be used to molecularly dissect the nAChR-binding site. Heteromeric nAChRs generally contain either a beta2 or beta4 subunit in addition to an alpha subunit at the ligand-binding interface. Alpha-conotoxin BuIA kinetically distinguishes between beta2- and beta4-containing nAChRs, with long off times for the latter. Mutational studies were used to assess the influence of residues that line the putative acetylcholine-binding pocket but differ between beta2 and beta4 subunits. Residues Thr/Lys59, Val/Ile111, and Phe/Gln119 of the respective beta2 and beta4 subunits are critical to off-rate differences. Among these residues, Thr59 of nAChR beta2 may interfere with effective access to the binding site, whereas Lys59 may facilitate this binding.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City 84112-0840, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Shiembob
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Charles W
authors.initials: CW
authors.lastname: Luetje
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D020916:Conotoxins; D021122:Protein Subunits; D011978:Receptors, Nicotinic