Determinants of alpha-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit

Biochemistry. 2006 Sep 19;45(37):11200-7. doi: 10.1021/bi0611715.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Conotoxins / chemistry*
  • Conotoxins / metabolism*
  • Kinetics
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Subunits
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism*
  • Substrate Specificity


  • Conotoxins
  • Protein Subunits
  • Receptors, Nicotinic