Molecular characterization of the specificity of interactions of various neurotoxins on two distinct nicotinic acetylcholine receptors

Eur J Pharmacol. 2000 Mar 30;393(1-3):197-204. doi: 10.1016/s0014-2999(00)00095-9.

Abstract

Snake curaremimetic toxins are currently classified as short-chain and long-chain toxins according to their size and their number of disulfide bonds. All these toxins bind with high affinity to muscular-type nicotinic acetylcholine receptor, whereas only long toxins recognize the alpha7 receptor with high affinity. On the basis of binding experiments with Torpedo or neuronal alpha7 receptors using wild-type and mutated neurotoxins, we characterized the molecular determinants involved in these different recognition processes. The functional sites by which long and short toxins interact with the muscular-type receptor include a common core of highly conserved residues and residues that are specific to each of toxin families. Furthermore, the functional sites through which alpha-cobratoxin, a long-chain toxin, interacts with muscular and alpha7 receptors share similarities but also marked differences. Our results reveal that the three-finger fold toxins have evolved toward various specificities by displaying distinct functional sites.

MeSH terms

  • Animals
  • Binding, Competitive
  • Cells, Cultured
  • Cobra Neurotoxin Proteins / genetics
  • Cobra Neurotoxin Proteins / pharmacology*
  • Drug Interactions
  • Humans
  • Models, Molecular
  • Mutation
  • Neurotoxins / genetics
  • Neurotoxins / pharmacology*
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Torpedo
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Chrna7 protein, human
  • Cobra Neurotoxin Proteins
  • Neurotoxins
  • Receptors, Nicotinic
  • Recombinant Proteins
  • alpha7 Nicotinic Acetylcholine Receptor
  • alpha-cobratoxin