The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment Academic Article uri icon

abstract

  • An α-helical II—III loop segment of the dihydropyridine receptor activates the ryanodine receptor calcium-release channel. We describe a novel manipulation in which this agonist's activity is increased by modifying its surface structure to resemble that of a toxin molecule. In a unique system, native β-sheet scorpion toxins have been reported to activate skeletal muscle ryanodine receptor calcium channels with high affinity by binding to the same site as the lower-affinity α-helical dihydropyridine receptor segment. We increased the alignment of basic residues in the α-helical peptide to mimic the spatial orientation of active residues in the scorpion toxin, with a consequent 2—20-fold increase in the activity of the α-helical peptide. We hypothesized that, like the native peptide, the modified peptide and the scorpion toxin may bind to a common site. This was supported by (i) similar changes in ryanodine receptor channel gating induced by the native or modified α-helical peptide and the β-sheet toxin, a 10—100-fold reduction in channel closed time, with a ≤2-fold increase in open dwell time and (ii) a failure of the toxin to further activate channels activated by the peptides. These results suggest that diverse structural scaffolds can present similar conformational surface properties to target common receptor sites.

authors

  • GREEN, Daniel
  • PACE, Suzi
  • CURTIS, Suzanne M
  • SAKOWSKA, Magdalena
  • LAMB, Graham D
  • DULHUNTY, Angela F
  • CASAROTTO, Marco G

publication date

  • March 1, 2003