Probing the structure and function of potassium channels with α-K toxin blockers

Abstract

This review examines recent work aimed at revealing the molecular structures of the potassium channel vestibules using the α-K toxin (α-KTx) peptide blockers from the venoms of scorpions. The three subfamilies of α-K toxins are discussed in terms of their specificity for voltage-gated potassium (Kv) channels and for the large-conductance calcium-activated (maxi-K) channel. Among the α-KTx subfamilies, the three-dimensional solution structures all share a common β sheet/helix motif. However, there are differences in the toxin electrostatic structures and subtle differences in their α-carbon backbone structures that may underlie potassium channel specificity. The binding of these α-KTx's to the extracellular potassium channel pore is modulated by electrostatic interactions and by the channel gating conformation. Thus, these toxins are exceptional sensors of the electrostatic environment of the channel vestibule. Changes in toxin binding free energy, resulting from site-specific toxin mutants, have revealed a low resolution image of the α-KTx receptor surface and consequently the K channel vestibule. Interactions between specific residues on the toxin and on the channel were revealed by applying the principle of additivity of binding free energy to identify pairwise toxin:channel contacts. These interactions provide structural information about amino acids that line the Shaker potassium channel pore.

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Correspondence to Kathleen M. Giangiacomo.

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Giangiacomo, K.M., Gabriel, J., Fremont, V. et al. Probing the structure and function of potassium channels with α-K toxin blockers. Perspectives in Drug Discovery and Design 15, 167–186 (1999). https://doi.org/10.1023/A:1017020325315

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  • electrostatics
  • interaction energies
  • alpha-KTx receptor surface
  • maxi-K, shaker