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

This review examines recent work aimed at revealing the molecular structures of the potassium channel vestibules using the alpha-K toxin (alpha-KTx) peptide blockers from the venoms of scorpions. The three subfamilies of alpha-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 alpha-KTx subfamilies, the three-dimensional solution structures all share a common beta sheet/helix motif. However, there are differences in the toxin electrostatic structures and subtle differences in their alpha-carbon backbone structures that may underlie potassium channel specificity. The binding of these alpha-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 alpha-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.