A common “hot spot” confers hERG blockade activity to α-scorpion toxins affecting K+ channels

While α-KTx peptides are generally known for their modulation of the Shaker-type and the Ca2+-activated potassium channels, γ-KTxs are associated with hERG channels modulation. An exception to the rule is BmTx3 which belongs to subfamily α-KTx15 and can block hERG channels. To explain the peculiar behavior of BmTx3, a tentative “hot spot” formed of 2 basic residues (R18 and K19) was suggested but never further studied [Huys I, et al. BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents. Biochem J 2004;378:745–52].In this work, we investigated if the “hot spot” is a commonality in subfamily α-KTx15 by testing the effect of (AmmTx3, Aa1, discrepin). Furthermore, single mutations altering the “hot spot” in discrepin, have introduced for the very first time a hERG blocking activity to a previously non-active α-KTx.Additionally, we could extend our results to other α-KTx subfamily members belonging to α-KTx1, 4 and 6, therefore, the “hot spot” represents a common pharmacophore serving as a predictive tool for yet to be discovered α-KTxs.