A common "hot spot" confers hERG blockade activity to alpha-scorpion toxins affecting K+ channels |
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Authors: | Abdel-Mottaleb Yousra Corzo Gerardo Martin-Eauclaire Marie-France Satake Honoo Céard Brigitte Peigneur Steve Nambaru Praveen Bougis Pierre-Edouard Possani Lourival D Tytgat Jan |
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Affiliation: | Laboratory of Toxicology, University of Leuven, O&N 2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium. |
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Abstract: | While alpha-KTx peptides are generally known for their modulation of the Shaker-type and the Ca(2+)-activated potassium channels, gamma-KTxs are associated with hERG channels modulation. An exception to the rule is BmTx3 which belongs to subfamily alpha-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 alpha-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 alpha-KTx. Additionally, we could extend our results to other alpha-KTx subfamily members belonging to alpha-KTx1, 4 and 6, therefore, the "hot spot" represents a common pharmacophore serving as a predictive tool for yet to be discovered alpha-KTxs. |
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Keywords: | hERG channels Scorpion toxins K+ channels α-KTx γ-KTxs |
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