A common "hot spot" confers hERG blockade activity to alpha-scorpion toxins affecting K+ channels.
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.
Abdel-Mottaleb
Yousra
Y
Laboratory of Toxicology, University of Leuven, O&N 2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium.
Corzo
Gerardo
G
Martin-Eauclaire
Marie-France
MF
Satake
Honoo
H
Céard
Brigitte
B
Peigneur
Steve
S
Nambaru
Praveen
P
Bougis
Pierre-Edouard
PE
Possani
Lourival D
LD
Tytgat
Jan
J
D000595:Amino Acid Sequence; D000818:Animals; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism*; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012605:Scorpions; D014982:Xenopus laevis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms