Abstract
Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the alpha-KTx6 structural family. These 34-residue toxins, cross-linked by four disulfide bridges, share 59% sequence identity and fold along the classical alpha/beta scaffold. Despite these structural similarities, they fully differ in their pharmacological profiles. MTX is highly active on small (SK) and intermediate (IK) conductance Ca(2+)-activated (K(+)) channels and on voltage-gated Kv1.2 channel, whereas HsTx1 potently blocks voltage-gated Kv1.1 and Kv1.3 channels only. Here, we designed and chemically produced MTX-HsTx1, a chimera of both toxins that contains the N-terminal helical region of MTX (sequence 1-16) and the C-terminal beta-sheet region of HsTx1 (sequence 17-34). The three-dimensional structure of the peptide in solution was solved by (1)H NMR. MTX-HsTx1 displays the activity of MTX on SK channel, whereas it exhibits the pharmacological profile of HsTx1 on Kv1.1, Kv1.2, Kv1.3, and IK channels. These data demonstrate that the helical region of MTX exerts a key role in SK channel recognition, whereas the beta-sheet region of HsTx1 is crucial for activity on all other channel types tested.
Highlights
Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the ␣-KTx6 structural family
MTX-HsTx1 underwent proper oxidative folding resulting in a toxin-like compound that still exhibits the classical ␣/ scaffold of scorpion toxins
This approach has never generated a compound with such clear distinct selectivity
Summary
Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the ␣-KTx6 structural family. These data demonstrate that the helical region of MTX exerts a key role in SK channel recognition, whereas the -sheet region of HsTx1 is crucial for activity on all other channel types tested. The choice of MTX and HsTx1 appears ideal to produce a chimera toxin because both peptides belong to the same structural family, are of similar length, possess four disulfide bridges, and share the same global fold but display divergent channel targets.
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