Abstract

OSK1, a toxin from the venom of the Asian scorpion Orthochirus scrobiculosus, is a 38-residue peptide cross-linked by three disulfide bridges. A structural analog of OSK1, [Lys¹⁶,Asp²⁰]-OSK1, was found previously to be one of the most potent blockers of the voltage-gated K⁺ channel Kv1.3 hitherto characterized. Here, we demonstrate that progressive trimming of the N-terminal domain of [Lys¹⁶,Asp²⁰]-OSK1 results in marked changes in its pharmacological profile, in terms of both K⁺ channel affinity and selectivity. Whereas the affinity to Kv1.1 and Kv1.3 did not change significantly, the affinity to Kv1.2 and K_Ca3.1 was drastically reduced with the truncations. It is surprising that a striking gain in potency was observed for Kv3.2. In contrast, a truncation of the C-terminal domain, expected to partially disrupt the toxin β-sheet structure, resulted in a significant decrease or a complete loss of activity on all channel types tested. These data highlight the value of structure-function studies on the extended N-terminal domain of [Lys¹⁶,Asp²⁰]-OSK1 to identify new analogs with unique pharmacological properties.