RT Journal Article SR Electronic T1 Pharmacological Profiling of Orthochirus scrobiculosus Toxin 1 Analogs with a Trimmed N-Terminal Domain JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 354 OP 362 DO 10.1124/mol.105.017210 VO 69 IS 1 A1 Stéphanie Mouhat A1 Georgeta Teodorescu A1 Daniel Homerick A1 Violeta Visan A1 Heike Wulff A1 Yingliang Wu A1 Stephan Grissmer A1 Hervé Darbon A1 Michel De Waard A1 Jean-Marc Sabatier YR 2006 UL http://molpharm.aspetjournals.org/content/69/1/354.abstract AB 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 KCa3.1 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.