PT  - JOURNAL ARTICLE
AU  - Stéphanie Mouhat
AU  - Georgeta Teodorescu
AU  - Daniel Homerick
AU  - Violeta Visan
AU  - Heike Wulff
AU  - Yingliang Wu
AU  - Stephan Grissmer
AU  - Hervé Darbon
AU  - Michel De Waard
AU  - Jean-Marc Sabatier
TI  - Pharmacological Profiling of <em>Orthochirus scrobiculosus</em> Toxin 1 Analogs with a Trimmed N-Terminal Domain
AID  - 10.1124/mol.105.017210
DP  - 2006 Jan 01
TA  - Molecular Pharmacology
PG  - 354--362
VI  - 69
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/69/1/354.short
4100  - http://molpharm.aspetjournals.org/content/69/1/354.full
SO  - Mol Pharmacol2006 Jan 01; 69
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.