Structural and functional consequences of the presence of a fourth disulfide bridge in the scorpion short toxins: Solution structure of the potassium channel inhibitor HsTX1

• DOI: 10.1110/ps.8.12.2672
• Publication Date: 2009-02-17T21:50:34Z
• Authors: Philippe Savarin; Régine Romi‐Lebrun; Sophie Zinn‐Justin; Bernard Gilquin; André Ménez; Bruno Lebrun; Terumi Nakajima
• Keywords: Potassium channel blocker; Bridge (graph theory); Scorpion toxin

Abstract We have determined the three‐dimensional structure of potassium channel inhibitor HsTX1, using nuclear magnetic resonance and molecular modeling. This protein belongs to scorpion short toxin family, which essentially contains blockers 29 39 amino acids three disulfide bridges. It is highly active on voltage‐gated Kv1.3 channels. Furthermore, it has particularity possess a fourth bridge. show that HsTX1 fold similar three‐disulfide‐bridged toxins conserves hydrophobic core found in toxins. Thus, bridge no influence global conformation HsTX1. Most residues spatially analogous those interacting with channels are conserved we propose Tyr21, Lys23, Met25, Asn26 involved biological activity As an additional positively charged residue always close aromatic blocking channels, as previous mutagenesis experiments shown critical role played by C‐terminus suggest Arg33 also important for four disulfide‐bridged toxin. Docking calculations confirm that, if Lys23 Met25 interact GYGDMH motif Kv1.3, can contact Asp386 and, thus, play functional site. original configuration binding site confirmed experimentally, offers new structural possibilities construction molecule