Referenced in: none

Automatically associated channels: Kv1.2 , Kv1.3

Title: A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels.

Authors: Sarrah M'Barek, Ignacio López-González, Nicolas Andreotti, Eric di Luccio, Violeta Visan, Stephan Grissmer, Susan Judge, Mohamed El Ayeb, Herve Darbon, Hervé Rochat, François Sampieri, Evelyne Beraud, Ziad Fajloun, Michel De Waard, Jean-Marc Sabatier

Journal, date & volume: J. Biol. Chem., 2003 Aug 15 , 278, 31095-104

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12783861

Abstract
Maurotoxin (MTX) is a 34-residue toxin that has been isolated initially from the venom of the scorpion Scorpio maurus palmatus. It presents a large number of pharmacological targets, including small conductance Ca2+-activated and voltage-gated K+ channels. Contrary to other toxins of the alpha-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic alpha/beta scaffold of scorpion toxins. Here, we developed an innovative strategy of chemical peptide synthesis to produce an MTX variant (MTXPi1) with a conventional pattern of disulfide bridging without any alteration of the toxin chemical structure. This strategy was used solely to address the impact of half-cystine pairings on MTX structural properties and pharmacology. The data indicate that MTXPi1 displays some marked changes in affinities toward the target K+ channels. Computed docking analyses using molecular models of both MTXPi1 and the various voltage-gated K+ channel subtypes (Shaker B, Kv1.2, and Kv1.3) were found to correlate with MTXPi1 pharmacology. A functional map detailing the interaction between MTXPi1 and Shaker B channel was generated in line with docking experiments.