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J. Biol. Chem., Vol. 278, Issue 33, 31095-31104, August 15, 2003

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A Maurotoxin with Constrained Standard Disulfide Bridging

INNOVATIVE STRATEGY OF CHEMICAL SYNTHESIS, PHARMACOLOGY, AND DOCKING ON K⁺ CHANNELS^*

From the ^aLaboratoire International Associé d'Ingénierie Biomoléculaire, CNRS Unité Mixte de Recherche 6560 Bd Pierre Dramard, 13916 Marseille Cedex 20, France, ^bInserm EMI 9931, Commissariat à l'Energie Atomique, Institut Fédératif de Recherche 27, Département de Recherche Dynamique Cellulaire, Canaux Ioniques et Signalization, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France, ^dUniversität Ulm, Albert Einstein-Allee 11, D-89081 Ulm, Germany, the ^eUniversity of Maryland School of Medicine, Baltimore, Maryland 21201-1509, the ^fLaboratoire des Venins et Toxines, Institut Pasteur de Tunis, P. O. Box 74, 1002 Belvédàre, Tunis, Tunisia, ^gArchitecture et Fonction des Macromolécules Biologiques, CNRS Unité Propre de Recherche 9039, 31 Chemin Joseph Aiguier, 13402 Marseille, France, and the ^hLaboratoire d'Immunologie, Faculté de Médecine Timone, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France

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 -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 / scaffold of scorpion toxins. Here, we developed an innovative strategy of chemical peptide synthesis to produce an MTX variant (MTX_Pi1) 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 MTX_Pi1 displays some marked changes in affinities toward the target K⁺ channels. Computed docking analyses using molecular models of both MTX_Pi1 and the various voltage-gated K⁺ channel subtypes (Shaker B, K_v1.2, and K_v1.3) were found to correlate with MTX_Pi1 pharmacology. A functional map detailing the interaction between MTX_Pi1 and Shaker B channel was generated in line with docking experiments.

Received for publication, April 23, 2003 , and in revised form, May 26, 2003.

^* This work was supported by CNRS, INSERM, the Commissariat à l'Energie Atomique, and Cellpep S.A. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^c A fellowship recipient from the French Ministry of Research and Technology.

ⁱ To whom correspondence should be addressed. Tel.: 33-4-91-69-88-52; Fax: 33-4-91-65-75-95; E-mail: sabatier.jm{at}jean-roche.univ-mrs.fr.

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