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Published online before print November 27, 2007, 10.1110/ps.073122908
Protein Science (2008), 17:107-118. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Chemical synthesis and 1H-NMR 3D structure determination of AgTx2-MTX chimera, a new potential blocker for Kv1.2 channel, derived from MTX and AgTx2 scorpion toxins

Cyril Pimentel1,4, Sarrah M'Barek2,4, Violetta Visan3, Stephan Grissmer3, François Sampieri2, Jean-Marc Sabatier2, Hervé Darbon1, and Ziad Fajloun2,5

1 Architecture et fonction des Macromolécules Biologiques (AFMB), Centre National de la Recherche Scientifique UMR6098, Aix-Marseille Universités, Parc Scientifique et Technologique de Luminy Case 932, 13288 Marseille Cedex 09, France
2 ERT62, IFR Jean Roche, Faculté de Médecine Nord, Cedex 15, France
3 Universität Ulm, 89081 Ulm, Germany

(RECEIVED July 23, 2007; FINAL REVISION September 27, 2007; ACCEPTED October 1, 2007)

Agitoxin 2 (AgTx2) is a 38-residue scorpion toxin, cross-linked by three disulfide bridges, which acts on voltage-gated K+ (Kv) channels. Maurotoxin (MTX) is a 34-residue scorpion toxin with an uncommon four-disulfide bridge reticulation, acting on both Ca2+-activated and Kv channels. A 39-mer chimeric peptide, named AgTx2-MTX, was designed from the sequence of the two toxins and chemically synthesized. It encompasses residues 1–5 of AgTx2, followed by the complete sequence of MTX. As established by enzyme cleavage, the new AgTx2-MTX molecule displays half-cystine pairings of the type C1–C5, C2–C6, C3–C7, and C4–C8, which is different from that of MTX. The 3D structure of AgTx2-MTX solved by 1H-NMR, revealed both {alpha}-helical and β-sheet structures, consistent with a common {alpha}/β scaffold of scorpion toxins. Pharmacological assays of AgTx2-MTX revealed that this new molecule is more potent than both original toxins in blocking rat Kv1.2 channel. Docking simulations, performed with the 3D structure of AgTx2-MTX, confirmed this result and demonstrated the participation of the N-terminal domain of AgTx2 in its increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicated that replacement of the N-terminal domain of MTX by the one of AgTx2 in the AgTx2-MTX chimera results in a reorganization of the disulfide bridge arrangement and an increase of affinity to the Kv1.2 channel.

Keywords: maurotoxin; agitoxin 2; scorpion toxin; K+ channels; synthetic peptide; NMR; solution structure; molecular docking


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