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J. Biol. Chem., Vol. 275, Issue 22, 16918-16924, June 2, 2000
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Generating a High Affinity Scorpion Toxin Receptor in KcsA-Kv1.3 Chimeric Potassium Channels*

Christian LegrosDagger , Verena PollmannDagger , Hans-Günther Knaus§, Angela M. FarrellDagger , Hervé Darbon, Pierre E. Bougis||, Marie-France Martin-Eauclaire||, and Olaf PongsDagger **

From the Dagger  Institut für Neurale Signalverarbeitung, Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, D-20246 Hamburg, Germany, § Institut für Biochemische Pharmakologie, Universität of Innsbruck, Innsbruck, Tirol, 6020, Austria,  Architecture et Fonction des Macromolécules Biologiques CNRS UPR 9039, Institut de Biologie Structurale et Microbiologie, F-13402 Marseille cedex 20, France, and || Ingenierie des Protéines CNRS UMR 6560, Institut Fédératif de Recherche Jean Roche, Université de la Méditerranée, Laboratoire de Biochimie, Faculté de Médecine Secteur Nord, F-13916 Marseille cedex 20, France

The crystal structure of the bacterial K+ channel, KcsA (Doyle, D. A., Morais, C. J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., Chait, B. T., and MacKinnon, R. (1998) Science 280, 69-77), and subsequent mutagenesis have revealed a high structural conservation from bacteria to human (MacKinnon, R., Cohen, S. L., Kuo, A., Lee, A., and Chait, B. T. (1998) Science 280, 106-109). We have explored this conservation by swapping subregions of the M1-M2 linker of KcsA with those of the S5-S6 linker of the human Kv-channel Kv1.3. The chimeric K+ channel constructs were expressed in Escherichia coli, and their multimeric state was analyzed after purification. We used two scorpion toxins, kaliotoxin and hongotoxin 1, which bind specifically to Kv1.3, to analyze the pharmacological properties of the KcsA-Kv1.3 chimeras. The results demonstrate that the high affinity scorpion toxin receptor of Kv1.3 could be transferred to KcsA. Our biochemical studies with purified KcsA-Kv1.3 chimeras provide direct chemical evidence that a tetrameric channel structure is necessary for forming a functional scorpion toxin receptor. We have obtained KcsA-Kv1.3 chimeras with kaliotoxin affinities (IC50 values of ~4 pM) like native Kv1.3 channels. Furthermore, we show that a subregion of the S5-S6 linker may be an important determinant of the pharmacological profile of K+ channels. Using available structural information on KcsA and kaliotoxin, we have developed a structural model for the complex between KcsA-Kv1.3 chimeras and kaliotoxin to aid future pharmacological studies of K+ channels.

* This work was supported in part by INSERM, the Bundesministerium für Bildung und Forschung, and the Deutsche Forschungsgemeinschaft.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Institut für Neurale Signalverarbeitung, ZMNH, Universität Hamburg, Martinistr. 52, D-20246 Hamburg, Germany. Tel.: 49 0 40 42803 5081; Fax: 49 0 40 42803 5102; E-mail: pointuri@uke.uni-hamburg.de.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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