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J. Biol. Chem., Vol. 280, Issue 29, 27093-27102, July 22, 2005

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A Variable Residue in the Pore of Kv1 Channels Is Critical for the High Affinity of Blockers from Sea Anemones and Scorpions^*

Bernard Gilquin, Sandrine Braud, Mats A. L. Eriksson, Benoît Roux, Timothy D. Bailey¶, Birgit T. Priest¶, Maria L. Garcia¶, André Ménez, and Sylvaine Gasparini||

From the Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'Energie Atomique Saclay, 91191 Gif sur Yvette cedex, France, Weill Medical College of Cornell University, Department of Biochemistry, New York, New York 10021, and ^¶Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey 07065

Animal toxins are associated with well defined selectivity profiles; however the molecular basis for this property is not understood. To address this issue we refined our previous three-dimensional models of the complex between the sea anemone toxin BgK and the S5-S6 region of Kv1.1 (Gilquin, B., Racape, J., Wrisch, A., Visan, V., Lecoq, A., Grissmer, S., Ménez, A., and Gasparini, S. (2002) J. Biol. Chem. 277, 37406-37413) using a docking procedure that scores and ranks the structures by comparing experimental and back-calculated values of coupling free energies G_int obtained from double-mutant cycles. These models further highlight the interaction between residue 379 of Kv1.1 and the conserved dyad tyrosine residue of BgK. Because the nature of the residue at position 379 varies from one channel subtype to another, we explored how these natural mutations influence the sensitivity of Kv1 channel subtypes to BgK using binding and electrophysiology experiments. We demonstrated that mutations at this single position indeed suffice to abolish or enhance the sensitivity of Kv1 channels for BgK and other sea anemone and scorpion toxins. Altogether, our data suggest that the residue at position 379 of Kv1 channels controls the affinity of a number of blocking toxins.

Received for publication, December 3, 2004 , and in revised form, May 12, 2005.

^* 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.

^|| To whom correspondence should be addressed. Tel.: 33-1-69-08-35-88; Fax: 33-1-69-08-90-71; E-mail: sylvaine.gasparini{at}cea.fr.

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