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J Biol Chem, Vol. 274, Issue 50, 35653-35661, December 10, 1999

Mapping the Functional Anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3
CLUES TO DESIGN ANALOGS WITH ENHANCED SELECTIVITY^*

Nicole Alessandri-Haber^§, Alain Lecoq^§¶, Sylvaine Gasparini^¶, Geraldine Grangier-Macmath^¶, Guy Jacquet, Alan L. Harvey, Cleane de Medeiros, Edward G. Rowan, Maurice Gola, André Ménez^¶, and Marcel Crest^**

From the  Laboratoire de Neurobiologie, CNRS UPR 9024, 31 chemin J. Aiguier, 13402 Marseille, France, the  Department of Physiology and Pharmacology, University of Strathclyde, Glasgow G1 1XW, United Kingdom, and the ^¶ Département d'Ingéniérie et d'Etudes des Protéines, CEA, Saclay, 91191 Gif-sur-Yvette cedex, France

BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K_D 50- and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.

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