Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3 - Clues to design analogs with enhanced selectivity

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 i ncluded three common residues (Ser-23, Lys-25, and Tyr-26) and a variable s et of additional residues depending on the particular channel. Shortening t he side chain of Lys-25 by taking out the four methylene groups dramaticall y decreased the BgK affinity to all Kv1 channels tested. However, the analo g K250rn displayed increased potency an Kv1.2, which makes this peptide a s elective blocker for Kv1.2 (K-D 50- and 300-fold lower than for Kv1.1 and K v1.3, respectively). BgK analogs with enhanced selectivity could also be ma de by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found t o be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These result s provide new information about the mechanisms by which a channel blocker d istinguishes individual channels among closely related isoforms and give cl ues for designing analogs with enhanced selectivity.