Voltage-gated potassium (K_V) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on K_V channels. From the nematocysts of the sea anemone Actinia bermudensis, a peptide that we named AbeTx1 was purified and functionally characterized on 12 different subtypes of K_V channels (K_V1.1⁻K_V1.6; K_V2.1; K_V3.1; K_V4.2; K_V4.3; K_V11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (Na_V1.2, Na_V1.4, and BgNa_V). AbeTx1 was selective for Shaker-related K⁺ channels and is capable of inhibiting K⁺ currents, not only by blocking the K⁺ current of K_V1.2 subtype, but by altering the energetics of activation of K_V1.1 and K_V1.6. Moreover, experiments using six synthetic alanine point-mutated analogs further showed that a ring of basic amino acids acts as a multipoint interaction for the binding of the toxin to the channel. The AbeTx1 primary sequence is composed of 17 amino acids with a high proportion of lysines and arginines, including two disulfide bridges (Cys1⁻Cys4 and Cys2⁻Cys3), and it is devoid of aromatic or aliphatic amino acids. Secondary structure analysis reveals that AbeTx1 has a highly flexible, random-coil-like conformation, but with a tendency of structuring in the beta sheet. Its overall structure is similar to open-ended cyclic peptides found on the scorpion κ-KTx toxins family, cone snail venoms, and antimicrobial peptides.

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