basic proteins that possess a net positive charge when present in neutral pH. Most of the positively charged amino acid residues of dendrotoxins are located in the lower part of the structure, creating a cationic domain on one side of the protein. Positive charge results from lysine (Lys) and arginine (Arg) residues that are concentrated in three primary regions of the protein: near the N-terminus (Arg3, Arg4, Lys5), near the C-terminus (Arg54, Arg55) and at the narrow β-turn region (Lys28, Lys29, Lys30). It is believed that these positively charged residues can play a critical role in dendrotoxin binding activity, as they can make potential interactions with the anionic sites (negatively charged amino acids) in the pore of potassium channels. Biological activity Pharmacology A single dendrotoxin molecule associates reversibly with a potassium channel in order to exert its inhibitory effect. It is proposed that this interaction is mediated by electrostatic interactions between the positively charged amino acid residues in the cationic domain of dendrotoxin and the negatively charged residues in the ion channel pore. Potassium channels, similar to other cation-selective channels, are believed to have a cloud of negative charges that precede the opening to the channel pore that help conduct potassium ions through the permeation pathway. It is generally believed (though not proven) that a dendrotoxin molecules bind to anionic sites near the extracellular surface of the channel and physically occlude the pore, thereby preventing ion conductance. However, Imredy and MacKinnon have proposed that delta-dendrotoxin may have an off-center binding site on their target proteins, and may inhibit the channel by altering the structure of the channel, rather than physically blocking the pore. Biologically important residues Many studies have attempted to identify which amino acid residues are important for binding activity of dendrotoxins to their potassium channel targets. Harvey et al. used residue-specific modifications to identify positively charged residues that were crucial to the blocking activity of dendrotoxin-I. They reported that acetylation of Lys5 near the N-terminal region and Lys29 in the beta-turn region led to substantial decreases in DTX-I binding affinity. Similar results have been shown with dendrotoxin-K using site-directed mutagenesis to substitute positively charged lysine and arginine residues to neutral alanines. These results, along with many others, have implicated that the positively charged lysines in the N-terminal half, particularly Lys5 in the 310-helix, play a very important role in the dendrotoxin binding to their potassium channel targets. The