Potassium channel functions are often deciphered by using selective and potent scorpion toxins.Among these toxins,only a limited subset is capable to selectively block small conductance Ca2+-activated K+ (SK) channels.By sequence alignment,we found that SK channel turret residues are highly conversed.And there are also some additional basic residues on the turret when compared with other potassium channels.So we presumed that there should be uniform structure bases of this selective SK channel recognition.In this work,SK3 channel is exampled to demonstrate the key role of the electric charges of two conserved arginine residues (R485 and R489) from the SK3 channel outer vestibule in the selective recognition by SK3-blocking BmP05 toxin.Indeed,individually substituting these residues by histidyl or lysyl (maintaining partially or fully the positive electric charge),while decreasing the affinity of BmP05,still preserves its toxin-sensitivity profile (as evidenced by the lack of recognition by many other potassium channel-sensitive charybdotoxin (ChTX)).In contrast,when R485 or R489 residue of SK3 channel is mutated towards an acidic (E) or alcoholic (S) amino acid residue,the channel loses its sensitivity to BmP05 and becomes susceptible to a new blocking activity by ChTX.Besides these basic SK3 channel residues important for sensitivity,two acidic D492 and D518 residues,also located in the SK3 channel outer vestibule,were identified as being critical for toxin affinity.Further,molecular modeling data indicate the existence of a compact SK3 channel turret conformation,like a peptide screener,where the basic rings of R485 and R489 residues are stabilized by strong ionic interactions with D492 and D518 residues.In conclusion,the unique properties of two conserved arginine residues (spatial orientations and molecular interactions) of SK channel account for its toxin-sensitivity profile.