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  • Role of individual disulfide bridges in the conformation and activity of spinoxin (α-KTx6.13), a potassium channel toxin from Heterometrus spinifer scorpion venom

    Author(s)
    Yamaguchi, Yoko
    Peigneur, Steve
    Liu, Junyi
    Uemura, Shiho
    Nose, Takeru
    Nirthanan, Selvanayagam
    Gopalakrishnakone, Ponnampalam
    Tytgat, Jan
    Sato, Kazuki
    Griffith University Author(s)
    Nirthanan, Niru
    Year published
    2016
    Metadata
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    Abstract
    Spinoxin (SPX; α-KTx6.13), isolated from venom of the scorpion Heterometrus spinifer, is a K+ channel-specific peptide toxin (KTx), which adopts a cysteine-stabilized α/β scaffold that is cross-linked by four disulfide bridges (Cys1–Cys5, Cys2–Cys6, Cys3–Cys7, and Cys4–Cys8). To investigate the role of the individual disulfide bonds in the structure-activity relationship of SPX, we synthesized four SPX analogs in which each pair of cysteine residues was replaced by alanine residues. The analysis of circular dichroism spectra and inhibitory activity against Kv1.3 channels showed that the SPX analogs lacking any of three ...
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    Spinoxin (SPX; α-KTx6.13), isolated from venom of the scorpion Heterometrus spinifer, is a K+ channel-specific peptide toxin (KTx), which adopts a cysteine-stabilized α/β scaffold that is cross-linked by four disulfide bridges (Cys1–Cys5, Cys2–Cys6, Cys3–Cys7, and Cys4–Cys8). To investigate the role of the individual disulfide bonds in the structure-activity relationship of SPX, we synthesized four SPX analogs in which each pair of cysteine residues was replaced by alanine residues. The analysis of circular dichroism spectra and inhibitory activity against Kv1.3 channels showed that the SPX analogs lacking any of three specific disulfide bonds (Cys1–Cys5, Cys2–Cys6, and Cys3–Cys7) were unable to form the native secondary structure and completely lost inhibitory activities. Thus, we conclude that Cys1–Cys5, Cys2–Cys6, and Cys3–Cys7 are required for the inhibition of the Kv1.3 channel by SPX. In contrast, the analog lacking Cys4–Cys8 retained both native secondary structure and inhibitory activity. Interestingly, one of the isomers of the analog lacking Cys1–Cys5 also showed inhibitory activities, although its inhibition was ∼18-fold weaker than native SPX. This isomer had an atypical disulfide bond pairing (Cys3–Cys4 and Cys7–Cys8) that corresponds to that of maurotoxin (MTX), another α-KTx6 family member. These results indicate that the Cys1–Cys5 and Cys2–Cys6 bonds are important for restricting the toxin from forming an atypical (MTX-type) disulfide bond pairing among the remaining four cysteine residues (Cys3, Cys4, Cys7, and Cys8) in native SPX.
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    Journal Title
    Toxicon
    Volume
    122
    DOI
    https://doi.org/10.1016/j.toxicon.2016.09.013
    Subject
    Pharmacology and pharmaceutical sciences
    Pharmacology and pharmaceutical sciences not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/100460
    Collection
    • Journal articles

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