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  • Active Sites of Spinoxin, a Potassium Channel Scorpion Toxin, Elucidated by Systematic Alanine Scanning

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    Submitted Manuscript (SM)
    Author(s)
    Peigneur, Steve
    Yamaguchi, Yoko
    Kawano, Chihiro
    Nose, Takeru
    Nirthanan, Selvanayagam
    Gopalakrishnakone, Ponnampalam
    Tytgat, Jan
    Sato, Kazuki
    Griffith University Author(s)
    Nirthanan, Niru
    Year published
    2016
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    Abstract
    Peptide toxins from scorpion venoms constitute the largest group of toxins that target the voltage-gated potassium channel (Kv). Spinoxin (SPX) isolated from the venom of scorpion Heterometrus spinifer is a 34-residue peptide neurotoxin cross-linked by four disulfide bridges. SPX is a potent inhibitor of Kv1.3 potassium channels (IC50 = 63 nM), which are considered to be valid molecular targets in the diagnostics and therapy of various autoimmune disorders and cancers. Here we synthesized 25 analogues of SPX and analyzed the role of each amino acid in SPX using alanine scanning to study its structure–function relationships. ...
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    Peptide toxins from scorpion venoms constitute the largest group of toxins that target the voltage-gated potassium channel (Kv). Spinoxin (SPX) isolated from the venom of scorpion Heterometrus spinifer is a 34-residue peptide neurotoxin cross-linked by four disulfide bridges. SPX is a potent inhibitor of Kv1.3 potassium channels (IC50 = 63 nM), which are considered to be valid molecular targets in the diagnostics and therapy of various autoimmune disorders and cancers. Here we synthesized 25 analogues of SPX and analyzed the role of each amino acid in SPX using alanine scanning to study its structure–function relationships. All synthetic analogues showed similar disulfide bond pairings and secondary structures as native SPX. Alanine replacements at Lys23, Asn26, and Lys30 resulted in loss of activity against Kv1.3 potassium channels, whereas replacements at Arg7, Met14, Lys27, and Tyr32 also largely reduced inhibitory activity. These results suggest that the side chains of these amino acids in SPX play an important role in its interaction with Kv1.3 channels. In particular, Lys23 appears to be a key residue that underpins Kv1.3 channel inhibition. Of these seven amino acid residues, four are basic amino acids, suggesting that the positive electrostatic potential on the surface of SPX is likely required for high affinity interaction with Kv1.3 channels. This study provides insight into the structure–function relationships of SPX with implications for the rational design of new lead compounds targeting potassium channels with high potency.
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    Journal Title
    Biochemistry
    Volume
    55
    Issue
    21
    DOI
    https://doi.org/10.1021/acs.biochem.6b00139
    Copyright Statement
    This document is the Pre-Print: unedited Author’s version of a Published Work that appeared in final form in Biochemistry, © 2016 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.6b00139
    Subject
    Medicinal and biomolecular chemistry
    Biochemistry and cell biology
    Biochemistry and cell biology not elsewhere classified
    Medical biochemistry and metabolomics
    Publication URI
    http://hdl.handle.net/10072/99824
    Collection
    • Journal articles

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