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

Steve Peigneur, Yoko Yamaguchi, Chihiro Kawano, Takeru Nose, Selvanayagam Nirthanan, Ponnampalam Gopalakrishnakone, Jan Tytgat, Kazuki Sato

研究成果: Contribution to journalArticle査読

4 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)2927-2935
ページ数9
ジャーナルBiochemistry
55
21
DOI
出版ステータス出版済み - 5 31 2016

All Science Journal Classification (ASJC) codes

  • 生化学

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