1hp9

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kappa-Hefutoxins: a novel Class of Potassium Channel Toxins from Scorpion venom

Structural highlights

1hp9 is a 1 chain structure with sequence from Chersonesometrus fulvipes. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 1 model
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KKX11_CHEFU Shows weak blocking activity on voltage-gated potassium channels Kv10.1/KCNH1/EAG1 (IC(50)=26 uM), Kv1.2/KCNA2 (Kd=150 uM), Kv1.3/KCNA3 (Kd=40 uM), Kv1.6/KCNA3 (16.6% inhibition at 40 uM toxin) (PubMed:12034709, PubMed:23726856, PubMed:27578329). The block is dose-dependent, voltage-independent, and reversible (PubMed:12034709). Also shows a weak inhibitory activity on the plant pathogen F.culmorum growth (IC(50)=18.8-37.7 uM) (PubMed:27578329).[1] [2] [3]

Publication Abstract from PubMed

An important and exciting challenge in the postgenomic era is to understand the functions of newly discovered proteins based on their structures. The main thrust is to find the common structural motifs that contribute to specific functions. Using this premise, here we report the purification, solution NMR, and functional characterization of a novel class of weak potassium channel toxins from the venom of the scorpion Heterometrus fulvipes. These toxins, kappa-hefutoxin1 and kappa-hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that kappa-hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any beta-sheets. Based on the presence of the functional diad (Tyr(5)/Lys(19)) at a distance (6.0 +/- 1.0 A) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. kappa-Hefutoxin 1 not only blocks the voltage-gated K(+)-channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of kappa-hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. Alanine mutants (Y5A, K19A, and Y5A/K19A) failed to block the channels, indicating the importance of the functional diad.

kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity.,Srinivasan KN, Sivaraja V, Huys I, Sasaki T, Cheng B, Kumar TK, Sato K, Tytgat J, Yu C, San BC, Ranganathan S, Bowie HJ, Kini RM, Gopalakrishnakone P J Biol Chem. 2002 Aug 16;277(33):30040-7. Epub 2002 May 28. PMID:12034709[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Srinivasan KN, Sivaraja V, Huys I, Sasaki T, Cheng B, Kumar TK, Sato K, Tytgat J, Yu C, San BC, Ranganathan S, Bowie HJ, Kini RM, Gopalakrishnakone P. kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity. J Biol Chem. 2002 Aug 16;277(33):30040-7. Epub 2002 May 28. PMID:12034709 doi:10.1074/jbc.M111258200
  2. ↑ Peigneur S, Yamaguchi Y, Goto H, Srinivasan KN, Gopalakrishnakone P, Tytgat J, Sato K. Synthesis and characterization of amino acid deletion analogs of κ-hefutoxin 1, a scorpion toxin on potassium channels. Toxicon. 2013 Sep;71:25-30. PMID:23726856 doi:10.1016/j.toxicon.2013.05.010
  3. ↑ Moreels L, Peigneur S, Yamaguchi Y, Vriens K, Waelkens E, Zhu S, Thevissen K, Cammue BPA, Sato K, Tytgat J. Expanding the pharmacological profile of κ-hefutoxin 1 and analogues: A focus on the inhibitory effect on the oncogenic channel K(v)10.1. Peptides. 2017 Dec;98:43-50. PMID:27578329 doi:10.1016/j.peptides.2016.08.008
  4. ↑ Srinivasan KN, Sivaraja V, Huys I, Sasaki T, Cheng B, Kumar TK, Sato K, Tytgat J, Yu C, San BC, Ranganathan S, Bowie HJ, Kini RM, Gopalakrishnakone P. kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity. J Biol Chem. 2002 Aug 16;277(33):30040-7. Epub 2002 May 28. PMID:12034709 doi:10.1074/jbc.M111258200

Contents


PDB ID 1hp9

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