posters 5th Asia-Pacific NMR Symposium 2013

Structural characterization of a scorpion venom ICK toxin with potassium channel-blocking activity (#130)

Peta J Harvey 1 , Bin Gao 2 , Shunyi Zhu 2 , David J Craik 1
  1. University of Queensland, St Lucia, QLD, Australia
  2. Chinese Academy of Sciences, Beijing, PR China

The ICK (inhibitor cystine knot) motif defines a large superfamily of polypeptides with high structural stability and functional diversity. Two disulfide bonds and their connecting backbone segments form an embedded ring while a third disulfide bridge threads through this ring. Previously, only a few scorpion venom peptides containing an ICK motif have been either structurally (imperatoxin A and maurocalcine) or functionally (ImKTx1 and hadrucalcin) identified.

In this work we describe a new potassium channel toxin derived from the venom of Mesobuthus eupeus, the lesser Asian scorpion, in terms of gene cloning, chemical synthesis, NMR spectroscopy, and electrophysiology [1]. Using data acquired at 298K, including 382 NOE distance restraints, 8 hydrogen bonds and 69 dihedral restraints, this peptide (named lambda-MeuKTx-1) was found to adopt an ICK fold that contains a three-strand anti-parallel beta-sheet and a 310-helix. Functionally, lambda-MeuKTx-1 selectively inhibits the Drosophila Shaker K+ channel but is inactive upon skeletal-type calcium release channels/ryanodine receptors, in contrast to previously known scorpion venom ICK peptides. The structural and functional characterization of the first scorpion venom ICK toxin with K+ channel-blocking activity provides valuable information on the evolution of this conserved scaffold of ancient origin.

[1] B. Gao, P. J. Harvey, D. J. Craik, M. Ronjat, M. De Waard, S. Zhu, Bioscience Reports 33, e00047 (2013).