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