Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin Isolated from the venom of the Australian scorpion Urodacus yaschenkoi

Authors

Karen S. Luna Ramirez, University of MelbourneFollow
Adam Bartok, University of Debrecen
Rita Restano-Cassulini, Universidad Nacional Autonoma de Mexico
Veronica Quintero-Hernandez, Universidad Nacional Autonoma de Mexico
Fredy I. V Coronas, Universidad Nacional Autonoma de Mexico
Janni Christensen, La Trobe University
Christine E. Wright, University of Melbourne
Gyorgy Panyi, University of Debrecen
Lourival D. Possani, Universidad Nacional Autonoma de Mexico

RIS ID

111089

Publication Details

Luna-Ramirez, K., Bartok, A., Restano-Cassulini, R., Quintero-Hernandez, V., Coronas, F. I. V., Christensen, J., Wright, C. E., Panyi, G. & Possani, L. D. (2014). Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin Isolated from the venom of the Australian scorpion Urodacus yaschenkoi. Molecular Pharmacology, 86 (1), 28-41.

Abstract

This communication reports the structural and functional characterization of urotoxin, the first K⁺ channel toxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi. It is a basic peptide consisting of 37 amino acids with an amidated C-terminal residue. Urotoxin contains eight cysteines forming four disulfide bridges with sequence similarities resembling the α-potassium channel toxin 6 (α-KTx-6) subfamily of peptides; it was assigned the systematic number of α-KTx-6.21. Urotoxin is a potent blocker of human voltage-gated potassium channel (K_v)1.2 channels, with an IC₅₀ of 160 pM, whereas its affinity for other channels tested was in the nanomolar range (hK_v1.1, IC₅₀ = 253 nM; hK_v1.3, IC₅₀ = 91 nM; and hK_Ca3.1, IC₅₀ = 70 nM). The toxin had no effect on hK_v1.4, hK_v1.5, human ether-à-go-go-related gene type 1 (hERG1), or human ether-à-go-go-like (hELK2) channels. Multiple sequence alignments from the venom gland transcriptome showed the existence of four other new peptides similar to urotoxin. Computer modeling of urotoxin's three-dimensional structure suggests the presence of the α/β-scaffold characteristic of other scorpion toxins, although very likely forming an uncommon disulfide pairing pattern. Using molecular dynamics, a model for the binding of this peptide to human K_v1.2 and hK_v1.1 channels is presented, along with the binding of an in silico mutant urotoxin (Lys25Ala) to both channels. Urotoxin enriches our knowledge of K⁺ channel toxins and, due to its high affinity for hK_v1.2 channels, it may be a good candidate for the development of pharmacologic tools to study the physiologic functions of K⁺ channels or related channelopathies and for restoring axonal conduction in demyelinated axons.