PMID:24723491

Citation	Luna-Ramírez, K, Bartok, A, Restano-Cassulini, R, Quintero-Hernández, V, Coronas, FI, Christensen, J, Wright, CE, Panyi, G and Possani, LD (2014) Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi. Mol. Pharmacol. 86:28-41
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 (Kv)1.2 channels, with an IC50 of 160 pM, whereas its affinity for other channels tested was in the nanomolar range (hKv1.1, IC50 = 253 nM; hKv1.3, IC50 = 91 nM; and hKCa3.1, IC50 = 70 nM). The toxin had no effect on hKv1.4, hKv1.5, 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 Kv1.2 and hKv1.1 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 hKv1.2 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.
Links	PubMed Online version:10.1124/mol.113.090183
Keywords	Amino Acid Sequence; Animals; CHO Cells; COS Cells; Cell Line; Cercopithecus aethiops; Cricetulus; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors; Humans; Models, Molecular; Molecular Dynamics Simulation; Molecular Sequence Data; Molecular Weight; Potassium Channel Blockers/chemistry; Scorpion Venoms/chemistry; Scorpions/metabolism; Sequence Alignment
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
UROYA:KAX6L		GO:0044361: envenomation resulting in modulation of transmission of nerve impulse in other organism	ECO:0000314:		P		Figure 5 shows the inhibition of current through the hKv1.1 channel by purified urotoxin. Figure 5, panel B shows the dose-dependent manner of inhibition. Figure 5 panel C shows that this is reversible and current is restored after urotoxin is no longer applied.	complete CACAO 10878

References

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