2. Academic Validation
  3. Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi

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

  • Mol Pharmacol. 2014 Jul;86(1):28-41. doi: 10.1124/mol.113.090183.
Karen Luna-Ramírez 1,  Adam Bartok 2,  Rita Restano-Cassulini 2,  Veronica Quintero-Hernández 2,  Fredy I V Coronas 2,  Janni Christensen 2,  Christine E Wright 2,  Gyorgy Panyi 2,  Lourival D Possani 1
Affiliations

Affiliations

  • 1 Australian Venom Research Unit and Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia (K.L.-R., C.E.W.); Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad, Cuernavaca, Mexico (R.R.-C., V.Q.-H., F.I.V.C., L.D.P.); Department of Biophysics and Cell Biology, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary (A.B., G.P.); MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary (G.P.); and Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia (J.C.) karenlr@student.unimelb.edu.au possani@ibt.unam.mx.
  • 2 Australian Venom Research Unit and Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia (K.L.-R., C.E.W.); Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad, Cuernavaca, Mexico (R.R.-C., V.Q.-H., F.I.V.C., L.D.P.); Department of Biophysics and Cell Biology, Research Center for Molecular Medicine, University of Debrecen, Debrecen, Hungary (A.B., G.P.); MTA-DE Cell Biology and Signaling Research Group, Debrecen, Hungary (G.P.); and Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia (J.C.).
PMID: 24723491 DOI: 10.1124/mol.113.090183
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.

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