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001-es BibID:	BIBFORM086320
035-os BibID:	(cikkazonosító)113782 (WoS)000527342900009 (Scopus)85077711551
Első szerző:	Luna-Ramirez, Karen
Cím:	Structural basis of the potency and selectivity of Urotoxin, a potent Kv1 blocker from scorpion venom / Karen Luna-Ramirez, Agota Csoti, Jeffrey R. McArthur, Yanni K. Y. Chin, Raveendra Anangi, Rosby del Carmen Najera, Lourival D. Possani, Glenn F. King, Gyorgy Panyi, Haibo Yu, David J. Adams, Rocio K. Finol-Urdaneta
Dátum:	2020
ISSN:	0006-2952
Megjegyzések:	Urotoxin (?-KTx 6), a peptide from venom of the Australian scorpion Urodacus yaschenkoi, is the most potent inhibitor of Kv1.2 described to date (IC = 160 pM). The native peptide also inhibits Kv1.1, Kv1.3 and KCa3.1 with nanomolar affinity but its low abundance in venom precluded further studies of its actions. Here we produced recombinant Urotoxin (rUro) and characterized the molecular determinants of Kv1 channel inhibition. The 3D structure of rUro determined using NMR spectroscopy revealed a canonical cysteine-stabilised ?/? (CS?/?) fold. Functional assessment of rUro using patch-clamp electrophysiology revealed the importance of C-terminal amidation for potency against Kv1.1?1.3 and Kv1.5. Neutralization of the putative pore-blocking K25 residue in rUro by mutation to Ala resulted in a major decrease in rUro potency against all Kv channels tested, without perturbing the toxin's structure. Reciprocal mutations in the pore of Uro-sensitive Kv1.2 and Uro-resistant Kv1.5 channels revealed a direct interaction between Urotoxin and the Kv channel pore. Our experimental work supports postulating a mechanism of action in which occlusion of the permeation pathway by the K25 residue in Urotoxin is the basis of its Kv1 inhibitory activity. Docking analysis was consistent with occlusion of the pore by K25 and the requirement of a small, non-charged amino acid in the Kv1 channel vestibule to facilitate toxin-channel interactions. Finally, computational studies revealed key interactions between the amidated C-terminus of Urotoxin and a conserved Asp residue in the turret of Kv1 channels, offering a potential rationale for potency differences between native and recombinant Urotoxin.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Biochemical Pharmacology. - 174 (2020), p. 1-15. -
További szerzők:	Csóti Ágota (1989-) (biológus) McArthur, Jeffrey R. Chin, Yanni K. Y. Anangi, Raveendra Najera, Rosby del Carmen Possani, Lourival Domingos King, Glenn F. Panyi György (1966-) (biofizikus) Yu, Haibo Adams, David J. Finol-Urdaneta, Rocio K.
Pályázati támogatás:	GINOP-2.3.2-15-2016-00044 GINOP NKFIH K119417 Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM052923
Első szerző:	Luna-Ramirez, Karen
Cím:	Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi / Karen Luna-Ramirez, Adam Bartok, Rita Restano-Cassulini, Veronica Quintero-Hernández, Fredy I. V. Coronas, Janni Christensen, Christine E. Wright, Gyorgy Panyi, Lourival D. Possani
Dátum:	2014
ISSN:	1521-0111
Megjegyzések:	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 ?-potassium channel toxin 6 (?-KTx-6) subfamily of peptides; it was assigned the systematic number of ?-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-ℓa-go-go-related gene type 1 (hERG1), or human ether-ℓa-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 ?/?-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.
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban scorpion toxin potassium channel
Megjelenés:	Molecular Pharmacology. - 86 : 1 (2014), p. 28-41. -
További szerzők:	Bartók Ádám (1984-) (biotechnológus) Restano-Cassulini, Rita Quintero-Hernandez, Veronica Coronas, Fredy I. V. Christensen, Janni Wright, Christine E. Panyi György (1966-) (biofizikus) Possani, Lourival Domingos
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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