| Structural highlights
Function
[KGX11_CENNO] Blocks human and rat Kv11.1/KCNH2/ERG1 and Kv11.3/KCNH7/ERG3, as well as rat (but not human) Kv11.2/KCNH6/ERG2 (PubMed:11755529, PubMed:11864985, PubMed:16497878, PubMed:17369411, PubMed:20600425) by binding to channel outer vestibule (S5P domain) with a 1:1 stoichiometry (PubMed:11755529, PubMed:11864985, PubMed:17369411, PubMed:20600425). Inhibition data are the following: hERG1 (reversible, IC(50)~7 nM) (PubMed:11755529, PubMed:11864985, PubMed:16497878, PubMed:17369411, PubMed:20600425), rERG1 (reversible, Kd=6.8 nM) (PubMed:16497878), rERG2 (irreversible, Kd=2.8 nM) (PubMed:16497878), hERG3 (irreversible, Kd=4.05 nM) (PubMed:16497878) and rERG3 (reversible, Kd=38.1 nM) (PubMed:16497878) potassium channels. The toxin potency is not affected by elevating potassium ion concentration from 2 to 98 mM (PubMed:11864985). This toxin only blocks channels in a closed state (PubMed:12860380). At high toxin concentrations, block of Kv11.1/KCNH2/ERG1 macroscopic current is incomplete (93.5%). This suggests a kinetic mechanism model with two different states of toxin-channel binding (T+C=TC*=TC; in the TC* state, the toxin binds the channel but does not occlude the pore, whereas in the TC state the toxin binds and occludes the pore). In this model, incomplete block is explained by the relatively fast dissociation rate from the blocked channel conformation (TC) relative to the rate of conversion of the toxin-channel encounter complex (TC*) to the blocked channel conformation (TC) (PubMed:17369411).[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The three-dimensional structure of chemically synthesized CnErg1 (Ergtoxin), which specifically blocks HERG (human ether-a-go-go-related gene) K+ channels, was determined by nuclear magnetic resonance spectroscopy. CnErg1 consists of a triple-stranded beta-sheet and an alpha-helix, as is typical of K+ channel scorpion toxins. The peptide structure differs from the canonical structures in that the first beta-strand is shorter and is nearer to the second beta-strand rather than to the third beta-strand on the C-terminus. There is also a large hydrophobic patch on the surface of the toxin, surrounding a central lysine residue, Lys13. We postulate that this hydrophobic patch is likely to form part of the binding surface of the toxin.
Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin.,Torres AM, Bansal P, Alewood PF, Bursill JA, Kuchel PW, Vandenberg JI FEBS Lett. 2003 Mar 27;539(1-3):138-42. PMID:12650941[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gurrola GB, Rosati B, Rocchetti M, Pimienta G, Zaza A, Arcangeli A, Olivotto M, Possani LD, Wanke E. A toxin to nervous, cardiac, and endocrine ERG K+ channels isolated from Centruroides noxius scorpion venom. FASEB J. 1999 May;13(8):953-62. PMID:10224238
- ↑ Pardo-Lopez L, Garcia-Valdes J, Gurrola GB, Robertson GA, Possani LD. Mapping the receptor site for ergtoxin, a specific blocker of ERG channels. FEBS Lett. 2002 Jan 2;510(1-2):45-9. PMID:11755529
- ↑ Pardo-Lopez L, Zhang M, Liu J, Jiang M, Possani LD, Tseng GN. Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel's outer vestibule. J Biol Chem. 2002 May 10;277(19):16403-11. Epub 2002 Feb 25. PMID:11864985 doi:http://dx.doi.org/10.1074/jbc.M200460200
- ↑ Milnes JT, Dempsey CE, Ridley JM, Crociani O, Arcangeli A, Hancox JC, Witchel HJ. Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Lett. 2003 Jul 17;547(1-3):20-6. PMID:12860380
- ↑ Restano-Cassulini R, Korolkova YV, Diochot S, Gurrola G, Guasti L, Possani LD, Lazdunski M, Grishin EV, Arcangeli A, Wanke E. Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system. Mol Pharmacol. 2006 May;69(5):1673-83. Epub 2006 Feb 23. PMID:16497878 doi:http://dx.doi.org/10.1124/mol.105.019729
- ↑ Hill AP, Sunde M, Campbell TJ, Vandenberg JI. Mechanism of block of the hERG K+ channel by the scorpion toxin CnErg1. Biophys J. 2007 Jun 1;92(11):3915-29. Epub 2007 Mar 16. PMID:17369411 doi:http://dx.doi.org/10.1529/biophysj.106.101956
- ↑ Jimenez-Vargas JM, Restano-Cassulini R, Quintero-Hernandez V, Gurrola GB, Possani LD. Recombinant expression of the toxic peptide ErgTx1 and role of Met35 on its stability and function. Peptides. 2011 Mar;32(3):560-7. doi: 10.1016/j.peptides.2010.06.018. Epub 2010, Jun 30. PMID:20600425 doi:http://dx.doi.org/10.1016/j.peptides.2010.06.018
- ↑ Torres AM, Bansal P, Alewood PF, Bursill JA, Kuchel PW, Vandenberg JI. Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin. FEBS Lett. 2003 Mar 27;539(1-3):138-42. PMID:12650941
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