Chemistry:Ergtoxin

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Short description: Family of toxins

Ergtoxin (CnErg1, CnErgTx1, ErgTx, ErgTx1, ɣ-KTx1.1) is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG (human Ether- à -go-go-Related Gene) potassium channels.[1]

Sources

The toxin is derived from the venomous gland of the Mexican scorpion Centruroides noxius,[1]

Chemistry

Structural Classification of Proteins ɣ-KTx's Class: Small proteins 
  Potassium channel toxins

(triple stranded β-sheet and one to two α-helices)

ɣ-KTx1.1, ɣ-KTx1.2, ɣ-KTx1.4, ɣ-KTx1.6,ɣ-KTx3.2, ɣ-KTx3.3, ɣ-KTx4.2, ɣ-KTx4.3, ɣ-KTx4.4, ɣ-KTx4.5, ɣ-KTx4.8, ɣ-KTx4.9, ɣ-KTx4.10, ɣ-KTx4.11, ɣ-KTx4.13, ɣ-KTx5.1, ɣ-KTx1.3, ɣ-KTx1.5 ɣ-KTx3.1, ɣ-KTx3.4, ɣ-KTx4.1, ɣ-KTx4.6, ɣ-KTx4.7, ɣ-KTx5.2, ɣ-KTx4.12, ɣ-KTx1.7, ɣ-KTx1.8

Species:

Centruroides noxius

Centruroides elegans

Centruroides sculpturatus

Centruroides exilicauda

Centruroides gracilis

Centruroides limpidus

Based on primary sequence alignment, there are 27 different ɣ-KTx's,[2] all of which belong to the larger group of scorpion short chain toxins that affect K+ channels (KTx).[3][4] The first member of this ɣ-KTx family, Ergtoxin (ɣ-KTx1.1), is a polypeptide composed of 42 amino acid residues. It has the following one-letter amino acid code:

DRDSCVDKSRCAKYGYYQECQDCCKNAGHNGGTCMFFKCKCA.[5]

The Ergtoxin sequence contains four disulfide bridges between Cys5-Cys23, Cys11-Cys34, Cys20-Cys39 and Cys24-Cys41 and has a molecular mass of 4730.8 ± 0.4 Da.[5] Ergtoxin displays two clusters of amino acids, one hydrophobic and one hydrophilic. Its structure is stabilized by five hydrogen bonds, HN15-O34, HN33-O40, HN35-O38, HN38-O35, HN40-O33.[6] All of the above data have led to the following prediction for its 3D Structure. The tertiary structure of Ergtoxin is comparable to that of another toxin called OSK1, in spite of sharing only 35% sequence identity [7]

Target

Ergtoxin can decrease hERG K+ activity by 50% at a concentration of 10 nM.[7] The binding of Ergtoxin to hERG has been suggested to be dependent on hydrophobic interactions with the channel pore,[8] specifically with a prominently exposed hydrophobic cluster of amino acids (Tyr 14, Phe 36 and Phe 37).[7] It has also been shown that natural oxidation of Met 35 decreases the affinity of the molecule for the hERG K+ channels by three orders of magnitude, suggesting that Met35 is a critical residue for either polypeptide 3D folding or interaction of the toxin with the channel.[9]

Mode of action

Ergtoxin effects are a result of the toxin binding to voltage- gated K+ channels[1] containing the Kv11.1 alpha subunit encoded by ether-a-go-go-genes (hERG1, hERG2 and hERG3) in the central nervous system of humans.[10][11] Two concurrent modes of action for the ɣ-KTx's have been reported: 1.) blocking channel conductance by interacting with the outer vestibule of the channel[4] or at the extracellular surface pore domains S5-S6,[12] and 2.) interference with channel gating through interaction with the voltage-sensing domain S1-S4.[12]

Toxicity

Ergtoxin blocks ERG-channels located in endocrine, nerve and heart cells in several species, and is more toxic than CsEKerg1.[13]

Treatment and therapeutic use

Ergtoxin may potentially have a role in treatment of patients with ovarian cancer by inhibiting the proliferation of cells and thus the progression of cancer.[14] However, while hERG K+ channels are expressed by SK-OV-3 cancer cells,[15] the specific mechanisms of channel function in proliferation and potential therapeutic uses for toxins targeting these channels are still not confirmed.[16]

References

  1. ↑ 1.0 1.1 1.2 Warmke, J. W.; Ganetzky, B. (April 1994). "A family of potassium channel genes related to eag in Drosophila and mammals.". Proc Natl Acad Sci U S A 91 (8): 3438–42. doi:10.1073/pnas.91.8.3438. PMID 8159766. Bibcode: 1994PNAS...91.3438W. 
  2. ↑ "Ergtoxin in UniProtKB". https://www.uniprot.org/uniprot/?query=ergtoxin&offset=25&sort=score. 
  3. ↑ Rodriquez de la Vega, R. C.; Merino, E; Merino, E.; Becerril, B.; Possani, L. D. (May 2003). "Novel interactions between K+ channels and scorpion toxins". Trends Pharmacol. Sci. 24 (5): 222–7. doi:10.1016/S0165-6147(03)00080-4. PMID 12767720. 
  4. ↑ 4.0 4.1 Tytgat, J.; Khandy, K. G.; Garcia, M. L.; Gutman, G. A.; Martin-Eauclaire, M. F.; van der Walt, J. J.; Possani, L. D. (November 1999). "A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies.". Trends Pharmacol Sci 20 (11): 444–7. doi:10.1016/S0165-6147(99)01398-X. PMID 10542442. 
  5. ↑ 5.0 5.1 Scaloni, A.; Bottiglieri, C.; Ferrata, L.; Corona, M.; Gurrola, G. B.; Batista, C.; Wanke, E.; Possani, L. D. (August 2000). "Disulfide bridges of ergtoxin, a member of a new sub-family of peptide blockers of the ether-a-go-go-related K+ channel.". FEBS Lett. 479 (3): 156–7. doi:10.1016/s0014-5793(00)01891-3. PMID 11023354. 
  6. ↑ Frenal, K.; Xu, C. Q.; Wolff, N.; Wecker, K.; Gurrola, B. B.; Zhu, S. Y.; Chi, C. W.; Possani, L. D. et al. (August 2004). "Exploring structural features of the interaction between the scorpion toxinCnErg1 and ERG K+ channels.". Proteins 56 (2): 367–75. doi:10.1002/prot.20102. PMID 15211519. 
  7. ↑ 7.0 7.1 7.2 Torres, A. M.; Bansal, B.; Alewood, P. F.; Burcill, J. A.; Kuchel, P. V.; Vanderberg, J. I. (March 2003). "Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin". FEBS Lett. 539 (1–3): 138–42. doi:10.1016/s0014-5793(03)00216-3. PMID 12650941. 
  8. ↑ Pardo-Lopez, L.; Garcia-Valdez, J.; Gurrola, G. B.; Robertson, G. A.; Possani, L. D. (January 2002). "Mapping the receptor site for ergtoxin, a specific blocker of ERG channels". FEBS Lett. 510 (1–2): 45–9. doi:10.1016/s0014-5793(01)03218-5. PMID 11755529. 
  9. ↑ Jimenes-Vargas, J. M.; Restano-Cassulini, R.; Quintero-Hernandez, V.; Gurrola, G. B.; Possani, L. D. (March 2011). "Recombinant Expression Of The Toxic Peptide Ergtx1 And Role Of Met35 On Its Stability And Function.". Peptides 32 (3): 560–7. doi:10.1016/j.peptides.2010.06.018. PMID 20600425. 
  10. ↑ Restano-Cassulini, R.; Olamendi-Portugal, T.; Zamudio, F.; Becerril, B.; Possani, L. D. (August 2008). "Two novel ergtoxins, blockers of K+-channels, purified from the Mexican scorpion Centruroides elegans elegans.". Neurochem. Res. 33 (8): 1525–33. doi:10.1007/s11064-008-9634-8. PMID 18338253. 
  11. ↑ Saganich, M. J.; Machado, E.; Rudy, B. (July 2001). "Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain.". J. Neurosci. 21 (13): 4609–24. doi:10.1523/jneurosci.21-13-04609.2001. PMID 11425889. 
  12. ↑ 12.0 12.1 Chtcheglova, L. A.; Atalar, F.; Ozbek, U.; Wildling, L.; Ebner, A.; Hinterdorfer, B. (April 2008). "Localization Of The Ergtoxin-1 Receptors On The Voltage Sensing Domain Of Herg K+ Channel By Afm Recognition Imaging.". Pflügers Arch. 456 (1): 247–54. doi:10.1007/s00424-007-0418-9. PMID 18286302. 
  13. ↑ "UniProt Consortium". UniProt KB. https://www.uniprot.org/uniprot/?query=ergtoxin&sort=score.. [yes|permanent dead link|dead link}}]
  14. ↑ Asher, V.; Sowter, H.; Shaw, R.; Bali, A.; Khan, R. (December 2010). "Eag and HERG potassium channels as novel therapeutic targets in cancer". World J. Surg. Oncol. 8 (113): 113. doi:10.1186/1477-7819-8-113. PMID 21190577. 
  15. ↑ Asher, V.; Warren, A.; Shaw, R.; Sowter, H.; Bali, A.; Khan, R. (March 2011). "The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line". Cancer Cell Int. 11 (6): 6. doi:10.1186/1475-2867-11-6. PMID 21392380. 
  16. ↑ Roy, J.; Vantol, B.; Cowley, E. A.; blay, J.; Linsdell, P. (June 2008). "Pharmacological separation of hEAG and hERG K+ channel function in the human mammary carcinoma cell line MCF-7.". Oncol. Rep. 19 (6): 1511–6. doi:10.3892/or.19.6.1511. PMID 18497958. 



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