Ergtoxin
Ergtoxin (CnErg1, CnErgTx1, ErgTx, ErgTx1, ɣ-KTx1.1) is a toxin from the venom of the Mexican scorpion
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 α-helices )
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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 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
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
- ^ PMID 8159766.
- ^ "Ergtoxin in UniProtKB".
- PMID 12767720.
- ^ PMID 10542442.
- ^ PMID 11023354.
- S2CID 25355251.
- ^ PMID 12650941.
- PMID 11755529.
- S2CID 13374786.
- S2CID 1026871.
- PMID 11425889.
- ^ PMID 18286302.
- ^ "UniProt Consortium". UniProt KB. Retrieved 15 October 2013.[permanent dead link]
- PMID 21190577.
- PMID 21392380.
- PMID 18497958.