Ergtoxin

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

Based on primary sequence alignment, there are 27 different ɣ-KTx's,{{Cite web|url=https://www.uniprot.org/uniprot/?query=ergtoxin&offset=25&sort=score|title = Ergtoxin in UniProtKB}} all of which belong to the larger group of scorpion short chain toxins that affect K⁺ channels (KTx).{{Cite journal

| last1 = Rodriquez de la Vega | first1 = R. C.

| last2 = Merino

| first2 = E

| last3 = Merino | first3 = E.

| last4 = Becerril | first4 = B.

| last5 = Possani | first5 = L. D.

| title = Novel interactions between K+ channels and scorpion toxins

| journal = Trends Pharmacol. Sci.

| volume = 24

| issue = 5

| pages = 222–7

|date=May 2003

| pmid = 12767720 | doi=10.1016/S0165-6147(03)00080-4

}}{{Cite journal

| last1 = Tytgat | first1 = J.

| last2 = Khandy | first2 = K. G.

| last3 = Garcia | first3 = M. L.

| last4 = Gutman | first4 = G. A.

| last5 = Martin-Eauclaire | first5 = M. F.

| last6 = van der Walt | first6 = J. J.

| last7 = Possani | first7 = L. D.

| title = A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies.

| journal = Trends Pharmacol Sci

| volume = 20

| issue = 11

| pages = 444–7

|date=November 1999

| pmid = 10542442 | doi=10.1016/S0165-6147(99)01398-X

}} 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.{{Cite journal

| last1 = Scaloni | first1 = A.

| last2 = Bottiglieri | first2 = C.

| last3 = Ferrata | first3 = L.

| last4 = Corona | first4 = M.

| last5 = Gurrola | first5 = G. B.

| last6 = Batista | first6 = C.

| last7 = Wanke | first7 = E.

| last8 = Possani | first8 = L. D.

| title = Disulfide bridges of ergtoxin, a member of a new sub-family of peptide blockers of the ether-a-go-go-related K+ channel.

| journal = FEBS Lett.

| volume = 479

| issue = 3

| pages = 156–7

|date=August 2000

| pmid = 11023354

| doi = 10.1016/s0014-5793(00)01891-3

| doi-access = free

| bibcode = 2000FEBSL.479..156B

}}

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. 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.{{Cite journal

| last1 = Frenal | first1 = K.

| last2 = Xu | first2 = C. Q.

| last3 = Wolff | first3 = N.

| last4 = Wecker | first4 = K.

| last5 = Gurrola | first5 = B. B.

| last6 = Zhu | first6 = S. Y.

| last7 = Chi | first7 = C. W.

| last8 = Possani | first8 = L. D.

| last9 = Tytgat | first9 = J.

| last10 = Delapierre | first10 = M.

| title = Exploring structural features of the interaction between the scorpion toxinCnErg1 and ERG K+ channels.

| journal = Proteins

| volume = 56

| issue = 2

| pages = 367–75

|date=August 2004

| pmid = 15211519 | doi=10.1002/prot.20102

| s2cid = 25355251

}}

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 {{Cite journal

| last1 = Torres | first1 = A. M.

| last2 = Bansal | first2 = B.

| last3 = Alewood | first3 = P. F.

| last4 = Burcill | first4 = J. A.

| last5 = Kuchel | first5 = P. V.

| last6 = Vanderberg | first6 = J. I.

| title = Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin

| journal = FEBS Lett.

| volume = 539

| issue = 1–3

| pages = 138–42

|date=March 2003

| pmid = 12650941 | doi=10.1016/s0014-5793(03)00216-3

| doi-access = free

| bibcode = 2003FEBSL.539..138T

}}

Ergtoxin can decrease hERG K+ activity by 50% at a concentration of 10 nM. The binding of Ergtoxin to hERG has been suggested to be dependent on hydrophobic interactions with the channel pore,{{Cite journal

| last1 = Pardo-Lopez | first1 = L.

| last2 = Garcia-Valdez | first2 = J.

| last3 = Gurrola | first3 = G. B.

| last4 = Robertson | first4 = G. A.

| last5 = Possani | first5 = L. D.

| title = Mapping the receptor site for ergtoxin, a specific blocker of ERG channels

| journal = FEBS Lett.

| volume = 510

| issue = 1–2

| pages = 45–9

|date=January 2002

| pmid = 11755529 | doi=10.1016/s0014-5793(01)03218-5

| doi-access = free

| bibcode = 2002FEBSL.510...45P

}} specifically with a prominently exposed hydrophobic cluster of amino acids (Tyr 14, Phe 36 and Phe 37). 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.{{Cite journal

| last1 = Jimenes-Vargas | first1 = J. M.

| last2 = Restano-Cassulini | first2 = R.

| last3 = Quintero-Hernandez | first3 = V.

| last4 = Gurrola | first4 = G. B.

| last5 = Possani | first5 = L. D.

| doi = 10.1016/j.peptides.2010.06.018

| title = Recombinant Expression Of The Toxic Peptide Ergtx1 And Role Of Met35 On Its Stability And Function.

| journal = Peptides

| volume = 32

| issue = 3

| pages = 560–7

|date=March 2011

| pmid = 20600425

| s2cid = 13374786

}}

Ergtoxin effects are a result of the toxin binding to voltage- gated K⁺ channels containing the Kv11.1 alpha subunit encoded by ether-a-go-go-genes (hERG1, hERG2 and hERG3) in the central nervous system of humans.{{Cite journal

| last1 = Restano-Cassulini | first1 = R.

| last2 = Olamendi-Portugal | first2 = T.

| last3 = Zamudio | first3 = F.

| last4 = Becerril | first4 = B.

| last5 = Possani | first5 = L. D.

| doi = 10.1007/s11064-008-9634-8

| title = Two novel ergtoxins, blockers of K⁺-channels, purified from the Mexican scorpion Centruroides elegans elegans.

| journal = Neurochem. Res.

| volume = 33

| issue = 8

| pages = 1525–33

|date=August 2008

| pmid = 18338253

| s2cid = 1026871

}}{{Cite journal

| last1 = Saganich | first1 = M. J.

| last2 = Machado | first2 = E.

| last3 = Rudy | first3 = B.

| title = Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain.

| journal = J. Neurosci.

| volume = 21

| issue = 13

| pages = 4609–24

|date=July 2001

| pmid = 11425889

| doi = 10.1523/jneurosci.21-13-04609.2001

| pmc = 6762370

| doi-access = free

}} 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 or at the extracellular surface pore domains S5-S6, and 2.) interference with channel gating through interaction with the voltage-sensing domain S1-S4.{{Cite journal

| last1 = Chtcheglova | first1 = L. A.

| last2 = Atalar | first2 = F.

| last3 = Ozbek | first3 = U.

| last4 = Wildling | first4 = L.

| last5 = Ebner | first5 = A.

| last6 = Hinterdorfer| first6 = B.

| doi = 10.1007/s00424-007-0418-9

| title = Localization Of The Ergtoxin-1 Receptors On The Voltage Sensing Domain Of Herg K+ Channel By Afm Recognition Imaging.

| journal = Pflügers Arch.

| volume = 456

| issue = 1

| pages = 247–54

|date=April 2008

| pmid = 18286302

| doi-access = free

}}

Ergtoxin blocks ERG-channels located in endocrine, nerve and heart cells in several species, and is more toxic than CsEKerg1.{{cite web|title=UniProt Consortium |url=https://www.uniprot.org/uniprot/?query=ergtoxin&sort=score. |publisher=UniProt KB |access-date=15 October 2013 }}{{dead link|date=December 2016 |bot=InternetArchiveBot |fix-attempted=yes }}

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.{{Cite journal

| last1 = Asher | first1 = V.

| last2 = Sowter | first2 = H.

| last3 = Shaw | first3 = R.

| last4 = Bali | first4 = A.

| last5 = Khan | first5 = R.

| doi = 10.1186/1477-7819-8-113

| title = Eag and HERG potassium channels as novel therapeutic targets in cancer

| journal = World J. Surg. Oncol.

| volume = 8

| issue = 113

| pages = 113

|date=December 2010

| pmid = 21190577

| pmc = 3022597

| doi-access = free

}} However, while hERG K+ channels are expressed by SK-OV-3 cancer cells,{{Cite journal

| last1 = Asher | first1 = V.

| last2 = Warren | first2 = A.

| last3 = Shaw | first3 = R.

| last4 = Sowter | first4 = H.

| last5 = Bali | first5 = A.

| last6 = Khan | first6 = R.

| doi = 10.1186/1475-2867-11-6

| title = The role of Eag and HERG channels in cell proliferation and apoptotic cell death in SK-OV-3 ovarian cancer cell line

| journal = Cancer Cell Int.

| volume = 11

| issue = 6

| pages = 6

|date=March 2011

| pmid = 21392380

| pmc = 3063814

| doi-access = free

}} the specific mechanisms of channel function in proliferation and potential therapeutic uses for toxins targeting these channels are still not confirmed.{{Cite journal

| last1 = Roy | first1 = J.

| last2 = Vantol | first2 = B.

| last3 = Cowley | first3 = E. A.

| last4 = blay | first4 = J.

| last5 = Linsdell | first5 = P.

| title = Pharmacological separation of hEAG and hERG K+ channel function in the human mammary carcinoma cell line MCF-7.

| journal = Oncol. Rep.

| volume = 19

| issue = 6

| pages = 1511–6

|date=June 2008

| pmid = 18497958 | doi=10.3892/or.19.6.1511

| doi-access = free

}}

{{reflist}}

{{Ion channel modulators}}

Category:Scorpion toxins

Category:Neurotoxins

Category:Ion channel toxins

Category:Potassium channel blockers

Category:HERG blocker