8.B.1 The Long (4C-C) Scorpion Toxin (L-ST) Superfamily

The NaC- L-ST superfamily contains a large number of scorpion-derived peptide toxins. These are tabulated below with descriptions. They include the well-characterized scorpion α- and β-toxins that act on tetrodotoxin-inhibitable, voltage-gated Na+ channels (TC #1.A.1.10). While the α-toxins (e.g., from Buthinea venom) prolong the Na+-inactivation phase of the activated action potential-causing channels, thereby blocking neuronal transmission, the β-toxins (e.g., from Centrurinae sculpturatus venom) affect the Na+-activation phase. These toxins are derived from a variety of scorpions. They can affect both insect and mammalian Na+ channel activities (Tian et al., 2007).

In many cases the details of their toxic actions are known. β-scorpion toxin, for example, targets neurotoxin receptor site 4 in Na+ channels and induces a negative shift in the voltage dependence of activation through a voltage sensor-trapping mechanism (Cestèle et al., 2006). A single organism may produce many of these toxins, some closely related, others more distantly related. This superfamily includes hundreds of sequenced members as revealed by PSI-BLAST searches with six iterations, some of which are reported to be non-toxic. They are usually characterized by four disulfide bridges, but some have three or five. 

Among scorpion species, the Buthidae produce the most deadly and painful venoms.  A pain-inducing α-toxin (CvIV4) was isolated from the venom of Centruroides vittatus and tested on five Na+ channel isoforms (Rowe et al. 2011).  CvIV4 slowed the fast inactivation of Na(v)1.7 (TC# 1.A.1.10.5), a Na+ channel expressed in peripheral pain-pathway neurons (nociceptors), but did not affect the Na(v)1.8-based sodium currents of these neurons (TC# 1.A.1.10.6). CvIV4 also slowed the fast inactivation of Na(v)1.2, Na(v)1.3 and Na(v)1.4. The effects of CvIV4 are similar to Old World α-toxins that target Na(v)1.7 (AahII, BmK MI, LqhIII, OD1), but the primary sequence of CvIV4 is not similar to these toxins. Mutant Na(v)1.7 channels (D1586A and E1589Q, DIV S3-S4 linker) reduced but did not abolish the effects of CvIV4.

This family belongs to the Defensin Superfamily.



Cestèle, S., Yarov-Yarovoy, V., Qu, Y., Sampieri, F., Scheuer, T., and Catterall, W.A. (2006). Structure and function of the voltage sensor of sodium channels probed by a β-scorpion toxin. J. Biol. Chem. 281: 21332-21344.

Cohen, L., Y. Moran, A. Sharon, D. Segal, D. Gordon, and M. Gurevitz. (2009). Drosomycin, an innate immunity peptide of Drosophila melanogaster, interacts with the fly voltage-gated sodium channel. J. Biol. Chem. 284: 23558-23563.

Fontecilla-Camps, J.C., Habersetzer-Rochat, C., and Rochat, H. (1988). Orthorhombic crystals and three-dimensional structure of the potent toxin II from the scorpion Androctonus australis Hector. Proc. Natl. Acad. Sci. USA 85: 7443-7447.

Guan, R.J., Xiang, Y., He, X.L., Wang, C.G., Wang, M., Zhang, Y., Sundberg, E.J., and Wang, D.C. (2004). Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins. J. Mol. Biol. 341: 1189-1204.

Ma, Z., J. Kong, D. Gordon, M. Gurevitz, and R.G. Kallen. (2013). Direct Evidence that Scorpion α-Toxins (Site-3) Modulate Sodium Channel Inactivation by Hindrance of Voltage-Sensor Movements. PLoS One 8: e77758.

Possani, L.D., Becerril, B., Delepierre, M., and Tytgat, J. (1999). Scorpion toxins specific for Na+-channels. Eur. J. Biochem. 264: 287-300.

Rowe, A.H., Y. Xiao, J. Scales, K.D. Linse, M.P. Rowe, T.R. Cummins, and H.H. Zakon. (2011). Isolation and characterization of CvIV4: a pain inducing α-scorpion toxin. PLoS One 6: e23520.

Tian, C., Y. Yuan, and S. Zhu. (2008). Positively selected sites of scorpion depressant toxins: possible roles in toxin functional divergence. Toxicon 51(4): 555-562.

Zhu, S., B. Gao, M. Deng, Y. Yuan, L. Luo, S. Peigneur, Y. Xiao, S. Liang, and J. Tytgat. (2010). Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels. Biochem Pharmacol 80: 1296-1302.

Zuo, X.P. and Ji, Y.H. (2004). Molecular mechanism of scorpion neurotoxins acting on sodium channels: insight into their diverse selectivity. Mol. Neurobiol. 30: 265-278.


TC#NameOrganismal TypeExample
8.B.1.1.1The α-neurotoxin BmK-MI precursor/x-ray structure known to 1.4 Å (Guan et al., 2004) (α-subfamily)ScorpionsBmK-MI of Mesobuthus (Buthus) martensii (84 aas; P45697)
8.B.1.1.2Markatoxin-III (MkTx-III) precursorScorpionsMkTx-III of Mesobuthus (Buthus) martensii (85 aas; P59853)
8.B.1.1.3Non-toxic immunogenic venom protein, NTxp, precursorScorpionsNTxp of Tityus serrulatus (84 aas; O77463)
8.B.1.1.4Depressant anti-insect-specific toxin 2 precursor, LqqIT2ScorpionsLqqIT2 of Leiurus quinquestriatus (82 aas; P19855)
8.B.1.1.5Excitatory insect-selective toxin 1 precursor, BmKIT1 (binds voltage independently to Na+ channels, shifting the voltage of activation to more negative potentials) ScorpionsBmKIT1 of Buthus martensii (88 aas; O61668)

Pain-inducing α-toxin of 97 aas, CvIV4 (Rowe et al. 2011).  CvIV4 slowed the fast inactivation of Na(v)1.7, a Na+ channel expressed in peripheral pain-pathway neurons (nociceptors), but did not affect the Na(v)1.8-based sodium currents of these neurons. CvIV4 also slowed the fast inactivation of Na(v)1.2, Na(v)1.3 and Na(v)1.4. The effects of CvIV4 are similar to Old World α-toxins that target Na(v)1.7 (AahII, BmK MI, LqhIII, OD1).


CvIV4 of Centruroides vittatus


AahII; neurotoxin 2 of 85 aas. Scorpion α-toxins bind voltage-independently at site-3 of sodium channels (Nav) and inhibit the inactivation of the activated channels, thereby blocking neuronal transmission. This toxin is active against mammals.


AahII of Androctonus australis (Sahara scorpion)


α-Neurotoxin of 67 aas from the yellow scorpion, LqhIII.  Binds voltage-independently at site-3 of sodium channels and inhibits the inactivation of the activated channels, modulating inactivation by hindering voltage-sensor movement, thereby blocking neuronal transmission (Ma et al. 2013). Dissociation is voltage-dependent. This alpha-like toxin is highly toxic to insects and competes with LqhaIT on binding to insect sodium channels. Differs from classical anti-mammalian alpha-toxins as it inhibits sodium channel inactivation in cell bodies of hippocampus brain neurons, on which the anti-mammalian Lqh2 is inactive, and is unable to affect Nav1.2 in the rat brain, on which Lqh2 is highly active (Rowe et al. 2011).

Animals (scorpions)

LqhIII of Leiurus quinquestriatus hebraeus


Drosomycin, an antimicrobial antifungal peptide of 70 aas and 1 N-terminal TMS.  Targets tetrodttoxin resistant Na+ channels (Zhu et al. 2010) including the Drosophila Na+ channel (Cohen et al. 2009).


Drosomycin of Drosophila melanogaster


TC#NameOrganismal TypeExample
8.B.1.2.1Anti-crustacean-specific toxin 1 (β-subfamily)ScorpionsAnti-crustacean-specific toxin 1 of Centruroides limpidus (66 aas; P45667)