8.B.21 The Spider Insecticidal Neurotoxin Cyrtautoxin (Cyrautoxin) Family

One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider, Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. Skinner et al. 1992 showed that recombinant Aps III (rAps III) is an atypical knottin peptide; three of the disulfide bridges form a classical inhibitor cystine knot motif while the fourth disulfide acts as a molecular staple that restricts the flexibility of an unusually large β-hairpin loop that often houses the pharmacophore in this class of toxins. The irreversible paralysis induced in insects by rAps III results from a potent block of insect voltage-gated sodium channels. Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel (Skinner et al. 1992).

This family belongs to the Conotoxin Superfamily.



Chen, J., M. Deng, Q. He, E. Meng, L. Jiang, Z. Liao, M. Rong, and S. Liang. (2008). Molecular diversity and evolution of cystine knot toxins of the tarantula Chilobrachys jingzhao. Cell Mol Life Sci 65: 2431-2444.

Fan, C.X., X.K. Chen, C. Zhang, L.X. Wang, K.L. Duan, L.L. He, Y. Cao, S.Y. Liu, M.N. Zhong, C. Ulens, J. Tytgat, J.S. Chen, C.W. Chi, and Z. Zhou. (2003). A novel conotoxin from Conus betulinus, kappa-BtX, unique in cysteine pattern and in function as a specific BK channel modulator. J. Biol. Chem. 278: 12624-12633.

Robinson, S.D. and R.S. Norton. (2014). Conotoxin gene superfamilies. Mar Drugs 12: 6058-6101.

Skinner, W.S., P.A. Dennis, J.P. Li, and G.B. Quistad. (1992). Identification of insecticidal peptides from venom of the trap-door spider, Aptostichus schlingeri (Ctenizidae). Toxicon 30: 1043-1050.


TC#NameOrganismal TypeExample

Mu-Cyrtautoxin-As1a or ApsIII insecticidal neurotoxin of 37 aas; an atypical knottin.  Blocks votage-gated Na+ channels in insects (Skinner et al. 1992).  It acts by pluging the outer vestibule of the channel, and also acts in combination with a weak (30%) voltage-independent block of insect voltage-gated calcium (Cav) channels (low-voltage and high-voltage channels). Tested on DUM neurons, it inhibits sodium currents with an IC50 of 540 nM.  The solution structure is available (PDB# 2M36).


APSIII of Aptostichus schlingeri


Conotoxin Gla-MrII of 94 aas and 1 TMS.

Conotoxin Gla-MrII of Conus marmoreus (Marble cone)


Trantula Jingzhaotoxin-59 (JzTx-59) or Theraphotoxin-Cj1a of 78 aas.  Possibly related to selenoprotein P (SelP) receptor, a knottin protein (TC family 9.B.87).  Fuctions to impair ion channels (Chen et al. 2008).


JzTx-59 of Chilobrachys guangxiensis


Nemetoxin-Csp1c or toxic peptide C of 39 aas.  Causes paralysis to insect larvae  such as H.virescens. This knottin toxin of the insecticidal toxin ABC family, is active only on insects.


Nemetoxin of Calisoga sp.


Uncharacterized protein of 65 aas


UP of Genlisea aurea


Putative toxin of 93 aas


Toxin of Colletotrichum orbiculare  (Cucumber anthracnose fungus) (Colletotrichum lagenarium)


I superfamily conotoxin of 71 aas

Animals (molluscs)

Conotoxin of Conus ebraeus (Hebrew cone)


Putative toxin, CtI-1 of 53 aas


CtI-1 of Dendrolimus kikuchii nucleopolyhedrovirus


Kappa conotoxin ViTx of 67 aas and 1 TMS.  Inhibits various potassium channels including Kv1.1, Kv1.2, Kv1.3 and Kv1.6 (Robinson and Norton 2014).

ViTx of Conus virgo (Virgin cone)


Kappa conotoxin BTx or BeTx of 70 aas and 1 N-terminal TMS.  It is a modulator of potassium channels, specifically up-modulating the calcium and voltage-gated BK channels. It has no effect on single channel conductance, but increases the open probability of BK channels (Fan et al. 2003).

BTx conotoxin of Conus betulinus (Beech cone)


TC#NameOrganismal TypeExample

Conotoxin of 76 aas.


Conotoxin of Tetrahymena thermophila


Uncharacterized protein of 82 aas and 1 TMS.

UP of Cochliobolus sativus (Common root rot and spot blotch fungus) (Bipolaris sorokiniana)


Uncharacterized protein of 63 aas and possibly one C-terminal TMS.

UP of Kordia sp.