Cl6b

Cl6b (μ-THTX-Cl6b) is a peptide toxin from the venom of the spider Cyriopagopus longipes. It acts as a sodium channel blocker: Cl6b significantly and persistently reduces currents through the tetrodotoxin-sensitive sodium channels Na_V1.2-1.4, Na_V1.6, and Na_V1.7.

Structure

The Cl6b peptide has a molecular weight of 3708.9 Da. It contains 33 amino acid residues, among which six cysteines that engage in three disulfide bonds to form a structural motif known as an inhibitor cystine knot (ICK).^[1] This structure grants stability^[2] to the toxin and has been identified previously in other spider peptide toxins that share high sequence similarity to Cl6b.

Family

Simultaneously with the isolation of Cl6b, another peptide toxin known as Cl6a was characterized from the same spider species. The two Cl6 peptides share a sequence identity of 78.8%, including the six cysteines that make both peptides adopt the ICK motif.^[1]

Target

Cl6b acts as a selective sodium channel blocker.

Source in nature

Cl6b has been isolated from Cyriopagopus longipes, an Asian spider mainly found in Thailand, Cambodia, Laos, and China.

Activity mechanism

Cl6b significantly reduces currents through the tetrodotoxin-sensitive sodium channels Na_V1.2, Na_V1.3, Na_V1.4, Na_V1.6, and Na_V1.7, with no effect on the tetrodotoxin-resistant sodium channels Na_V1.5, Na_V1.8, Na_V1.9. Cl6b exhibits a particularly high affinity to Na_V1.7 channels, which are present in great numbers in nociceptors (pain neurons) located at the dorsal root ganglion. The activity of Cl6b on Na_V1.7 has similar characteristics compared to previously reported Na_V1.7-peptide inhibitors, such as HWTX-IV.,^[1] as Cl6b binds to the domain II segments three and four, which are part of the domain's voltage sensor.^[1] The binding is high-affinity (half-maximal inhibitory concentration (IC₅₀) 18.80 ± 2.4 nM). It is also irreversible, which poises it as a candidate for the development of long-term in-vivo analgesia.

References

^ ^a ^b ^c ^d Zhang, Qingfeng; Si, Yuxin; Yang, Li; Wang, Li; Peng, Shuijiao; Chen, Yiming; Chen, Minzhi; Zhou, Xi; Liu, Zhonghua (September 2020). "Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels". Toxins. 12 (9): 529. doi:10.3390/toxins12090529. ISSN 2072-6651. PMC 7551932. PMID 32824960.
^ Craik, David J.; Daly, Norelle L.; Waine, Clement (1 January 2001). "The cystine knot motif in toxins and implications for drug design". Toxicon. 39 (1): 43–60. doi:10.1016/S0041-0101(00)00160-4. ISSN 0041-0101. PMID 10936622.

[cl6b_paper-1] Zhang, Qingfeng; Si, Yuxin; Yang, Li; Wang, Li; Peng, Shuijiao; Chen, Yiming; Chen, Minzhi; Zhou, Xi; Liu, Zhonghua (September 2020). "Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels". Toxins. 12 (9): 529. doi:10.3390/toxins12090529. ISSN 2072-6651. PMC 7551932. PMID 32824960.

[ICK_motif-2] Craik, David J.; Daly, Norelle L.; Waine, Clement (1 January 2001). "The cystine knot motif in toxins and implications for drug design". Toxicon. 39 (1): 43–60. doi:10.1016/S0041-0101(00)00160-4. ISSN 0041-0101. PMID 10936622.

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