{{Short description|Spider-derived neurotoxin}} {{Orphan|date=January 2024}}

'''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<sub>V</sub>1.2-1.4, Na<sub>V</sub>1.6, and Na<sub>V</sub>1.7.

==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).<ref name="cl6b_paper" /> This structure grants stability<ref name="ICK_motif">{{cite journal |last1=Craik |first1=David J. |last2=Daly |first2=Norelle L. |last3=Waine |first3=Clement |title=The cystine knot motif in toxins and implications for drug design |journal=Toxicon |date=1 January 2001 |volume=39 |issue=1 |pages=43–60 |doi=10.1016/S0041-0101(00)00160-4 |pmid=10936622 |bibcode=2001Txcn...39...43C |url=https://doi.org/10.1016/S0041-0101(00)00160-4 |language=en |issn=0041-0101|url-access=subscription }}</ref> 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.<ref name="cl6b_paper">{{cite journal |last1=Zhang |first1=Qingfeng |last2=Si |first2=Yuxin |last3=Yang |first3=Li |last4=Wang |first4=Li |last5=Peng |first5=Shuijiao |last6=Chen |first6=Yiming |last7=Chen |first7=Minzhi |last8=Zhou |first8=Xi |last9=Liu |first9=Zhonghua |title=Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels |journal=Toxins |date=September 2020 |volume=12 |issue=9 |pages=529 |doi=10.3390/toxins12090529 |pmid=32824960 |pmc=7551932 |language=en |issn=2072-6651|doi-access=free }}</ref>

==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<sub>V</sub>1.2, Na<sub>V</sub>1.3, Na<sub>V</sub>1.4, Na<sub>V</sub>1.6, and Na<sub>V</sub>1.7, with no effect on the tetrodotoxin-resistant sodium channels Na<sub>V</sub>1.5, Na<sub>V</sub>1.8, Na<sub>V</sub>1.9. Cl6b exhibits a particularly high affinity to Na<sub>V</sub>1.7 channels, which are present in great numbers in nociceptors (pain neurons) located at the dorsal root ganglion. The activity of Cl6b on Na<sub>V</sub>1.7 has similar characteristics compared to previously reported Na<sub>V</sub>1.7-peptide inhibitors, such as HWTX-IV.,<ref name="cl6b_paper" /> as Cl6b binds to the domain II segments three and four, which are part of the domain's voltage sensor.<ref name="cl6b_paper" /> The binding is high-affinity (half-maximal inhibitory concentration (IC<sub>50</sub>) 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 ==

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Category:Neurotoxins Category:Spider toxins Category:Sodium channel blockers Category:Ion channel toxins