| Delta Hexatoxin Hv1a | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 3D stick model of delta-hexatoxin-Hv1 (versutoxin) | |||||||||
| Identifiers | |||||||||
| Symbol | δ-HXTX-Hv1a | ||||||||
| Pfam | PF05353 | ||||||||
| InterPro | IPR008017 | ||||||||
| OPM superfamily | 112 | ||||||||
| OPM protein | 1vtx | ||||||||
| |||||||||
Delta hexatoxin Hv1 (δ-HXTX-Hv1a,Versutoxin, orVersutotoxin, formerly known asDelta atracotoxin Hv1 andδ-ACTX-Hv1a)[1] is aneurotoxiccomponent found in the venom of theAustralian funnel web spider (Atrax robustus).
Delta hexatoxin Hv1 can result in fatality for primates, bydownregulating the inactivation ofvoltage gated sodium ion channels (VGSCs) found in motorneurons.
The structure of versutoxin contains a central beta region with a cystine knot motif, commonly found in other neurotoxic polypeptides, but not found insea anemone oralpha-scorpion toxins despite their similar effects in terms ofsodium channel modulation.[2][3]
In 1997, Jamie I. Fletcher and his research associates introduced new nomenclature for classifying Australian funnel web spider toxins. They suggested replacing the trivial name 'versutoxin' with delta-hexatoxin-Hv1 instead. The delta represents the mainbiological activity of the neurotoxin;inhibiting sodium channels.[2]
In more recent research,atracotoxins have been rebranded ashexatoxins, but the two are still used interchangeably along with the abbreviations HXTX and ACTX. Delta and Hv1 are still used to specify the neurotoxic peptide versutoxin.
Delta hexatoxin Hv1 is a tightly foldedpolypeptide that contains a chain of 42 amino acid residues and has the chemical formula C206H318N58O60S9. The amino acid sequence of delta hexatoxin Hv1 is:
The tertiary structure ofδ-ACTX-Hv1 contains a coreβ region that is made up of the residuesCys1–Cys8,Cys14–Val21, andSer30–Ser33, withTyr22–Gly29 protruding outwards. Theβ region has a three-strandedantiparallelβ sheet comprisingAsn6–Trp7 (β1),Met18–Val21 (β2), and Ser30–Ser33 (β3). The C-terminal end of the shortβ1 is held in place by a bifurcated hydrogen bond between the Cys8 amide proton and the carbonyl oxygens of the two residues precedingβ strand 3 (Gln28 and Gly29). Theβ region also contains type IIβ turns at Lys3–Asn6 and Cys15–Met18 with a rarecis peptide bond at Cys16–Met 17. The nonpolarC-terminal310 helix formed byIle35–Lys41, bordering Lys40 and Lys41 and connecting toβ region with adisulphide bond next to aβ turn. Theβ region contains hydrophobic cysteine sidechains bordered by a lysine sidechain.Three of the four disulphide bonds form theICK. The structure of the cystine knot motif found in versutoxin is similar to the one found ingurmarin, a 35-residue plant polypeptide used to test the inhibition of sweet taste receptors.[2]
The peptides found in various venomous animals are capable of reducing inflammation, inactivating ion channels, and altering neurotransmitter production. Therefore, understanding the neurotoxins produced by these animals can potentially used as therapeutics for slowing down neurodegeneration. There are still many limitations in this research due to a lack of sufficient natural resources, however usingrecombinant DNA is used a way to mitigate this issue by promotingheterologous protein expression andpeptide chemical synthesis.[6]
Versutoxin, in particular, is capable of affecting the voltage-gated sodium channels of prey. Studies conducted on primates show that δ-hexatoxin causes the neurotoxic effects by binding to VGSCs on neurons. δ-ACTX affects VGSCs similarly to α-scorpion and sea anemone toxins. Both of these types of toxins bind specifically to site 3 on the sodium channel. Despite versutoxin having aICK which both α-scorpion and sea anemone toxins lack, researchers determined several other similarities in their anionic and cationic residue topography and confirmed that versutoxin also binds to site 3. They tested this by seeing how purifieddelta-ACTX-Hv1a affects the isolated cockroach (Periplaneta americana)dorsal unpaired median (DUM) neurons using adouble sucrose-gap technique and comparing it to how it affected ratdorsal root ganglion (DRGs) neurons. They noted how delta-ACTX-Hv1a specifically affected voltage-gated Na+ channels of both specimens resulting in incomplete steady-state Na+ channel inactivation.[7]
Voltage gated sodium channels have been used as therapeutic targets in various modes of research, allowing versutoxin to also be used in the process. Some notable diseases versutoxin has been used as a potential therapeutic tool in include: Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, and sclerosis.[6]
Versutoxin has also been used inbiopesticide research. The structure ofrecombinantNemertide α-1 (a neurotoxin found in carnivorous marine ribbon worms) was compared against recombinant delta-hexatoxin-Hv1 due to their similar VSGC targeting abilities. However, as of right now, not enough research has been done about the off target effects.[8]