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HNTX-I, the positively charged residues and a vicinal hydrophobic patch have most influence on the binding to the sodium channels. HNTX-IV has a positively charged patch containing the amino acids Arg26, Lys27, His28, Arg29 and Lys32, of which Lys27, Arg29 and Lys32 are the most important for interaction with the TTX-S VGSCs. HNTX-V also shows an interface of positively charged amino acids that are responsible for the binding with the TTX-S VGSCs, where also Lys27 and Arg29 are the most important. Subtle differences in the positively charged patch can result in altered electrostatic properties, causing altered pharmacological effects.
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For the blockage of sodium channels, electrostatic interactions or hydrogen bonds are needed. Important for the electrostatic interaction is the presence of a positively charged region in the toxin, because the receptor site of the sodium channel contains a lot of negatively charged residues. In
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HNTX-I, HNTX-III, HNTX-IV, and HNTX-V are thought to bind to site 1 of voltage-dependent sodium channels, similar to TTX, and thereby block the channel pore. They do not alter activation and inactivation kinetics. Ion selectivity of the VGSCs is not changed by hainantoxin. The mode of action of
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HNTX-IV has 35 amino acid residues with a total molecular weight of 3989 Da. The first strand consists of an antiparallel beta-sheet. The complete amino acid sequence of HNTX-IV is NH2-ECLGFG KGCNPS NDQCCK SSNLVC SRKHRW CKYEI-CONH2. Lys 27, His28, Arg29 and Lys 32 are the neuroactive amino acid
142:
are not affected. HNTX-III and HNTX-IV are part of the
Huwentoxin-I family. Toxins from the Huwentoxin-I family are thought to bind to site 1 on the sodium channels. Other hainantoxins bind at site 3 of the sodium channels. HNTX-I specifically blocks mammalian
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HNTX-V consists of 35 amino acid residues. The whole amino acid residue sequence of HNTX-V is NH2-ECLGFG KGCNPS NDQCCK SANLVC SRKHRW CKYEI-COOH. At the active binding site of HNTX-V, Lys27 and Arg 29 are the most important.
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Liu Z et al. Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the
Chinese bird spider Selenocosmia hainana. Cell Mol Life Sci. 2003 May;60(5):972-8.
34:, thereby causing blockage of neuromuscular transmission and paralysis. Currently, 13 different hainantoxins are known (HNTX-I – HNTX-XIII), but only HNTX-I, -II, -III, -IV and -V have been investigated in detail.
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Xiao YC, Liang SP. Purification and characterization of
Hainantoxin-V, a tetrodotoxin-sensitive sodium channel inhibitor from the venom of the spider Selenocosmia hainana. Toxicon. 2003 May;41(6):643-50.
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Xiao YC, Liang SP. Inhibition of sodium channels in rat dorsal root ganglion neurons by
Hainantoxin-IV, a novel spider toxin. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003 Jan;35(1):82-5.
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Li D et al. Structure--activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers. J Biol Chem. 2004 Sep 3;279(36):37734-40. Epub 2004 Jun 16.
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Hainantoxins selectively inhibit tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs). Voltage-gated Ca2+ channels (VGCCs), tetrodotoxin-resistant (TTX-R) VGSCs and rectifier-delayed
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Liu Y et al. A positively charged surface patch is important for hainantoxin-IV binding to voltage-gated sodium channels. J Pept Sci. 2012 Oct;18(10):643-9. doi: 10.1002/psc.2451. Epub 2012 Aug 27.
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Li D, et al. Function and solution structure of hainantoxin-I, a novel insect sodium channel inhibitor from the
Chinese bird spider Selenocosmia hainana. FEBS Lett. 2003 Dec 18;555(3):616-22.
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Zeng XZ et al. Sequence-specific assignment of 1H-NMR resonance and determination of the secondary structure of
Jingzhaotoxin-I. Acta Biochim Biophys Sin (Shanghai). 2005 Aug;37(8):567-72.
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Xu X et al. Solid-phase synthesis and biological characterization of S12A-HNTX-IV and R29A-HNTX-IV: two mutants of hainantoxin-IV. Sheng Wu Gong Cheng Xue Bao. 2005 Jan;21(1):92-6.
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HNTX-II has a molecular weight of 4253 Da and contains 37 amino acid residues. The complete amino acid sequence of HNTX-II is NH2-LFECSV SCEIEK EGNKD CKKKK CKGGW KCKFN MCVKV-COOH.
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Xiao Y, Liang S. Inhibition of neuronal tetrodotoxin-sensitive Na+ channels by two spider toxins: hainantoxin-III and hainantoxin-IV. Eur J Pharmacol. 2003 Sep 5;477(1):1-7.
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Hainantoxins can affect both vertebrates and invertebrates. HNTX-I has no significant effect on insects or rats. HNTX-III and HNTX-IV cause spontaneous contractions of the
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Wang RL et al. Mechanism of action of two insect toxins huwentoxin-III and hainantoxin-VI on voltage-gated sodium channels. J Zhejiang Univ Sci B. 2010 Jun;11(6):451-7.
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The structure of HNTX-III consists of 33-35 amino acid residues, which form a beta-sheet with connections between Asp7 and Cys9, Tyr21 and Ser23, and Lys27 and Val30.
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Honma T et al. Novel peptide toxins from acrorhagi, aggressive organs of the sea anemone
Actinia equina. Toxicon. 2005 Dec 1;46(7):768-74. Epub 2005 Sep 23.
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is HNTX-I. It has 33 amino acid residues, with a total molecular weight of 3605-3608 Da. HNTX-I contains a short triple-stranded anti-parallel
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Nicholson GM. Insect-selective spider toxins targeting voltage-gated sodium channels. Toxicon. 2007 Mar 15;49(4):490-512. Epub 2006 Dec 5.
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of 1.41 μg/g. The intraperitoneal LD50 value of HNTX-IV in mice is 0.2 mg/kg. HNTX-III is 40 times more potent that HNTX-IV.
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Pan J-Y, Yu Z-Q. Isolation and characterization of
Hainantoxin-II, a new neurotoxic peptide from the Chinese bird spider (
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smooth muscle of the rat. HNTX-III and HNTX-IV are able to paralyze cockroaches, and HNTX-IV can even paralyze rats.
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HNTX-III and HNTX-IV have an antagonistic effect on the toxin BMK-I, a toxic protein in the venom of the scorpion
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Hainantoxins I, III, IV and V show high homology, including the presence of three disulfide bonds that form an
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oocytes. HNTX-I is a weak antagonist of the vertebrate TTX-S VGSCs, but is more potent on insect VGSCs.
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91:. The amino acid residues His28 and Asp26 are needed for the bioactivity of HNTX-I.
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XIONG Xia et al. Effects of Arg26 and Lys27 mutation on the bioactivity of HNTX-IV
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HNTX-I, HNTX-III, HNTX-IV and HNTX-V are made by the
Chinese bird spider
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HNTX-II is unclear, but is unlikely to involve sodium channels.
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Intracerebroventricular injection in mice with HNTX-II shows a
335:"Family:%22huwentoxin-1 family%22 in UniProtKB"
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26:. Hainantoxins specifically inhibit
79:The main component of the venom of
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32:Voltage-gated sodium channels
512:). Zool. Res. 2010 6:570-4.
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16:Hainantoxins (HNTX) are
69:inhibitor cysteine knot
48:Ornithoctonus hainana
52:Selenocosmia hainana
510:Haplopelma hainanum
44:Haplopelma hainanum
23:Haplopelma hainanum
546:Ion channel toxins
140:potassium channels
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71:(ICK) motif.
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28:tetrodotoxin
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541:Neurotoxins
30:-sensitive
18:neurotoxins
535:Categories
276:References
116:residues.
89:beta-turns
85:beta-sheet
81:O. hainana
163:Table 1:
87:and four
63:Structure
58:Chemistry
244:and the
236:Symptoms
231:Toxicity
215:42.3 nM
205:44.6 nM
191:HNTX-III
155:Affinity
103:HNTX-III
201:HNTX-IV
195:1.1 nM
134:Channel
111:HNTX-IV
95:HNTX-II
38:Sources
211:HNTX-V
185:68 μM
181:HNTX-I
145:Nav1.2
129:Target
120:HNTX-V
75:HNTX-I
175:IC50
258:LD50
252:LD50
165:IC50
54:).
537::
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50:,
46:(=
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