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Hg1 (toxin)

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Hg1 (toxin)
Identifiers
  • N[C@@]([H])(CCSC)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(C(C)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(C)C(=O)NCC(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(C(C)C)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CS2)C(=O)N[C@@]([H])(CC(C)C)C(=O)N[C@@]([H])(CC(C)C)C(=O)N1[C@@]([H])(CCC1)C(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)NCC(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(CCCCN)C(=O)NCC(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CC(=O)O)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)NCC(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)NCC(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(CS2)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)NCC(=O)N[C@@]([H])(Cc1ccccc1)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(Cc1ccccc1)C(=O)NCC(=O)NCC(=O)N[C@@]([H])(CCCCN)C(=O)O
Properties
C441H666N124O120S7
Molar mass 9849.35 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Hg1/Delta-Ktx 1.1
Hg1 Neurotoxin
Identifiers
Organism Hadrurus gertschi
Symbol N/A
UniProt P0C8W3
Search for
Structures Swiss-model
Domains InterPro

Hg1 (also known as Delta-Ktx 1.1) is a Kunitz-type peptide ion channel toxin derived from the scorpion Hadrurus gertschi. Its mode of action is that it selectively inhibits the potassium channel Kv1.3 and, with a lower affinity, channels Kv1.1 and Kv1.2.

Etymology and source

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The Hg1 toxin is named after the Mexican scorpion Hadrurus gertschi that produces it, which belongs to the Caraboctonidae family.[1][2] This scorpion is also known as Hoffmannihadrurus gertschi.[3] The alternative name of Hg1 is Delta-Ktx 1.1.[4]

Chemistry

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Hg1 has a sequence of 88 amino acids with three disulfide bonds between Cys29-Cys79, Cys38-Cys62 and Cys54-Cys75.[4] Hg1 has a molecular weight of 9,855 Da.[4] It belongs to the Kunitz-type potassium channel family toxins.[5] These toxins are classified in three different groups, according to their disulfide bridge pattern.[5] Hg1 is classified as a member of the first group, showing classical disulfide pairing, comparable to the HWTX-XI toxin in spiders, dendrotoxin K in snakes, and APEKTx1 in sea anemones.[5]

Amino acid sequence [4]

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MIIFYGLFSILVLTSINIAEAGHHNRVNCLLPPKTGPCKGSFARYYFDIETGSCKAFIYGGCEGNSNNFSEKHHCEKRCRGFRKFGGK

Target

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The toxin primarily inhibits voltage-gated potassium channels and is highly selective for channel Kv1.3 with an IC50 of 6.2 ± 1.2 nM.[5] With a lower affinity the toxin also inhibits potassium channels Kv1.1 and Kv1.2.[5]

Channel Reduction in ion channel conductance (1 μM Hg1) [4][5]
Kv1.1 <50%
Kv1.2 <50%
Kv1.3 ≈80%

Similar to other Kunitz-type toxins, recombinant Hg1 was revealed to inhibit the serine protease trypsin (dissociation constant (Kd) = 107 nM), having the highest affinity to it compared to other Kunitz-type potassium channel toxins, such as LmKTT-1a (Kd = 140 nM), LmKTT-1b (Kd = 160 nM), LmKTT-1c (Kd = 124 nM), and BmKTT-1 (Kd = 136 nM).[5]

Mode of action

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Compared to other Kunitz-type toxins that act on potassium channels through their N-terminal regions, alanine-scanning supports that the Hg1 toxin interacts with the Kv1.3 channel through its residues on the C-terminal region.[5] Based on computational modelling, the toxin is thought to inhibit the channel through pore-blocking mechanisms of its Lys-56 residue and hydrophobic interactions between residues of the toxin (Arg-57, Phe-61, Lys-63) and residues of the Kv1.3 channel.[5]

References

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  1. ^ Ding, Li; Wang, Xiaobo; Liu, Hongyan; San, Mingkui; Xu, Yue; Li, Jian; Li, Shan; Cao, Zhijian; Li, Wenxin; Wu, Yingliang; Chen, Zongyun (2015-11-01). "A new Kunitz-type plasmin inhibitor from scorpion venom". Toxicon. 106: 7–13. Bibcode:2015Txcn..106....7D. doi:10.1016/j.toxicon.2015.09.004. ISSN 0041-0101. PMID 26363290.
  2. ^ Schwartz, Elisabeth F.; Diego-Garcia, Elia; Rodríguez de la Vega, Ricardo C.; Possani, Lourival D. (2007-05-16). "Transcriptome analysis of the venom gland of the Mexican scorpion Hadrurus gertschi (Arachnida: Scorpiones)". BMC Genomics. 8 (1): 119. doi:10.1186/1471-2164-8-119. ISSN 1471-2164. PMC 1904202. PMID 17506894.
  3. ^ Francke, Oscar F.; Prendini, Lorenzo (June 2008). "Phylogeny and classification of the giant hairy scorpions, Hadrurus Thorell (Iuridae Thorell): A reappraisal". Systematics and Biodiversity. 6 (2): 205–223. Bibcode:2008SyBio...6..205F. doi:10.1017/S1477200008002697. ISSN 1477-2000.
  4. ^ a b c d e "UniProt". www.uniprot.org. Retrieved 2024-10-22.
  5. ^ a b c d e f g h i Chen, Zong-Yun; Hu, You-Tian; Yang, Wei-Shan; He, Ya-Wen; Feng, Jing; Wang, Bin; Zhao, Rui-Ming; Ding, Jiu-Ping; Cao, Zhi-Jian; Li, Wen-Xin; Wu, Ying-Liang (April 2012). "Hg1, Novel Peptide Inhibitor Specific for Kv1.3 Channels from First Scorpion Kunitz-type Potassium Channel Toxin Family". Journal of Biological Chemistry. 287 (17): 13813–13821. doi:10.1074/jbc.m112.343996. ISSN 0021-9258. PMC 3340210. PMID 22354971.
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