ImKTX58

Last updated
ImKTX58
Identifiers
3D model (JSmol)
  • InChI=1S/C183H283N57O52S8/c1-15-91(8)143(236-159(269)111(34-21-25-57-187)215-178(288)145(94(11)244)237-163(273)121(68-101-73-197-87-206-101)223-174(284)141(89(4)5)234-148(258)105(188)46-49-133(189)248)177(287)216-115(53-62-294-14)158(268)229-128-81-297-299-83-130(169(279)220-118(64-97-40-44-103(247)45-41-97)161(271)224-123(181(291)292)65-98-70-200-106-30-17-16-29-104(98)106)232-179(289)146(95(12)245)238-171(281)131-84-300-298-82-129-168(278)221-120(67-100-72-196-86-205-100)150(260)202-76-137(252)233-140(88(2)3)176(286)239-144(93(10)243)173(283)203-75-136(251)209-108(35-26-58-198-182(191)192)151(261)207-92(9)147(257)218-119(66-99-71-195-85-204-99)149(259)201-74-135(250)208-107(31-18-22-54-184)152(262)227-126(166(276)214-114(52-61-293-13)157(267)222-122(69-134(190)249)162(272)211-109(32-19-23-55-185)153(263)210-110(155(265)230-131)33-20-24-56-186)79-295-296-80-127(167(277)219-117(63-96-38-42-102(246)43-39-96)160(270)217-116(48-51-139(255)256)180(290)240-60-28-37-132(240)172(282)231-129)228-156(266)113(47-50-138(253)254)213-154(264)112(36-27-59-199-183(193)194)212-164(274)124(77-241)226-175(285)142(90(6)7)235-165(275)125(78-242)225-170(128)280/h16-17,29-30,38-45,70-73,85-95,105,107-132,140-146,200,241-247H,15,18-28,31-37,46-69,74-84,184-188H2,1-14H3,(H2,189,248)(H2,190,249)(H,195,204)(H,196,205)(H,197,206)(H,201,259)(H,202,260)(H,203,283)(H,207,261)(H,208,250)(H,209,251)(H,210,263)(H,211,272)(H,212,274)(H,213,264)(H,214,276)(H,215,288)(H,216,287)(H,217,270)(H,218,257)(H,219,277)(H,220,279)(H,221,278)(H,222,267)(H,223,284)(H,224,271)(H,225,280)(H,226,285)(H,227,262)(H,228,266)(H,229,268)(H,230,265)(H,231,282)(H,232,289)(H,233,252)(H,234,258)(H,235,275)(H,236,269)(H,237,273)(H,238,281)(H,239,286)(H,253,254)(H,255,256)(H,291,292)(H4,191,192,198)(H4,193,194,199)/t91-,92-,93+,94+,95+,105-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,140-,141-,142-,143-,144-,145-,146-/m0/s1
    Key: YZPIASKHVZBKSO-ABEJSSCSSA-N
  • N[C@@]([H])(CCC(=O)N)C(=O)N[C@@]([H])(C(C)C)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])([C@]([H])(CC)C)C(=O)N[C@@]([H])(CCSC)C(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(C(C)C)C(=O)N[C@@]([H])(CO)C(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(CCC(=O)O)C(=O)N1[C@@]([H])(CCC1)C(=O)N[C@@]([H])(CS5)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)NCC(=O)N[C@@]([H])(C(C)C)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)NCC(=O)N[C@@]([H])(CCCNC(=N)N)C(=O)N[C@@]([H])(C)C(=O)N[C@@]([H])(CC1=CN=C-N1)C(=O)NCC(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CS4)C(=O)N[C@@]([H])(CCSC)C(=O)N[C@@]([H])(CC(=O)N)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CCCCN)C(=O)N[C@@]([H])(CS5)C(=O)N[C@@]([H])([C@]([H])(O)C)C(=O)N[C@@]([H])(CS3)C(=O)N[C@@]([H])(Cc1ccc(O)cc1)C(=O)N[C@@]([H])(CC(=CN2)C1=C2C=CC=C1)C(=O)O
Properties
C183H283N57O52S8
Molar mass 4370.10 g·mol−1
Related compounds
Related compounds
 LmKTX10, ImKTx88
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

ImKTX58 (also known as kappa-Buthitoxin-Im1a) is a peptide toxin from the venom of the scorpion species Isometrus maculatus (also known as the lesser brown scorpion). It is known for its selective inhibition of Kv1.3 channels, on which it acts as a pore-blocker.

Contents

Etymology

The name of ImKTX58 stems from its origin in the scorpion species Isometrus maculatus (Im), its action on potassium channels (K), its categorization as a toxin (TX), and its identification as the 58th clone in the Isometrus maculatus cDNA library (58). [1] The protein is also referred to as kappa-Buthitoxin-Im1a, in line with the rational nomenclature system used for toxins produced by venomous species. [1] [2]

Source

ImKTX58 is derived from the venom secreted by the glands of Isometrus maculatus (also known as the lesser brown scorpion) which belongs to the Buthidae family. [1] It was first reported from Isometrus maculatus specimens found in Hainan, China. [1]

Chemistry

Structure

The entire cDNA of ImKTX58 comprises 404 base pairs and codes for a 60 amino acid precursor, including a signal peptide of 22 amino acids. [1] The mature ImKTX58 protein consists of 38 amino acid residues and has a molecular mass of 4370.14 Da. [1] It features an α-helix at the N-terminus and β-sheet framework at the C-terminus reinforced by cysteine residues and three disulfide bridges, which contribute to its stability. [1]

Amino acid sequence of the mature protein: QVHTKIMCSVSRECYEPCHGVTGRAHGKCMNKKCTCYW. [1]

Family and homology

ImKTX58 is a small polypeptide toxin from the α-KTX subfamily. [1] It shares sequence homology with other potassium channel blockers from the same subfamily, such as LmKTX10 [3] (74% similarity) and ImKTX88 [4] (54% similarity). [1]

Target and channel specificity

ImKTX58 is a potent selective blocker of the Kv1.3 channel, which is a voltage-gated potassium channel essential in regulating neuronal excitability, and in the activation and proliferation of effector memory T cells. [1] Electrophysiological recordings show that ImKTX58 effectively inhibits Kv1.3-mediated currents in Jurkat T cells (IC50 = 39.41 ± 11.4 nM) and HEK293T cells (IC50 = 10.42 ± 1.46 nM). [1]

Moreover, ImKTX58 demonstrates a high selectivity for the Kv1.3 channel over other voltage-gated potassium channels, such as Kv1.1, Kv1.2, Kv1.5, as well as calcium-activated potassium channels SK2, SK3, BK, and voltage-gated sodium channels Nav1.4, Nav1.5, Nav1.7. [1]

Mode of action

ImKTX58 exerts a partially reversible pore-blocking effect by forming a protein complex with Kv1.3 channels. [1] The amino acid residues at the C-terminus of the toxin, specifically Lys28, Asn31, Arg24, and Tyr37, are significant for the interaction between ImKTX58 and Kv1.3 channels. [1] These residues act through mechanisms such as hydrogen bonding, salt bridges, and hydrophobic interactions. [1] In particular, the Lys28 residue is crucial for effectively blocking the pore of the Kv1.3 channel. [1] This pore blockage leads to increased cellular excitability, ultimately disrupting the regulation of the cell membrane potential. [1] In neurons with higher Kv1.3 expression this results in a higher frequency of action potentials, a slight reduction in their amplitude, and a modest depolarization. [1]

Toxicity

The toxicity of ImKTX58 has not been thoroughly characterized. However, Isometrus maculatus has been identified as a species with venom of relatively weak overall toxicity. [5]

Related Research Articles

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<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion Hoffmanihadrurus gertschi that is a reversible blocker of the Shaker B K+-channel, a type of voltage-gated potassium channels.

<span class="mw-page-title-main">ImKTx88</span>

ImKTx88 is a selective inhibitor of the Kv1 ion channel family that can be isolated from the venom of the Isometrus maculatus. This peptide belongs to the α-KTx subfamily and is classified as a pore-blocking toxin.

BmP02, also known as α-KTx 9.1 or Bmkk(6), is a toxin from the Buthus Martensi Karsch (BmK) scorpion. The toxin acts on potassium channels, blocking Kv1.3 and slowing the deactivation of Kv4.2. BmP02 is not toxic to humans or mice.

<span class="mw-page-title-main">Tst26</span> Toxin from scorpion venom

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<span class="mw-page-title-main">OdK2</span>

OdK2 is a toxin found in the venom of the Iranian scorpion Odonthobuthus doriae. It belongs to the α-KTx family, and selectively blocks the voltage-gated potassium channel Kv1.3 (KCNA3).

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

<span class="mw-page-title-main">OSK3</span>

OSK3, from the venom of the scorpion Orthochirus scrobiculosus, is a potassium channel blocker that belongs to the α-KTx8 subfamily and targets the voltage-gated potassium channels KCNA2 (Kv1.2), and KCNA3 (Kv1.3).

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<span class="mw-page-title-main">LmKTT-1a</span> Scorpion Toxin

LmKTT-1a is a bifunctional Kunitz-type toxin belonging to the ẟ-KTx subfamily, which can be found in the venom of Lychasmucronatus. As a bifunctional toxin, it both inhibits trypsin activity and blocks Kv1 channels with a weak selectivity towards Kv1.3 channels.

<span class="mw-page-title-main">Ctri9577</span> Scorpion toxin

Ctri9577 (α-KTx15.10) is a neurotoxin present in the venom of the Chaerilus tricostatus scorpion, which is a potent blocker of the voltage-gated potassium channel Kv1.3, and a gating modifier of Kv4.3 channels.

κ-KTx2.5 is a toxin found in the venom of the scorpion, Opisthacanthuscayaporum. The toxin belongs to the κ-KTx family, a channel blocker family that targets voltage-gated potassium channels (Kv) 1.1 and 1.4.

Cm28, a scorpion toxin from Centruroides margaritatus, selectively blocks voltage-gated potassium channels KV1.2 and KV1.3 with high affinity. It also suppresses the activation of human CD4+ effector memory T cells, suggesting its potential as a therapeutic agent for autoimmune diseases. Phylogenetic analysis reveals that Cm28 belongs to a new α-KTx subfamily, highlighting its unique structural and functional properties for potential drug development.

<span class="mw-page-title-main">Hg1 (toxin)</span> Hg1 scorpion toxin

Hg1 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.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Zhang, Xu; Zhao, Qianru; Yang, Fan; Lan, Zhen; Li, Yi; Xiao, Min; Yu, Hui; Li, Ziyi; Zhou, Yongsheng; Wu, Yingliang; Cao, Zhijian; Yin, Shijin (2022). "Mechanisms underlying the inhibition of KV1.3 channel by scorpion toxin ImKTX58". Molecular Pharmacology. 102 (3): 150–160. doi: 10.1124/molpharm.121.000480 . ISSN   0026-895X. PMID   35764383.
  2. ↑ King, Glenn F.; Gentz, Margaret C.; Escoubas, Pierre; Nicholson, Graham M. (2008). "A rational nomenclature for naming peptide toxins from spiders and other venomous animals". Toxicon. 52 (2): 264–276. Bibcode:2008Txcn...52..264K. doi:10.1016/j.toxicon.2008.05.020. hdl: 10453/9701 . ISSN   0041-0101. PMID   18619481.
  3. ↑ Liu, Jun; Ma, Yibao; Yin, Shijin; Zhao, Ruiming; Fan, Shaozhong; Hu, Youtian; Wu, Yingliang; Cao, Zhijian; Li, Wenxin (2009). "Molecular cloning and functional identification of a new K+ channel blocker, LmKTx10, from the scorpion Lychas mucronatus". Peptides. 30 (4): 675–680. doi:10.1016/j.peptides.2008.11.015. ISSN   0196-9781. PMID   19103241.
  4. ↑ Han, Song; Hu, Youtian; Zhang, Ruhong; Yi, Hong; Wei, Jingjing; Wu, Yingliang; Cao, Zhijian; Li, Wenxin; He, Xiaohua (2011). "ImKTx88, a novel selective Kv1.3 channel blocker derived from the scorpion Isometrus maculates". Toxicon. 57 (2): 348–355. Bibcode:2011Txcn...57..348H. doi:10.1016/j.toxicon.2010.12.015. ISSN   0041-0101. PMID   21194541.
  5. ↑ Kawachi, Tomoyuki; Miyashita, Masahiro; Nakagawa, Yoshiaki; Miyagawa, Hisashi (2013). "Isolation and characterization of an anti-insect β-toxin from the venom of the scorpion Isometrus maculatus". Bioscience, Biotechnology, and Biochemistry. 77 (1): 205–207. doi:10.1271/bbb.120697. ISSN   1347-6947. PMID   23291760.
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