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Jingzhaotoxin III

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Jingzhaotoxin III is a selective blocker of NaV1.5 channels with IC50 value of 348 nM. It is selective for NaV1.5 channels and shows no effect on other isoforms. It inhibits the activation of cardiac sodium channels by binding to the NaV1.5 S3-S4 linker of domain II. It has no effect on sodium channels in dorsal root ganglion neurons.

Category

Peptide Inhibitors

Catalog number

BAT-010361

CAS number

925463-91-8

Molecular Formula

C174H241N47O46S6

Molecular Weight

3918.44

Specification
Reference Reading

IUPAC Name

(2S)-1-[(2S)-2-[[(2S)-4-carboxy-2-[[(2S)-3-methyl-2-[[(2S)-2-[[(1R,7S,13S,19S,25S,28R,33R,36S,42S,45S,48S,51S,54R,57S,60S,66S,69R,74R,83S,86S,89S,92S)-13,48,66,92-tetrakis(4-aminobutyl)-74-[[(2S)-2-[[2-[[(2S)-2-amino-3-carboxypropanoyl]amino]acetyl]amino]-4-carboxybutanoyl]amino]-83-benzyl-7-(3-carbamimidamidopropyl)-45-[(1R)-1-hydroxyethyl]-51-(hydroxymethyl)-60-[(4-hydroxyphenyl)methyl]-36,42,86,89-tetrakis(1H-indol-3-ylmethyl)-57-methyl-a,2,5,8,11,14,20,26,35,38,41,44,47,50,53,56,59,62,65,68,75,78,81,84,87,90,93-heptacosaoxo-30,31,71,72,96,97-hexathia-3,6,9,12,15,21,27,34,37,40,43,46,49,52,55,58,61,64,67,76,79,82,85,88,91,94,99-heptacosazapentacyclo[52.40.4.228,69.015,19.021,25]hectane-33-carbonyl]amino]propanoyl]amino]butanoyl]amino]butanoyl]amino]propanoyl]pyrrolidine-2-carboxylic acid

Synonyms

H-Asp-Gly-Glu-Cys(1)-Gly-Gly-Phe-Trp-Trp-Lys-Cys(2)-Gly-Arg-Gly-Lys-Pro-Pro-Cys(3)-Cys(1)-Lys-Gly-Tyr-Ala-Cys(2)-Ser-Lys-Thr-Trp-Gly-Trp-Cys(3)-Ala-Val-Glu-Ala-Pro-OH; L-alpha-aspartyl-glycyl-L-alpha-glutamyl-L-cysteinyl-glycyl-glycyl-L-phenylalanyl-L-tryptophyl-L-tryptophyl-L-lysyl-L-cysteinyl-glycyl-L-arginyl-glycyl-L-lysyl-L-prolyl-L-prolyl-L-cysteinyl-L-cysteinyl-L-lysyl-glycyl-L-tyrosyl-L-alanyl-L-cysteinyl-L-seryl-L-lysyl-L-threonyl-L-tryptophyl-glycyl-L-tryptophyl-L-cysteinyl-L-alanyl-L-valyl-L-alpha-glutamyl-L-alanyl-L-proline (4->19),(11->24),(18->31)-tris(disulfide)

Appearance

White Lyophilized Solid

Purity

>98%

Sequence

DGECGGFWWKCGRGKPPCCKGYACSKTWGWCAVEAP (Disulfide bridge: Cys4 and Cys19, Cys11 and Cys24, Cys18 and Cys31)

Storage

Store at -20°C

Solubility

Soluble in Water, Aqueous Buffer

InChI

InChI=1S/C174H241N47O46S6/c1-89(2)143(168(261)206-115(53-55-141(234)235)153(246)196-92(5)170(263)221-63-29-47-132(221)173(266)267)217-146(239)91(4)195-163(256)126-85-270-273-88-129-166(259)215-128-87-272-269-83-124(213-155(248)114(52-54-140(232)233)198-135(227)77-188-147(240)105(179)70-142(236)237)151(244)189-75-133(225)187-76-134(226)201-118(64-94-30-8-7-9-31-94)158(251)207-122(69-99-74-186-109-39-17-13-35-104(99)109)161(254)208-121(68-98-73-185-108-38-16-12-34-103(98)108)160(253)204-112(41-19-23-57-176)154(247)212-125(152(245)193-78-136(228)197-110(44-26-60-182-174(180)181)148(241)190-79-137(229)199-116(43-21-25-59-178)171(264)220-62-28-46-131(220)172(265)219-61-27-45-130(219)167(260)216-129)84-268-271-86-127(211-145(238)90(3)194-157(250)117(65-95-48-50-100(224)51-49-95)200-138(230)80-191-149(242)111(203-164(128)257)40-18-22-56-175)165(258)210-123(82-222)162(255)205-113(42-20-24-58-177)156(249)218-144(93(6)223)169(262)209-119(66-96-71-183-106-36-14-10-32-101(96)106)150(243)192-81-139(231)202-120(159(252)214-126)67-97-72-184-107-37-15-11-33-102(97)107/h7-17,30-39,48-51,71-74,89-93,105,110-132,143-144,183-186,222-224H,18-29,40-47,52-70,75-88,175-179H2,1-6H3,(H,187,225)(H,188,240)(H,189,244)(H,190,241)(H,191,242)(H,192,243)(H,193,245)(H,194,250)(H,195,256)(H,196,246)(H,197,228)(H,198,227)(H,199,229)(H,200,230)(H,201,226)(H,202,231)(H,203,257)(H,204,253)(H,205,255)(H,206,261)(H,207,251)(H,208,254)(H,209,262)(H,210,258)(H,211,238)(H,212,247)(H,213,248)(H,214,252)(H,215,259)(H,216,260)(H,217,239)(H,218,249)(H,232,233)(H,234,235)(H,236,237)(H,266,267)(H4,180,181,182)/t90-,91-,92-,93+,105-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,143-,144-/m0/s1

InChI Key

OKELXNUZHJLTAQ-BXANJWBOSA-N

Canonical SMILES

CC1C(=O)NC2CSSCC3C(=O)NCC(=O)NC(C(=O)NCC(=O)NC(C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CSSCC(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC2=O)CO)CCCCN)C(C)O)CC6=CNC7=CC=CC=C76)CC8=CNC9=CC=CC=C98)C(=O)NC(C)C(=O)NC(C(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(C)C(=O)N2CCCC2C(=O)O)C(=O)NC(CSSCC(C(=O)NCC(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N3)CCCCN)CC2=CNC3=CC=CC=C32)CC2=CNC3=CC=CC=C32)CC2=CC=CC=C2)NC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(CC(=O)O)N)C(=O)NC(C(=O)NCC(=O)NC(C(=O)N1)CC1=CC=C(C=C1)O)CCCCN)CCCCN)CCCNC(=N)N

1. Solution structure of Jingzhaotoxin-III, a peptide toxin inhibiting both Nav1.5 and Kv2.1 channels

Yucheng Xiao, Kuan Peng, Chunhua Yuan, Songping Liang, Zhi Liao Toxicon . 2007 Jul;50(1):135-43. doi: 10.1016/j.toxicon.2007.03.006.

Jingzhaotoxin-III (JZTX-III) is a peptide toxin isolated from the venom of the Chinese spider Chilobrachys jingzhao that inhibits Nav channels of rat cardiac myocytes by modifying voltage-dependent gating and also binds to Kv2.1 channel (Kd = 0.43 microM) with an action model similar to that of hanatoxin1 and SGTx1. The solution structure of JZTX-III was determined by (1)H 2D NMR method. The toxin adopts an ICK motif composed of three beta-strands connected by four turns. Structural comparison of JZTX-III with those of other ICK motif peptides shows that they all adopt a conserved surface profile, a hydrophobic patch surrounded by charged residues, which might be the crucial site for voltage-gating ion channel inhibition. Furthermore, the similar action model of JZTX-III affecting both Kv and Nav channels implies that JZTX-III recognized a conserved receptor within the voltage sensing domains, which is similar to that of hanatoxin1 binding to both Kv and Cav channels.

2. Jingzhaotoxin-III, a novel spider toxin inhibiting activation of voltage-gated sodium channel in rat cardiac myocytes

Jinyun Xie, Xiongzhi Zeng, Yuejun Yang, Jianzhou Tang, Meichi Wang, Songping Liang, Yucheng Xiao, Weijun Hu J Biol Chem . 2004 Jun 18;279(25):26220-6. doi: 10.1074/jbc.M401387200.

We have isolated a cardiotoxin, denoted jingzhaotoxin-III (JZTX-III), from the venom of the Chinese spider Chilobrachys jingzhao. The toxin contains 36 residues stabilized by three intracellular disulfide bridges (I-IV, II-V, and III-VI), assigned by a chemical strategy of partial reduction and sequence analysis. Cloned and sequenced using 3'-rapid amplification of cDNA ends and 5'-rapid amplification of cDNA ends, the full-length cDNA encoded a 63-residue precursor of JZTX-III. Different from other spider peptides, it contains an uncommon endoproteolytic site (-X-Ser-) anterior to mature protein and the intervening regions of 5 residues, which is the smallest in spider toxin cDNAs identified to date. Under whole cell recording, JZTX-III showed no effects on voltage-gated sodium channels (VGSCs) or calcium channels in dorsal root ganglion neurons, whereas it significantly inhibited tetrodotoxin-resistant VGSCs with an IC(50) value of 0.38 microm in rat cardiac myocytes. Different from scorpion beta-toxins, it caused a 10-mV depolarizing shift in the channel activation threshold. The binding site for JZTX-III on VGSCs is further suggested to be site 4 with a simple competitive assay, which at 10 microm eliminated the slowing currents induced by Buthus martensi Karsch I (BMK-I, scorpion alpha-like toxin) completely. JZTX-III shows higher selectivity for VGSC isoforms than other spider toxins affecting VGSCs, and the toxin hopefully represents an important ligand for discriminating cardiac VGSC subtype.

3. Effects and mechanism of gating modifier spider toxins on the hERG channel

Shuji Li, Yingyi Wang, Xiaowen Li, Zhengyi Luo, Chunhua Yuan, Sheng Lei Toxicon . 2021 Jan 15;189:56-64. doi: 10.1016/j.toxicon.2020.11.008.

Jingzhaotoxin-I, -III, -IV, -XIII, and -35 (JZTX-I, -III, -IV, -XIII, and -35), gating modifier toxins isolated from the venom of the Chinese tarantula Chilobrachys Jingzhao, were reported to act on cardiac sodium channels and Kv channels. JZTX-I and JZTX-XIII inhibited the hERG channel with the IC50value of 626.9 nM and 612.6 nM, respectively. JZTX-III, -IV, and -35 share high sequence similarity with JZTX-I and JZTX-XIII, but they showed much lower affinity on the hERG channel compared with JZTX-I and JZTX-XIII. The inhibitory potency of the above five toxins on the hERG channel was not in accordance with their affinity on the Nav1.5 and Kv2.1 channels, indicating that the bioactive surfaces of the five toxins interacting with hERG, Nav1.5 and Kv2.1 are at least in part different. Structure-function analysis of the gating modifier toxins suggested that the functional bioactive surface binding to the hERG channel consists of a conserved hydrophobic patch, surrounding acidic residues (Glu10 in JZTX-XIII, Glu11 in JZTX-I), and basic residues which may be different from residues binding to the Kv2.1 channel.