8bwb

Spider toxin Pha1b (PnTx3-6) from Phoneutria nigriventer targeting CaV2.x calcium channels and TRPA1 channel

Structural highlights

8bwb is a 1 chain structure with sequence from Phoneutria nigriventer. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TX90B_PHONI Potent blocker of nociceptor cation channels TRPA1 and high voltage-activated calcium channels (PubMed:12470700, PubMed:15933156, PubMed:27759880). It acts mainly on P/Q-type (Cav2.1/CACNA1A) calcium channels and has a minor effect on L- (Cav1/CACNA1) and N-type (Cav2.2/CACNA1B) calcium channels (PubMed:12470700, PubMed:15933156). Blocks glutamate release in synaptic transmission mediated by calcium channels (PubMed:12470700). The toxin also inhibits the KCl-induced increase of intrasynaptosomal free calcium (PubMed:12470700). It also shows antiproliferative effects on different glioma cell lines (M059J, U-138MG and U-251MG) (PubMed:28202361). In vivo, it shows analgesic effects in rodent models of pain (PubMed:18774645). In addition, it selectively blocks nocifensive responses evoked by reactive TRPA1 channel agonist (PubMed:27759880). Furthermore, it also reduces the TRPA1 channel-dependent hyperalgesia in a model of neuropathic pain induced by the chemotherapeutic agent BTZ (PubMed:27759880). In addition, it causes reduction of tumor area in the mouse glioma model, that is induced by the orthotopic injection of GL261 cells into the brain (PubMed:28202361).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Phalpha1beta (PnTx3-6) is a neurotoxin from the spider Phoneutria nigriventer venom, originally identified as an antagonist of two ion channels involved in nociception: N-type voltage-gated calcium channel (Ca(V)2.2) and TRPA1. In animal models, Phalpha1beta administration reduces both acute and chronic pain. Here, we report the efficient bacterial expression system for the recombinant production of Phalpha1beta and its (15)N-labeled analogue. Spatial structure and dynamics of Phalpha1beta were determined via NMR spectroscopy. The N-terminal domain (Ala1-Ala40) contains the inhibitor cystine knot (ICK or knottin) motif, which is common to spider neurotoxins. The C-terminal alpha-helix (Asn41-Cys52) stapled to ICK by two disulfides exhibits the micros-ms time-scale fluctuations. The Phalpha1beta structure with the disulfide bond patterns Cys1-5, Cys2-7, Cys3-12, Cys4-10, Cys6-11, Cys8-9 is the first spider knottin with six disulfide bridges in one ICK domain, and is a good reference to other toxins from the ctenitoxin family. Phalpha1beta has a large hydrophobic region on its surface and demonstrates a moderate affinity for partially anionic lipid vesicles at low salt conditions. Surprisingly, 10 microM Phalpha1beta significantly increases the amplitude of diclofenac-evoked currents and does not affect the allyl isothiocyanate (AITC)-evoked currents through the rat TRPA1 channel expressed in Xenopus oocytes. Targeting several unrelated ion channels, membrane binding, and the modulation of TRPA1 channel activity allow for considering Phalpha1beta as a gating modifier toxin, probably interacting with S1-S4 gating domains from a membrane-bound state.

Recombinant Production, NMR Solution Structure, and Membrane Interaction of the Phalpha1beta Toxin, a TRPA1 Modulator from the Brazilian Armed Spider Phoneutria nigriventer.,Lyukmanova EN, Mironov PA, Kulbatskii DS, Shulepko MA, Paramonov AS, Chernaya EM, Logashina YA, Andreev YA, Kirpichnikov MP, Shenkarev ZO Toxins (Basel). 2023 Jun 3;15(6):378. doi: 10.3390/toxins15060378. PMID:37368679^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vieira LB, Kushmerick C, Reis HJ, Diniz CR, Cordeiro MN, Prado MA, Kalapothakis E, Romano-Silva MA, Gomez MV. PnTx3-6 a spider neurotoxin inhibits K+-evoked increase in [Ca2+](i) and Ca2+-dependent glutamate release in synaptosomes. Neurochem Int. 2003 Mar;42(4):277-82. PMID:12470700 doi:10.1016/s0197-0186(02)00130-4
↑ Vieira LB, Kushmerick C, Hildebrand ME, Garcia E, Stea A, Cordeiro MN, Richardson M, Gomez MV, Snutch TP. Inhibition of high voltage-activated calcium channels by spider toxin PnTx3-6. J Pharmacol Exp Ther. 2005 Sep;314(3):1370-7. PMID:15933156 doi:10.1124/jpet.105.087023
↑ Souza AH, Ferreira J, Cordeiro MDN, Vieira LB, De Castro CJ, Trevisan G, Reis H, Souza IA, Richardson M, Prado MAM, Prado VF, Gomez MV. Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom. Pain. 2008 Nov 15;140(1):115-126. PMID:18774645 doi:10.1016/j.pain.2008.07.014
↑ Nicoletti NF, Erig TC, Zanin RF, Roxo MR, Ferreira NP, Gomez MV, Morrone FB, Campos MM. Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression. Toxicon. 2017 Apr;129:58-67. PMID:28202361 doi:10.1016/j.toxicon.2017.02.001
↑ Lyukmanova EN, Mironov PA, Kulbatskii DS, Shulepko MA, Paramonov AS, Chernaya EM, Logashina YA, Andreev YA, Kirpichnikov MP, Shenkarev ZO. Recombinant Production, NMR Solution Structure, and Membrane Interaction of the Phα1β Toxin, a TRPA1 Modulator from the Brazilian Armed Spider Phoneutria nigriventer. Toxins (Basel). 2023 Jun 3;15(6):378. PMID:37368679 doi:10.3390/toxins15060378

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Vieira LB, Kushmerick C, Reis HJ, Diniz CR, Cordeiro MN, Prado MA, Kalapothakis E, Romano-Silva MA, Gomez MV. PnTx3-6 a spider neurotoxin inhibits K+-evoked increase in [Ca2+](i) and Ca2+-dependent glutamate release in synaptosomes. Neurochem Int. 2003 Mar;42(4):277-82. PMID:12470700 doi:10.1016/s0197-0186(02)00130-4

[2] Vieira LB, Kushmerick C, Hildebrand ME, Garcia E, Stea A, Cordeiro MN, Richardson M, Gomez MV, Snutch TP. Inhibition of high voltage-activated calcium channels by spider toxin PnTx3-6. J Pharmacol Exp Ther. 2005 Sep;314(3):1370-7. PMID:15933156 doi:10.1124/jpet.105.087023

[3] Souza AH, Ferreira J, Cordeiro MDN, Vieira LB, De Castro CJ, Trevisan G, Reis H, Souza IA, Richardson M, Prado MAM, Prado VF, Gomez MV. Analgesic effect in rodents of native and recombinant Ph alpha 1beta toxin, a high-voltage-activated calcium channel blocker isolated from armed spider venom. Pain. 2008 Nov 15;140(1):115-126. PMID:18774645 doi:10.1016/j.pain.2008.07.014

[4] Nicoletti NF, Erig TC, Zanin RF, Roxo MR, Ferreira NP, Gomez MV, Morrone FB, Campos MM. Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression. Toxicon. 2017 Apr;129:58-67. PMID:28202361 doi:10.1016/j.toxicon.2017.02.001

[5] Lyukmanova EN, Mironov PA, Kulbatskii DS, Shulepko MA, Paramonov AS, Chernaya EM, Logashina YA, Andreev YA, Kirpichnikov MP, Shenkarev ZO. Recombinant Production, NMR Solution Structure, and Membrane Interaction of the Phα1β Toxin, a TRPA1 Modulator from the Brazilian Armed Spider Phoneutria nigriventer. Toxins (Basel). 2023 Jun 3;15(6):378. PMID:37368679 doi:10.3390/toxins15060378

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8bwb

Spider toxin Pha1b (PnTx3-6) from Phoneutria nigriventer targeting CaV2.x calcium channels and TRPA1 channel

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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