| Structural highlights
Function
TXPR2_THRPR Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
ProTx-II is a disulfide-rich peptide toxin from tarantula venom able to inhibit the human voltage-gated sodium channel 1.7 (hNaV1.7), a channel reported to be involved in nociception, and thus might have potential as a pain therapeutic. ProTx-II acts by binding to the membrane-embedded voltage sensor domain of hNaV1.7 but the precise peptide-channel binding site and the importance of membrane binding on the inhibitory activity of ProTx-II remains unknown. In this study we examined the structure and membrane-binding properties of ProTx-II and several analogues using NMR spectroscopy, surface plasmon resonance, fluorescence spectroscopy and molecular dynamics simulations. Our results show a direct correlation between ProTx-II membrane binding affinity and its potency as a hNaV1.7 channel inhibitor. The data support a model whereby a hydrophobic patch on the ProTx-II surface anchors the molecule at the cell surface in a position that optimizes interaction of the peptide with the binding site on the voltage sensor domain. This is the first study which demonstrates that binding of ProTx-II to the lipid membrane is directly linked to its potency as a hNaV1.7 channel inhibitor.
Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes is a Prerequisite for its Inhibition of Human Voltage-gated Sodium Channel NaV1.7.,Henriques ST, Deplazes E, Lawrence N, Cheneval O, Chaousis S, Inserra M, Thongyoo P, King GF, Mark AE, Vetter I, Craik DJ, Schroeder CI J Biol Chem. 2016 Jun 16. pii: jbc.M116.729095. PMID:27311819[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
- ↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:http://dx.doi.org/10.1016/j.toxicon.2006.09.014
- ↑ Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97. Epub 2007 Mar 5. PMID:17339321 doi:http://dx.doi.org/10.1074/jbc.M610462200
- ↑ Sokolov S, Kraus RL, Scheuer T, Catterall WA. Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II. Mol Pharmacol. 2008 Mar;73(3):1020-8. Epub 2007 Dec 21. PMID:18156314 doi:http://dx.doi.org/10.1124/mol.107.041046
- ↑ Edgerton GB, Blumenthal KM, Hanck DA. Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon. 2008 Sep 1;52(3):489-500. Epub 2008 Jul 9. PMID:18657562 doi:http://dx.doi.org/S0041-0101(08)00401-7
- ↑ Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008 Nov;74(5):1476-84. doi: 10.1124/mol.108.047670. Epub 2008 Aug, 26. PMID:18728100 doi:http://dx.doi.org/10.1124/mol.108.047670
- ↑ Henriques ST, Deplazes E, Lawrence N, Cheneval O, Chaousis S, Inserra M, Thongyoo P, King GF, Mark AE, Vetter I, Craik DJ, Schroeder CI. Interaction of Tarantula Venom Peptide ProTx-II with Lipid Membranes is a Prerequisite for its Inhibition of Human Voltage-gated Sodium Channel NaV1.7. J Biol Chem. 2016 Jun 16. pii: jbc.M116.729095. PMID:27311819 doi:http://dx.doi.org/10.1074/jbc.M116.729095
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