2n9t | pdb_00002n9t
NMR solution structure of ProTx-II
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 PubMedProTx-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
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