6btv | pdb_00006btv
Solution NMR structures for CcoTx-II
Structural highlights
FunctionTX2_CERMR Inhibits several voltage-gated sodium channels and only one voltage-gated calcium channel (Cav2.2/CACNA1B (IC(50)=1100 nM) and Nav1.2/SCN2A (IC(50)=8-80 nM), Nav1.3/SCN3A (88-5570 nM), Nav1.1/SCN1A (170-407 nM), Nav1.7/SCN9A (230 nM), Nav1.6/SCN6A (3990 nM), Nav1.4/SCN4A (400 nM or >10 uM), Nav1.5/SCN5A (1634 nM or >10 uM)) (PubMed:16267209, PubMed:28880874). The toxin acts by shifting the voltage dependence of channel activation to more depolarized potentials and by blocking the inward component of the sodium current (PubMed:16267209). In vivo, this toxin causes general ataxia, lack of response to stimuli, and semiparalysis (PubMed:16267209). After a few minutes, the mice are unable to stand, and breathing is reduced in rhythm and intensity (PubMed:16267209). Symptoms gradually increase with progressive slowing of breathing and flaccid paralysis; death occurred within 10 to 20 minutes post injection (PubMed:16267209). Animals remain totally flaccid, and no symptoms of excitatory neurotoxicity are observed (PubMed:16267209).[1] [2] Publication Abstract from PubMedGating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures that modulate activity of disease-relevant voltage-gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here we examined whether there is a relationship among spider GMT amphipathicity, membrane binding and potency or selectivity for voltage-gated sodium (NaV) channels. We used NMR spectroscopy and in silico calculations to examine the structures and physicochemical properties of a panel of nine GMTs and deployed surface plasmon resonance to measure GMT affinity for lipids putatively found in proximity to NaV channels. Electrophysiology was used to quantify GMT activity on NaV1.7, an ion channel linked to chronic pain. Selectivity of the peptides was further examined against a panel of NaV channel subtypes. We show that GMTs adsorb to the outer leaflet of anionic lipid bilayers through electrostatic interactions. We did not observe a direct correlation between GMT amphipathicity and affinity for lipid bilayers. Furthermore, GMT-lipid bilayer interactions did not correlate with potency or selectivity for NaVs. We therefore propose that increased membrane binding is unlikely to improve subtype selectivity and that the conserved amphipathic GMT surface profile is an adaptation that facilitates simultaneous modulation of multiple NaVs. Gating modifier toxins isolated from spider venom: modulation of voltage-gated sodium channels and the role of lipid membranes.,Agwa AJ, Peigneur S, Chow CY, Lawrence N, Craik DJ, Tytgat J, King GF, Henriques ST, Schroeder CI J Biol Chem. 2018 Apr 27. pii: RA118.002553. doi: 10.1074/jbc.RA118.002553. PMID:29703751[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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