6BR0
Solution NMR structure for CcoTx-I
Summary for 6BR0
| Entry DOI | 10.2210/pdb6br0/pdb |
| NMR Information | BMRB: 30376 |
| Descriptor | Beta-theraphotoxin-Cm1a (1 entity in total) |
| Functional Keywords | spider, toxin, disulfide, ick, pain, nav1.7, voltage gated ion channel |
| Biological source | Ceratogyrus marshalli (Straighthorned baboon tarantula) |
| Total number of polymer chains | 1 |
| Total formula weight | 4057.69 |
| Authors | Agwa, A.J.,Schroeder, C.I. (deposition date: 2017-11-29, release date: 2018-05-16, Last modification date: 2024-10-30) |
| Primary citation | Agwa, A.J.,Peigneur, S.,Chow, C.Y.,Lawrence, N.,Craik, D.J.,Tytgat, J.,King, G.F.,Henriques, S.T.,Schroeder, C.I. Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. J. Biol. Chem., 293:9041-9052, 2018 Cited by PubMed Abstract: Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures and 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 (Na) channels. We used NMR spectroscopy and 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 Na channels. Electrophysiology was used to quantify GMT activity on Na1.7, an ion channel linked to chronic pain. Selectivity of the peptides was further examined against a panel of Na 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 Nas. 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 Nas. PubMed: 29703751DOI: 10.1074/jbc.RA118.002553 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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