6BTV

Solution NMR structures for CcoTx-II

6BTV の概要

• エントリーDOI: 10.2210/pdb6btv/pdb
• 関連するPDBエントリー: 6BR0
• NMR情報: BMRB: 30377
• 分子名称: Beta-theraphotoxin-Cm1b (1 entity in total)
• 機能のキーワード: spider, toxin, disulfide, ick, pain, nav1.7, voltage gated ion channel
• 由来する生物種: Ceratogyrus marshalli (Straighthorned baboon tarantula)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4105.77

構造登録者

Agwa, A.J.,Schroeder, C.I. (登録日: 2017-12-07, 公開日: 2018-05-09, 最終更新日: 2024-11-20)

主引用文献

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

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: 29703751
DOI: 10.1074/jbc.RA118.002553

実験手法

SOLUTION NMR