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Structure paper

タイトル	Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.
ジャーナル・号・ページ	Cell, Vol. 176, Issue 4, Page 702-715.e14, Year 2019
掲載日	2019年2月7日
著者	Hui Xu / Tianbo Li / Alexis Rohou / Christopher P Arthur / Foteini Tzakoniati / Evera Wong / Alberto Estevez / Christine Kugel / Yvonne Franke / Jun Chen / Claudio Ciferri / David H Hackos / Christopher M Koth / Jian Payandeh /
PubMed 要旨	Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and ...Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable ∼10 Å translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists.
リンク	Cell / PubMed:30661758
手法	EM (単粒子) / X線回折
解像度	3.541 - 4.2 Å
構造データ	0341 6n4q EMDB-0341, PDB-6n4q: CryoEM structure of Nav1.7 VSD2 (actived state) in complex with the gating modifier toxin ProTx2 手法: EM (単粒子) / 解像度: 3.6 Å 0342 6n4r EMDB-0342, PDB-6n4r: CryoEM structure of Nav1.7 VSD2 (deactived state) in complex with the gating modifier toxin ProTx2 手法: EM (単粒子) / 解像度: 4.2 Å PDB-6n4i: Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin 手法: X-RAY DIFFRACTION / 解像度: 3.541 Å
化合物	ChemComp-6OU: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / POPE / リン脂質*YM
由来	homo sapiens (ヒト) arcobacter butzleri (strain rm4018) (バクテリア) thrixopelma pruriens (クモ) mouse (ネズミ) mus musculus (ハツカネズミ)
キーワード	METAL TRANSPORT / sodium channel (ナトリウムチャネル) / toxin (毒素) / gating-modifier / voltage-gated (電位依存性イオンチャネル) / MEMBRANE PROTEIN (膜タンパク質) / voltage-gated sodium channel (ナトリウムチャネル) / gating modifier toxin