2M50

Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin, Huwentoxin-IV (-TRTX-Hh2a).

2M50 の概要

• エントリーDOI: 10.2210/pdb2m50/pdb
• 関連するPDBエントリー: 2M4X 2M4Z
• NMR情報: BMRB: 19032
• 分子名称: Mu-theraphotoxin-Hh2a (1 entity in total)
• 機能のキーワード: venom toxin, toxin
• 由来する生物種: Haplopelma schmidti (Chinese bird spider,Chinese golden earth tiger)
• 細胞内の位置: Secreted: P83303
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 4062.76

構造登録者

Gibbs, A.,Minassian, N.,Flinspach, M.,Wickenden, A. (登録日: 2013-02-12, 公開日: 2013-06-19, 最終更新日: 2023-11-29)

主引用文献

Minassian, N.A.,Gibbs, A.,Shih, A.Y.,Liu, Y.,Neff, R.A.,Sutton, S.W.,Mirzadegan, T.,Connor, J.,Fellows, R.,Husovsky, M.,Nelson, S.,Hunter, M.J.,Flinspach, M.,Wickenden, A.D.
Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV ( mu-TRTX-Hh2a).
J.Biol.Chem., 288:22707-22720, 2013

PubMed Abstract: Voltage-gated sodium channels (VGSCs) are essential to the normal function of the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of disorders, including epilepsy, arrhythmia, and pain. A large number of animal toxins target these ion channels and may have significant therapeutic potential. Most of these toxins, however, have not been characterized in detail. Here, by combining patch clamp electrophysiology and radioligand binding studies with peptide mutagenesis, NMR structure determination, and molecular modeling, we have revealed key molecular determinants of the interaction between the tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and NMR studies indicated that folding was normal for several key mutants, suggesting that these amino acids probably make specific interactions with sodium channel residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC interactions. Our structural and functional data were used to model the docking of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight into the structural and molecular basis of sodium channel block by huwentoxin-IV and may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity.

PubMed: 23760503
DOI: 10.1074/jbc.M113.461392

実験手法

SOLUTION NMR