7K48

Structure of NavAb/Nav1.7-VS2A chimera trapped in the resting state by tarantula toxin m3-Huwentoxin-IV

Summary for 7K48

• Entry DOI: 10.2210/pdb7k48/pdb
• EMDB information: 22661
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Ion transport protein,Sodium channel protein type 9 subunit alpha chimera, Mu-theraphotoxin-Hs2a (2 entities in total)
• Functional Keywords: ion channel, voltage-gated sodium channel, gating-modifier toxin, membrane protein
• Biological source: Escherichia coli (strain K12); More
• Total number of polymer chains: 8
• Total formula weight: 290075.36

Authors

Wisedchaisri, G.,Tonggu, L.,Gamal El-Din, T.M.,McCord, E.,Zheng, N.,Catterall, W.A. (deposition date: 2020-09-15, release date: 2020-12-02, Last modification date: 2024-10-23)

Primary citation

Wisedchaisri, G.,Tonggu, L.,Gamal El-Din, T.M.,McCord, E.,Zheng, N.,Catterall, W.A.
Structural Basis for High-Affinity Trapping of the Na V 1.7 Channel in Its Resting State by Tarantula Toxin.
Mol.Cell, 81:38-48.e4, 2021

PubMed Abstract: Voltage-gated sodium channels initiate electrical signals and are frequently targeted by deadly gating-modifier neurotoxins, including tarantula toxins, which trap the voltage sensor in its resting state. The structural basis for tarantula-toxin action remains elusive because of the difficulty of capturing the functionally relevant form of the toxin-channel complex. Here, we engineered the model sodium channel NaAb with voltage-shifting mutations and the toxin-binding site of human Na1.7, an attractive pain target. This mutant chimera enabled us to determine the cryoelectron microscopy (cryo-EM) structure of the channel functionally arrested by tarantula toxin. Our structure reveals a high-affinity resting-state-specific toxin-channel interaction between a key lysine residue that serves as a "stinger" and penetrates a triad of carboxyl groups in the S3-S4 linker of the voltage sensor. By unveiling this high-affinity binding mode, our studies establish a high-resolution channel-docking and resting-state locking mechanism for huwentoxin-IV and provide guidance for developing future resting-state-targeted analgesic drugs.

PubMed: 33232657
DOI: 10.1016/j.molcel.2020.10.039

Experimental method

ELECTRON MICROSCOPY (3.6 Å)