| Autor: |
Goragot, Wisedchaisri, Lige, Tonggu, Tamer M, Gamal El-Din, Eedann, McCord, Ning, Zheng, William A, Catterall |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Mol Cell |
| ISSN: |
1097-4164 |
| Popis: |
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 Na(V)Ab with voltage-shifting mutations and the toxin-binding site of human Na(V)1.7, an attractive pain target. This mutant chimera enabled us to determine the 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 andresting-statelockingmechanism for huwentoxin-IV and provide guidance for developing future resting-state-targeted analgesic drugs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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