Molecular determinants of μ-conotoxin KIIIA interaction with the human voltage-gated sodium channel NaV1.7
Open Access
- 16 March 2023
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Pharmacology
- Vol. 14, 1156855
- https://doi.org/10.3389/fphar.2023.1156855
Abstract
The voltage-gated sodium (NaV) channel subtype NaV1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human NaV1.7 channel (hNaV1.7). We developed a structural model of hNaV1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNaV1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNaV1.7 model and the cryo-EM structure of KIIIA-hNaV1.2 revealed key similarities and differences between NaV channel subtypes with potential implications for the molecular mechanism of toxin block. The accuracy of our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations, suggests that Rosetta structural predictions will be useful for rational design of novel biologics targeting specific NaV channels.Funding Information
- National Institutes of Health (U01HL126273 R01HL128537 R01NS096317 GM099608)
- American Heart Association
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