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- Title
Molecular determinants of μ-conotoxin KIIIA interaction with the human voltage-gated sodium channel Na<sub>V</sub>1.7.
- Authors
Kimball, Ian H.; Nguyen, Phuong T.; Olivera, Baldomero M.; Sack, Jon T.; Yarov-Yarovoy, Vladimir
- 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.
- Subjects
SODIUM channels; MOLECULAR dynamics; SOCIAL interaction; PYRETHROIDS; MOLECULAR docking; MOLECULAR interactions; DRUG target
- Publication
Frontiers in Pharmacology, 2023, Vol 14, p1
- ISSN
1663-9812
- Publication type
Article
- DOI
10.3389/fphar.2023.1156855