Structural Modeling of Toxin Interactions with the Human Voltage-Gated Sodium Channel Pore

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Voltage-gated sodium (Nav) channel subtypes are targets for the development of novel analgesics. We are constraining structural models of human Nav subtypes, as the lack of high-resolution structures of channels makes rational drug design challenging. The human Nav1.4 channel is associated with paralysis and human Nav1.7 channel plays an important role in pain signaling. We used the bacterial Nav channel NavRh (pdb id: 4DXW) as a template to generate homology/de novo models of human Nav1.4 and Nav1.7 channel pore-forming domains. Due to significant sequence differences between human and bacterial Nav channels in the P2 helix region of the selectivity filter, we predicted the structure of these regions de novo using Rosetta loop modeling methods. We simulated interactions of human Nav1.4 and Nav1.7 channels with pore blocking toxins - tetrodotoxin, saxitoxin, and μ-conotoxin KIIIA - using Rosetta methods and molecular dynamics in an all-atom explicit membrane environment. Virtual alanine scans of key residues forming toxin receptor sites within human Nav1.4 and Nav1.7 channel pore-forming domains showed good correlation with available experimental data. High-resolution structural models of the human Nav channels provide critical starting points for design of novel analgesics.