Structural Modeling of the Human Nav1.7 Sodium Channel Pore

Abstract

Voltage-gated sodium channels expressed in peripheral sensory neurons, play an important role in pain signaling. The human isoform hNav1.7 is a key target for the development of new analgesics for pain treatment. However, high-resolution structures of mammalian voltage-gated sodium channels that could be useful for rational drug design are not available. X-ray structures of bacterial voltage-gated sodium channels, NavAb and NavRh, have been recently been solved and serve as useful templates for homology modeling of mammalian voltage-gated sodium channels. Notably, both NavAb and NavRh structures show asymmetric dimer-of-dimers configuration of the pore-forming domain. We generated homology/de novo models of the asymmetric Nav1.7 pore-forming domain using a Rosetta-membrane homology modeling method and the NavAb structure (pdb id: 4DXW) as a template. Multiple sequence alignments of the second pore helix region between hNav1.7 and NavAb have been explored and compared with experimental data concerning side-chain orientation and ligand binding. Docking of tetrodotoxin, u-conotoxin-KIIIA, and the local anesthetic lidocaine to the pore-forming domain of hNav1.7 using Rosetta-Dock and molecular dynamics simulations were performed to test the ability of structural models to fit available experimental data. Structural models of the pore-forming domain of hNav1.7 may be useful for design of analgesics targeting human voltage-gated sodium channels.