The voltage-gated sodium channel Na v 1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo–electron microscopy structure of human Na v 1.2 bound to a peptidic pore blocker, the m-conotoxin KIIIA, in the presence of an auxiliary subunit, b2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of b2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys 7 at the entrance to the selectivity filter. Many interacting residues are specific to Na v 1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na v channels.
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