|Title||Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Pan, X, Li, Z, Huang, X, Huang, G, Gao, S, Shen, H, Liu, L, Lei, J, Yan, N|
|Date Published||2019 Feb 14|
The voltage-gated sodium channel Nav1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Nav1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit β2 to an overall resolution of 3.0 Å. The immunoglobulin (Ig) domain of β2 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 Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Nav1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for rational design of subtype-specific blockers for Navchannels.