Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA.

TitleMolecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA.
Publication TypeJournal Article
Year of Publication2019
AuthorsPan, X, Li, Z, Huang, X, Huang, G, Gao, S, Shen, H, Liu, L, Lei, J, Yan, N
JournalScience
Date Published2019 Feb 14
ISSN1095-9203
Abstract

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.

DOI10.1126/science.aaw2999
Alternate JournalScience
PubMed ID30765605