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Papers of the Week


Papers: 16 Feb 2019 - 22 Feb 2019


Human Studies, Pharmacology/Drug Development


2019 03 22


Science


363


6433

Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA.

Authors

Pan X, Li Z, Huang X, Huang G, Gao S, Shen H, Liu L, Lei J, Yan N
Science. 2019 03 22; 363(6433):1309-1313.
PMID: 30765605.

Abstract

The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 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 Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for rational design of subtype-specific blockers for Na channels.