Molecular basis for pore blockade of human Na + channel Na v 1.2 by the m-conotoxin KIIIA

Xiaojing Pan, Zhangqiang Li, Xiaoshuang Huang, Gaoxingyu Huang, Shuai Gao, Huaizong Shen, Lei Liu, Jianlin Lei, Nieng Yan

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37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1309-1313
Number of pages5
JournalScience
Volume363
Issue number6433
DOIs
StatePublished - Mar 22 2019

All Science Journal Classification (ASJC) codes

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    Pan, X., Li, Z., Huang, X., Huang, G., Gao, S., Shen, H., Liu, L., Lei, J., & Yan, N. (2019). Molecular basis for pore blockade of human Na + channel Na v 1.2 by the m-conotoxin KIIIA. Science, 363(6433), 1309-1313. https://doi.org/10.1126/science.aaw2999