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

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

  • Science. 2019 Mar 22;363(6433):1309-1313. doi: 10.1126/science.aaw2999.
Xiaojing Pan # 1 2 3,  Zhangqiang Li # 1 2 3,  Xiaoshuang Huang # 1 2 3,  Gaoxingyu Huang # 1 2 3,  Shuai Gao 4,  Huaizong Shen 1 2 3,  Lei Liu 2 4,  Jianlin Lei 5,  Nieng Yan 6 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
  • 2 Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
  • 3 Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
  • 4 Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 5 Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 6 State Key Laboratory of Membrane Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. [email protected].
  • # Contributed equally.
PMID: 30765605 DOI: 10.1126/science.aaw2999
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 angstroms. The immunoglobulin 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 the rational design of subtype-specific blockers for Nav channels.

Figures
Products