Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism

Claire Bagnéris, Paul G. DeCaen, Claire E. Naylor, David C. Pryde, Irene Nobeli, David E. Clapham*, B. A. Wallace

*Corresponding author for this work

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Voltage-gated sodium channels are important targets for the development of pharmaceutical drugs, because mutations in different human sodium channel isoforms have causal relationships with a range of neurological and cardiovascular diseases. In this study, functional electrophysiological studies show that the prokaryotic sodium channel from Magnetococcus marinus (NavMs) binds and is inhibited by eukaryotic sodium channel blockers in a manner similar to the human Nav1.1 channel, despite millions of years of divergent evolution between the two types of channels. Crystal complexes of the NavMs pore with several brominated blocker compounds depict a common antagonist binding site in the cavity, adjacent to lipid-facing fenestrations proposed to be the portals for drug entry. In silico docking studies indicate the full extent of the blocker binding site, and electrophysiology studies of NavMs channels with mutations at adjacent residues validate the location. These results suggest that the NavMs channel can be a valuable tool for screening and rational design of human drugs.

Original languageEnglish (US)
Pages (from-to)8428-8433
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number23
DOIs
StatePublished - Jun 10 2014

Keywords

  • Crystal structure
  • Pharmacology

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism'. Together they form a unique fingerprint.

  • Cite this