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

DOI: 10.1073/pnas.1406855111 DOI Help
PMID: 24850863 PMID Help

Authors: C. Bagneris (Birkbeck College) , P. G. Decaen (Howard Hughes Medical Institute) , C. E. Naylor (Birkbeck College) , D. C. Pryde (Pfizer Neusentis) , I. Nobeli (Birkbeck College) , D. E. Clapham (Howard Hughes Medical Institute) , B. A. Wallace (Birkbeck College)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 111 (23) , PAGES 8428 - 8433

State: Published (Approved)
Published: June 2014

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.

Journal Keywords: Amino; Bacterial; Binding; Crystallography; X-Ray; HEK293; Humans; Ion; Membrane; Models; Molecular; Mutation; NAV1.1; Protein; Tertiary; Sequence; Amino; Sodium; Sodium; Triazines

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ESRF

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