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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 23; pp. 8428 - 8433
• Main Authors: Bagnéris, Claire, DeCaen, Paul G., Naylor, Claire E., Pryde, David C., Nobeli, Irene, Clapham, David E., Wallace, B. A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.06.2014; National Acad Sciences
• Subjects: Alphaproteobacteria - chemistry; Alphaproteobacteria - genetics; Alphaproteobacteria - metabolism; Amino Acid Sequence; Atoms; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Binding sites; Binding Sites - genetics; Biological Sciences; Bromine; Cardiovascular disease; Channel blockers; Crystal structure; Crystallography, X-Ray; Crystals; Eukaryotes; HEK293 Cells; Humans; Ion Channel Gating - drug effects; Ion Channel Gating - genetics; Ion Channel Gating - physiology; Local anesthetics; Membrane Potentials - drug effects; Membrane Potentials - physiology; Models, Molecular; Molecular Sequence Data; Mutation; NAV1.1 Voltage-Gated Sodium Channel - chemistry; NAV1.1 Voltage-Gated Sodium Channel - genetics; NAV1.1 Voltage-Gated Sodium Channel - metabolism; Prokaryotes; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Sodium; Sodium Channel Blockers - metabolism; Sodium Channel Blockers - pharmacology; Sodium channels; Sodium Channels - chemistry; Sodium Channels - genetics; Sodium Channels - metabolism; Triazines - metabolism; Triazines - pharmacology; crystal structure; pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1406855111

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 Na v 1.1 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.