Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism.
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.
['Bagnéris|Claire|C|', 'DeCaen|Paul G|PG|', 'Naylor|Claire E|CE|', 'Pryde|David C|DC|', 'Nobeli|Irene|I|', 'Clapham|David E|DE|', 'Wallace|B A|BA|']
D020561:Alphaproteobacteria D000595:Amino Acid Sequence D001426:Bacterial Proteins D001665:Binding Sites D018360:Crystallography, X-Ray D057809:HEK293 Cells D006801:Humans D015640:Ion Channel Gating D000077213:Lamotrigine D008564:Membrane Potentials D008958:Models, Molecular D008969:Molecular Sequence Data D009154:Mutation D062550:NAV1.1 Voltage-Gated Sodium Channel D017434:Protein Structure, Tertiary D017386:Sequence Homology, Amino Acid D026941:Sodium Channel Blockers D015222:Sodium Channels D014227:Triazines
crystal structure pharmacology