Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 23, Pages 8428-8433Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1406855111
Keywords
crystal structure; pharmacology
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Funding
- United Kingdom Biotechnology and Biological Science Research Council [BB/H01070X, BB/L006790, BB/J020702]
- National Institutes of Health [T32-HL007572]
- BBSRC [BB/L026252/1, BB/L006790/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L006790/1, BB/L026252/1] Funding Source: researchfish
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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.
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