Structural Basis Of Nav1.7 Inhibition By An Isoform ... - PubMed

Full text links CiteDisplay options Display options Format AbstractPubMedPMID

Abstract

Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.

Copyright © 2015, American Association for the Advancement of Science.

PubMed Disclaimer

Publication types

• Research Support, N.I.H., Extramural Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Research Support, U.S. Gov't, Non-P.H.S. Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

MeSH terms

• Amino Acid Sequence Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Cell Membrane / chemistry Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Crystallization / methods Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Crystallography, X-Ray Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• DNA Mutational Analysis Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Humans Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Models, Molecular Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Molecular Sequence Data Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• NAV1.7 Voltage-Gated Sodium Channel / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• NAV1.7 Voltage-Gated Sodium Channel / genetics Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Pain Perception / drug effects Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Engineering Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Isoforms / antagonists & inhibitors Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Isoforms / chemistry Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Structure, Secondary Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Structure, Tertiary Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sodium Channel Blockers / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sodium Channel Blockers / pharmacology* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sulfonamides / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sulfonamides / pharmacology* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Thiadiazoles / chemistry* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Thiadiazoles / pharmacology* Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

Substances

• GX-936 Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• NAV1.7 Voltage-Gated Sodium Channel Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Protein Isoforms Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• SCN9A protein, human Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sodium Channel Blockers Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Sulfonamides Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search
• Thiadiazoles Actions
  • Search in PubMed
  • Search in MeSH
  • Add to Search

Associated data

• PDB/5EK0 Actions
  • Search in PubMed
  • Search in Structure

LinkOut - more resources

• Full Text Sources

  • Atypon

• Other Literature Sources

  • H1 Connect - Access expert opinions and insights on biomedical research.
  • The Lens - Patent Citations Database

• Molecular Biology Databases

  • GlyGen glycoinformatics resource