2. Academic Validation
  3. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist

Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist

  • Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464.
Shivani Ahuja 1,  Susmith Mukund 1,  Lunbin Deng 2,  Kuldip Khakh 3,  Elaine Chang 3,  Hoangdung Ho 1,  Stephanie Shriver 1,  Clint Young 3,  Sophia Lin 3,  J P Johnson Jr 3,  Ping Wu 1,  Jun Li 4,  Mary Coons 1,  Christine Tam 1,  Bobby Brillantes 1,  Honorio Sampang 1,  Kyle Mortara 1,  Krista K Bowman 1,  Kevin R Clark 5,  Alberto Estevez 1,  Zhiwei Xie 3,  Henry Verschoof 3,  Michael Grimwood 6,  Christoph Dehnhardt 6,  Jean-Christophe Andrez 6,  Thilo Focken 6,  Daniel P Sutherlin 4,  Brian S Safina 4,  Melissa A Starovasnik 1,  Daniel F Ortwine 4,  Yvonne Franke 1,  Charles J Cohen 3,  David H Hackos 7,  Christopher M Koth 8,  Jian Payandeh 8
Affiliations

Affiliations

  • 1 Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA.
  • 2 Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA.
  • 3 Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada.
  • 4 Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA.
  • 5 Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
  • 6 Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada.
  • 7 Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.
  • 8 Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.
PMID: 26680203 DOI: 10.1126/science.aac5464
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.

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