Shivani Ahuja, Susmith Mukund, Lunbin Deng, Kuldip Khakh, Elaine Chang, Hoangdung Ho, Stephanie Shriver, Clint Young, Sophia Lin, J P Johnson, Ping Wu, Jun Li, Mary Coons, Christine Tam, Bobby Brillantes, Honorio Sampang, Kyle Mortara, Krista K Bowman, Kevin R Clark, Alberto Estevez, Zhiwei Xie, Henry Verschoof, Michael Grimwood, Christoph Dehnhardt, Jean-Christophe Andrez, Thilo Focken, Daniel P Sutherlin, Brian S Safina, Melissa A Starovasnik, Daniel F Ortwine, Yvonne Franke, Charles J Cohen, David H Hackos, Christopher M Koth, Jian Payandeh
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...
December 18, 2015: Science