title: Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.
abstract: Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors.
authors.affiliation: School of Applied Sciences and Health Innovations Research Institute, RMIT University, Melbourne, VIC 3001, Australia;
authors.forename: Céline
authors.initials: C
authors.lastname: Boiteux
authors.affiliation: Department of Chemistry, University of California, Davis, CA 95616;
authors.forename: Igor
authors.initials: I
authors.lastname: Vorobyov
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Calgary, AB Canada T2N 4N1;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: French
authors.affiliation: Deparmtent of Medicine, University of Melbourne, Melbourne, VIC 3010 Australia; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: French
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, CA 95616.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: School of Applied Sciences and Health Innovations Research Institute, RMIT University, Melbourne, VIC 3001, Australia; Department of Chemistry, University of California, Davis, CA 95616; toby.allen@rmit.edu.au.
authors.forename: Toby W
authors.initials: TW
authors.lastname: Allen
mesh_terms: D000595:Amino Acid Sequence; D000779:Anesthetics, Local / Q000737:chemistry / Q000378:metabolism*; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism*; D020640:Arcobacter / Q000378:metabolism*; D001566:Benzocaine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D008567:Membranes, Artificial; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010672:Phenytoin / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013816:Thermodynamics; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D000927:Anticonvulsants; D008567:Membranes, Artificial; D021122:Protein Subunits; D061566:Voltage-Gated Sodium Channels; D010672:Phenytoin; D001566:Benzocaine
keywords: bacterial sodium channel; drug binding