title: Binding modes and functional surface of anti-mammalian scorpion α-toxins to sodium channels.
abstract: Scorpion α-toxins bind to the voltage-sensing domains of voltage-gated sodium (Na(V)) channels and interfere with the inactivation mechanisms. The functional surface of α-toxins has been shown to contain an NC-domain consisting of the five-residue turn (positions 8-12) and the C-terminus (positions 56-64) and a core-domain centered on the residue 18. The NC- and core-domains are interconnected by the linker-domain (positions 8-18). Here with atomistic molecular dynamics simulations, we examine the binding modes between two α-toxins, the anti-mammalian AahII and the anti-insect LqhαIT, and the voltage-sensing domain of rat Na(V)1.2, a subtype of Na(V) channels expressed in nerve cells. Both toxins are docked to the extracellular side of the voltage-sensing domain of Na(V)1.2 using molecular dynamics simulations, with the linker-domain assumed to wedge into the binding pocket. Several salt bridges and hydrophobic clusters are observed to form between the NC- and core-domains of the toxins and Na(V)1.2 and stabilize the toxin-channel complexes. The binding modes predicted are consistent with available mutagenesis data and can readily explain the relative affinities of AahII and LqhαIT for Na(V)1.2. The dissociation constants for the two toxin-channel complexes are derived, which compare favorably with experiment. Our models demonstrate that the functional surface of anti-mammalian scorpion α-toxins is centered on the linker-domain, similar to that of β-toxins.
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT 0200, Australia. rong.chen@anu.edu.au
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Shin-Ho
authors.initials: SH
authors.lastname: Chung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000378:metabolism*; D012605:Scorpions / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; C568253:Scn2A protein, rat; D012604:Scorpion Venoms