title: The unique pharmacology of the scorpion alpha-like toxin Lqh3 is associated with its flexible C-tail.
abstract: The affinity of scorpion alpha-toxins for various voltage-gated sodium channels (Na(v)s) differs considerably despite similar structures and activities. It has been proposed that key bioactive residues of the five-residue-turn (residues 8-12) and the C-tail form the NC domain, whose topology is dictated by a cis or trans peptide-bond conformation between residues 9 and 10, which correlates with the potency on insect or mammalian Na(v)s. We examined this hypothesis using Lqh3, an alpha-like toxin from Leiurus quinquestriatus hebraeus that is highly active in insects and mammalian brain. Lqh3 exhibits slower association kinetics to Na(v)s compared with other alpha-toxins and its binding to insect Na(v)s is pH-dependent. Mutagenesis of Lqh3 revealed a bi-partite bioactive surface, composed of the Core and NC domains, as found in other alpha-toxins. Yet, substitutions at the five-residue turn and stabilization of the 9-10 bond in the cis conformation did not affect the activity. However, substitution of hydrogen-bond donors/acceptors at the NC domain reduced the pH-dependency of toxin binding, while retaining its high potency at Drosophila Na(v)s expressed in Xenopus oocytes. Based on these results and the conformational flexibility and rearrangement of intramolecular hydrogen-bonds at the NC domain, evident from the known solution structure, we suggest that acidic pH or specific mutations at the NC domain favor toxin conformations with high affinity for the receptor by stabilizing the bound toxin-receptor complex. Moreover, the C-tail flexibility may account for the slower association rates and suggests a novel mechanism of dynamic conformer selection during toxin binding, enabling alpha-like toxins to affect a broad range of Na(v)s.
authors.affiliation: Department of Plant Sciences, George S.Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors.forename: Izhar
authors.initials: I
authors.lastname: Karbat
authors.forename: Roy
authors.initials: R
authors.lastname: Kahn
authors.forename: Lior
authors.initials: L
authors.lastname: Cohen
authors.forename: Nitza
authors.initials: N
authors.lastname: Ilan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
authors.forename: Gerardo
authors.initials: G
authors.lastname: Corzo
authors.forename: Oren
authors.initials: O
authors.lastname: Froy
authors.forename: Maya
authors.initials: M
authors.lastname: Gur
authors.forename: Gudrun
authors.initials: G
authors.lastname: Albrecht
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Dalia
authors.initials: D
authors.lastname: Gordon
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevitz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004331:Drosophila melanogaster; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C114939:Lqh III toxin; D012604:Scorpion Venoms; D015222:Sodium Channels