title: A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels.
abstract: Maurotoxin (MTX) is a 34-residue toxin that has been isolated initially from the venom of the scorpion Scorpio maurus palmatus. It presents a large number of pharmacological targets, including small conductance Ca2+-activated and voltage-gated K+ channels. Contrary to other toxins of the alpha-KTx6 family (Pi1, Pi4, Pi7, and HsTx1), MTX exhibits a unique disulfide bridge organization of the type C1-C5, C2-C6, C3-C4, and C7-C8 (instead of the conventional C1-C5, C2-C6, C3-C7, and C4-C8, herein referred to as Pi1-like) that does not prevent its folding along the classic alpha/beta scaffold of scorpion toxins. Here, we developed an innovative strategy of chemical peptide synthesis to produce an MTX variant (MTXPi1) with a conventional pattern of disulfide bridging without any alteration of the toxin chemical structure. This strategy was used solely to address the impact of half-cystine pairings on MTX structural properties and pharmacology. The data indicate that MTXPi1 displays some marked changes in affinities toward the target K+ channels. Computed docking analyses using molecular models of both MTXPi1 and the various voltage-gated K+ channel subtypes (Shaker B, Kv1.2, and Kv1.3) were found to correlate with MTXPi1 pharmacology. A functional map detailing the interaction between MTXPi1 and Shaker B channel was generated in line with docking experiments.
authors.affiliation: Laboratoire International Associé d'Ingénierie Biomoléculaire, CNRS Unité Mixte de Recherche 6560 Bd Pierre Dramard, 13916 Marseille Cedex 20, France.
authors.forename: Sarrah
authors.initials: S
authors.lastname: M'Barek
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lopez-Gonzalez
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.forename: Eric
authors.initials: E
authors.lastname: di Luccio
authors.forename: Violeta
authors.initials: V
authors.lastname: Visan
authors.forename: Stephan
authors.initials: S
authors.lastname: Grissmer
authors.forename: Susan
authors.initials: S
authors.lastname: Judge
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Ayeb
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.forename: Hervé
authors.initials: H
authors.lastname: Rochat
authors.forename: François
authors.initials: F
authors.lastname: Sampieri
authors.forename: Evelyne
authors.initials: E
authors.lastname: Béraud
authors.forename: Ziad
authors.initials: Z
authors.lastname: Fajloun
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D004220:Disulfides / Q000737:chemistry*; D007457:Iodine Radioisotopes; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D012605:Scorpions / Q000737:chemistry*; D020539:Sequence Analysis, Protein; D051637:Shaker Superfamily of Potassium Channels; D013574:Synaptosomes / Q000187:drug effects; D014981:Xenopus
chemical_list: D004220:Disulfides; D007457:Iodine Radioisotopes; C104751:Pi1 toxin; D015221:Potassium Channels; D012604:Scorpion Venoms; D051637:Shaker Superfamily of Potassium Channels; C104498:maurotoxin; D001030:Apamin