TAILIEUCHUNG - Báo cáo khoa học: The unique pharmacology of the scorpion a-like toxin Lqh3 is associated with its flexible C-tail

The affinity of scorpiona-toxins for various voltage-gated sodium channels (Navs) 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 ortrans peptide-bond conformation between residues 9 and 10, which correlates with the potency on insect or mammalian Navs. | ễFEBS Journal The unique pharmacology of the scorpion a-like toxin Lqh3 is associated with its flexible C-tail Izhar Karbat1 Roy Kahn1 Lior Cohen1 Nitza Ilan1 Nicolas Gilles2 Gerardo Corzo3 Oren Froy1 Maya Gur1 Gudrun Albrecht4 Stefan H. Heinemann4 Dalia Gordon1 and Michael Gurevitz1 1 Department of Plant Sciences George S. Wise Faculty of Life Sciences TelAviv University Ramat Aviv TelAviv Israel 2 CEA Saclay Departement d Ingenierie des Proteines Gif-sur Yvette France 3 Instituto de Biotecnologia Universidad NacionalAutonoma de Mexico Cuernavaca Morelos Mexico 4 Center for Molecular Biomedicine Department of Biophysics Friedrich Schiller University Jena Germany Keywords pH-dependent toxin binding scorpion a-like toxin structure-function relationships toxin effect on inactivation toxin receptor site on sodium channel Correspondence D. Gordon and M. Gurevitz Department of Plant Sciences George S. Wise Faculty of Life Sciences TelAviv University Ramat Aviv TelAviv 69978 Israel Fax 972 3 6406100 Tel 972 3 6409844 E-mail dgordon@ mamgur@ Received 9 January 2007 revised 6 February 2007 accepted 12 February 2007 doi The affinity of scorpion a-toxins for various voltage-gated sodium channels Navs 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 Navs. We examined this hypothesis using Lqh3 an a-like toxin from Leiurus quinquestriatus hebraeus that is highly active in insects and mammalian brain. Lqh3 exhibits slower association kinetics to Navs compared with other a-toxins and its binding to insect Navs is pH-dependent. Mutagenesis of Lqh3 revealed a bi-partite bioactive surface composed of the Core and NC domains as found

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