NMR structures and activity of a novel alpha-like toxin from the scorpion Leiurus quinquestriatus hebraeus

• Published in: Journal of molecular biology Vol. 285; no. 4; p. 1749
• Main Authors: Krimm, I, Gilles, N, Sautière, P, Stankiewicz, M, Pelhate, M, Gordon, D, Lancelin, J M
• Format: Journal Article
• Language: English
• Published: England 29.01.1999
• Subjects: Amino Acid Sequence; Animals; Axons - drug effects; Axons - metabolism; Binding Sites; Cockroaches; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Neurotoxins - chemistry; Neurotoxins - genetics; Neurotoxins - toxicity; Peptides - chemistry; Peptides - genetics; Peptides - toxicity; Protein Conformation; Protein Structure, Secondary; Rats; Scorpion Venoms - chemistry; Scorpion Venoms - genetics; Scorpion Venoms - toxicity; Scorpions - chemistry; Scorpions - genetics; Sequence Homology, Amino Acid; Sodium Channels - drug effects; Sodium Channels - metabolism; Static Electricity
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1006/jmbi.1998.2418

NMR structures of a new toxin from the scorpion Leiurus quinquestriatus hebraeus (Lqh III) have been investigated in conjunction with its pharmacological properties. This toxin is proposed to belong to a new group of scorpion toxins, the alpha-like toxins that target voltage-gated sodium channels with specific properties compared with the classical alpha-scorpion toxins. Electrophysiological analysis showed that Lqh III inhibits a sodium current inactivation in the cockroach axon, but induces in addition a resting depolarization due to a slowly decaying tail current atypical to other alpha-toxin action. Binding studies indicated that radiolabeled Lqh III binds with a high degree of affinity (Ki=2.2 nM) on cockroach sodium channels and that the alpha-toxin from L quinquestriatus hebraeus highly active on insects (LqhalphaIT) and alpha-like toxins compete at low concentration for its receptor binding site, suggesting that the alpha-like toxin receptor site is partially overlapping with the receptor site 3. Conversely, in rat brain, Lqh III competes for binding of the most potent anti-mammal alpha-toxin from Androctonus australis Hector venom (AaH II) only at very high concentration. The NMR structures were used for the scrutiny of the similarities and differences with representative scorpion alpha-toxins targeting the voltage-gated sodium channels of either mammals or insects. Three turn regions involved in the functional binding site of the anti-insect LqhalphaIT toxin reveal significant differences in the Lqh III structure. The electrostatic charge distribution in the Lqh III toxin is also surprisingly different when compared with the anti-mammal alpha-toxin AaH II. Similarities in the electrostatic charge distribution are, however, recognized between alpha-toxins highly active on insects and the alpha-like toxin Lqh III. This affords additional important elements to the definition of the new alpha-like group of scorpion toxins and the mammal versus insect scorpion toxin selectivities.