Structural Basis for the Voltage-gated Na+ Channel Selectivity of the Scorpion α-Like Toxin BmK M1

Xiang, Ye; Bosmans, Frank; Li, Chong; Zhang, Ying; Wang, Da Cheng; Tytgat, Jan

doi:10.1016/j.jmb.2005.08.068

Cited by 35 publications

(41 citation statements)

References 45 publications

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“…This analysis highlighted a functional discontinuous surface composed of non-polar and charged amino acids clustered around the main α-helical motif and the C-tail. Among the charged residues, Glu30 is a putative hot-spot and is shielded from bulk solvent by a hydrophobic gasket (Tyr26 and Val34), a phenomenon also observed with scorpion α-like toxins (Ye et al, 2005). Furthermore, another study confirmed the mandatory role for toxin action of Glu30 together with Glu15 .…”

Section: Introductionmentioning

confidence: 60%

“…Next, capped cRNA's were synthetized from the linearised plasmid using the large-scale SP6 mMESSAGE-mMACHINE transcription kit (Ambion, U.S.A.). The harvesting of oocytes from anaesthetized female Xenopus laevis frogs was as previously described (Ye et al, 2005). Oocytes were injected with 50 nl of cRNA at a concentration of ±1 ng nl −1 (1:1 mixture for both rNa v 1.2a/β 1 and DmNav1/tipE) using a Drummond microinjector (U.S.A.).…”

Section: Voltage-activated Sodium Channel Expressionmentioning

confidence: 99%

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Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Bosmans

Martin‐Eauclaire²,

Tytgat

2007

Toxicology and Applied Pharmacology

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In general, scorpion β-toxins have been well examined. However, few in-depth studies have been devoted to species selectivity and affinity comparisons on the different voltage-activated Na + channels since they have become available as cloned channels that can be studied in heterologous expression systems. As a result, their classification is largely historical and dates from early in vivo experiments on mice and cockroach and fly larvae.In this study, we aimed to provide an updated overview of selectivity and affinity of scorpion β-toxins towards voltage-activated Na + channels of vertebrates or invertebrates. As pharmacological tools, we used the classic β-toxins AaHIT, Css II, Css IV, Css VI and Ts VII and tested them on the neuronal vertebrate voltage-activated Na + channel, rNa v 1.2a. For comparison, its invertebrate counterpart, DmNav1, was also tested. Both these channels were expressed in Xenopus laevis oocytes and the currents measured with the two-electrode voltage-clamp technique. We supplemented this data with several binding displacement studies on rat brain synaptosomes. The results lead us to propose a general classification and a novel nomenclature of scorpion β-toxins based on pharmacological activity.

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Section: Introductionmentioning

confidence: 60%

Section: Voltage-activated Sodium Channel Expressionmentioning

confidence: 99%

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Bosmans

Martin‐Eauclaire²,

Tytgat

2007

Toxicology and Applied Pharmacology

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“…As residues of the five-residue turn in the ␣-toxins Lqh␣IT and BmKM1 have previously been shown to be involved in bioactivity (20,21,38), we have substituted one by one their equivalents (Asp 8 , Asp 9 , and Val 10 ) in Lqh2. Surprisingly, these substitutions had no effect on activity at rNa v 1.2a ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In previous work it was suggested that the shape of the NC domain in scorpion ␣-toxins determines their selectivity (21,22,38,39,49). It was further proposed that the shape of the NC domain is established by the peptide bond conformation between residues 9 and 10 in the five-residue turn.…”

Section: Hismentioning

confidence: 99%

Molecular Requirements for Recognition of Brain Voltage-gated Sodium Channels by Scorpion α-Toxins

Kahn

Karbat

Ilan

et al. 2009

Journal of Biological Chemistry

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The scorpion ␣-toxin Lqh2 (from Leiurus quinquestriatus hebraeus) is active at various mammalian voltage-gated sodium channels (Na v s) and is inactive at insect Na v s. To resolve the molecular basis of this preference we used the following strategy: 1) Lqh2 was expressed in recombinant form and key residues important for activity at the rat brain channel rNa v 1.2a were identified by mutagenesis. These residues form a bipartite functional surface made of a conserved "core domain" (residues of the loops connecting the secondary structure elements of the molecule core), and a variable "NC domain" (five-residue turn and the C-tail) as was reported for other scorpion ␣-toxins.2) The functional role of the two domains was validated by their stepwise construction on the similar scaffold of the anti-insect toxin Lqh␣IT. Analysis of the activity of the intermediate constructs highlighted the critical role of Phe 15 of the core domain in toxin potency at rNa v 1.2a, and has suggested that the shape of the NC-domain is important for toxin efficacy. 3) Based on these findings and by comparison with other scorpion ␣-toxins we were able to eliminate the activity of Lqh2 at rNa v 1.4 (skeletal muscle), hNa v 1.5 (cardiac), and rNa v 1.6 channels, with no hindrance of its activity at Na v 1.1-1.3. These results suggest that by employing a similar approach the design of further target-selective sodium channel modifiers is imminent.

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“…The bioactive surface of ␣-toxins, studied over three decades through various complementary approaches, encompasses two regions corresponding to one side of the molecule core, and the N-and C-terminal region, respectively (72). Recent initial modeling of the interaction of ␣-toxin LqhII, a close homologue of AahII, with the Na v channel has led to suggest that residues Phe-15, Arg-18, Trp-38, and Asn-44 at the side of the toxin core would recognize the voltage-sensing (gating) module in domain IV of the channel, whereas residues Lys-2, Thr-57, and Lys-58 in the toxin N-and C-terminal region would recognize the pore module in domain I of the channel (73).…”

Section: Chemical and Functional Quality Of Fab4c1 And Fab9c2-mentioning

confidence: 99%

Structural Insights into Antibody Sequestering and Neutralizing of Na+ Channel α-Type Modulator from Old World Scorpion Venom

Fabrichny

Mondielli

Conrod

et al. 2012

Journal of Biological Chemistry

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Background:The antigenic specificity of scorpion ␣-toxins, which target Na v channels, hinders efficient antiserum production. Results: Structures of two antibodies, which together neutralize the main toxins in a threatening venom, were solved in toxin-bound and unbound forms, respectively. Conclusion: Selective toxin trapping involves distinctive molecular determinants and bound toxin orientations. Significance: These complementary templates will help design new neutralizing molecules suitable for immunotherapy.

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Structural Basis for the Voltage-gated Na+ Channel Selectivity of the Scorpion α-Like Toxin BmK M1

Cited by 35 publications

References 45 publications

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Molecular Requirements for Recognition of Brain Voltage-gated Sodium Channels by Scorpion α-Toxins

Structural Insights into Antibody Sequestering and Neutralizing of Na+ Channel α-Type Modulator from Old World Scorpion Venom

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