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The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels.
Biochem Pharmacol. 2013 May 15; 85(10):1542-54.BP

Abstract

One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. However, its disulfide-connectivity, three-dimensional structure, and mode of action have not been determined. Here we show that recombinant Aps III (rAps III) is an atypical knottin peptide; three of the disulfide bridges form a classical inhibitor cystine knot motif while the fourth disulfide acts as a molecular staple that restricts the flexibility of an unusually large β hairpin loop that often houses the pharmacophore in this class of toxins. We demonstrate that the irreversible paralysis induced in insects by rAps III results from a potent block of insect voltage-gated sodium channels. Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel.

Authors+Show Affiliations

Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23473802

Citation

Bende, Niraj S., et al. "The Insecticidal Neurotoxin Aps III Is an Atypical Knottin Peptide That Potently Blocks Insect Voltage-gated Sodium Channels." Biochemical Pharmacology, vol. 85, no. 10, 2013, pp. 1542-54.
Bende NS, Kang E, Herzig V, et al. The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels. Biochem Pharmacol. 2013;85(10):1542-54.
Bende, N. S., Kang, E., Herzig, V., Bosmans, F., Nicholson, G. M., Mobli, M., & King, G. F. (2013). The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels. Biochemical Pharmacology, 85(10), 1542-54. https://doi.org/10.1016/j.bcp.2013.02.030
Bende NS, et al. The Insecticidal Neurotoxin Aps III Is an Atypical Knottin Peptide That Potently Blocks Insect Voltage-gated Sodium Channels. Biochem Pharmacol. 2013 May 15;85(10):1542-54. PubMed PMID: 23473802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels. AU - Bende,Niraj S, AU - Kang,Eunji, AU - Herzig,Volker, AU - Bosmans,Frank, AU - Nicholson,Graham M, AU - Mobli,Mehdi, AU - King,Glenn F, Y1 - 2013/03/06/ PY - 2013/01/31/received PY - 2013/02/24/revised PY - 2013/02/27/accepted PY - 2013/3/12/entrez PY - 2013/3/12/pubmed PY - 2013/6/15/medline SP - 1542 EP - 54 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 85 IS - 10 N2 - One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. However, its disulfide-connectivity, three-dimensional structure, and mode of action have not been determined. Here we show that recombinant Aps III (rAps III) is an atypical knottin peptide; three of the disulfide bridges form a classical inhibitor cystine knot motif while the fourth disulfide acts as a molecular staple that restricts the flexibility of an unusually large β hairpin loop that often houses the pharmacophore in this class of toxins. We demonstrate that the irreversible paralysis induced in insects by rAps III results from a potent block of insect voltage-gated sodium channels. Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23473802/The_insecticidal_neurotoxin_Aps_III_is_an_atypical_knottin_peptide_that_potently_blocks_insect_voltage_gated_sodium_channels_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00153-6 DB - PRIME DP - Unbound Medicine ER -