The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors

Nys, Mieke, Zarkadas, Eleftherios, Brams, Marijke, Mehregan, Aujan, Kambara, Kumiko, Kool, Jeroen, Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719, Bertrand, Daniel, Baenziger, John E., Nury, Hugues and Ulens, Chris (2022) 'The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors'. Nature Communications, Vol 13, Issue 1, e4543.

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Abstract

Bites by elapid snakes (e.g. cobras) can result in life-threatening paralysis caused by venom neurotoxins blocking neuromuscular nicotinic acetylcholine receptors. Here, we determine the cryo-EM structure of the muscle-type Torpedo receptor in complex with ScNtx, a recombinant short-chain α-neurotoxin. ScNtx is pinched between loop C on the principal subunit and a unique hairpin in loop F on the complementary subunit, thereby blocking access to the neurotransmitter binding site. ScNtx adopts a binding mode that is tilted toward the complementary subunit, forming a wider network of interactions than those seen in the long-chain α-Bungarotoxin complex. Certain mutations in ScNtx at the toxin-receptor interface eliminate inhibition of neuronal α7 nAChRs, but not of human muscle-type receptors. These observations explain why ScNtx binds more tightly to muscle-type receptors than neuronal receptors. Together, these data offer a framework for understanding subtype-specific actions of short-chain α-neurotoxins and inspire strategies for design of new snake antivenoms.

Item Type:	Article
Additional Information:	Author Correction: The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors Correction to: Nature Communications https://doi.org/10.1038/s41467-022-32174-7, published online 04 August 2022 In the original version of this Article, the Acknowledgements section incorrectly omitted two of the funding sources. A sentence ‘CU was supported by grants G0C1319N and G087921N from FWO-Vlaanderen.’ has been now added. This has been corrected in both the PDF and HTML versions of the Article.
Subjects:	QV Pharmacology > Toxicology > General Toxicology > QV 600 General works QV Pharmacology > Toxicology > General Toxicology > QV 601 Antidotes and other therapeutic measures WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1038/s41467-022-32174-7
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	18 Oct 2022 13:53
Last Modified:	06 Jun 2024 13:24
URI:	https://archive.lstmed.ac.uk/id/eprint/20932

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