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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:, 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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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
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):
SWORD Depositor: JISC Pubrouter
Depositing User: JISC Pubrouter
Date Deposited: 18 Oct 2022 13:53
Last Modified: 18 Oct 2022 13:53


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