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

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.

• Authors: Mieke Nys, Eleftherios Zarkadas, Marijke Brams, Aujan Mehregan, Kumiko Kambara, Jeroen Kool, Nicholas R Casewell, Daniel Bertrand, John E Baenziger, Hugues Nury, Chris Ulens
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 4543 (08 04 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35927270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Bungarotoxins
• Neurotoxins
• Receptors, Nicotinic

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• Bungarotoxins (metabolism)
• Elapidae
• Humans
• Muscles (metabolism)
• Neurotoxins (chemistry)
• Receptors, Nicotinic (metabolism)