Widespread evolution of molecular resistance to snake venom α-neurotoxins in vertebrates

Muzaffar A. Khan, Daniel Dashevsky, Harald Kerkkamp, Dušan Kordiš, Merijn A.G. de Bakker, Roel Wouters, Jory van Thiel, Bianca op den Brouw, Freek Vonk, R. Manjunatha Kini, Jawad Nazir, Bryan G. Fry*, Michael K. Richardson

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (α-neurotoxins) in their venom. These toxins bind the alpha-1 nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction, causing paralysis and asphyxia. Several venomous snakes and their predators have evolved resistance to α-neurotoxins. The resistance is conferred by steric hindrance from N-glycosylated asparagines at amino acids 187 or 189, by an arginine at position 187 that has been hypothesized to either electrostatically repulse positively charged neurotoxins or sterically interfere with α-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit α-neurotoxin binding through structural changes in the receptor. Here, we analyzed this domain in 148 vertebrate species, and assessed its amino acid sequences for resistance-associated mutations. Of these sequences, 89 were sequenced de novo. We find widespread convergent evolution of the N-glycosylation form of resistance in several taxa including venomous snakes and their lizard prey, but not in the snake-eating birds studied. We also document new lineages with the arginine form of inhibition. Using an in vivo assay in four species, we provide further evidence that N-glycosylation mutations reduce the toxicity of cobra venom. The nAChR is of crucial importance for normal neuromuscular function and is highly conserved throughout the vertebrates as a result. Our research shows that the evolution of α-neurotoxins in snakes may well have prompted arms races and mutations to this ancient receptor across a wide range of sympatric vertebrates. These findings underscore the inter-connectedness of the biosphere and the ripple effects that one adaption can have across global ecosystems.

Original languageEnglish
Article number638
Pages (from-to)1-20
Number of pages20
Issue number10
Publication statusPublished - Oct 2020


We acknowledge financial support of the research project from the Leids Universiteits Fonds, Netherlands (Grant reference: 6113/21-6-16, Elise Mathilde Fonds); and Ecology Fund of the Royal Netherlands Academy of Arts and Sciences (KNAWWF/713/18015). HMIK was supported by the Top Sector Syngenopep grant (nr 731.014.206) from the Netherlands Organization for Scientific Research (NWO) and by Naturalis Biodiversity Center (no grant number). BGF was funded by the Australian Research Council Grant DP190100304.

FundersFunder number
Leids Universiteits Fonds6113/21-6-16
Top Sector Syngenopep731.014.206
Australian Research CouncilDP190100304
Koninklijke Nederlandse Akademie van WetenschappenKNAWWF/713/18015
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Naturalis Biodiversity Center


    • CHRNA1
    • Elapidae
    • Evolutionary arms race
    • N-glycosylation
    • Nicotinic acetylcholine receptor (nAChR)
    • Resistance
    • Venom


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