{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:19:28Z","timestamp":1791065968863,"version":"4.1.0"},"reference-count":84,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T00:00:00Z","timestamp":1601596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (\u03b1-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 \u03b1-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 \u03b1-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit \u03b1-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 \u03b1-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.<\/jats:p>","DOI":"10.3390\/toxins12100638","type":"journal-article","created":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T09:39:25Z","timestamp":1601631565000},"page":"638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Widespread Evolution of Molecular Resistance to Snake Venom \u03b1-Neurotoxins in Vertebrates"],"prefix":"10.3390","volume":"12","author":[{"given":"Muzaffar A.","family":"Khan","sequence":"first","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Dashevsky","sequence":"additional","affiliation":[{"name":"Toxin Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia"},{"name":"Australian National Insect Collection, Commonwealth Science &amp; Industry Research Organisation, Acton, ACT 2601, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Kerkkamp","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du\u0161an","family":"Kordi\u0161","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, Josef Stefan Institute, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merijn A. G.","family":"de Bakker","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel","family":"Wouters","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5187-7342","authenticated-orcid":false,"given":"Jory","family":"van Thiel","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"},{"name":"Division of BioAnalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3650-5129","authenticated-orcid":false,"given":"Bianca","family":"op den Brouw","sequence":"additional","affiliation":[{"name":"Toxin Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia"},{"name":"Australian Venom Research Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freek J.","family":"Vonk","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"},{"name":"Division of BioAnalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands"},{"name":"Naturalis Biodiversity Center Leiden, 2333 CR Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6100-3251","authenticated-orcid":false,"given":"R. Manjunatha","family":"Kini","sequence":"additional","affiliation":[{"name":"Department of Biological Science, National University of Singapore, Singapore 117543, Singapore"},{"name":"Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawad","family":"Nazir","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Veterinary and Animal Sciences, Lahore 54000, Pakistan"},{"name":"Treidlia Biovet, 36\/45 Powers Road, Seven Hills, NSW 2147, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-1283","authenticated-orcid":false,"given":"Bryan G.","family":"Fry","sequence":"additional","affiliation":[{"name":"Toxin Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Institute of Biology Leiden, Leiden University, Sylvius Laboratory, 2333 BE Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tree.2012.10.020","article-title":"Complex cocktails: The evolutionary novelty of venoms","volume":"28","author":"Casewell","year":"2013","journal-title":"Trends Ecol. 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