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However, the predators of venomous animals may exploit feeding adaptation strategies to overcome toxins their prey produce. Much remains unknown about the genetic and molecular game process in the toxin-dominant food chain model. Here, we show an evolutionary strategy in different trophic levels of scorpion-eating amphibians, scorpions and insects, representing each predation relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions preying on insects, we found that the scorpion \u03b1-toxins irreversibly activate the skeletal muscle sodium channel of their prey (insect, BgNaV1) through a membrane delivery mechanism and an efficient binding with the Asp\/Lys-Tyr motif of BgNaV1. However, in the predatory game between frogs and scorpions, with a single point mutation (Lys to Glu) in this motif of the frog's skeletal muscle sodium channel (fNaV1.4), fNaV1.4 breaks this interaction and diminishes muscular toxicity to the frog; thus, frogs can regularly prey on scorpions without showing paralysis. Interestingly, this molecular strategy also has been employed by some other scorpion-eating amphibians, especially anurans. In contrast to these amphibians, the Asp\/Lys-Tyr motifs are structurally and functionally conserved in other animals that do not prey on scorpions. Together, our findings elucidate the protein-protein interacting mechanism of a toxin-dominant predator-prey system, implying the evolutionary game theory at a molecular level.<\/jats:p>","DOI":"10.1093\/nsr\/nwz097","type":"journal-article","created":{"date-parts":[[2019,7,11]],"date-time":"2019-07-11T11:10:49Z","timestamp":1562843449000},"page":"1191-1200","source":"Crossref","is-referenced-by-count":11,"title":["Molecular game theory for a toxin-dominant food chain model"],"prefix":"10.1093","volume":"6","author":[{"given":"Bowen","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences\/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Washington University 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of Zoology, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences\/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China"},{"name":"Department of Biological Sciences, Columbia University, New York, NY 10027, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyuan","family":"Su","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences\/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Neurobiology, Department of Biophysics and 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