Honey badgers (Mellivora capensis) prey upon and survive bites from venomous snakes (Family: Elapidae),
but the molecular basis of their venom resistance is unknown. The muscular nicotinic cholinergic
receptor (nAChR), targeted by snake a-neurotoxins, has evolved in some venom-resistant mammals to no
longer bind these toxins. Through phylogenetic analysis of mammalian nAChR sequences, we show that
honey badgers, hedgehogs, and pigs have independently acquired functionally equivalent amino acid
replacements in the toxin-binding site of this receptor. These convergent amino acid changes impede
toxin binding by introducing a positively charged amino acid in place of an uncharged aromatic residue.
In venom-resistant mongooses, different replacements at these same sites are glycosylated, which is
thought to disrupt binding through steric effects. Thus, it appears that resistance to snake venom aneurotoxin
has evolved at least four times among mammals through two distinct biochemical mechanisms
operating at the same sites on the same receptor.
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