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Peptide and protein neurotoxins, such as α-conotoxins from Cone snails and α-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of α7 nAChR towards peptide and protein neurotoxins and found that α-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human α7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in α-conotoxin analogues affinities, ten single mutants of rat α7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for α-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human α7 nAChR. On the other hand, the reverse mutation R185K in human α7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mutation hα7[S183N, R185K] made the potency of the receptor for them as high as that of rat α7 nAChR. The effects of mutations at position 185 were investigated also with some other α-conotoxins and cobra venom α-cobratoxin and found to have similar but much less pronounced effects on their species specificity. Molecular modeling provided possible explanation for the high species selectivity of [K11A]TxIB and [H5D]RegIIA towards α7 nAChR, opening the new way for design of their analogues with improved affinity to the human receptor.α-Conotoxin [K11A]TxIB and [H5D]RegIIA are more potent on rat versus human α7 nAChR.Lys185 in rα7 subunit mainly confers high specificity of [K11A]TxIB and [H5D]RegIIA.The residue 185 had effects on the α7 species specificity towards other neurotoxins.Molecular modeling provided explanation for the high species selectivity of α7 nAChR.