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J Biol Chem, Vol. 274, Issue 49, 34851-34858, December 3, 1999

Variability among the Sites by Which Curaremimetic Toxins Bind to Torpedo Acetylcholine Receptor, as Revealed by Identification of the Functional Residues of -Cobratoxin

From the CEA Département d'Ingénierie et d'Etudes des Protéines, CE-Saclay, 91191 Gif-sur-Yvette, France

-Cobratoxin, a long chain curaremimetic toxin from Naja kaouthia venom, was produced recombinantly (r-Cbtx) from Escherichia coli. It was indistinguishable from the snake toxin. Mutations at 8 of the 29 explored toxin positions resulted in affinity decreases for Torpedo receptor with G higher than 1.1 kcal/mol. These are R33E > K49E > D27R > K23E > F29A  W25A > R36A  F65A. These positions cover a homogeneous surface of approximately 880 Å² and mostly belong to the second toxin loop, except Lys-49 and Phe-65 which are, respectively, on the third loop and C-terminal tail. The mutations K23E and K49E, and perhaps R33E, induced discriminative interactions at the two toxin-binding sites. When compared with the short toxin erabutoxin a (Ea), a number of structurally equivalent residues are commonly implicated in binding to muscular-type nicotinic acetylcholine receptor. These are Lys-23/Lys-27, Asp-27/Asp-31, Arg-33/Arg-33, Lys-49/Lys-47, and to a lesser and variable extent Trp-25/Trp-29 and Phe-29/Phe-32. In addition, however, the short and long toxins display three major differences. First, Asp-38 is important in Ea in contrast to the homologous Glu-38 in -Cbtx. Second, all of the first loop is insensitive to mutation in -Cbtx, whereas its tip is functionally critical in Ea. Third, the C-terminal tail may be specifically critical in -Cbtx. Therefore, the functional sites of long and short curaremimetic toxins are not identical, but they share common features and marked differences that might reflect an evolutionary pressure associated with a great diversity of prey receptors.

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