Crystal structures of two alpha-like scorpion toxins: Non-proline cis peptide bonds and implications for new binding site selectivity on the sodium channel

The crystal structures of two group III alpha-like toxins from the scorpion Buthus martensii Karsch, BmK M1 and BmK M4, were determined at 1.7 Angstro m and 1.3 Angstrom resolution and refined to R factors of 0.169 and 0.166, respectively. The first high-resolution structures of the alpha-like scorpi on toxin show some striking features compared with structures of the "class ical" alpha-toxin. Firstly, a non-proline cis peptide bond between residues 9 and 10 unusually occurs in the five-member reverse turn 8-12. Secondly, the cis peptide 9-10 mediates the spatial relationship between the turn 8-1 2 and the C-terminal stretch 58-64 through a pair of main-chain hydrogen bo nds between residues 10 and 64 to form a unique tertiary arrangement which features the special orientation of the terminal residues 62-64. Finally, i n consequence of the peculiar orientation of the C-terminal residues, the f unctional groups of Arg58, which are crucial for the toxin-receptor interac tion, are exposed and accessible in BmK M1 and M4 rather than buried as in the classical alpha-toxins. Sequence alignment and characteristics analysis suggested that the above structural features observed in BmK M1 and M4 occ ur in all group III alpha-like toxins. Recently, some group III alpha-like toxins were demonstrated to occupy a receptor site different from the class ical alpha-toxin. Therefore, the distinct structural features of BmK M1 and M4 presented here may provide the structural basis for the newly recognize d toxin-receptor binding site selectivity. Besides, the non-proline cis pep tide bonds found in these two structures play a role in the formation of th e structural characteristics and in keeping accurate positions of the funct ionally crucial residues. This manifested a way to achieve high levels of m olecular specificity and atomic precision through the strained backbone geo metry. (C) 1999 Academic Press.