Abstract
Marine macrolide toxins of trisoxazole family target actin with high affinity and specificity and have promising pharmacological properties. We present X-ray structures of actin in complex with two members of this family, kabiramide C and jaspisamide A, at a resolution of 1.45 and 1.6 Å, respectively. The structures reveal the absolute stereochemistry of these toxins and demonstrate that their trisoxazole ring interacts with actin subdomain 1 while the aliphatic side chain is inserted into the hydrophobic cavity between actin subdomains 1 and 3. The binding site is essentially the same as the one occupied by the actin-capping domain of the gelsolin superfamily of proteins. The structural evidence suggests that actin filament severing and capping by these toxins is also analogous to that of gelsolin. Consequently, these macrolides may be viewed as small molecule biomimetics of an entire class of actin-binding proteins.
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Acknowledgements
The authors thank A. Evdokimov for the help with Gaussian 98a, E. Egelman and S. Khaitlina for the comments on the manuscript and E. Wise for the help in preparation of figures. We thank K. Suwanborirux for help in the collection of the sponges used in the purification of kabiramide C.
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Klenchin, V., Allingham, J., King, R. et al. Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin. Nat Struct Mol Biol 10, 1058–1063 (2003). https://doi.org/10.1038/nsb1006
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DOI: https://doi.org/10.1038/nsb1006
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