Solid State and Solution Conformation of [Ala7]-Phalloidin: A Synthetic Phallotoxin Analogue

Phallotoxins are toxic compds. produced by poisonous mushroom Amanita phalloides and belong to the class of bicyclic peptides with a transannular thioether bridge. Their intoxication mechanism in the liver involves a specific binding of the toxins to F-actin that, consequently, prevents the depolymn. equil. with G-actin. Even though the conformational features of phallotoxins have been worked out in soln., the exact mechanism of interaction with F-actin is still unknown. In this study a toxic phalloidin synthetic deriv., bicyclo(Ala1-D-Thr2-Cys3-cis-4-hydroxy-Pro4-Ala5-2-mercapto-Trp6-Ala7)(S-3®6) has been synthesized. A substitution at position 7, with an Ala residue replaces the 4,5-dihydroxy-Leu present in the natural phalloidin. This analog has formed crystals suitable for x-ray anal., and represents the first case for such a class of compds. The solid-state structure as well as the soln. conformation have been evaluated. NMR techniques have been used to ext. interproton distances as restraints in subsequent mol. dynamics calcns. Finally, a direct comparison between structures in soln. and in the solid state is presented.