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Solid State and Solution Conformation of [Ala 7 ]‐Phalloidin: A Synthetic Phallotoxin Analogue
Author(s) -
Zanotti Giancarlo,
Falcigno Lucia,
Saviano Michele,
D'Auria Gabriella,
Bruno Bianca Maria,
Campanile Tiziano,
Paolillo Livio
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20010401)7:7<1479::aid-chem1479>3.0.co;2-2
Subject(s) - amanita phalloides , phalloidin , stereochemistry , thioether , chemistry , actin , amanita , nucleophile , bicyclic molecule , derivative (finance) , biology , organic chemistry , biochemistry , paleontology , botany , cytoskeleton , financial economics , economics , cell , catalysis
Phallotoxins are toxic compounds 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 depolymerization equilibrium with G‐actin. Even though the conformational features of phallotoxins have been worked out in solution, the exact mechanism of interaction with F‐actin is still unknown. In this study a toxic phalloidin synthetic derivative, bicyclo(Ala 1 ‐ D ‐Thr 2 ‐Cys 3 ‐ cis ‐4‐hydroxy‐Pro 4 ‐Ala 5 ‐2‐mercapto‐Trp 6 ‐Ala 7 )(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 analogue has formed crystals suitable for X‐ray analysis, and represents the first case for such a class of compounds. The solid‐state structure as well as the solution conformation have been evaluated. NMR techniques have been used to extract interproton distances as restraints in subsequent molecular dynamics calculations. Finally, a direct comparison between structures in solution and in the solid state is presented.