Conformations of Amatoxins in the Crystalline State

G. Shoham*, W. N. Lipscomb, Th Wieland

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The amatoxins consist of a family of bicyclic octapeptides present in the poisonous mushroom Amanita phalloides and their synthetic derivatives. The crystal structures of the slightly toxic (S)-sulfoxide isomer of omethyl-α-amanitin (7) and the highly toxic O-methyl-S-oxo-α-amanitin (8) have been determined by single-crystal X-ray diffraction techniques. The structures were solved by direct methods and refined by least-squares procedures to final R factors of 0.063 and 0.068 for 7 and 8, respectively. Both crystals display the symmetry of the orthorhombic space group P212121 with 4 formula units in the unit cell. Unit cell dimensions of 7 are a = 15.883 Å, b = 18.245 Å, and c = 20.247 Å, and there are 6 methanol molecules and a water molecule in each crystallographic asymmetric unit. Unit cell dimensions of 8 are a = 16.123 Å, b= 18.358 Å, and c = 20.119 Å, and there are 3 ethanol molecules and 4 water molecules in each asymmetric unit. The conformations of amatoxins 7 and 8 are very rigid and they are almost identical. The distorted “T” shape conformation is dominated by five rather strong intramolecular hydrogen bonds: 2 backbone (5→1 and 4→1) hydrogen bonds and 3 backbone/side chain hydrogen bonds. The solvent molecules in both crystals form continuous “channels” along the crystal b axis and participate in extensive hydrogen bond networks with the peptides. The structure and conformation of 7 and 8 are similar, for the most part, with those of the toxic β-amanitin (2) and the nontoxic S-deoxo-Ile3-amaninamide (10), in the crystalline state. Nevertheless, the backbones of 2 and 10 are significantly more similar to each other than to 7 and 8, primarily due to a 90° rotation of the plane of the peptide bond between Cys-8 and Asn-1 which occurs only in 7 and 8. There are a few more local conformational differences between the four amatoxin derivatives, but they do not seem to be of functional importance. The structure-activity relationships in the amatoxin series are discussed, mainly on a 3-dimensional structural basis, and it is suggested that most of the differences in the biological activities of amatoxins result from differences in the chemical structure and not from differences in the conformations.

Original languageAmerican English
Pages (from-to)4791-4809
Number of pages19
JournalJournal of the American Chemical Society
Volume111
Issue number13
DOIs
StatePublished - 1989

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