Crystal and Molecular Structure of S-Deoxo[Ile^3]amaninamide: A Synthetic Analog of Amanita Toxins

The crystal structure of S-deoxo[Ile^3]amaninamide, a nontoxic synthetic derivative of the Amanita phalloides mushroom toxins (amatoxins), has been determined by single-crystal X-ray diffraction. The crystals are monoclinic, space group P2_1, with 2 formula units per unit cell. Cell dimensions are a = 12.147 Å, b = 11.250 Å, c = 19.267 Å, and (β = 92.41°. The structure was determined by molecular replacement methods and refined by least-squares techniques to a final R value of 0.065 for 3894 independent observations. Six intramolecular hydrogen bonds hold the bicyclic octapeptide in a compact conformation, which is very similar to the conformation of the naturally occurring (and toxic) amatoxin, (β-amanitin. The study demonstrates that the 30-fold reduction in binding affinity to RNA polymerase B of the title amatoxin, and probably of most of the other amatoxin analogues with altered side chain 3, is not due to alteration of backbone conformation. The three water molecules and two ethanol molecules, crystallized with the amatoxin, form a strong and extensive intermolecular hydrogen-bonding system