STRUCTURE OF 2 MICROCYSTINS - REFINEMENT WITH NUCLEAR OVERHAUSER EFFECTS AND ENSEMBLE CALCULATIONS

Ensemble calculations employing restraints developed from H-1-nmr were used to examine the conformational states of the two microcystins LR and LY. Despite the fast ''flip-flop'' dynamics about the N-methyl-deh ydroalanine residue and adjacent residues, the main conformational cha racteristics of the cyclic heptapeptides consist of a compact ring for med by five of the seven amino acid residues with expulsion of a dipep tide portion out of the plane and the unnatural C20 beta-amino acid -m ethoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid pointing upward from the ring. This structure of microcyst in LR shows high degrees of similarity with the energy-minimized structure of nodularin, a cyclic pentapeptide of identical inhibitory potency against protein phosphat ases 1 and 2A. Comparison of these structures with those of the less t oxic LY variant and with the structurally unrelated okadaic acid, know n as potent inhibitor of the protein phosphatases 1 and 2A, allowed us to propose a rational binding mode of th is structural diverse set of natural inhibitors. (C) 1995 John Wiley & Sons, Inc.