THE BINDING MODE OF CALYCULIN-A TO PROTEIN PHOSPHATASE-1 - A NOVEL SPIROKETAL VECTOR MODEL

The catalytic subunits of serine/threonine protein phosphatases 1 and 2A are subject to inhibition by various toxins such as the microcyst i ns, the nodularins, okadaic acid, tautomycin, and the calyculins. A re cent paper (Bagu, J. R., Sykes, B. D, Craig, M. M., and Holmes, C. F. B. (1997) J. Biol. Chem. 272, 5087-5097) reported the successful docki ng of the crystal structure of calyculin A to the crystal structure of protein phosphatase-1. Unfortunately, the model presented there is ba sed on the structure of the unnatural enantiomer of calyculin A and mu st therefore be incorrect. We have developed a spiroketal vector model which appears to account for the spatial orientation of the hydrophob ic and basic chains extending from the spiroketal-phosphate core of ca lyculin A. The model also clearly demonstrates why the unnatural enant iomer of calyculin A does not fit properly into the pocket of the acti ve site. Based on our model, we present a possible open binding mode f or calyculin A in the enzyme, This open structure is conceptually simi lar to the predicted binding mode of the peptide inhibitor DARPP-32 to the enzyme; the hydrophobic, metal-binding, and electrostatic interac tions are all retained in this model.