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 microcystins, the nodularins, okadaic acid, tautomycin, and the calyculins. A recent 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 docking of the crystal structure of calyculin A to the crystal structure of protein phosphatase-1. Unfortunately, the model presented there is based on the structure of the unnatural enantiomer of calyculin A and must therefore be incorrect. We have developed a spiroketal vector model which appears to account for the spatial orientation of the hydrophobic and basic chains extending from the spiroketal-phosphate core of calyculin A. The model also clearly demonstrates why the unnatural enantiomer of calyculin A does not fit properly into the pocket of the active site. Based on our model, we present a possible open binding mode for calyculin A in the enzyme. This open structure is conceptually similar to the predicted binding mode of the peptide inhibitor DARPP-32 to the enzyme; the hydrophobic, metal-binding, and electrostatic interactions are all retained in this model.