title: The binding mode of calyculin A to protein phosphatase-1. A novel spiroketal vector model.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Oulu, Linnanmaa, FIN-90570 Oulu, Finland.
authors.forename: M K
authors.initials: MK
authors.lastname: Lindvall
authors.forename: P M
authors.initials: PM
authors.lastname: Pihko
authors.forename: A M
authors.initials: AM
authors.lastname: Koskinen
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D008387:Marine Toxins; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry; D010080:Oxazoles / Q000737:chemistry*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010750:Phosphoproteins; D054645:Protein Phosphatase 1; D012984:Software; D013237:Stereoisomerism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D008387:Marine Toxins; D009419:Nerve Tissue Proteins; D010080:Oxazoles; D010750:Phosphoproteins; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1