ABSTRACT
The interactions of the okadaic acid class of compounds, with special emphasis on the solution structures of calyculin A and dephosphonocalyculin A with PP1 are reported. After examination of the interactions of all docked structures, a receptor based pharmacophore model for the interactions of the protein phosphatase inhibitors has been developed. Calyculin A or dephosphonocalyculin A can interact with the enzyme in either a manner similar to the reported crystal structure, or in an extended form. The inhibitors require two essential regions interacting with the hydrophobic region and the central metal binding regions of the enzyme. This simplified model is consistent with previously published models of the okadaic acid class of compounds with PP1.
Subject(s)
Enzyme Inhibitors/metabolism , Nerve Tissue Proteins , Okadaic Acid/metabolism , Oxazoles/metabolism , Phosphoprotein Phosphatases/metabolism , Crystallography, X-Ray , Dopamine and cAMP-Regulated Phosphoprotein 32 , Hydrogen Bonding , Marine Toxins , Microcystins , Models, Molecular , Mutagenesis, Site-Directed , Peptides, Cyclic/chemistry , Peptides, Cyclic/metabolism , Phosphoprotein Phosphatases/genetics , Phosphoproteins/metabolism , Protein BindingABSTRACT
The NMR solution structure of calyculin A (1) in chloroform exhibits intramolecular interactions, resembling the original crystal structure. In methanol, calyculin A has the hydrogen bonding moieties solvent exposed. Dephosphonocalyculin A in chloroform resembles calyculin A in chloroform and the crystal structure of calyculin A. Dephosphonocalyculin A in methanol resembles calyculin A in methanol.
