A study of the binding requirements of calyculin A and dephosphonocalyculin A with PP1, development of a molecular recognition model for the binding interactions of the okadaic acid class of compounds with PP1

• Published in: European journal of pharmaceutical sciences 2001, Vol.12 (3), p.181-194
• Main Authors: Volter, Katie E., Embrey, Kevin J., Pierens, Gregory K., Quinn, Ronald J.
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Calyculin A; Crystallography, X-Ray; Dephosphonocalyculin A; Dopamine and cAMP-Regulated Phosphoprotein 32; Enzyme Inhibitors - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrogen Bonding; Hydrolases; Microcystin; Microcystins; Models, Molecular; Mutagenesis, Site-Directed; Nerve Tissue Proteins; Nodularin; Okadaic acid; Okadaic Acid - metabolism; Oxazoles - metabolism; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Phosphoproteins - metabolism; Protein Binding; Protein phosphatases
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/S0928-0987(00)00116-0

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.