title: A model for binding of structurally diverse natural product inhibitors of protein phosphatases PP1 and PP2A.
abstract: Protein phosphatases play significant roles in signal transduction pathways pertaining to cell proliferation, gene expression, and neurotransmission. Serine/threonine phosphatases PP1 and PP2A, which are closely related in primary structure (approximately 50%), are inhibited by a structurally diverse group of natural toxins. As part of our study toward understanding the mechanism of inhibition displayed by these toxins, we have developed research in two directions: (1) The standardization of an assay to be used in acquisition of the structure--activity relationship of inhibition data is reported. This nonradioactive assay affords detection levels of molecular phosphate released from a phosphorylated hexapeptide in subnanomolar quantities. The comparison of our IC50 values of these inhibitors against corresponding literature data provided validation for our method. (2) Computational analysis provided a global model for binding of these inhibitors to PP1. The natural toxins were shown to possess remarkably similar three-dimensional motifs upon superimposition and van der Waals minimization within the PP1 active site.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles 90095, USA.
authors.forename: V
authors.initials: V
authors.lastname: Gupta
authors.forename: A K
authors.initials: AK
authors.lastname: Ogawa
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
authors.forename: R W
authors.initials: RW
authors.lastname: Armstrong
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008387:Marine Toxins; D052998:Microcystins; D008958:Models, Molecular; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011487:Protein Conformation; D011714:Pyrans; D015398:Signal Transduction; D013141:Spiro Compounds; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014118:Toxins, Biological / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; D010080:Oxazoles; D010456:Peptides, Cyclic; D011714:Pyrans; D013141:Spiro Compounds; D014118:Toxins, Biological; C063998:nodularin; C053079:tautomycin; D019319:Okadaic Acid; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; C057862:cyanoginosin LR