title: Phospho-pivot modeling predicts specific interactions of protein phosphatase-1 with a phospho-inhibitor protein CPI-17.
abstract: Phospho-amino acids in proteins are directly associated with phospho-receptor proteins, including protein phosphatases. Here we produced and tested a scheme for docking together interacting phospho-proteins whose monomeric 3D structures were known. The phosphate of calyculin A, an inhibitor for protein phosphatase-1 and 2A (PP1 and PP2A), or phospho-CPI-17, a PP1-specific inhibitor protein, was docked at the active site of PP1. First, a library of 186,624 virtual complexes was generated in silico, by pivoting the phospho-ligand at the phosphorus atom by step every 5 degrees on three rotational axes. These models were then graded for probability according to atomic proximity between two molecules. The predicted structure of PP1 x calyculin A complex fitted to the crystal structure with r.m.s.d. of 0.23 A, providing a validate test of the modeling method. Modeling of PP1 x phospho-CPI-17 complex yielded one converged structure. The segment of CPI-17 around phospho-Thr38 is predicted to fit in the active site of PP1. Positive charges at Arg33/36 of CPI-17 are in close proximity to Glu274 of PP1, where the sequence is unique among Ser/Thr phosphatases. Single mutations of these residues in PP1 reduced the affinity against phospho-CPI-17. Thus, the interface of the PP1 x CPI-17 complex predicted by the phospho-pivot modeling accounts for the specificity of CPI-17 against PP1.
authors.affiliation: Celestar Lexico-Sciences, Inc, MTG D17, Chiba 261-8501.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Matsuzawa
authors.forename: Sei-ich
authors.initials: SI
authors.lastname: Aikawa
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Ohki
authors.forename: Masumi
authors.initials: M
authors.lastname: Eto
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D008387:Marine Toxins; D008958:Models, Molecular; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D054645:Protein Phosphatase 1; D011817:Rabbits; D013816:Thermodynamics
chemical_list: D008387:Marine Toxins; D010080:Oxazoles; D010750:Phosphoproteins; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1