© 2005 The Japanese Biochemical Society
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Phospho-Pivot Modeling Predicts Specific Interactions of Protein Phosphatase-1 with a Phospho-Inhibitor Protein CPI-17
1 Celestar Lexico-Sciences, Inc, MTG D17, Chiba 261-8501; 2 Japan Advanced Institute of Science and Technology (JAIST), Ishikawa 923-1292; and 3 University of Virginia School of Medicine, Center for Cell Signaling and Department of Molecular Physiology and Biological Physics, Charlottesville, VA22908-0577, USA
* To whom correspondence should be addressed. Phone: +1-434-982-0812, Fax: +1-434-243-2829, E-mail: me2h{at}virginia.edu
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° on three rotational axes. These models were then graded for probability according to atomic proximity between two molecules. The predicted structure of PP1·calyculin A complex fitted to the crystal structure with r.m.s.d. of 0.23 Å, providing a validate test of the modeling method. Modeling of PP1·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·CPI-17 complex predicted by the phospho-pivot modeling accounts for the specificity of CPI-17 against PP1.
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