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| Theoretical models of catalytic domains of protein phosphatases 1 and 2A withZn2+ and Mn2+ metal dications and putative bioligands in their catalytic centers. J Ciarkowski, S Ołdziej, E Woźniak-Celmer Acta Biochim Polon 2002; 48(1):35-52 ICID: 146504 |
| IC™ Value: 6.80 |
| The oligomeric metalloenzymes protein phosphatases dephosphorylate OH groupsof Ser/Thr or Tyr residues of proteins whose actions depend on the phosphorus signal. The catalytic unitsof Ser/Thr protein phosphatases 1, 2A and 2B (PP1c, PP2Ac and PP2Bc, respectively), which exhibit about45% sequence similarity, have their active centers practically identical. This feature strongly suggeststhat the unknown structure of PP2Ac could be successfully homology-modeled from the known structuresof PP1c and/or PP2Bc. Initially, a theoretical model of PP1c was built, including a phosphate and a metaldication in its catalytic site. The latter was modeled, together with a structural hydroxyl anion, asa triangular pseudo-molecule (Zno or Mno), composed of two metal cations (double Zn2+ or Mn2+, respectively)and the OH- group. To the free PP1c two inhibitor sequences R29RRRPpTPAMLFR40 of DARPP-32 and R30RRRPpTPATLVLT42of Inhibitor-1, and two putative substrate sequences LRRApSVA and QRRQRKpRRTI were subsequently docked.In the next step, a free PP2Ac model was built via homology re-modeling of the PP1c template and thesame four sequences were docked to it. Thus, together, 20 starting model complexes were built, allowingfor combination of the Zno and Mno pseudo-molecules, free enzymes and the peptide ligands docked in thecatalytic sites of PP1c and PP2Ac. All models were subsequently subjected to 250-300 ps molecular dynamicsusing the AMBER 5.0 program. The equilibrated trajectories of the final 50 ps were taken for furtheranalyses. The theoretical models of PP1c complexes, irrespective of the dication type, exhibited increasedmobilities in the following residue ranges: 195-200, 273-278, 287-209 for the inhibitor sequences and21-25, 194-200, 222-227, 261, 299-302 for the substrate sequences. Paradoxically, the analogous PP2Acmodels appeared much more stable in similar simulations, since only their "prosegment" residues 6-10and 14-18 exhibited an increased mobility in the inhibitor complexes while no areas of increased mobilitywere found in the substrate complexes. Another general observation was that the complexes with Mn dicationswere more stable than those with Zn dications for both PP1c and PP2Ac units. |
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ICID 146504 PMID 11440182 - click here to show this article in PubMed database |
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