ArticleThe journal of physical chemistry. B2009
Mechanism of Cdc25B phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations.
Article in The journal of physical chemistry. B, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors.Molecules (Basel, Switzerland) · 2022Review
- PolarizableMolecules (Basel, Switzerland) · 2018Article
- Development of a Novel Nonradioisotopic Assay and Cdc25B Overexpression Cell Lines for Use in Screening for Cdc25B Inhibitors.Yonsei medical journal · 2018Article
- Multiscale Quantum Mechanics/Molecular Mechanics Simulations with Neural Networks.Journal of chemical theory and computation · 2016Article
- Protein expression, characterization and activity comparisons of wild type and mutant DUSP5 proteins.BMC biochemistry · 2014Article
- Noncovalent Interaction Analysis in Fluctuating Environments.Journal of chemical theory and computation · 2013Article
- In silico screening of 393 mutants facilitates enzyme engineering of amidase activity in CalB.PeerJ · 2013Article
- Revelation of a catalytic calcium-binding site elucidates unusual metal dependence of a human apyrase.Journal of the American Chemical Society · 2012Article
- Catalytic mechanism of 4-oxalocrotonate tautomerase: significances of protein-protein interactions on proton transfer pathways.The journal of physical chemistry. B · 2012Article
- Article
- Conical intersections in solution: formulation, algorithm, and implementation with combined quantum mechanics/molecular mechanics method.The Journal of chemical physics · 2011Article
- Autocatalytic intramolecular isopeptide bond formation in gram-positive bacterial pili: a QM/MM simulation.Journal of the American Chemical Society · 2011Article
- Concerted O atom-proton transfer in the O-O bond forming step in water oxidation.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Development and application of ab initio QM/MM methods for mechanistic simulation of reactions in solution and in enzymes.Theochem · 2009Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Cdc25B is a dual-specificity phosphatase that catalyzes the dephosphorylation of the Cdk2/CycA protein complex. This enzyme is an important regulator of the human cell cycle and has been identified as a potential anticancer target. In general, protein tyrosine phosphatases are thought to bind the dianionic form of the phosphate and employ general acid catalysis via the Asp residue in the highly conserved WPD-loop. However, the Cdc25 phosphatases form a special subfamily based on their distinct differences from other protein tyrosine phosphatases. Although Cdc25B contains the (H/V)CX(5)R catalytic motif present in all other protein tyrosine phosphatases, it lacks an analogous catalytic acid residue. No crystallographic data currently exist for the complex of Cdc25B with Cdk2/CycA, so in addition to its natural protein substrate, experimental and theoretical studies are often carried out with small molecule substrates. In an effort to gain understanding of the dephosphorylation mechanism of Cdc25B with a commonly used small molecule substrate, we have performed simulations of the rate-limiting step of the reaction catalyzed by Cdc25B with the substrate p-nitrophenyl phosphate using the recently developed QM/MM Minimum Free Energy Path method (Hu et al. J. Chem. Phys. 2008, 034105). We have simulated the first step of the reaction with both the monoanionic and the dianionic forms of the substrate, and our calculations favor a mechanism involving the monoanionic form. Thus, Cdc25 may employ a unique dephosphorylation mechanism among protein tyrosine phosphatases, at least in the case of the small molecule substrate p-nitrophenyl phosphate.
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