جهت دسترسی به کاربرگه ی زیر، از این لینک استفاده کنید. http://dl.pgu.ac.ir/handle/10722/168373
Title: Mechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations
Keywords: Binding Sites;Catalysis;Computer Simulation;Models, Chemical;Nitrophenols - Chemistry - Metabolism;Organophosphorus Compounds - Chemistry - Metabolism;Quantum Theory;Cdc25 Phosphatases - Chemistry - Metabolism
Publisher: American Chemical Society. The Journal's web site is located at http://pubs.acs.org/journal/jpcbfk;United States
Description: 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 5R 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. © 2009 American Chemical Society.;link_to_subscribed_fulltext
Other Identifiers: Journal Of Physical Chemistry B, 2009, v. 113 n. 15, p. 5217-5224
4199957
10.1021/jp805137x
5224
WOS:000265030500033
1520-6106
15
19301836
eid_2-s2.0-65249157950
5217
http://hdl.handle.net/10722/168373
113
Type Of Material: Article
Appears in Collections:Department of Chemistry

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