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Article: Mechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations
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TitleMechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations
 
AuthorsParks, JM2 1
Hu, H2 1
Rudolph, J2 1
Yang, W2 1
 
Issue Date2009
 
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journal/jpcbfk
 
CitationJournal Of Physical Chemistry B, 2009, v. 113 n. 15, p. 5217-5224 [How to Cite?]
DOI: http://dx.doi.org/10.1021/jp805137x
 
AbstractCdc25B 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.
 
ISSN1520-6106
2013 Impact Factor: 3.377
2013 SCImago Journal Rankings: 1.575
 
DOIhttp://dx.doi.org/10.1021/jp805137x
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorParks, JM
 
dc.contributor.authorHu, H
 
dc.contributor.authorRudolph, J
 
dc.contributor.authorYang, W
 
dc.date.accessioned2012-10-08T03:18:07Z
 
dc.date.available2012-10-08T03:18:07Z
 
dc.date.issued2009
 
dc.description.abstractCdc25B 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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Physical Chemistry B, 2009, v. 113 n. 15, p. 5217-5224 [How to Cite?]
DOI: http://dx.doi.org/10.1021/jp805137x
 
dc.identifier.citeulike4199957
 
dc.identifier.doihttp://dx.doi.org/10.1021/jp805137x
 
dc.identifier.epage5224
 
dc.identifier.issn1520-6106
2013 Impact Factor: 3.377
2013 SCImago Journal Rankings: 1.575
 
dc.identifier.issue15
 
dc.identifier.pmid19301836
 
dc.identifier.scopuseid_2-s2.0-65249157950
 
dc.identifier.spage5217
 
dc.identifier.urihttp://hdl.handle.net/10722/168373
 
dc.identifier.volume113
 
dc.languageeng
 
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journal/jpcbfk
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Physical Chemistry B
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshBinding Sites
 
dc.subject.meshCatalysis
 
dc.subject.meshComputer Simulation
 
dc.subject.meshModels, Chemical
 
dc.subject.meshNitrophenols - Chemistry - Metabolism
 
dc.subject.meshOrganophosphorus Compounds - Chemistry - Metabolism
 
dc.subject.meshQuantum Theory
 
dc.subject.meshCdc25 Phosphatases - Chemistry - Metabolism
 
dc.titleMechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations
 
dc.typeArticle
 
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<description.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 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. &#169; 2009 American Chemical Society.</description.abstract>
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Author Affiliations
  1. University of Colorado at Boulder
  2. Duke University