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Article: Mechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations

TitleMechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculations
Authors
Issue Date2009
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journal/jpcbfk
Citation
Journal Of Physical Chemistry B, 2009, v. 113 n. 15, p. 5217-5224 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/168373
ISSN
2015 Impact Factor: 3.187
2015 SCImago Journal Rankings: 1.414
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorParks, JMen_US
dc.contributor.authorHu, Hen_US
dc.contributor.authorRudolph, Jen_US
dc.contributor.authorYang, Wen_US
dc.date.accessioned2012-10-08T03:18:07Z-
dc.date.available2012-10-08T03:18:07Z-
dc.date.issued2009en_US
dc.identifier.citationJournal Of Physical Chemistry B, 2009, v. 113 n. 15, p. 5217-5224en_US
dc.identifier.issn1520-6106en_US
dc.identifier.urihttp://hdl.handle.net/10722/168373-
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.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journal/jpcbfken_US
dc.relation.ispartofJournal of Physical Chemistry Ben_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshCatalysisen_US
dc.subject.meshComputer Simulationen_US
dc.subject.meshModels, Chemicalen_US
dc.subject.meshNitrophenols - Chemistry - Metabolismen_US
dc.subject.meshOrganophosphorus Compounds - Chemistry - Metabolismen_US
dc.subject.meshQuantum Theoryen_US
dc.subject.meshCdc25 Phosphatases - Chemistry - Metabolismen_US
dc.titleMechanism of cdc25b phosphatase with the small molecule substrate p-nitrophenyl phosphate from QM/MM-MFEP calculationsen_US
dc.typeArticleen_US
dc.identifier.emailHu, H:haohu@hku.hken_US
dc.identifier.authorityHu, H=rp00707en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/jp805137xen_US
dc.identifier.pmid19301836-
dc.identifier.scopuseid_2-s2.0-65249157950en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-65249157950&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume113en_US
dc.identifier.issue15en_US
dc.identifier.spage5217en_US
dc.identifier.epage5224en_US
dc.identifier.isiWOS:000265030500033-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridParks, JM=10143634800en_US
dc.identifier.scopusauthoridHu, H=7404097564en_US
dc.identifier.scopusauthoridRudolph, J=7103011865en_US
dc.identifier.scopusauthoridYang, W=35265650900en_US
dc.identifier.citeulike4199957-

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