Document Detail

How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study.
MedLine Citation:
PMID:  15686389     Owner:  NLM     Status:  MEDLINE    
We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton delivered by the substrate peptide. Among the key interactions in the active site, the Mg(2+) ions, glycine rich loop, and Lys72 are found to stabilize the transition state through electrostatic interactions. On the other hand, Lys168, Asn171, Asp184, and the conserved waters bound to Mg(2+) ions do not directly contribute to lower the energy barrier of the phosphorylation reaction, and possible roles for these residues are proposed. The QM/MM calculations with different QM/MM partition schemes or different initial structures yield consistent results. In addition, we have carried out 12 ns molecular dynamics simulations on both wild type and K168A mutated PKA, respectively, to demonstrate that the catalytic role of Lys168 is to keep ATP and substrate peptide in the near-attack reactive conformation.
Yuhui Cheng; Yingkai Zhang; J Andrew McCammon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  127     ISSN:  0002-7863     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-02-02     Completed Date:  2005-03-22     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1553-62     Citation Subset:  IM    
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0365, USA.
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MeSH Terms
Adenosine Triphosphate / chemistry,  metabolism
Amino Acid Sequence
Binding Sites
Cyclic AMP-Dependent Protein Kinases / chemistry*,  metabolism*
Magnesium / chemistry,  metabolism
Models, Molecular
Molecular Sequence Data
Quantum Theory
Static Electricity
Reg. No./Substance:
56-65-5/Adenosine Triphosphate; 7439-95-4/Magnesium; EC AMP-Dependent Protein Kinases

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