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    
Abstract/OtherAbstract:
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.
Authors:
Yuhui Cheng; Yingkai Zhang; J Andrew McCammon
Related Documents :
3010319 - Overlapping promoters and their control in escherichia coli: the gal case.
11948789 - Molecular dynamics simulations of the acyl-enzyme and the tetrahedral intermediate in t...
10218819 - Design and syntheses of three haptens to generate catalytic antibodies that cleave amid...
25423189 - Structure of putrescine aminotransferase from escherichia coli provides insights into t...
21661729 - Transient enzyme-substrate recognition monitored by real-time nmr.
25348769 - Roles of ala-149 in the catalytic activity of diadenosine tetraphosphate phosphorylase ...
2166559 - Structural and functional changes associated with modification of the ubiquitin methion...
21409209 - Kinetics of inhibition of firefly luciferase by dehydroluciferyl-coenzyme a, dehydroluc...
15005609 - Insights into signal transduction involving pas domain oxygen-sensing heme proteins fro...
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    
Affiliation:
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. ycheng@mccammon.ucsd.edu
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / chemistry,  metabolism
Amino Acid Sequence
Binding Sites
Catalysis
Cyclic AMP-Dependent Protein Kinases / chemistry*,  metabolism*
Kinetics
Magnesium / chemistry,  metabolism
Models, Molecular
Molecular Sequence Data
Phosphorylation
Quantum Theory
Static Electricity
Chemical
Reg. No./Substance:
56-65-5/Adenosine Triphosphate; 7439-95-4/Magnesium; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  New insights into the stereoselectivity of the aryl zinc addition to aldehydes.
Next Document:  Structures and properties of self-assembled monolayers of bistable [2]rotaxanes on Au (111) surfaces...