Ligand-induced global transitions in the catalytic domain of protein kinase A

Conformational transitions play a central role in the phosphorylation mechanisms of protein kinase. To understand the nature of these transitions, we investigated the dynamics of nucleotide binding to the catalytic domain of PKA, a prototype for the protein kinase enzyme family. The open-to-closed t...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-03, Vol.106 (9), p.3023-3028
Main Authors: Hyeon, Changbong, Jennings, Patricia A, Adams, Joseph A, Onuchic, José N
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Binding sites
Biochemistry
Biological Sciences
Brownian motion
Catalytic Domain
Computer Simulation
Crystal structure
Cyclic AMP-Dependent Protein Kinases - chemistry
Cyclic AMP-Dependent Protein Kinases - metabolism
Energy
Enzymes
Kinases
Kinetics
Ligands
Models, Molecular
Molecules
Phosphorylation
Physical Sciences
Protein Structure, Tertiary
Proteins
Trajectories
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Summary:Conformational transitions play a central role in the phosphorylation mechanisms of protein kinase. To understand the nature of these transitions, we investigated the dynamics of nucleotide binding to the catalytic domain of PKA, a prototype for the protein kinase enzyme family. The open-to-closed transition in PKA was constructed as a function of ATP association by using available X-ray data and Brownian dynamics. Analyzing the multiple kinetic trajectories at the residue level, we find that the spatial rearrangement of the residues around the nucleotide-binding pocket, along with suppressed local fluctuations, controls the compaction of the entire molecule. In addition, to accommodate the stresses induced by ATP binding at the early transition stage, partial unfoldings (cracking) and reformations of several native contacts occur at the interfaces between the secondary structure motifs enveloping the binding pocket. This suggests that the enzyme experiences local structural deformations while reaching its functional, ATP-bound state. Our dynamical view of the ligand-induced transitions in PKA suggests that the kinetic hierarchy of local and global dynamics, the variable fluctuation of residues and the necessity of partial local unfolding may be fundamental components in other large scale allosteric transitions.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0813266106