title: Dynamic architecture of a protein kinase.
abstract: Protein kinases are dynamically regulated signaling proteins that act as switches in the cell by phosphorylating target proteins. To establish a framework for analyzing linkages between structure, function, dynamics, and allostery in protein kinases, we carried out multiple microsecond-scale molecular-dynamics simulations of protein kinase A (PKA), an exemplar active kinase. We identified residue-residue correlated motions based on the concept of mutual information and used the Girvan-Newman method to partition PKA into structurally contiguous "communities." Most of these communities included 40-60 residues and were associated with a particular protein kinase function or a regulatory mechanism, and well-known motifs based on sequence and secondary structure were often split into different communities. The observed community maps were sensitive to the presence of different ligands and provide a new framework for interpreting long-distance allosteric coupling. Communication between different communities was also in agreement with the previously defined architecture of the protein kinase core based on the "hydrophobic spine" network. This finding gives us confidence in suggesting that community analyses can be used for other protein kinases and will provide an efficient tool for structural biologists. The communities also allow us to think about allosteric consequences of mutations that are linked to disease.
authors.affiliation: Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: McClendon
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093 Department of Pharmacology, akornev@ucsd.edu staylor@ucsd.edu.
authors.forename: Alexandr P
authors.initials: AP
authors.lastname: Kornev
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, and.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.affiliation: Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093 Department of Pharmacology, akornev@ucsd.edu staylor@ucsd.edu.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D020134:Catalytic Domain; D008024:Ligands; D008274:Magnesium / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D011494:Protein Kinases / Q000737:chemistry*; D015203:Reproducibility of Results; D013698:Templates, Genetic
chemical_list: D008024:Ligands; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D008274:Magnesium
keywords: community analysis; molecular dynamics; phosphorylation