Systematic comparison of protein kinase structures revealed a conserved framework that provides effective functioning and secure regulation of these essential enzymes. This framework consists of a large hydrophobic helix and two structural elements termed �spines� that provide firm but flexible connection between distant parts of the kinase core. Recent mutation analysis of the �spine� residues demonstrated that not only the spines but also their surrounding residues, termed �shell�, are important for the kinase function and regulation. Although the concept of �spines� and their �shell� provided an important guidance for understanding of protein kinase function, many aspects of long distance allosteric effects of single mutations or ligand binding remain unclear. Here we propose a new approach for analysis of the protein kinase core dynamics. It is based on the community analysis of  molecular dynamic simulations of a protein kinase molecule. �Community� in this analysis is a set of residues that move in cohesion and represent an autonomous dynamic object within the molecule. Preliminary results, obtained from protein kinase-A simulations, demonstrated that a fully active kinase molecule can be subdivided into 6-8 communities which usually include 40-60 residues. Community maps revealed an intricate set of connections between the communities that represent communication between the communities. Major communities can be clearly associated with a particular role played in the protein kinase function and/or regulation. The previously identified �spine� based framework is consistent with the detected community maps and obviously plays a role of the major connector between the communities. As the �spine� based architecture in protein kinases proved to be highly conserved through the whole kinome, we propose that the community structure of protein kinase core will also be found to be a universal feature of all kinases. This opens a door to mechanistic understanding of the allosteric signaling within protein kinase molecules.

Dynamic infrastructure of a protein kinase core and allosteric signaling

248th National Meeting (2014)

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