Evolutionary variation and adaptation in a conserved protein kinase allosteric network: implications for inhibitor design.

The activation of protein kinases involves conformational changes in key functional regions of the kinase domain, a detailed understanding of which is essential for the design of selective protein kinase inhibitors. Through statistical analysis of protein kinase sequences and crystal structures from diverse organisms, we recently proposed that the activation of protein kinases involves a hidden strain switch in the catalytic loop. Specifically, we demonstrated that the backbone torsion-angles of residues in the catalytic loop switch from a "relaxed" to "strained" conformation upon kinase activation and the strained geometry results in a network of hydrogen bonds involving conserved non-catalytic residues in the ATP and substrate binding lobes. Here, we further explore this activation mechanism by analyzing families that lack the canonical hydrogen bonding interactions with the strained backbone. We find that alternative mechanisms have evolved to maintain catalytic loop strain. In PIM kinase, for example, two water molecules account for the lack of a conserved aspartate in the substrate binding by hydrogen bonds to the strained backbone. We discuss the relevance of these findings in the design of family-specific allosteric inhibitors, and in predicting the structural and functional impact of cancer mutations that alter the strain associated hydrogen bonding network. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).