Allosteric regulation and inhibition of protein kinases

Abstract

The human genome encodes more than 500 different protein kinases: signaling enzymes with tightly regulated activity. Enzymatic activity within the conserved kinase domain is influenced by numerous regulatory inputs including the binding of regulatory domains, substrates, and the effect of post-translational modifications such as autophosphorylation. Integration of these diverse inputs occurs via allosteric sites that relate signals via networks of amino acid residues to the active site and ensures controlled phosphorylation of kinase substrates. Here, we review mechanisms of allosteric regulation of protein kinases and recent advances in the field.

Keywords: allosteric regulation; drug discovery and design; kinases.

Figure 1.. The Regulatory, Catalytic, and Dynamically Coupled Spines in Src Kinase

Regulatory spine (R-spine) (cyan), catalytic spine (C-spine) (green), dynamically coupled spine (DC spine) (blue and cyan). R-spine residues are also shared with the DC spine. PDB 3G5D.

Figure 2.. Binding Modes of Selected Allosteric Kinase Inhibitors

The allosteric inhibitor (blue) that binds each kinase domain (grey) are indicated. Only kinase domain residues and the inhibitors are shown for simplicity, and all other non-protein atoms, including ions, waters, and other ligands, are omitted. Chain A was selected for visualization from crystal structures with multiple copies of the kinase in the asymmetric unit.