Structural features of the protein kinase domain and targeted binding by small molecule inhibitors

Protein kinases are key components in cellular signalling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr and Tyr residues. The catalytic activity of protein kinases are regulated, and they can be thought of as molecular switches that are controlled through protein-protein interactions and post-translational modifications. Protein kinases exhibit diverse structural mechanisms of regulation and have been fascinating subjects for structural biologists from the first crystal structure of a protein kinase over thirty years ago, to recent insights into kinase assemblies enabled by the breakthroughs in cryo-electron microscopy. Protein kinases are high-priority targets for drug discovery in oncology and other disease settings and kinase inhibitors have transformed the outcomes of specific groups of patients. Most kinase inhibitors are ATP-competitive, deriving potency by occupying the deep hydrophobic pocket at the heart of the kinase domain. Selectivity of inhibitors depends on exploiting differences between the amino acids that line the ATP site, and exploring the surrounding pockets that are present in inactive states of the kinase. More recently, allosteric pockets outside the ATP site are being targeted to achieve high selectivity and to overcome resistance to current therapeutics. Here we review the key regulatory features of the protein kinase family, describe the different types of kinase inhibitors, and highlight examples where the understanding of kinase regulatory mechanisms has gone hand-in-hand with the development of inhibitors.