Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors
2022/07/10 by Chris Arter, Luke Trask, Sarah Ward +2 · 198 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · #Allosteric regulation #Biochemistry #Biology #Cell biology #Chemistry #Computational biology #Cyclin-dependent kinase 2 #Enzyme #Gene #Kinase #MAP2K7 #Melanoma and MAPK Pathways #PI3K/AKT/mTOR signaling in cancer #Protein Kinase Regulation and GTPase Signaling #Protein kinase A #Protein kinase domain #Structural biology #c-Raf
paper · pdf · doi:10.1016/j.jbc.2022.102247
published in Journal of Biological Chemistry 298(8), 102247 (Elsevier BV)
openalex publication_date 2022/07/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Abstract
Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The catalytic activity of protein kinases is 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 30 years ago, to recent insights into kinase assemblies enabled by the breakthroughs in cryo-EM. 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.
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