The Landscape of Atypical and Eukaryotic Protein Kinases

Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes. Despite their low sequence similarity, most atypical kinases share the same characteristic eukaryotic protein kinase fold.The atypical kinases lack the highly conserved kinase motifs (e.g., the GxGxxG motif) and contain a mirrored catalytic HRD motif.Atypical kinases have altered regulatory and catalytic hydrophobic spines compared with the eukaryotic kinases.SNPs and cancer mutations occurring in the catalytic cleft of the kinases are mutually exclusive in location in both atypical and eukaryotic kinases and can interfere with inhibitor binding.Atypical kinase inhibitors currently explore a limited number of binding modes compared with eukaryotic kinase inhibitors.Selective kinase inhibitors can be designed by rationally exploiting selectivity hotspots or by targeting alternative allosteric binding sites.