The Landscape of Atypical and Eukaryotic Protein Kinases

Georgi K. Kanev, Chris de Graaf, Iwan J.P. de Esch, Rob Leurs, Thomas Würdinger, Bart A. Westerman*, Albert J. Kooistra

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)818-832
Number of pages15
JournalTrends in Pharmacological Sciences
Volume40
Issue number11
Early online date31 Oct 2019
DOIs
Publication statusPublished - Nov 2019

Keywords

  • catalytic kinase domain structures
  • eukaryotic and atypical protein kinases
  • oncogenic mutations
  • selective kinase inhibitor design
  • small-molecule kinase inhibitors
  • SNP

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