Cyclin-Dependent Kinase-Like 5 (CDKL5); A Target Enabling Package

The protein kinase CDKL5 is best known for harbouring loss of function mutations that cause a variant of Rett syndrome, CDKL5 deficiency disorder, that predisposes to seizures and mental retardation. Recent kinome-wide screening has identified CDKL5 as a therapeutic target to ameliorate acute kidney injury, which is a common complication of hospitalisation that can lead to chronic kidney disease. There are currently no proven treatments. We prepared recombinant proteins for the kinase domains of CDKL1, CDKL2, CDKL3 and CDKL5 and solved the structures of these kinases in complex with identified inhibitors at resolutions from 1.5 to 2.4 Å. Overall, the structures capture the kinases with both active and inactive conformations and provide a model to explain the effects of CDKL5 mutation. An in vitro kinase assay showed the importance of a C-terminal αJ helix for the activity of CDKL2 and CDKL3, but not CDKL1 and CDKL5. Functional analyses of the single orthologue in C. elegans CDKL-1 also suggested that CDKL proteins can limit cilia length, which could potentially contribute to the neurological defects in CDKL5 deficiency syndrome. AST-487 and ASC67 present inhibitors of CDKL5 that could be developed for treating acute kidney injury. However, future work is needed to improve selectivity in this drug development.