Function
Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK) is a member of a 5-member family of evolutionary conserved protein kinases. DYRK1A is associated with both neuropathological phenotypes and cancer susceptibility in patients with Down syndrome[1]. DYRK2 is a 26S proteasome-regulating kinase.
Disease
Relevance
DYRK1A protects against insulin resistance in the brain by elevating insulin receptor substrate 1 expression[2]. DYRK1A inhibitors attenuate cognitive dysfunction in animal models for Down syndrome and Alzheimer Disease. DYRK1A is a potential cancer therapeutic target because of its role in the regulation of cell cycle progression by affecting both tumor suppressors and oncogenes. Some DYRK1A inhibitors block the tau phosphorylation that is a hallmark of Alzheimer's disease[3]. DYRK2 is a therapeutic target for multiple myeloma and triple-negative breast cancer[4].
Structural highlights
The complex of human DYRK1A kinase domain with an inhibitor shows numerous interactions between the protein ATP pocket and the inhibitor including with the catalytic Lys residue and the gatekeeper Phe residue[5]. The gatekeeper Phe is a vital residue which is responsible for the selectivity of inhibitors[6].
