Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids

Death-associated
protein kinase 1 (DAPK1) is a 160 kDa serine/threonine
protein kinase that belongs to the Ca2+/calmodulin-dependent
protein kinase subfamily. DAPK1 is a possible target for the treatment
of acute ischemic stroke and endometrial adenocarcinomas. In the present
study, we investigated the binding characteristics of 17 natural flavonoids
to DAPK1 using a 1-anilinonaphthalene-8-sulfonic acid competitive
binding assay and revealed that morin was the strongest binder among
the selected compounds. The crystallographic analysis of DAPK1 and
7 selected flavonoid complexes revealed the structure–binding
affinity relationship in atomic-level detail. It was suggested that
the high affinity of morin could be accounted for by the ionic interaction
between 2′-OH and K42 and that such an interaction would not
take place with either cyclin-dependent protein kinases or PIM kinases
because of their broader entrance regions. Thus, morin would be a
more selective inhibitor of DAPK1 than either of these other types
of kinases. In addition, we found that the binding of kaempferol to
DAPK1 was associated with a chloride ion. The present study provides
a better understanding of the molecular properties of the ATP site
of DAPK1 and may be useful for the design of specific DAPK1 inhibitors.