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J Med Chem. 2015 Sep 24;58(18):7400-8. doi: 10.1021/acs.jmedchem.5b00893. Epub 2015 Sep 4.

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

Author information

1
Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.

Abstract

Death-associated protein kinase 1 (DAPK1) is a 160 kDa serine/threonine protein kinase that belongs to the Ca(2+)/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.

PMID:
26322379
DOI:
10.1021/acs.jmedchem.5b00893
[Indexed for MEDLINE]

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