title: Structural Insight into the Interactions between Death-Associated Protein Kinase 1 and Natural Flavonoids.
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.
authors: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors: Takeshi
authors: T
authors: Yokoyama
authors: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors: Yuto
authors: Y
authors: Kosaka
authors: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors: Mineyuki
authors: M
authors: Mizuguchi
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000817:Anilino Naphthalenesulfonates / Q000737:chemistry; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry*; D044949:Kaempferols / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D047309:Flavones
chemical_list: D000255:Adenosine Triphosphate; D000817:Anilino Naphthalenesulfonates; D064550:Death-Associated Protein Kinases; D005419:Flavonoids; D044949:Kaempferols; C027132:1-anilino-8-naphthalenesulfonate; C006552:kaempferol; C008548:morin; D047309:Flavones