Abstract
Death-associated protein kinase 1 (DAPK1) is a large multidomain protein with an N-terminal serine/threonine protein kinase domain. DAPK1 is considered to be a promising molecular target for the treatment of Alzheimer's disease (AD). In the present study, the inhibitory potency of resveratrol (RSV), a dietary polyphenol found in red wine, against the catalytic activity of DAPK1 was investigated. Kinetic and fluorescent probe competitive binding analyses revealed that RSV directly inhibited the catalytic activity of DAPK1 by binding to the ATP-binding site. Crystallographic analysis of DAPK1 in complex with RSV revealed that the A-ring of RSVoccupied the nucleobase-binding position. Determination of the binding mode provided a structural basis for the design of more potent DAPK1 inhibitors. In conclusion, the data here clearly show that RSV is an ATP-competitive inhibitor of DAPK1, encouraging speculation that RSV may be useful for the development of AD inhibitors.
Highlights
Resveratrol (RSV; 3,40,5-trihydroxy-trans-stilbene; Fig. 1) is a natural polyphenolic phytoalexin found in grapes, peanuts, berry fruits and olives (Wang, Catana et al, 2002)
The ATPase activities of Death-associated protein kinase 1 (DAPK1) and ephrin type-A receptor 3 (EphA3) were clearly observed and increased in an ATP concentrationdependent manner, indicating that the ATP molecules were hydrolyzed by the kinases [Fig. 2(a)]
The intrinsic ATPase activity of EphA3 was remarkably lower in comparison to that of DAPK1
Summary
Resveratrol (RSV; 3,40,5-trihydroxy-trans-stilbene; Fig. 1) is a natural polyphenolic phytoalexin found in grapes, peanuts, berry fruits and olives (Wang, Catana et al, 2002). Red wine contains a high concentration of RSV, ranging from 1 to 25 mM depending on the grape varieties used (Gu et al, 1999). RSV has attracted considerable attention owing to its cardioprotective activity, and has been suggested to be responsible for the ‘French paradox’, i.e. the inverse relationship between the consumption of red wine and cardiovascular disease rates in France (Renaud & de Lorgeril, 1992). Several studies have indicated that RSV directly or indirectly modulates signaling pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway, the protein kinase C (PKC) signaling pathway and the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) signaling pathway (Kundu & Surh, 2008). Several protein kinases are associated with these pathways, only PKC isozymes and proto-oncogene serine/threonine-protein kinase (PIM1) have been shown to be inhibited by RSV, and there is no structural information on the interactions between RSV and protein kinases (Slater et al, 2003; Kim et al, 2020)
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