8IE8

Crystal structure of DAPK1 in complex with isorhapontigenin

Summary for 8IE8

• Entry DOI: 10.2210/pdb8ie8/pdb
• Descriptor: Death-associated protein kinase 1, 5-[(~{E})-2-(3-methoxy-4-oxidanyl-phenyl)ethenyl]benzene-1,3-diol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34246.80

Authors

Yokoyama, T. (deposition date: 2023-02-15, release date: 2023-05-24, Last modification date: 2023-10-04)

Primary citation

Yokoyama, T.,Kusaka, K.
Characterization of the molecular interactions between resveratrol derivatives and death-associated protein kinase 1.
Febs J., 290:4465-4479, 2023

PubMed Abstract: Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-regulated serine/threonine kinase, regulates cell apoptosis and autophagy and has been implicated in the pathogenesis of Alzheimer's disease (AD). Targeting DAPK1 may be a promising approach for treating AD. In our previous study, we found that a natural polyphenol, resveratrol (1), is a moderate DAPK1 inhibitor. In the present study, we investigated the interactions between natural and synthetic derivatives of 1 and DAPK1. Binding assays including intrinsic fluorescence quenching, protein thermal shift and isothermal titration calorimetry indicated that oxyresveratrol (3), a hydroxylated derivative, and pinostilbene (5), a methoxylated derivative, bind to DAPK1 with comparable affinity to 1. The enzymatic assay showed that 3 more effectively inhibits the intrinsic ATPase activity of DAPK1 compared with 1. Crystallographic analysis revealed that the binding modes of the methoxylated derivatives were different from those of 1 and 3, resulting in a unique interaction. Our results suggest that 3 may be helpful in treating AD and provide a clue for the development of promising DAPK1 inhibitors.

PubMed: 37171222
DOI: 10.1111/febs.16817

Experimental method

X-RAY DIFFRACTION (1.75 Å)