5ZTN

The crystal structure of human DYRK2 in complex with Curcumin

Summary for 5ZTN

• Entry DOI: 10.2210/pdb5ztn/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 2, (1Z,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (3 entities in total)
• Functional Keywords: inhibitor of kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 99778.61

Authors

Ji, C.G.,Xiao, J.Y. (deposition date: 2018-05-04, release date: 2018-07-18, Last modification date: 2024-10-16)

Primary citation

Banerjee, S.,Ji, C.,Mayfield, J.E.,Goel, A.,Xiao, J.,Dixon, J.E.,Guo, X.
Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2.
Proc. Natl. Acad. Sci. U.S.A., 115:8155-8160, 2018

PubMed Abstract: Curcumin, the active ingredient in , has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.

PubMed: 29987021
DOI: 10.1073/pnas.1806797115

Experimental method

X-RAY DIFFRACTION (2.496 Å)