PDB 3ANR deposited: 2010-09-06 modified: 2010-11-24
Title human DYRK1A/harmine complex
Authors Goto, T., Hagiwara, M., Hiramatsu, T., Hosoya, T., Ikura, T., Ito, N., Kii, I., Nonaka, Y., Ogawa, Y., Ohnishi, E., Onogi, H., Shibuya, H., Yoshida, M.
Structure factors resolution 2.6 rfactor 0.232 rfree 0.264
DPI 0.96 theoretical min: 0.41
Related PDB Entries 3ANQ

Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) is a serine/threonine kinase essential for brain development and function, and its excessive activity is considered a pathogenic factor in Down syndrome. The development of potent, selective inhibitors of Dyrk1A would help to elucidate the molecular mechanisms of normal and diseased brains, and may provide a new lead compound for molecular-targeted drug discovery. Here, we report a novel Dyrk1A inhibitor, INDY, a benzothiazole derivative showing a potent ATP-competitive inhibitory effect with IC(50) and K(i) values of 0.24 and 0.18 μM, respectively. X-ray crystallography of the Dyrk1A/INDY complex revealed the binding of INDY in the ATP pocket of the enzyme. INDY effectively reversed the aberrant tau-phosphorylation and rescued the repressed NFAT (nuclear factor of activated T cell) signalling induced by Dyrk1A overexpression. Importantly, proINDY, a prodrug of INDY, effectively recovered Xenopus embryos from head malformation induced by Dyrk1A overexpression, resulting in normally developed embryos and demonstrating the utility of proINDY in vivo.

Nat Commun 2010 ; 1:1-9 doi:10.1038/ncomms1090

Cross References
Database source Identifier Description
PubMed 20981014
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3ANR/1 3ANR 1 monomer 0 1 1 2500
3ANR/2 3ANR 2 monomer 0 1 1 2490
3ANR/3 3ANR 3 monomer 0 1 1 2508
3ANR/4 3ANR 4 monomer 0 1 1 2452