Summary
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.
Method X-RAY DIFFRACTION
Structure factors resolution 2.6 rfactor 0.232 rfree 0.264
DPI 0.96 theoretical min: 0.41
Related PDB Entries 3ANQ
Citations

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