3ANR

human DYRK1A/harmine complex

Summary for 3ANR

• Entry DOI: 10.2210/pdb3anr/pdb
• Related: 3ANQ
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, 7-METHOXY-1-METHYL-9H-BETA-CARBOLINE (3 entities in total)
• Functional Keywords: protein kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus speckle: Q13627
• Total number of polymer chains: 4
• Total formula weight: 171464.96

Authors

Nonaka, Y.,Hosoya, T.,Hagiwara, M.,Ito, N. (deposition date: 2010-09-06, release date: 2010-11-10, Last modification date: 2024-11-13)

Primary citation

Ogawa, Y.,Nonaka, Y.,Goto, T.,Ohnishi, E.,Hiramatsu, T.,Kii, I.,Yoshida, M.,Ikura, T.,Onogi, H.,Shibuya, H.,Hosoya, T.,Ito, N.,Hagiwara, M.
Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A
Nat Commun, 1:1-9, 2010

PubMed Abstract: 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.

PubMed: 20981014
DOI: 10.1038/ncomms1090

Experimental method

X-RAY DIFFRACTION (2.6 Å)