4B7T

Glycogen Synthase Kinase 3 Beta complexed with Axin Peptide and Leucettine L4

Summary for 4B7T

• Entry DOI: 10.2210/pdb4b7t/pdb
• Related: 1DK8 1EMU 1GNG 1H8F 1I09 1J1B 1J1C 1O6K 1O6L 1O9U 1PYX 1Q3D 1Q3W 1Q41 1Q4L 1Q5K 1R0E 1UV5 2JDO 2JDR 2JLD 2UW9 2X37 2X39 2XH5 3ZRK 3ZRL 3ZRM 4ACC 4ACD 4ACG 4ACH 4AFJ 4B0K 4B0L
• Descriptor: GLYCOGEN SYNTHASE KINASE-3 BETA, AXIN-1, (5Z)-5-(1,3-benzodioxol-5-ylmethylidene)-3-methyl-2-(propan-2-ylamino)imidazol-4-one, ... (4 entities in total)
• Functional Keywords: transferase-peptide complex, transferase, insulin pathway, wnt signaling pathway, inhibitor, transferase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 42229.53

Authors

Oberholzer, A.E.,Pearl, L.H. (deposition date: 2012-08-22, release date: 2013-01-30, Last modification date: 2023-12-20)

Primary citation

Tahtouh, T.,Elkins, J.M.,Filippakopoulos, P.,Soundararajan, M.,Burgy, G.,Durieu, E.,Cochet, C.,Schmid, R.S.,Lo, D.C.,Delhommel, F.,Oberholzer, A.E.,Pearl, L.H.,Carreaux, F.,Bazureau, J.,Knapp, S.,Meijer, L.
Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B.
J.Med.Chem., 55:9312-, 2012

PubMed Abstract: DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.

PubMed: 22998443
DOI: 10.1021/JM301034U

Experimental method

X-RAY DIFFRACTION (2.772 Å)