4aze
Human DYRK1A in complex with Leucettine L41
Structural highlights
DiseaseDYR1A_HUMAN Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.[1] FunctionDYR1A_HUMAN May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.[2] Publication Abstract from PubMedDYRKs (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 co-crystallized with DYRK1A, DYRK2, CLK3, PIM1 and GSK-3beta. The selectivity of L41 was studied by activity & interaction assays of recombinant kinases and affinity chromatography & 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 multi-target 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. Selectivity, co-crystal structures and neuroprotective properties of Leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid Leucettamine B.,Tahtouh T, Elkins JM, Filippakopoulos P, Soundararajan M, Burgy G, Durieu E, Cochet C, Schmid R, Lo D, Delhommel F, Oberholzer A, Laurence P, Carreaux F, Bazureau JP, Knapp S, Meijer L J Med Chem. 2012 Sep 21. PMID:22998443[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
