4azf
From Proteopedia
Human DYRK2 in complex with Leucettine L41
Structural highlights
Function[DYRK2_HUMAN] Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] 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[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Non-specific serine/threonine protein kinase | Bazureau, J P | Bountra, C | Burgy, G | Carreaux, F | Cochet, C | Delhommel, F | Durieu, E | Edwards, A | Elkins, J M | Knapp, S | Lo, D C | Lozach, O | Meijer, L | Muniz, J R.C | Schmid, R S | Soundararajan, M | Tahtouh, T | Transferase
