8auz

Crystal structure of GSK3 beta (GSK3b) in complex with FL291.

spinqualitylabelsall models 8auz, resolution 2.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8auz is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.66Å Ligands: O9C, PTR, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GSK3B_HUMAN Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Publication Abstract from PubMed The 2-(3-pyridyl)oxazolo[5,4-f]quinoxalines CD-07 and FL-291 are ATP-competitive GSK-3 kinase inhibitors. Here, we investigated the impact of FL-291 on neuroblastoma cell viability and showed that treatment at 10 muM (i.e. approximately 500 times the IC(50) against the GSK-3 isoforms) has no significant effect on the viability of NSC-34 motoneuron-like cells. A study performed on primary neurons (non-cancer cells) led to similar results. The structures co-crystallized with GSK-3beta revealed similar binding modes for FL-291 and CD-07, with their hinge-oriented planar tricyclic system. Both GSK isoforms show the same orientations for the amino acids at the binding pocket except for Phe130 (alpha) and Phe67 (beta), leading to a larger pocket on the opposite side of the hinge region for the alpha isoform. Calculations of the thermodynamic properties of the binding pockets highlighted the required features of potential ligands; these should have a hydrophobic core (which could be larger in the case of GSK-3beta) surrounded by polar areas (a little more polar in the case of GSK-3alpha). A library of 27 analogs of FL-291 and CD-07 was thus designed and synthesized by taking advantage of this hypothesis. While the introduction of substituents at different positions of the pyridine ring, the replacement of the pyridine by other heterocyclic moieties, or the replacement of the quinoxaline ring by a quinoline moiety did not lead to any improvement, the replacement of the N-(thio)morpholino of FL-291/CD-07 by a slightly more polar N-thiazolidino led to a significant result. Indeed, the new inhibitor MH-124 showed clear selectivity for the alpha isoform, with IC(50) values of 17 nM and 239 nM on GSK-3alpha and GSK-3beta, respectively. Finally, the efficacy of MH-124 was evaluated on two glioblastoma cell lines. Although MH-124 alone did not have a significant impact on cell survival, its addition to temozolomide (TMZ) significantly reduced the TMZ IC(50) values on the cells tested. The use of the Bliss model allowed a synergy to be evidenced at certain concentrations. Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3alpha (GSK-3alpha): Development and impact on temozolomide treatment of glioblastoma cells.,Hasyeoui M, Lassagne F, Erb W, Nael M, Elokely KM, Chaikuad A, Knapp S, Jorda A, Valles SL, Quissac E, Verreault M, Robert T, Bach S, Samarat A, Mongin F Bioorg Chem. 2023 May;134:106456. doi: 10.1016/j.bioorg.2023.106456. Epub 2023 , Mar 4. PMID:36913879 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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