6gn1
From Proteopedia
Crystal Structure of Glycogen synthase kinase-3 beta (GSK3B) in Complex with PIK-75
Structural highlights
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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedPIK-75 is a phosphoinositide-3-kinase (PI3K) alpha-isoform-selective inhibitor with high potency. Although published SAR data show the importance of the NO2 and the Br substituents in PIK-75, none of the published studies could correctly assign the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3beta. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3beta that is likely stabilized by an atypical intramolecular Br...NO2 halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding competent pre-configuration of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies. An Unusual Intramolecular Halogen Bond guides Conformational Selection.,Tesch R, Becker C, Muller MP, Beck ME, Quambusch L, Getlik M, Lategahn J, Uhlenbrock N, Costa FN, Poleto MD, de Sena Murteira Pinheiro P, Rodrigues DA, Sant'Anna CM, Ferreira FF, Verli H, Fraga CAM, Rauh D Angew Chem Int Ed Engl. 2018 Jun 6. doi: 10.1002/anie.201804917. PMID:29873877[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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