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Yorodumi- PDB-5t31: Exploiting an Asp-Glu switch in Glycogen Synthase Kinase 3 to des... -
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-Basic information
Entry | Database: PDB / ID: 5t31 | |||||||||
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Title | Exploiting an Asp-Glu switch in Glycogen Synthase Kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia | |||||||||
Components | Glycogen synthase kinase-3 beta | |||||||||
Keywords | TRANSFERASE/TRANSFERASE inhibitor / glycogen synthase 3 alpha beta mutant / TRANSFERASE-TRANSFERASE inhibitor complex | |||||||||
Function / homology | Function and homology information regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / negative regulation of mesenchymal stem cell differentiation / beta-catenin destruction complex disassembly / negative regulation of type B pancreatic cell development / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation ...regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / negative regulation of mesenchymal stem cell differentiation / beta-catenin destruction complex disassembly / negative regulation of type B pancreatic cell development / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of protein localization to centrosome / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of cilium assembly / negative regulation of protein acetylation / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / beta-catenin destruction complex / tau-protein kinase / CRMPs in Sema3A signaling / heart valve development / regulation of microtubule-based process / regulation of protein export from nucleus / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / Maturation of nucleoprotein / cellular response to interleukin-3 / Wnt signalosome / negative regulation of protein localization to nucleus / negative regulation of TOR signaling / regulation of long-term synaptic potentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / dopamine receptor signaling pathway / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / ER overload response / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / Regulation of HSF1-mediated heat shock response / epithelial to mesenchymal transition / canonical Wnt signaling pathway / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / presynaptic modulation of chemical synaptic transmission / excitatory postsynaptic potential / negative regulation of insulin receptor signaling pathway / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / hippocampus development / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / peptidyl-threonine phosphorylation / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / positive regulation of protein-containing complex assembly / Degradation of beta-catenin by the destruction complex / tau protein binding / negative regulation of canonical Wnt signaling pathway / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / beta-catenin binding / positive regulation of GTPase activity / circadian rhythm / positive regulation of protein catabolic process / cellular response to amyloid-beta / Regulation of RUNX2 expression and activity / neuron projection development / positive regulation of neuron apoptotic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / positive regulation of protein binding / insulin receptor signaling pathway / negative regulation of neuron projection development / kinase activity Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å | |||||||||
Authors | Stein, A.J. / Holson, E.B. / Wagner, F.F. / Cambell, A.J. | |||||||||
Citation | Journal: Sci Transl Med / Year: 2018 Title: Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia. Authors: Wagner, F.F. / Benajiba, L. / Campbell, A.J. / Weiwer, M. / Sacher, J.R. / Gale, J.P. / Ross, L. / Puissant, A. / Alexe, G. / Conway, A. / Back, M. / Pikman, Y. / Galinsky, I. / DeAngelo, D. ...Authors: Wagner, F.F. / Benajiba, L. / Campbell, A.J. / Weiwer, M. / Sacher, J.R. / Gale, J.P. / Ross, L. / Puissant, A. / Alexe, G. / Conway, A. / Back, M. / Pikman, Y. / Galinsky, I. / DeAngelo, D.J. / Stone, R.M. / Kaya, T. / Shi, X. / Robers, M.B. / Machleidt, T. / Wilkinson, J. / Hermine, O. / Kung, A. / Stein, A.J. / Lakshminarasimhan, D. / Hemann, M.T. / Scolnick, E. / Zhang, Y.L. / Pan, J.Q. / Stegmaier, K. / Holson, E.B. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5t31.cif.gz | 146.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5t31.ent.gz | 111.5 KB | Display | PDB format |
PDBx/mmJSON format | 5t31.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t3/5t31 ftp://data.pdbj.org/pub/pdb/validation_reports/t3/5t31 | HTTPS FTP |
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-Related structure data
Related structure data | 5kpkC 5kplC 5kpmC 4pteS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 46895.219 Da / Num. of mol.: 2 / Mutation: D133E Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase #2: Chemical | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.76 Å3/Da / Density % sol: 55.36 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 20% PEG MME 5,000 and 0.1 M Bis-Tris pH 6.5 |
-Data collection
Diffraction | Mean temperature: 90 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97875 Å |
Detector | Type: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 15, 2016 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97875 Å / Relative weight: 1 |
Reflection | Resolution: 2.85→50 Å / Num. obs: 24568 / % possible obs: 99 % / Redundancy: 3.8 % / Net I/σ(I): 13.3 |
Reflection shell | Resolution: 2.85→2.95 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 1.8 |
-Processing
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4PTE Resolution: 2.85→47.41 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.906 / SU B: 18.442 / SU ML: 0.332 / Cross valid method: THROUGHOUT / ESU R: 0.964 / ESU R Free: 0.376 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 79.21 Å2
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Refinement step | Cycle: 1 / Resolution: 2.85→47.41 Å
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Refine LS restraints |
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