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- PDB-5kpl: Glycogen Synthase Kinase 3 beta Complexed with BRD0705 -

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Basic information

Entry
Database: PDB / ID: 5kpl
TitleGlycogen Synthase Kinase 3 beta Complexed with BRD0705
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / inhibitor / 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 / G protein-coupled dopamine receptor signaling pathway / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / establishment of cell polarity / regulation of axonogenesis / 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 / negative regulation of osteoblast differentiation / canonical Wnt signaling pathway / 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 / negative regulation of insulin receptor signaling pathway / excitatory postsynaptic potential / positive regulation of protein export from nucleus / positive regulation of GTPase activity / 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 / negative regulation of canonical Wnt signaling pathway / tau protein binding / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / beta-catenin binding / 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 / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / presynapse / positive regulation of protein binding / insulin receptor signaling pathway / negative regulation of neuron projection development / kinase activity
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...Glycogen synthase kinase 3, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6VL / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLakshminarasimhan, D. / White, A. / Nadupalli, A. / Suto, R.K.
CitationJournal: 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
DepositionJul 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 14, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,0024
Polymers94,3592
Non-polymers6432
Water1,74797
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5012
Polymers47,1791
Non-polymers3211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5012
Polymers47,1791
Non-polymers3211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.625, 85.428, 112.071
Angle α, β, γ (deg.)90.000, 95.080, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Glycogen synthase kinase-3 beta / GSK-3 beta / Serine/threonine-protein kinase GSK3B


Mass: 47179.484 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Plasmid: PACg2T Baculogold / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6VL / (4~{S})-4-ethyl-7,7-dimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one


Mass: 321.416 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.64 Å3/Da / Density % sol: 53.47 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: Reservoir: 0.1 M Bis-Tris, pH 6.5, 25% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 7, 2015
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 30464 / % possible obs: 100 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.05 / Rrim(I) all: 0.098 / Χ2: 1.046 / Net I/av σ(I): 14.925 / Net I/σ(I): 11.3 / Num. measured all: 114626
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.6-2.693.70.6040.7821100
2.69-2.83.70.4530.871100
2.8-2.933.70.3290.921100
2.93-3.083.80.2190.9591100
3.08-3.283.80.1640.981100
3.28-3.533.80.110.9871100
3.53-3.883.80.0770.9921100
3.88-4.453.80.0730.9931100
4.45-5.63.80.0690.991100
5.6-503.80.0580.993199.7

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0103refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→50 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.929 / SU B: 11.162 / SU ML: 0.232 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.438 / ESU R Free: 0.284 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2438 1552 5.1 %RANDOM
Rwork0.1785 ---
obs0.1818 28790 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 193.46 Å2 / Biso mean: 70.589 Å2 / Biso min: 38.56 Å2
Baniso -1Baniso -2Baniso -3
1--3.94 Å2-0 Å20.28 Å2
2---2.06 Å2-0 Å2
3---5.86 Å2
Refinement stepCycle: final / Resolution: 2.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5422 0 48 97 5567
Biso mean--57.87 59.38 -
Num. residues----680
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0195614
X-RAY DIFFRACTIONr_bond_other_d0.0020.025407
X-RAY DIFFRACTIONr_angle_refined_deg1.7191.9977655
X-RAY DIFFRACTIONr_angle_other_deg1.037312434
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5075676
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.49423.017242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.96315925
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0961546
X-RAY DIFFRACTIONr_chiral_restr0.0880.2860
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0216226
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021272
X-RAY DIFFRACTIONr_mcbond_it5.4246.8322719
X-RAY DIFFRACTIONr_mcbond_other5.4236.832718
X-RAY DIFFRACTIONr_mcangle_it7.92910.2263390
LS refinement shellResolution: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 117 -
Rwork0.276 2073 -
all-2190 -
obs--98.56 %

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