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- PDB-2o5k: Crystal Structure of GSK3beta in complex with a benzoimidazol inh... -

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Basic information

Entry
Database: PDB / ID: 2o5k
TitleCrystal Structure of GSK3beta in complex with a benzoimidazol inhibitor
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / GSK3beta / benzoimidazol inhibitor
Function / homology
Function and homology information


negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 ...negative regulation of glycogen (starch) synthase activity / neuron projection organization / regulation of microtubule anchoring at centrosome / 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 / regulation of microtubule-based process / CRMPs in Sema3A signaling / regulation of protein export from nucleus / heart valve development / 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 / regulation of axon extension / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / positive regulation of cell-matrix adhesion / negative regulation of calcineurin-NFAT signaling cascade / dopamine receptor signaling pathway / regulation of dendrite morphogenesis / negative regulation of phosphoprotein phosphatase activity / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / protein kinase A catalytic subunit binding / NF-kappaB binding / canonical Wnt signaling pathway / Regulation of HSF1-mediated heat shock response / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / regulation of cellular response to heat / cellular response to retinoic acid / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / excitatory postsynaptic potential / presynaptic modulation of chemical synaptic transmission / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / Ubiquitin-dependent degradation of Cyclin D / hippocampus development / positive regulation of protein-containing complex assembly / 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 / negative regulation of canonical Wnt signaling pathway / tau protein binding / Degradation of beta-catenin by the destruction complex / B-WICH complex positively regulates rRNA expression / regulation of circadian rhythm / beta-catenin binding / positive regulation of GTPase activity / circadian rhythm / neuron projection development / cellular response to amyloid-beta / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / presynapse / insulin receptor signaling pathway / positive regulation of protein binding / kinase activity / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation
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-HBM / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsShin, D. / Lee, S.C. / Heo, Y.S. / Cho, Y.S. / Kim, Y.E. / Hyun, Y.L. / Cho, J.M. / Lee, Y.S. / Ro, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Design and synthesis of 7-hydroxy-1H-benzoimidazole derivatives as novel inhibitors of glycogen synthase kinase-3beta
Authors: Shin, D. / Lee, S.C. / Heo, Y.S. / Lee, W.Y. / Cho, Y.S. / Kim, Y.E. / Hyun, Y.L. / Cho, J.M. / Lee, Y.S. / Ro, S.
History
DepositionDec 6, 2006Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 23, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glycogen synthase kinase-3 beta
A: 2-(2,4-DICHLORO-PHENYL)-7-HYDROXY-1H-BENZOIMIDAZOLE-4-CARBOXYLIC ACID [2-(4-METHANESULFONYLAMINO-PHENYL)-ETHYL]-AMIDE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7852
Polymers42,2651
Non-polymers5191
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.940, 72.632, 81.795
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glycogen synthase kinase-3 beta / / GSK-3 beta


Mass: 42265.406 Da / Num. of mol.: 1 / Fragment: residues 22-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: modified pET21b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P49841, tau-protein kinase
#2: Chemical ChemComp-HBM / 2-(2,4-DICHLORO-PHENYL)-7-HYDROXY-1H-BENZOIMIDAZOLE-4-CARBOXYLIC ACID [2-(4-METHANESULFONYLAMINO-PHENYL)-ETHYL]-AMIDE / 2-(2,4-DICHLOROPHENYL)-4-HYDROXY-N-(2-{4-[(METHYLSULFONYL)AMINO]PHENYL}ETHYL)-1H-BENZIMIDAZOLE-7-CARBOXAMIDE


Mass: 519.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20Cl2N4O4S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.49 Å3/Da / Density % sol: 50.63 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M HEPES Na, 0.1M Proline, 20% PEG3350, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jan 25, 2005
RadiationMonochromator: double mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 3.2→30 Å / Num. all: 7359 / Num. obs: 6785 / % possible obs: 92.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.2 % / Biso Wilson estimate: 14.5 Å2 / Rmerge(I) obs: 0.092 / Net I/σ(I): 9.8
Reflection shellResolution: 3.2→3.4 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.1 / Num. unique all: 38 / % possible all: 79

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Processing

Software
NameVersionClassification
CNS1.1refinement
CrystalCleardata collection
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R0E

1r0e


Resolution: 3.2→25.53 Å / Rfactor Rfree error: 0.021 / Data cutoff high absF: 680379.7 / Data cutoff low absF: 0 / Isotropic thermal model: OVERALL / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: The structure was refined also with REFMAC 5.0.
RfactorNum. reflection% reflectionSelection details
Rfree0.309 207 3.1 %RANDOM
Rwork0.24 ---
all0.251 7345 --
obs0.24 6574 89.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 98.5675 Å2 / ksol: 0.424287 e/Å3
Displacement parametersBiso mean: 43.3 Å2
Baniso -1Baniso -2Baniso -3
1--20.82 Å20 Å20 Å2
2--16.01 Å20 Å2
3---4.81 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.46 Å0.35 Å
Luzzati d res low-5 Å
Luzzati sigma a0.54 Å0.44 Å
Refinement stepCycle: LAST / Resolution: 3.2→25.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2790 0 34 0 2824
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d23.4
X-RAY DIFFRACTIONc_improper_angle_d0.95
LS refinement shellResolution: 3.2→3.4 Å / Rfactor Rfree error: 0.054 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.299 31 2.9 %
Rwork0.268 1023 -
obs-38 88.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3HBI.paramHBI.top
X-RAY DIFFRACTION4ion.paramion.top

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