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- PDB-8auz: Crystal structure of GSK3 beta (GSK3b) in complex with FL291. -

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Basic information

Entry
Database: PDB / ID: 8auz
TitleCrystal structure of GSK3 beta (GSK3b) in complex with FL291.
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase / GSK3B / inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium ...regulation of microtubule anchoring at centrosome / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of dopaminergic neuron differentiation / positive regulation of protein localization to centrosome / maintenance of cell polarity / 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 / negative regulation of TOR signaling / Wnt signalosome / negative regulation of protein localization to nucleus / 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 epithelial to mesenchymal transition / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / G protein-coupled dopamine receptor signaling pathway / regulation of axonogenesis / regulation of dendrite morphogenesis / tau-protein kinase activity / establishment of cell polarity / glycogen metabolic process / ER overload response / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / NF-kappaB binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / canonical Wnt signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / presynaptic modulation of chemical synaptic transmission / positive regulation of GTPase activity / positive regulation of protein export from nucleus / excitatory postsynaptic potential / negative regulation of cell migration / positive regulation of protein ubiquitination / hippocampus development / mitochondrion organization / Ubiquitin-dependent degradation of Cyclin D / peptidyl-threonine phosphorylation / positive regulation of cell differentiation / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / positive regulation of protein-containing complex assembly / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / regulation of circadian rhythm / 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 / 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 / p53 binding / positive regulation of protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / insulin receptor signaling pathway / kinase activity
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / : / 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
Similarity search - Domain/homology
Chem-O9C / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.66 Å
AuthorsChaikuad, A. / Mongin, F. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Chem. / Year: 2023
Title: Oxazolo[5,4-f]quinoxaline-type selective inhibitors of glycogen synthase kinase-3 alpha (GSK-3 alpha ): Development and impact on temozolomide treatment of glioblastoma cells.
Authors: Hasyeoui, M. / Lassagne, F. / Erb, W. / Nael, M. / Elokely, K.M. / Chaikuad, A. / Knapp, S. / Jorda, A. / Valles, S.L. / Quissac, E. / Verreault, M. / Robert, T. / Bach, S. / Samarat, A. / Mongin, F.
History
DepositionAug 26, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)84,2386
Polymers83,3802
Non-polymers8594
Water52229
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2120 Å2
ΔGint-33 kcal/mol
Surface area32650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.417, 114.880, 67.530
Angle α, β, γ (deg.)90.000, 99.370, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: _ / Auth seq-ID: 27 - 381 / Label seq-ID: 2 - 356

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 41689.750 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Plasmid: pNIC-CH / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-O9C / 8-morpholin-4-yl-2-pyridin-3-yl-[1,3]oxazolo[5,4-f]quinoxaline


Mass: 333.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.09 Å3/Da / Density % sol: 60.25 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 14% PEG 3350, 0.1 M ammonium sulfate and 0.1 M bis-tris pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.526
11-L, -K, -H20.474
ReflectionResolution: 2.66→66.63 Å / Num. obs: 29204 / % possible obs: 99.9 % / Redundancy: 3.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.054 / Rrim(I) all: 0.103 / Net I/σ(I): 10.9
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.6 %

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.66-2.80.545242700.5340.3920.75999.9
8.41-66.630.0469500.9980.0270.05499.8

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0253refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1q3d

1q3d


Resolution: 2.66→66.63 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.921 / SU B: 14.312 / SU ML: 0.155 / SU R Cruickshank DPI: 0.1035 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.104 / ESU R Free: 0.06 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2291 1455 5 %RANDOM
Rwork0.1688 ---
obs0.1717 27720 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 173.74 Å2 / Biso mean: 68.211 Å2 / Biso min: 30.36 Å2
Baniso -1Baniso -2Baniso -3
1--31.52 Å2-0 Å2-9.72 Å2
2--42.34 Å20 Å2
3----10.82 Å2
Refinement stepCycle: final / Resolution: 2.66→66.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5584 0 60 29 5673
Biso mean--45.25 44.84 -
Num. residues----702
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0135808
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175394
X-RAY DIFFRACTIONr_angle_refined_deg1.1971.6527918
X-RAY DIFFRACTIONr_angle_other_deg1.071.57812504
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8645702
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.57521.088294
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.63915944
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.9851544
X-RAY DIFFRACTIONr_chiral_restr0.0450.2752
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.026628
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021240
Refine LS restraints NCS

Ens-ID: 1 / Number: 11061 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.06 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.66→2.725 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.395 83 -
Rwork0.249 1975 -
obs--94.23 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.59610.37570.32091.1854-0.61572.50650.03240.0438-0.1052-0.1073-0.03720.02010.02220.00020.00480.29030.0379-0.02080.0811-0.01170.038825.0829-7.03673.2892
20.63440.33090.08860.73170.62111.29280.0308-0.06430.0698-0.0146-0.12940.0849-0.0955-0.0630.09860.24460.026-0.00280.0742-0.01190.014126.569514.719521.2722
33.3761-0.59610.66682.9183-0.43331.75040.11820.02410.279-0.06790.097-0.1083-0.0474-0.1239-0.21520.21390.013-0.01320.11110.00330.0818-9.11549.382232.4807
41.064-0.5391-0.07880.5044-0.19761.2418-0.06060.0362-0.0606-0.039-0.03630.0320.28020.00180.09680.318-0.02110.00780.0609-0.01770.01738.521-12.254136.5886
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A27 - 94
2X-RAY DIFFRACTION2A95 - 381
3X-RAY DIFFRACTION3B27 - 94
4X-RAY DIFFRACTION4B95 - 381

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