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- PDB-7b6f: GSK3-beta in complex with compound (S)-5c -

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Basic information

Entry
Database: PDB / ID: 7b6f
TitleGSK3-beta in complex with compound (S)-5c
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / kinase inhibitors / structure-based drug design / GSK3-beta inhibitor / Structural Genomics Consortium / SGC
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
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-SZW / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsTesch, R. / Andreev, S. / Koch, P. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)397659447 Germany
CitationJournal: To be published
Title: GSK3-beta in complex with compound (S)-5c
Authors: Tesch, R. / Andreev, S. / Koch, P. / Knapp, S. / Structural Genomics Consortium (SGC)
History
DepositionDec 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,3756
Polymers41,6901
Non-polymers6855
Water3,333185
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area750 Å2
ΔGint-22 kcal/mol
Surface area15870 Å2
Unit cell
Length a, b, c (Å)57.692, 63.191, 132.180
Angle α, β, γ (deg.)90.000, 97.408, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2

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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.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Production host: Escherichia coli (E. coli)
References: UniProt: P49841, tau-protein kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SZW / 3-[(3~{S})-3-[(7-chloranyl-9~{H}-pyrimido[4,5-b]indol-4-yl)-methyl-amino]piperidin-1-yl]propanenitrile


Mass: 368.863 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21ClN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 185 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.87 Å3/Da / Density % sol: 57.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: protein solution: 10 mg/ml in buffer 25mM HEPES, pH 7.5, 200mM NaCl, 5% glycerol, 0.5mM TCEP reservoir:12% PEG 8000, 1 mM MgCl2, 0.5M NaCl and 0.1M Tris pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→42.41 Å / Num. obs: 28973 / % possible obs: 97.7 % / Redundancy: 2.7 % / Biso Wilson estimate: 35.79 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.036 / Net I/σ(I): 11.1
Reflection shellResolution: 2.05→2.11 Å / Redundancy: 2.5 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2204 / CC1/2: 0.713 / Rpim(I) all: 0.373 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PHENIX1.15.2_3472refinement
XDSdata processing
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GN1

6gn1


Resolution: 2.05→42.41 Å / SU ML: 0.2561 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.4381
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2093 1417 4.89 %
Rwork0.1739 27546 -
obs0.1756 28963 97.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.91 Å2
Refinement stepCycle: LAST / Resolution: 2.05→42.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2675 0 44 185 2904
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082818
X-RAY DIFFRACTIONf_angle_d0.8623864
X-RAY DIFFRACTIONf_chiral_restr0.0536443
X-RAY DIFFRACTIONf_plane_restr0.0061514
X-RAY DIFFRACTIONf_dihedral_angle_d4.83642308
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.120.34111290.28552677X-RAY DIFFRACTION95.83
2.12-2.210.28871490.22782736X-RAY DIFFRACTION97.37
2.21-2.310.23941390.19852761X-RAY DIFFRACTION98.47
2.31-2.430.23191400.18652791X-RAY DIFFRACTION98.65
2.43-2.580.21751530.18272746X-RAY DIFFRACTION98.5
2.58-2.780.24621400.1882791X-RAY DIFFRACTION98.45
2.78-3.060.21761390.19262684X-RAY DIFFRACTION95.53
3.06-3.510.19361550.18242781X-RAY DIFFRACTION98.56
3.51-4.420.19891390.14372791X-RAY DIFFRACTION97.8
4.42-42.410.17171340.1532788X-RAY DIFFRACTION95.27
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)
12.657415533640.49480513072-1.314525793942.231715645631.295847466424.09754677012-0.011576824064-0.3139833257560.06325458358890.1974366976550.0650008139135-0.006673354156180.02345186029260.311328044686-0.04691748837240.2866344791050.0370925233841-0.003625095096260.244815346892-0.02392404503020.239986234215-7.5913053345811.984110336238.6480742029
22.54630315239-0.273519399112-0.5473721995181.776764528720.3525566199962.367273678590.0704119704358-0.1707848737930.150282045805-0.036535022789-0.0300963182764-0.0920880861270.04643999822850.342014570145-0.03263302784060.2004640851090.007309220561380.0008647142855560.2532355468850.008401672157550.1929590399141.999684619872.284185497115.2841365136
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 36 through 138 )
2X-RAY DIFFRACTION2chain 'A' and (resid 139 through 382 )

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