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- PDB-3du8: Crystal structure of GSK-3 beta in complex with NMS-869553A -

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Basic information

Entry
Database: PDB / ID: 3du8
TitleCrystal structure of GSK-3 beta in complex with NMS-869553A
ComponentsGlycogen synthase kinase-3 beta
KeywordsTRANSFERASE / Protein kinase / Alternative splicing / ATP-binding / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase
Function / homology
Function and homology information


neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation ...neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of protein localization to centrosome / positive regulation of cilium assembly / beta-catenin destruction complex / CRMPs in Sema3A signaling / heart valve development / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / tau-protein kinase / regulation of microtubule-based process / regulation of protein export from nucleus / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / negative regulation of protein localization to nucleus / Disassembly of the destruction complex and recruitment of AXIN to the membrane / AKT phosphorylates targets in the cytosol / negative regulation of calcineurin-NFAT signaling cascade / regulation of axon extension / Maturation of nucleoprotein / tau-protein kinase activity / negative regulation of epithelial to mesenchymal transition / G protein-coupled dopamine receptor signaling pathway / positive regulation of cell-matrix adhesion / regulation of axonogenesis / regulation of dendrite morphogenesis / glycogen metabolic process / ER overload response / regulation of neuron projection development / establishment of cell polarity / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / dynactin binding / epithelial to mesenchymal transition / Regulation of HSF1-mediated heat shock response / negative regulation of osteoblast differentiation / NF-kappaB binding / canonical Wnt signaling pathway / negative regulation of protein-containing complex assembly / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / regulation of cellular response to heat / extrinsic apoptotic signaling pathway / cellular response to retinoic acid / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of autophagy / Transcriptional and post-translational regulation of MITF-M expression and activity / presynaptic modulation of chemical synaptic transmission / regulation of microtubule cytoskeleton organization / response to endoplasmic reticulum stress / negative regulation of cell migration / hippocampus development / positive regulation of protein export from nucleus / positive regulation of protein ubiquitination / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H2AS121 kinase activity / histone H3S57 kinase activity / excitatory postsynaptic potential / histone H3S28 kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / histone H2BS36 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / AMP-activated protein kinase activity / histone H3T11 kinase activity / histone H3T3 kinase activity / 3-phosphoinositide-dependent protein kinase activity / Ubiquitin-dependent degradation of Cyclin D / histone H3T45 kinase activity / mitochondrion organization / positive regulation of cell differentiation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / positive regulation of protein-containing complex assembly / negative regulation of canonical Wnt signaling pathway / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2
Similarity search - Function
Glycogen synthase kinase 3, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Glycogen synthase kinase 3, catalytic domain / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-553 / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsBossi, R.T.
CitationJournal: J.Med.Chem. / Year: 2009
Title: First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery.
Authors: Menichincheri, M. / Bargiotti, A. / Berthelsen, J. / Bertrand, J.A. / Bossi, R. / Ciavolella, A. / Cirla, A. / Cristiani, C. / Croci, V. / D'Alessio, R. / Fasolini, M. / Fiorentini, F. / ...Authors: Menichincheri, M. / Bargiotti, A. / Berthelsen, J. / Bertrand, J.A. / Bossi, R. / Ciavolella, A. / Cirla, A. / Cristiani, C. / Croci, V. / D'Alessio, R. / Fasolini, M. / Fiorentini, F. / Forte, B. / Isacchi, A. / Martina, K. / Molinari, A. / Montagnoli, A. / Orsini, P. / Orzi, F. / Pesenti, E. / Pezzetta, D. / Pillan, A. / Poggesi, I. / Roletto, F. / Scolaro, A. / Tato, M. / Tibolla, M. / Valsasina, B. / Varasi, M. / Volpi, D. / Santocanale, C. / Vanotti, E.
History
DepositionJul 17, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Aug 30, 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
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,4614
Polymers93,9112
Non-polymers5512
Water3,855214
1
A: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2312
Polymers46,9551
Non-polymers2751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Glycogen synthase kinase-3 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2312
Polymers46,9551
Non-polymers2751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.599, 85.810, 178.043
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 46955.383 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSK3B / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49841, tau-protein kinase
#2: Chemical ChemComp-553 / (7S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one


Mass: 275.282 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H14FN5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 3.36 Å3/Da / Density % sol: 63.39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20% w/v PEG 3350, 100 mM Hepes pH 8.0, 20 mM MgCl2, 10% v/v Glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.009 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 6, 2008
RadiationMonochromator: Single crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.009 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. obs: 58862 / % possible obs: 90.5 % / Rmerge(I) obs: 0.082 / Χ2: 1.183 / Net I/σ(I): 12
Reflection shellResolution: 2.2→2.28 Å / Rmerge(I) obs: 0.446 / Num. unique all: 3016 / Χ2: 1.294 / % possible all: 47.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å29.67 Å
Translation2.5 Å29.67 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.006data extraction
MxCuBEdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1Q3D

1q3d


Resolution: 2.2→30 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.929 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.862 / SU B: 4.006 / SU ML: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.204 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.246 2973 5.1 %RANDOM
Rwork0.214 ---
obs0.215 58807 90.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 108.49 Å2 / Biso mean: 48.234 Å2 / Biso min: 21.74 Å2
Baniso -1Baniso -2Baniso -3
1--0.22 Å20 Å20 Å2
2--2.59 Å20 Å2
3----2.37 Å2
Refinement stepCycle: LAST / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5390 0 40 214 5644
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0225568
X-RAY DIFFRACTIONr_angle_refined_deg1.6251.9887579
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8315669
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.55122.893242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.03615923
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4211545
X-RAY DIFFRACTIONr_chiral_restr0.1080.2854
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024223
X-RAY DIFFRACTIONr_nbd_refined0.2090.22362
X-RAY DIFFRACTIONr_nbtor_refined0.3120.23775
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2247
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2190.224
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.5760.23
X-RAY DIFFRACTIONr_mcbond_it1.1011.53491
X-RAY DIFFRACTIONr_mcangle_it1.87225541
X-RAY DIFFRACTIONr_scbond_it2.72132356
X-RAY DIFFRACTIONr_scangle_it4.2214.52038
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 108 -
Rwork0.258 2029 -
all-2137 -
obs--45.24 %

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